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CHAPTER FIVE The Antidepressant Era

The title of this chapter derives from a book of the same title by David Healy (1997). Healy points out the important but overlooked fact that depression proper (what the DSM-5 calls Major Depressive Disorder) [American Psychiatric Association (APA), 2013] was basically unheard of as recently as 50 years ago. For Healy, the antidepressant era unfolded against a backdrop of battles within the psychiatric profession (people endorsing the medical model perspective battling those endorsing models emphasizing a psychological perspective), regulatory agencies such as the Food and Drug Administration (FDA), and the pharmaceutical industry. Antidepressant medications are among the medications most advertised directly to consumers and evidence is mounting that this does not in fact increase consumer knowledge about depression and antidepressants but rather increases misperceptions like the discredited chemical imbalance theory of depression (Park, 2013).

This chapter is divided into seven sections. Section One provides an overview of the current impact of antidepressants and Major Depressive Disorder. Section Two describes early theories of antidepressant action. Section Three covers the neurotrophic/plasticity theory of antidepressant action and other newer findings. Section Four begins coverage of the classes of antidepressant medications with what are called first generation antidepressants. Section Five is devoted to selective serotonin reuptake inhibitors (second generation antidepressants). Section Six covers third-generation antidepressants like bupriopion and duloxetine and experimental drugs like ketamine. Section Seven covers important psychological, cultural, and social perspectives on anti-depressants including the concerns about violent behavior being correlated with antidepressant therapy.

SECTION ONE: THE CURRENT IMPACT OF ANTIDEPRESSANTS

Learning Objectives

• Know what the point and lifetime prevalence of Major Depressive Disorder is.

• Understand the conditions that are often comorbid with depression.

• Be able to articulate sex differences in reported rates of depression.

• Know what meta-analytic studies note as the overall efficacy of antidepressants.

A television commercial features a grimacing young man with his face against a wall. The commercial's narrator lists several symptoms of fear and anxiety related to Social Anxiety Disorder (previously Social Phobia in DSM-IV). The last scene in the commercial shows the same young man smiling, rising from a table in a crowded room apparently to receive acclaim for some accomplishment. The ad ends by repeating the name of the medication and informing the viewer, “Your life is waiting.” As we noted in  Chapter Four , there is vigorous debate as to whether such ads are a valuable source of information or prey on the misconceptions many people have about such drugs being “magic potions” to change their lives.

At this writing, antidepressants are still one of the most advertised and prescribed psychotropic medications. Over $11 billion is spent annually for antidepressants and it is estimated that between 17 million (Ross, 2012) and 22 million Americans (IMS Health, 2014) take them. In the late-20th century prescriptions for antidepressants for children increased at an exponential rate (Bostic, Wilens, Spencer, & Biederman, 1997) despite scant evidence to support their use for children and growing evidence that these drugs may exacerbate symptoms such as suicidal ideation in child and adolescents. In 2003, the FDA issued a public health advisory about the risk of suicidality in children taking SSRI antidepressants, which led to the “black box warning” on antidepressants. After this point prescription rates for children and adolescents declined (Libby et al., 2007). About 65% of antidepressants are prescribed for depression and about 16% for anxiety disorders (Mark, 2010). In the early part of the 21st century, meta-analytic studies began suggesting that the efficacy of anti-depressants is about the same as the placebo, in other words 50%. The efficacy increases as the severity of depression in the subjects increases but there does not seem to be any difference in efficacy between the antidepressant drugs (Del Ra, Spielmans, Fluckiger, & Wampold, 2013; Kirsch & Low, 2013). Some chalk this up to methodological problems (Petkova, Tarpey, Huang, & Deng, 2012) but it is clear there is a strong placebo response in studies on antidepressants that needs further exploration.

Antidepressants are used both on and off label for numerous disorders. When antidepressant medications were introduced in the mid-20th century, physicians primarily used them to treat depression. Currently, antidepressants are used to treat a variety of disorders, including a number of anxiety disorders, impulsive aggression, and even chronic pain. Although antidepressants may help people with a variety of depressive symptoms, most studies on antidepressants examine their use in treating Major Depressive Disorder as defined by DSM-5. Thus, before discussing the history of antidepressants, let's review Major Depressive Disorder proper.

MAJOR DEPRESSIVE DISORDER (MDD)

The 12-month prevalence of MDD is approximately 7% with significant differences across age groups. For example, the prevalence in 18–29 year olds is three times higher than in people 60 years or older. It seems that male children are more prone to depression than female children but after puberty, females have a 1.5–3 fold higher reported rate than males (American Psychiatric Association, 2013).

MDD is diagnosed when a person meets five criteria from a list of nine in DSM-5. Practitioners using the International Classification of Diseases Mental and Behavioral Disorders (WHO, 1992) can choose from specifiers of severity based on the number of symptoms a client has. Symptoms in both manuals include vegetative symptoms like increase or decrease in ability to sleep, increased or decreased eating and weight changes, decreased sex drive, difficulty concentrating, and anhedonia (loss of pleasure in things the person used to enjoy). The depressed person may also have inappropriate guilt, recurrent thoughts of death, fatigue most of the day, and feelings of worthlessness. It is important to note that we have no clear understanding of why the antidepressant drugs covered in this chapter would directly reduce the symptoms listed. There are different theories but we have yet to understand why people get depressed and, when medication helps them, why it helps them. That said though, we know that the more vegetative symptoms a client with depression has, the better candidate they are for an antidepressant. We should note that it is important to add that depression is also part of the symptom profile in many disorders including Bipolar I Disorder, Bipolar II Disorder, Persistent Depressive Disorder (previously Dysthymia in DSM-IV ), Schizoaffective Disorder, Cyclothymia, and Substance Use Disorders.

COMORBIDITY OF DEPRESSION AND ANXIETY

Depression and anxiety, two of the most common symptom types seen by mental health professionals, are often comorbid (occur together) in adults as well as children. This is so much the case that the study groups for DSM-5 considered a Mixed Anxiety and Depression diagnosis though it did not appear in the final draft. This highlights the importance of an accurate diagnosis, because a client may suffer from depression with some secondary anxiety, anxiety with some secondary depression, or from both an anxiety disorder as well as a mood disorder. Even when a client's symptoms fall into one diagnostic cluster at the time of intake, such a client may later show symptoms outside that cluster. Diagnosis is a process that continues throughout the therapeutic relationship and goes well beyond the limited categories of the DSM. Although we focus mainly on depression and antidepressants in this chapter and on anxiety and anxiolytics in  Chapter Six , these are rather artificial distinctions we use for instructive purposes. Just as students must learn the “laws” of Newtonian physics before they can understand the exceptions to those laws that occur in particle physics, they must also learn how classes of medications evolved around diagnostic categories and how market and clinical forces exploit the permeable nature of these classes. In the next section, we discuss theories of antidepressant action from the medical model perspective.

ANTIDEPRESSANT EFFICACY

When an antidepressant “works,” what does that mean and how does it work? The drug “working” usually means is some but not all symptoms decrease or go into remission. How the drug works is a harder question to answer. The simple answer is “we don't know.” We have theories but we don't know. It is interesting that when we were writing the first edition of this book, published reports of antidepressant efficacy estimated the drugs worked approximately 65%. This figure came from analyzing published results; however, as became known in the late 20th century, when pharmaceutical companies started paying to have research done on their own medications, they often retained the rights to all results and in many cases chose to suppress unfavorable results and redesign the study to increase the probability of favorable results (Petersen, 2009). That was when the debate began about true efficacy. Researchers began analyzing not just published studies but all studies logged in the FDA database. Based on this initial findings were that efficacy rates seemed closer to 50% (Armstrong & Winstein, 2008). As noted, the debate on efficacy is ongoing but there is a robust placebo response seen in antidepressant studies that you do not see in studies treating disorders like Schizophrenia. This may be because depression is overdetermined, meaning there are many ways one could get depressed (Ingersoll & Marquis, 2014) whereas Schizophrenia (though we still don't know its etiology) seems more rooted in the brain and nervous system.

Review Questions

• What are the point and lifetime prevalences for Major Depressive Disorder?

• What conditions are most commonly comorbid with Major Depressive Disorder?

• What are the sex differences in reported rates of depression?

• What do meta-analyses suggest the overall efficacy of antidepressants to be?

SECTION TWO: THEORIES OF ANTIDEPRESSANT ACTION

Learning Objectives

• Be able to describe the amine, reuptake inhibition and downregulation theories as they relate to antidepressant action.

• Understand how each of these theories built on its predecessor.

• Understand the barriers and failed attempts at measuring levels of neurotransmitters in the brain.

Researchers have sought to delineate profiles of clients with depression, to gauge the degree to which a particular client's depression is biological in nature. They have assumed that clients with depression that was more biological in nature would be better candidates for antidepressant medications, whereas clients whose depression was more psychological in nature would be better candidates for counseling or psychotherapy. As Stahl (2000) concluded, however, “The search for any biological markers of depression, let alone those that might be predictive of antidepressant responsiveness, has been disappointing” (p. 145). Today, the field of pharmacogenetics aims to match antidepressant response to idiosyncrasies of client's genomes but this research has just begun and it remains to be seen if it will bear results that are applicable (Jones & Perlis, 2006).

How do antidepressants work? Various theories from the medical model perspective are proposed to explain antidepressant action. Each tends to build on its predecessors. In this sense, these theories actually demonstrate one of the ideals of scientific method— new theories ideally are built on older theories. However, although these theories do build on one another, scientists still do not understand why antidepressants alter mood. Perhaps Healy (2002) captured the ultimate usefulness of theories when he stated, “[H]aving a theory is scientifically useful primarily because having a theory leads to action” (p. 118). In this case, the action depends on the theory. From an integrative perspective, we will see that even rigorous theories of how antidepressants work only correlate the drug mechanisms of action with symptom relief. It must be noted, however, that this correlation is not causation. In the case of depression, many times the theories about medications lead to diagnoses rather than the other way around. This has been emphasized both by psychiatrists with knowledge of pharmacology (such as Healy) and by laypeople such as Elizabeth Wurtzel. In her memoir of suffering from depression, Wurtzel (1994) commented that once she was prescribed Prozac, she had a diagnosis. She wrote,

Rather than defining my disease as a way to lead us to fluoxetine, the invention of this drug has brought us to my disease. Which seems backward, but … this is a typical course of events in psychiatry, that the discovery of a drug to treat, say, schizophrenia, will tend to result in many more patients being diagnosed as schizophrenics. This is strictly Marxian psychopharmacology, where the material—or rather, pharmaceutical—means determine the way an individual's case history is interpreted. (p. 265)

Amine Theory

The amine theory of depression began as the  catecholaminergic hypothesis of depression  proposed by Ernst Albert Zeller and his research team (Zeller, Barsky, Fouts, Kirchheimer, Van Orden, 1952). Catecholamines are organic compounds derived from the amino acid tyrosine and include the neurotransmitters norepinephrine (NE), dopamine (DA), and epinephrine (Epi). A broader chemical class is the amines that are compounds derived from ammonia by replacing one or more hydrogen atoms with organic groups. The neurotransmitters serotonin (5-HT), DA, NE, Epi, and acetylcholine (Ach) are all amines. Thus, as soon as researchers began to suspect serotonin (5-HT) played a role in depression the catecholamine hypothesis was made broader into the amine hypothesis.

The  amine hypothesis  began with researchers observing the effects of antidepressants on norepinephrine. Simply put, the amine hypothesis proposed that people who suffered from depression did not have enough amines, particularly NE, in their synapses, and if you could increase the NE then they would not be depressed. It was a parsimonious theory and, as with most parsimonious theories, it did not address the complexity of the situation. It is important to note though that researchers in the mid-20th century can be forgiven for adhering to the overly simple amine hypothesis because at that point all they knew about the drugs was that they somehow increased amines.

The first step in the amine hypothesis is credited to Ernst Albert Zeller (mentioned above) who was working as a biochemist at Northwestern University in the 1950s. Zeller and his research team had discovered that one function of the enzyme monoamine oxidase (MAO) was to disable neurotransmitters after they had been fired from the terminal button (Zeller et al., 1952). This made sense because scientists knew neurotransmitters did not just float in the synapse forever and that the body must have a way to disable them. While screening chemicals for this disabling ability, Zeller found that iproniazid/Marsilid (the antitubercular drug Nathan Klein used as an antidepressant) was a powerful inhibitor of MAO (thus the name MAO inhibitor) (Snyder, 1996). Further research confirmed that iproniazid/Marsilid, by disabling MAO, did indeed raise NE levels in the synapse. In 1957, Udenfriend, Weissback, and Bogdanski (1957) observed that iproniazid/Marsilid also increased the release of serotonin (5-HT) in the brain.

It is widely believed that scientists at the time used a drug called reserpine/Serpalan to deplete the brain of amines and cause an animal model of depression. The story is that researchers gave both reserpine/Serpalan and iproniazid/Marsilid to monkeys. First the reserpine/Serpalan made them appear lethargic and fatigued (the animal model of depression) and then the iproniazid/Marsilid led the monkeys to become highly animated. This then led to the notion that perhaps iproniazid/Marsilid was a  psychic energizer  (Snyder, 1996) or what the reserpine research team called a “marsilizer” referring to the trade name of the compound (Lopez-Munoz & Alamo, 2009). This was found to be more speculation than fact on the part of Nathan Klein (1970) who popularized the MAO Inhibitors for their antidepressant properties (Baumeister, Hawkins, & Uzelac, 2003).

Researchers later discovered that reserpine/Serpalan did cause both norepinephrine and serotonin to leak out of the synaptic vesicles into the synaptic cleft, where MAO disables it. Thus, disabling MAO greatly increases the newly leaked norepinephrine and serotonin in the synaptic cleft, allowing more binding to area receptors than does an undrugged state. These discoveries (exaggerated though they seem to have been) were the primary support for the amine theory. Historical review of the reserpine/Serpalan studies revealed that in actuality only a subset of patients developed depressive symptoms while on reserpine/Serpalan (Akiskal & McKinney, 1973). Again, to clarify, the amine theory of depression was that people who are depressed do not have enough amines (such as norepinephrine) in the synapses between important neurons. Drugs that increased the amines thus alleviated depression.

To this point, this first MAO inhibitor (iproniazid/Marsilid) had only been used to treat tuberculosis. It was noticed that the drug also had power to stimulate the CNS in patients being treated. This was initially thought to be a side effect (Selikoff, Robitzek, & Ornstein, 1952). This then led Jackson Smith (1953) to try the drug on depressed patients. They noted improvement in 2 of the 11 in the group and other studies followed [it is thought that one of the later researchers, Max Lurie, coined the term antidepressant (Lopez-Munoz & Alamo, 2009)]. Nathan Klein carried out the same procedures on subjects and reported that 70% showed substantial improvement (Loomer, Saudners, & Kline, 1958). Given that the response rate in Smith's study was only 18%, it is curious that response rates in Klein's studies rocketed to 70%. To date we are not aware of any re-analysis of this early work. Be that as it may, iproniazid/Marsilid, was on the map as an antidepressant.

Tricyclic antidepressants evolved in Europe through the work of Roland Kuhn (1958) about the same time MAO inhibitors were developing in the United States. Given the MAO research, Kuhn and his colleagues thought tricyclics worked in the same way, by disabling MAO or some related enzyme and increasing NE in the synaptic cleft. The clinical actions of both drugs, after all, were quite similar. This assumption soon ran into problems, however, when researchers discovered that much of the MAO in the nervous system exists inside the cells rather than in the synaptic cleft. Also, all antidepressants seemed to have a time lag of at least two weeks before they took effect. This didn't make sense, because MAO began to inhibit iproniazid within hours after the patient took the first dose.

As noted, the amine theory proved too parsimonious. For one thing, the idea of depressed clients being deficient in a neurotransmitter should correlate with lower levels of the metabolite for the neurotransmitter they are supposed to be lacking. Although some subjects in studies show this correlation, others do not. Stahl (2000) noted that when the metabolite for serotonin (5-HT) is low, it is more likely correlated with impulsive behavior than with depression proper. Plus, the amine theory did not explain why it took the antidepressants four to six weeks to work.

The Discovery of Reuptake Inhibition

The next researcher to make important discoveries in this area was Arvid Carlsson who discovered how tricyclics blocked reuptake of serotonin at the brain level (Carlsson, Fuxe, & Ungerstedt, 1968). After this discovery, Izyaslav Lapin and Gregory Oxenkrug (1969) postulated the serotonergic theory of depression, similar to the amine theory only focusing on serotonin rather than norepinephrine. In the 1950s, working at the National Institutes of Health in Bethesda, Maryland, Julius Axelrod discovered that with tricyclic antidepressants, norepinephrine was increased in the synaptic cleft when the drug inhibited the reuptake mechanism discovered by Carlsson. The mechanism works like this: When norepinephrine is released into the synaptic cleft, it has a period of time to bind to receptors. After this period, it is either broken down by MAO or a transporter molecule attaches to the NE neurotransmitter and takes it back inside the cell that released it in the first place, where enzymes store it in synaptic vesicles so it can be released again. In this way, the transporter molecule provides something like a recycling service.

Other researchers have identified a similar mechanism for most other neurotransmitters, with the exception of acetylcholine, which is deactivated by the enzyme acetylcholinesterase (just as norepinephrine can be deactivated by monoamine oxidase). This discovery only served to reinforce the amine theory of depression, because researchers eventually discovered that drugs such as tricyclic antidepressants work by inhibiting this reuptake mechanism and thus allowing released neurotransmitters to stay longer in the synaptic cleft. For his work in this area, Axelrod shared the 1970 Nobel Prize in Medicine with Ulf von Euler and Sir Bernard Katz. (It is one of the few Nobel prizes awarded for work related to psychotropic medications because most discoveries in the area of psychotropic medications are more luck and serendipity than the result of carefully crafted hypotheses).

Nevertheless, the same time lag noted for MAO inhibitors existed with tricyclic antidepressant drugs that inhibited reuptake. For example, about an hour after the person takes a tricyclic antidepressant the reuptake inhibition begins and the amount of neurotransmitter in the synaptic cleft increases, but symptoms do not abate for between two and four weeks (maybe even as long as six weeks). So, despite making important contributions to the understanding of reuptake inhibition, Axelrod had not solved the riddle of how tricyclic antidepressants actually work to change mood.

Downregulation Theory

Although enzyme deactivation and reuptake inhibition are important elements in most antidepressants' mechanism of action, they still don't account for the two- to six-week lag of the antidepressant effect. The reuptake properties of tricyclic antidepressants and selective serotonin reuptake inhibitors begin increasing levels of neurotransmitters within an hour of someone's taking the medicine. Another problem is that other drugs that dramatically boost the levels of similar neurotransmitters (cocaine) do not act as antidepressants. Although they may induce euphoria, they also cause an emotional “crash” when the drug wears off. This knowledge contributed to the development of postsynaptic receptor desensitization (downregulation) theory as a complement to the amine theory. This theory proposes that initially the receptors in the depressed person are hypersensitive to neurotransmitter because depressed people have less of that neurotransmitter (remember these are just theories that were partially but not totally accurate). Because there was supposedly less neurotransmitter, the researchers hypothesized that receptors act as if they are “starved” for it, so they upregulate (increase in number). (Remember, this is a theory using metaphors—not concrete truths. In the metaphor used to explain this theory, receptors are not really “starved” for a neurotransmitter but if they had human qualities one might say they would act as if they were. Such  anthropomorphizing  of things like neurons is replete with ways it can be misunderstood). With antidepressant treatment, as more neurotransmitter becomes available, the receptors get more neurotransmitter than is needed because they previously increased in number (upregulated) to make use of the available neurotransmitter in the synaptic cleft. At this point, the cell gets bombarded with neurotransmitter, because the increased levels of neurotransmitter are now binding with the increased numbers of receptors. The theory suggested that the cells then adjust by decreasing the number and sensitivity of receptors, because more neurotransmitter is available. Theoretically, this normalizes transmission or provides the “balance” that is correlated with decrease of symptoms. So according to downregulation theory, the antidepressant effect is the result of two mechanisms. The first is the increase of neurotransmitter released into the synapse (accomplished through reuptake inhibition or enzymatic inhibition), and the second is the downregulation of receptors to a “normal” level of responsiveness (to adapt to the increased levels of neurotransmitter). The time frame required for neurons to decrease the number of receptors correlates closely with the lag time between taking a drug and experiencing the antidepressant effect (two to six weeks depending on the client and dosage of medication) (Stahl, Hauger, Rausch, Flieshaker, & Hubbell-Alberts, 1993).

The downregulation theory led researchers to consider the role of receptor sensitivity in mental/emotional disorders. This combination of the amine theory and downregulation theory was used to account for the action of antidepressants until very recently. Remember, these were and still are just theories. Researchers never had conclusive evidence that the theories fully explained the function of antidepressants nor that there was any “chemical imbalance” that caused depression. To be clear, there is no direct way to measure an extracellular level of any neurotransmitter in the human brain. Some postmortem studies on the brains of people who committed suicide suggested there were low levels of 5-HT in the brain stem tissue but without a baseline it is not possible to say what is “low.” Also the amount of 5-HT in tissue is not necessarily reflective of extracellular amounts (amounts in the synapse) (Jacobson, Medvedev, & Caron, 2012). For decades, researchers have probed the brain with indirect measures looking for biomarkers of 5-HT. Cerebrospinal fluid (CSF) levels of the 5-HT metabolite 5 hydroxyindoleacetic acid (5-HIAA) have been thought to reflect brain levels of 5-HT but the correlations between lower levels of this metabolite are more consistent with things like aggression, suicidality and impulsivity than depression (Placidi et al., 2001).

There have been so-called challenge methods where 5-HT in the central nervous system is challenged with another agent and the resulting changes in things linked to 5-HT have been observed. For example, fenfluramine/Pondimin has been used in depressed subjects in this manner. Fenfluramine/Pondimin stimulates 5-HT to trigger secretion of prolactin. The prolactin is measured and a blunted response was thought to reflect low 5-HT level and a robust prolactin response to reflect a high 5-HT level (Mann, McBride, Malone, DeMeo, & Keilp, 1995). The problem with this is that the triggering of prolactin secretion is a complex process involving not just 5-HT but gamma-amino-butyric acid (GABA), peptides, and oxytocin (Emiliano & Fudge, 2004). As these examples illustrate, “… the association of 5-HT deficiency, or any other singular biochemical anomaly, with major depression as the all-encompassing syndrome is inconclusive” (Jacobson et al., 2012).

Variations on these theories were proposed, such as the permissive theory, which restated the amine hypothesis but included serotonin rather than exclusively focusing on norepinephrine. The permissive theory also tried to explain the role of serotonin in regulating levels of norepinephrine and dopamine. Although all these theories expanded available data on antidepressant action, none fully accounted for antidepressant effects or the strong placebo responses in many studies of antidepressants (we return to these later). The latest hypothesis to explain antidepressant effects takes the discussion deeper into the mysteries of the cells called neurons, as we describe next.

Neurotransmitter Receptor Hypothesis

The neurotransmitter receptor hypothesis asserts that in depression, something is wrong with particular receptors for monoamine neurotransmitters. Researchers think this “something wrong” leads to depression. It is also related to the upregulation of receptors discussed earlier. Because this hypothesis focuses on the receptors and because receptors are a function of gene expression, this hypothesis also considers that depression may relate to some function (or malfunction) of gene expression. Certainly this is a possibility; however, where genetics is concerned it is important to state hypotheses tentatively and concisely to avoid lapsing into word magic. Although admitting that direct evidence to support the genetic hypothesis is lacking, Stahl (2000) discusses the previously outlined postmortem studies of the brains of suicide victims where test results show that the tissue in parts of these brains have increased numbers of 5-HT2 receptors. He concludes that further research may support a genetic variation of the neurotransmitter receptor hypothesis.

Review Questions

• What are the theories of amine theory, reuptake inhibition, and downregulation, and how do they relate to antidepressant action?

• How did each of the theories in question (1) build on each other?

• What efforts have been made to measure neurotransmitter levels in the brain? Why have these failed?

SECTION THREE: THE NEUROTROPHIC/PLASTICITY HYPOTHESIS AND NEW THEORIES OF ANTIDEPRESSANT ACTION

Learning Objectives

• Be able to articulate the basic steps in the neurotrophic/plasticity theory of depression and antidepressant actions.

• Have a general understanding of signaling pathways in cells and how they may figure into antidepressant action.

• Be able to give an overview of the neuropsychological theory of antidepressant action and re-learning in recovery from depression.

The neurotrophic/plasticity hypothesis began as the cellular/molecular theory of antidepressant action (Duman, Heninger, & Nestler, 1997). This required advances in medical technology that allowed scientists to peer inside neurons. The result is a theory that transcends the other theories outlined so far. At the outset, we want to stress that this is unlikely to be the final word on the biological theories of depression, because it also leaves many questions unanswered.

The cellular/molecular theory of depression was first outlined by Duman et al. (1997). In a sense it is a metatheory, in that it encompasses and transcends its predecessor theories in a way that it is a theory about the previous theories. The authors begin by summarizing the complementarity of amine theory and downregulation theory, noting that these theories accurately outline certain actions of antidepressants but fail to explain why such actions would improve mood. They then assert that increases in the levels of available neurotransmitters and the resulting downregulation are merely the beginning of antidepressant action. Next they document intracellular changes in response to someone taking antidepressant medications. Note that these authors maintain that once a person takes an antidepressant medication, these intracellular changes occur after the drug increases the neurotransmitter levels and persist after downregulation. These authors explain that within the cell, antidepressants cause an increase in cyclic adenosine monophosphate (cyclic AMP or cAMP). Cyclic AMP is a second messenger molecule with many functions. Some of these functions are activating enzymes in the neuron, amplifying the effects of hormones and neurotransmitters, and providing other vital functions in the cell. The cAMP levels raised by taking antidepressants apparently do not return to lower levels as the person adjusts to the presence of the drug. Interestingly, cAMP governs the production and processing of neurotrophins called brain-derived neurotrophic factors (BDNFs). BDNF is a neurotrophin in the brain that plays an important role in regulating neurogenesis (creation of new neurons), differentiating neural pathways during neurodevelopment, and modulating synaptic plasticity as well as dendritic growth.

So after administration of antidepressants, as cAMP increases in response to the antidepressant medication, these neurotrophins (BDNF) also increase. You can think of the neurotrophins as akin to brain cell nutrients in that they trigger changes associated with neurogenesis and maintenance of existing neurons. Many of the changes following antidepressant treatment occur in the hippocampus, which is part of the limbic system.

Without unpacking all the molecular biology involved, let's say the basic idea is that the cell goes through many changes after an antidepressant is introduced into the system and that the increase in neurotrophins (cell nutrients) may be one of the most important. The developers of the cellular/molecular theory of depression are proposing that stress and disease processes cause neurological atrophy ranging from reversible to irreversible. One manifestation of this hypothesized atrophy is depression. Such damage may be reversed by an increase in cell nutrients that is one of the many results of taking an antidepressant medication. Brain-derived neurotrophic factor holds promise for treating degenerative brain disorders such as Parkinson's disease. In a recent study in the United Kingdom, researchers injected neurotrophic factor directly into the brain of patients suffering from Parkinson's disease. These patients experienced dramatic decreases in their symptoms (Schorr, 2004). It has also been shown that infusion of BDNF into the hippocampus of rats produced what appeared to be antidepressant effects (Hurley et al., 2013). Such work may hold promise for mental and emotional disorders that have clear biological correlates, but those correlates must be conclusively determined.

The following flow chart summarizes these theories of depression and how each one builds on previous ones.

Not only does the neurotrophic/plasticity theory of depression hold promise for providing a fuller understanding of how antidepressants work, it also promises a fuller understanding of nonpharmacologic approaches to treating depression. Scientists have known for some time that physical exercise is effective in reducing depressive symptoms (De Melo Coelho et al., 2013; Salmon, 2001). Researchers have already documented that general physical exercise rapidly increases brain-derived neurotrophic factors (Russo-Neustadt, Beard, & Cotman,1999). In studies using brain scan technology, depressed participants taking an antidepressant medication and depressed participants engaging in interpersonal therapy showed similar changes in their brain scans as their depression improved. Although the therapy group took longer to manifest these changes, they were as significant as the changes in the group taking the antidepressant (Brody et al., 2001). Apparently exercise and counseling/psychotherapy may induce the same types of intracellular changes as antidepressants. If future research supports this hypothesis, it is important for counselors and other mental health professionals to understand, because this radically expands a client's treatment options. This is also why we emphasize an integrative openness regarding the mind–brain issue in this book: Mind—intention, attention, and awareness—may well be as effective—or more effective—than pharmacologic interventions.

NEWER HYPOTHESES AND THEORIES

Since the advent of the neurotrophic/plasticity theory, researchers have learned many new things about how antidepressants seem to work in the brain. First, BDNF has been traced to genes. The gene for BDNF is on chromosome 11 and is about 1300 letters long. In most animals, letter 192 is “G” (for guanine) but in some it is “C” (cytosine). This causes a slightly different protein to be built with methioline rather than valine at the 66th position. Thus, with regard to the gene for BDNF there are three types of people in the world:

1. Val-vals

2. Val-mets

3. Met-mets

In research on the five-factor model of personality, the most neurotic to least neurotic are supposedly val-vals (most neurotic), val-mets, and met-mets (least neurotic). Thus, building BDNF proteins with methioline may serve a protective factor from things like depression and anxiety (Kourmouli et al., 2013). This is the type of research necessary to address the complexity of how genes may contribute to developing symptoms like depression.

The Emerging Science of the Role of Signaling Pathways in Depression

We have already noted that antidepressants seem to increase cAMP, which then increases BDNF. We have further learned that there is signaling pathway for cAMP that may be pivotal in therapeutic response to antidepressants. We noted that cAMP is a second messenger that has many functions including transferring into cells the effects of hormones that cannot pass through the cell membrane. There are also multiple signaling pathways used by cells to regulate cellular processes. cAMP also qualifies as one of these. In the cAMP pathway, cAMP activates molecules called effectors that bind to proteins to regulate their biological activity.

One effector that may play a role in antidepressant effects is protein kinase and in particular on family of enzymes labeled protein kinase A (PKA). It seems that PKA activity is increased after four to six weeks of antidepressant treatment. PKA activity in turn activates the cAMP response element binding protein (CREB), which is a transcription factor (a protein that binds to specific DNA sequences). This in turn affects the expression of several genes involved in cell survival, neuroplasticity, and cognition. Again we can see that the more current theories of antidepressant action are increasingly sophisticated regarding how complex the human nervous system is compared to earlier theories like the amine theory. CREB has been implicated in both depression and antidepressant treatments (Pilar-Cuellar et al., 2013). The implication is that things that affect cAMP and BDNF have ripples far down the signaling pathway increasing the variables that may play a role in alleviating depression whether the client is involved in antidepressant therapy, exercise, or psychotherapy or all of the above.

The next pathway that may play a role in antidepressant response is called the Wnt/B-Catenin pathway (Wnt). The Wingless-type family of proteins play key roles during neurodevelopment like neural differentiation, formation of the hippocampus, dendritic arborization, axon guidance, and formation of synapses. On a larger scale, this family of proteins plays a role in memory and spatial learning (Pilar-Cuellar et al., 2013). Wnt is also implicated in the etiology and treatment of depression (Hernandez, Nido, Avila, & Villanueva, 2009). In the absence of Wnt signaling, important functions in the cell are blocked by glycogen synthase kinase-3 and other ligands. This “blocking” seems undone in some (but not all) clients with antidepressant and so-called mood-stabilizing medications (Jope & Bijur, 2002).

A third pathway that may be important in antidepressant treatment is called the mTOR pathway and is related to rampamycin genes. Thus, the abbreviation mTOR is derived from the original name for this pathway “mammalian target of rampamycin.” This pathway is important in apoptosis (cell death) and has mainly been studied in cancer, and a number of neurological diseases like Alzheimer's-type dementia. Recent studies associate mTOR signaling in depression because of the fast-acting effects of ketamine (discussed below) as an antidepressant (Mathew, Keegan, & Smith, 2005).

Reviewing physiological theories of how antidepressants work can be dizzying as well as impressive. The key is to not forget that although these theories encompass truths about antidepressants and depression, they are only partial truths. These theories give us important truths from the medical model perspective. However, they are only partial truths; resist the temptation to simplify the complexity of something such as recovering from depression with word magic claiming that antidepressants corrected a “chemical imbalance.” When clients respond to antidepressants, that response is only partial in some cases. As Ross (1995) pointed out, even in those studies up to 30% of the clients may respond to placebo, but this finding is never systematically followed up. Finally, Stahl (2000) noted that in terms of recovery, follow-up studies of depressed clients after one year of treatment indicate that approximately 40% still meet the criteria for the same diagnosis and 20% never recover fully or meet the criteria for dysthymia (low-grade depression). Further, Stahl notes that in 18-month follow-ups, many clients who respond to antidepressants report that the antidepressants stop working. This is given the highly technical name “pooping out.” The percentage of clients whose antidepressants “poop out” after 18 months is as high as 20 to 30% in some studies.

TOWARD AN INTEGRATIVE THEORY OF ANTIDEPRESSANT ACTION

It seems that as our technologies improve, we are peering deeper and deeper into the brain, the neurons, glial cells, and the universe within each cell. At some point, it is reasonable to ask how far down this path we can go and get results. At some point, we will reach the subatomic level and will we yet have a complete picture of depression and antidepressant action? Some theorists are positing an integrative approach that moves from the top down and the bottom up. The “bottom up” part is the theories of antidepressants that we have covered thus far. The “top down” is a new theory called the cognitive neuropsychological theory of antidepressant action.

This theory was laid out in the context of selective serotonin reuptake inhibitors (SSRIs) but can be generalized across antidepressants. The basis of the theory is this: that depression comes with a negative cognitive bias and antidepressants, even after only one day of treatment, are correlated with a decrease in negative bias and an increase in positive bias (Harmer & Cowen, 2013). This theory can be traced back to Crews and Harrison (1995). The essence of the idea is that people who are depressed show a negative emotional bias that has sometimes been called “depressive realism” because they are more accurate at picking out negative realities than “healthy” controls (Kronbrot, Msetfi, & Grimwood, 2013; Moore & Fresco, 2012). The neuropsychological theory of antidepressant action suggests that the time lag for therapeutic effect (two to six weeks) may be as much a function of time spent “re-learning” how to interpret life events as much as a physiological process. There are studies comparing depressed people with normal controls and testing their interpretations of faces they are shown. The depressed people are more likely to judge a facial expression negatively than the controls (Beck, 2008).

Interestingly, even in studies where nondepressed controls are given antidepressants, a statistically significant percentage have an increase in expressed positive bias (Harmer et al., 2003). This seems to be the case except when the antidepressant is administered intravenously. Because we know antidepressants promote synaptic plasticity in animal models, it may be that the antidepressants are providing a chemical “window of opportunity” for the clients to rewire their experience through experiencing a more positive bias. This raises more ethically tricky questions like would drugs that seem relatively harmless like cannabis and induce positive mental states also function as antidepressants?

Review Questions

• Describe the additions of the neurotrophic/plasticity theory to amine, reuptake and downregulation theories—specifically—describe what happens with cAMP and BDNF.

• What is the healthiest genetic combination for hearty BDNF?

• Describe how the neuropsychological theory of antidepressants could bring the best of the pharmacological and psychotherapeutic worlds together.

SECTION FOUR: OVERVIEW OF FIRST-GENERATION ANTIDEPRESSANT MEDICATIONS

Learning Objectives

• Understand how vegetative symptoms are important to gauge therapeutic response.

• Be able to describe the primary mechanisms of action for MAO Inhibitors and Tricyclic Antidepressants.

• Know the potential side effects for MAOIs and TCIs.

In this section of the chapter, we convey a more standard presentation of the antidepressants. It is difficult to make global statements about the efficacy of antidepressants in general; however, the literature does seem to agree that all the different classes of antidepressants are about equally effective. Stahl (2000) summarized this agreement, noting it is a “good news/bad news” scenario. The good news is that 50–60% of depressed clients on any antidepressant respond positively to it, and even more may respond if tried on several different compounds. Half of these responders may progress into full remission within six months of treatment. In addition, antidepressants seem to significantly reduce relapses as well. The bad news is that many responders never reach full remission and that in 20 to 30% of the people who respond at all to antidepressants, the effects tend to “poop out” or wear off after about 18 months.

Although Stahl emphasizes the medical model perspective of depression, equating it with diabetes or hypertension, the “bad news” merely means that in some cases biological interventions are time limited. This is only truly “bad news” if in fact there are no other treatments for depression, which is not the case. Given that many people don't maintain their response to antidepressants, it makes sense to view a response as a time-limited window of opportunity within which to employ an integrative approach to treatment. An integrative approach uses all the perspectives we have been discussing in this book.

The Role of Vegetative Symptoms

In the treatment of MDD, note that the more  vegetative symptoms  a client suffers from, the better candidate the person is for antidepressant medication, because these symptoms are most affected by the medication. Maybe because depression is overdetermined (meaning it may be caused by biological, psychological, cultural, social, and perhaps even spiritual factors), a preponderance of vegetative symptoms point toward a stronger biological component in etiology.  Table 5.1  contains a list of common vegetative symptoms for MDD.

TABLE 5.1 Common Vegetative Symptoms in Major Depressive Disorder

Sleep disturbance (early morning waking, frequent awakening, occasional hypersomnia)

Appetite disturbance (decreased or increased appetite with accompanying weight fluctuations)

General fatigue

Decreased sex drive

Restlessness, agitation, or psychomotor retardation

Diurnal variations in mood (usually feeling worse in the morning)

Impaired concentration and forgetfulness

Pronounced anhedonia (loss of pleasure in most or all things)

Generic Name	Brand Name	Common Daily Dosage Range
Selegiline	L-Deprenyl	10 mg
Isocarboxazid	Marplan	20–50 mg
Moclobemide	Manerix	150–500 mg (available in Canada)
Phenelzine	Nardil	30–75 mg
Tranylcypromine	Parnate	20–40 mg

© Cengage Learning®

Monoamine Oxidase (MAO) Inhibitors

We noted that the first MAO inhibitor was iproniazid/Marsilid, but this compound fell into disfavor because some physicians reported hepatotoxicity (liver toxicity). The drug seemed to cause a type of cell death in the liver. Less toxic MAOIs such as isocarboxazid/Marplan and phenelzine/Nardil have been introduced. To review the mechanism of action, MAOIs inhibit the enzyme (MAO) that breaks down neurotransmitters thought to be related to depression (specifically norepinephrine). When the drugs inhibit this enzyme, more NE is in the synaptic cleft to bind to receptors. This binding then presumably causes downregulation of receptors and the cellular/molecular changes described earlier though those effects are studied more specifically with SSRIs. When this chain of events occurs, the person's depressive symptoms tend to improve.

MAO inhibitors are not specific to any type of MAO, so they inhibit all types of MAO throughout the body and not just in specified areas thought related to depressive symptoms. In addition, the effects of older MAOIs are irreversible; such irreversible effects are rare in psychopharmacology.

TABLE 5.2 Examples of MAO Inhibitor Antidepressants and Common Daily Dosage Ranges

© Cengage Learning®

Thus, the chemical bond of the MAO inhibitor with the MAO cannot be broken and enzyme function returns to normal only when the body creates new enzymes. This attribute has earned MAO inhibitors the nickname “suicide inhibitors,” because their binding to MAO is irreversible meaning that the MAO molecule “suicidally” binds and “goes down with the ship.” Further, there are two types of MAO in the body, labeled MAO A and MAO B. Both forms are inhibited by the older, original MAO inhibitors, which are nonselective. The MAO A form metabolizes the neurotransmitters most closely linked to depression (serotonin and norepinephrine). The MAO B form is thought to convert some ligands (called prototoxins) into toxins that cause cell damage. Researchers have linked MAO B inhibition to prevention of neurodegenerative processes such as those in Parkinson's disease (Finberg, 2014).  Table 5.2  lists some available MAO inhibitors by brand and generic names and dosage range. Please note that the dosage ranges are those common in the United States and that dosage range, as well as minimum effective dose, changes from nation to nation.

Common Side Effects of MAOIs

The side effects of MAOIs are more severe and more frequent than those of other antidepressants. Most are related to the increased activity of norepinephrine, but some are related to the enzyme inhibition that causes the NE increases.  Table 5.3  lists common side effects of MAOIs.

TABLE 5.3 Common Side Effects of MAO Inhibitors

Orthostatic hypotension (a drop in blood pressure that results in dizziness on standing)

Nighttime insomnia, daytime sedation

Headache

Muscle cramps

Weight gain

Difficulty urinating

Tyramine intolerance

© Cengage Learning®

Inhibition of MAO A and Tyramine Intolerance

One of the most dangerous side effects of traditional MAO inhibitors is tyramine intolerance. We noted that MAO A metabolizes neurotransmitters that are linked to depression. By slowing down this metabolism, the neurotransmitters remain active longer and this sets in motion the events correlated with symptom improvement. MAO A also metabolizes tyramine, a dietary amine. If the MAO A is not there to break it down, this amine can build up and cause the release of norepinephrine and other sympathomimetic amines, raising blood pressure. In severe reactions, the blood pressure elevation can cause hemorrhage and death. The side effect is easily controlled with a diet low in tyramine-containing foods.  Table 5.4  lists examples of foods to avoid when taking MAO inhibitors. A physician should give a complete list to the clients for whom they prescribe these medications.

Obviously, because most MAOIs bind irreversibly, there is no specific antagonist that people can take if they accidentally ingest a food high in tyramine while taking their MAOIs. In such a situation, clients are usually advised not to lie down as this will exacerbate the increase in blood pressure. Clients are usually directed to go to an emergency room for treatment. Treatment may include taking a calcium-channel blocker such as nifedipine that can lower blood pressure to avert a hypertensive crisis. A note on discontinuation: If MAOIs are stopped, the client should maintain dietary restrictions for about two weeks. That's how long it takes to build up an adequate level of monoamine oxidase. The same holds for making a transition from an MAO inhibitor to another antidepressant medication.

TABLE 5.4 Examples of Foods High in Tyramine Content to Avoid When Taking MAOIs

Cheeses (cream cheese, such as the common Philadelphia brand, and cottage cheese are safe)

Chicken liver and beef liver

Yeast preparations (avoid brewer's yeast, and powdered and caked yeast as sold in health food stores)

Broad beans and fava beans

Herring

Beer, sherry, ale, red wine, liqueurs

Canned figs

Protein extracts (such as soup cubes and commercial gravies)

© Cengage Learning®

In general, MAOIs are used to treat depression that has been resistant to treatment with other types of antidepressants. This is more due to the side effect profile than to questions of efficacy, because this MAOI class of antidepressants is just as effective as the other classes. In addition to being used against depression, MAO inhibitors have been used with mixed results in treating Bulimia Nervosa, Social Anxiety Disorder, migraine headaches, neurodermatitis, Borderline Personality Disorder, and Panic Disorder.

Contraindications for MAOI Therapy

Clients with a history of liver disease, congestive heart failure, recreational drug use/abuse/dependence, hypertension, or uncontrollable tyramine consumption are not good candidates for MAOI therapy. In addition, clients who, for whatever reason, are unlikely to abide by the dietary restrictions are also poor candidates for this type of therapy.

Newer MAO Inhibitors

We briefly want to note two developments in MAO inhibitors. The latest efforts of pharmaceutical companies have resulted in MAO inhibitors that form reversible bonds with MAO. These are called RIMAs (reversible inhibitors of MAO). Their mechanism of action is precluding the breakdown of NE, 5-HT, and DA. Also, certain MAO inhibitors are selective for A and B. One new drug that offers both developments is selegiline/Eldepryl and L-Deprenyl. This drug is metabolized to an amphetamine molecule, which slows dopamine reuptake. It is reversible, and in low doses (5 to 10 mg a day) it affects only MAO B. At low doses, no dietary restrictions seem necessary. It does not act as an antidepressant at low doses, however. The prescribing professional must raise the dosage to get an antidepressant effect, and at this level the drug affects both MAO A and MAO B. At this level, although still reversible, dietary restrictions are necessary. Other RIMAs are being developed, one that would focus on MAO-A and still aim for an antidepressant effect (Fowler et al., 2010).

Although MAO inhibitors are rarely the medication of first choice, they may be used after other medications have failed to provide results. The following case illustrates that dynamic while also illustrating the inadequacy of strictly viewing a client's symptoms through the medical model perspective.

The Case of Allan

Allan, a 54-year-old lower-middle-class Caucasian male of Baptist faith, was referred for treatment as part of coordinated services at a mental health agency. Ten years prior to referral he was diagnosed as severely depressed and prescribed a tricyclic anti-depressant (TCA) (imiprimine/Tofranil) that he took for about 10 weeks. During this period he was hospitalized twice, more for his complaints about his reactions to the medication than his depression. After the second hospitalization, he was prescribed an SSRI (fluoxetine/Prozac) for his ongoing depression and buspirone/BuSpar for his bouts of anxiety. At no time in the record of his assessment was there any mention of personality impairment or disorder.

Within two weeks of beginning fluoxetine/Prozac, Allan became very agitated, anxious, and paranoid, and had to be hospitalized a third time. The treatment team felt Allan might be suffering from an Atypical Depression, and he was taken off the fluoxetine/Prozac and put on an MAOI (tranylcypromine/Parnate). Allan was advised about the important dietary restrictions he had to follow while on tranylcypromine/Parnate. Soon after, his condition did improve and some of the depressive symptoms lifted. A month later, Allan was transferred to a different case manager because his current one left the agency. Within two weeks he was hospitalized a fourth time for a severe allergy reaction. It was soon determined that Allan had deliberately eaten some cheese because he was in a rage about losing his case manager. By the time Allan was discharged and assigned to a counselor, he was threatening suicide almost daily and refusing to come to counseling. Eventually, however, he began to attend counseling.

The treatment was very challenging, and because of Allan's feelings and suspicions about his care he basically did all he could to undermine his counselor's efforts. Gradually the counselor learned three very important facts about Allan and his life. The first was his enormous fear and then absolute rage about being abandoned and then turned over to someone else for care. The second was his great skill and talent as an electrician and his very fragile self-appraisal of his skills. The third was his gradual discovery of his homosexuality and deep attraction to his male therapist.

The therapist developed a treatment plan to address all three themes. He and Allan planned better for therapeutic interruptions by improving backup support, he referred Allan to a vocational rehabilitation office for additional training in electronics, and he helped Allan talk more concerning his feelings of homosexuality. Gradually Allan stopped taking all medications and worked on his issues in therapy. Here is an example of a case where the client masked severe issues in both psychological and cultural realms and presented a picture of a complex clinical depression. It took time, a great deal of disruption, medication changes, hospitalizations, and careful listening to get a more accurate therapeutic focus on Allan. Being alert only to a client's depressive symptoms with the sole intent of administering psychotropic medications would inevitably have missed the important integrative aspects of Alan's dilemmas. Overall, Allan's MAOI treatment stabilized him for several years. He continued with the medication in conjunction with bimonthly psychotherapy until he was 62. Then he was titrated off the MAOI and saw his therapist only on an as-needed basis. He continues to work as an apartment superintendent 40 hours a week in his neighborhood.

TRICYCLIC ANTIDEPRESSANTS

As noted, the word tricyclic in “tricyclic antidepressants” refers to the three-ring molecular core of the drugs in this class of compounds. According to Stahl (2000), the term “tricyclic antidepressant” is outdated by the standards of current psychopharmacology. Newer and similar agents can have more than three rings to their structure, and these agents are used on-label for a variety of disorders other than depression. Nevertheless, for instructional purposes we use the term tricyclic antidepressants, or TCAs. As noted in the history section in the introduction to Part Two, the TCAs were unexpectedly born from chlorpromazine, the first antipsychotic, also known as a neuroleptic. TCAs were created because drug companies were seeking compounds with fewer side effects and with application to other disorders.  Table 5.5  lists commonly prescribed TCAs by their brand and generic names and the typical dosage range for each compound.

The primary mechanism of action in all TCAs is inhibition of the reuptake norepinephrine and serotonin (and to a slight extent dopamine). As the cellular theory of depression described earlier suggests, researchers assume that other changes in the affected neurons are related to the reuptake inhibition. In addition, all tricyclic compounds block receptors on acetylcholine, histamine, and epinephrine neurons. These additional mechanisms of action have no therapeutic effects for depression and cause most of the side effects of taking TCAs.

TABLE 5.5 Examples of Tricyclic Antidepressants and Common Daily Dosage Ranges

Generic Name	Brand Name	Common Daily
Dosage Range
Amitriptyline	Elavil	75–250 mg
Amoxapine	Asendin	200–300 mg
Clomipramine	Anafranil	50–200 mg
Doxepin	Sinequan, Adapin	75–250 mg
Imipramine	Tofranil	75–250 mg
Nortriptyline	Pamelor	50–100 mg
Maprotiline	Ludiomil	50–200 mg

© Cengage Learning®

Side Effects of TCAs

We have listed the side effects of TCAs in  Table 5.6  by class. As noted, the side effects come from the drug molecules binding to certain receptors and blocking them. In  Chapter Two  we described this “blocking” as an antagonist effect, meaning the molecule binds, does not initiate an effect on the neuron, and prevents other ligands from binding and exerting their effect. Because this is an antagonistic action, we use the prefix “anti-” when describing the side effect. For example, a TCA molecule blocking an acetylcholine receptor exerts an “anticholinergic” effect. A TCA molecule blocking a histamine receptor exerts an “antihistaminic” effect. Conversely, if a drug molecule has an agonist action we do not use the “anti-” prefix and we simply say the drug had a cholinergic or histaminic effect.  Table 5.6  is just a general introduction to possible side effects, not an exhaustive list. Please note that not every TCA drug produces every side effect and that effects also vary depending on the specific responses of the individual taking the drug.

TABLE 5.6 Common TCA Side Effects Listed by Class

Class	Description of Side Effect
Anticholinergic	Dry mouth, dizziness, constipation, difficulty urinating, blurred vision
Adrenergic	Sexual dysfunction, sweating, orthostatic hypotension
Antihistaminic	Sedation and weight gain

© Cengage Learning®

TCAs also have potent effects on the peripheral nervous system. Especially in combination with other medications, they can cause cardiac depression and increased electrical activity that results in arrhythmia. Both can lead to heart failure.

For a prescribing professional, choosing the right TCA seems to be a matter of preference based on matching the TCA to the client's symptoms. It does appear that because more safety risks come with TCAs (e.g., cardiac arrhythmia) they require closer therapeutic drug monitoring than other classes of antidepressants (Ostad, Heimke, & Pfuhlmann, 2012). Some TCAs are more sedating (Elavil), others are more stimulating (Norpramin). Pointing out the contrast to some of the other classes of anti-depressants, Schatzberg and Nemeroff (1998) have argued that if a client does not respond to one TCA, it is unlikely that he or she will respond to any other TCA and the prescribing professional is best advised to try another class of antidepressants. Note that some other medications can significantly raise or lower a client's TCA plasma level. For example, SSRI antidepressants or stimulants such as methylphenidate (Ritalin) can increase TCA plasma levels as much as eightfold, whereas substances such as carbamazepine (Tegretol) and nicotine can significantly lower TCA plasma levels. This simply indicates that clients need quality care from the professional prescribing the medications. Medical professionals are trained to be alert to drug–drug interactions, which is becoming a crucial aspect of psychopharmacology as more and more compounds come to market. TCAs are indicated for depression and are approved by the FDA for childhood enuresis, and Obsessive-Compulsive Disorder (OCD). Off-label uses include insomnia, Panic Disorder, PTSD, Generalized Anxiety Disorder (GAD), chronic pain (all classes of antidepressants have been tested as analgesics for chronic pain and frequently are more effective than placebo), and Bulimia Nervosa.

Tricyclic Derivatives

There is a subclass of antidepressants derived from TCAs that is referred to by several labels, including “secondary amines,” “second-generation antidepressants,” or “atypical” antidepressants. The numerous labels are unfortunate because they make it hard to tell what is being referred to, because some of the labels (such as “second-generation antidepressants”) are also used to refer to totally different classes of drugs. To avoid confusion, we call these compounds tricyclic derivatives. Most have a two-ring molecular structure and have been discovered from metabolites of the tricyclic antidepressants (which is a common practice as we will see in examining other drugs). One strategy for creating marketable compounds is to examine the metabolites of a parent compound. The metabolites can be found in the urine of people taking the parent compound. If the metabolites are active, they can be synthesized into a similar agent that acts like the parent compound but is possibly weaker in therapeutic and side effects. As such, these compounds may still produce the desired therapeutic effect with lower levels of side effects.  Table 5.7  lists some examples of TCA derivatives. Note how the generic name is similar to the parent compound.

TABLE 5.7 Examples of TCA Derivatives and Their Parent Compounds

TCA Derivative Generic Name	Parent Compound Generic Name	Dosage Range
Nortriptyline	Amitriptyline	50–100 mg
Desipramine	Imipramine	75–250 mg

© Cengage Learning®

Benefits and Drawbacks to TCAs and TCA Derivatives: A Summary

As you have read this chapter, you probably have already guessed what the benefits and drawbacks of TCAs and TCA derivatives are. The benefits center around two things. First, these drugs are among the most extensively studied psychotropic medications on the market. This is largely because they have been on the market almost 60 years. When TCAs were put on the market, their only competition was MAO inhibitors. Because MAOIs had the potentially dangerous “cheese effect” related to tyramine intolerance, they were quickly displaced by the TCAs, which did not require a focused dietary regimen (other than avoiding alcohol and other drugs that may interact). Thus, TCAs became the drug of first choice for depression and remained so well into the 1980s, when Prozac was introduced. Once established as a drug of first choice, they then provided the baseline against which all other newer antidepressants were measured. The result is a wealth of information on the TCAs, a situation that makes even conservative medical practitioners comfortable prescribing them to patients. Although the SSRIs (which we discuss next) are currently thought of as the drug of first choice for people with depression, no one disputes that far more data are available on the TCAs. The other advantage to TCAs is their lower cost. After a pharmaceutical company is approved to sell a drug for a given purpose and if the patent was applied for after 1995, the company can get patent rights to the compound for up to 20 years. After this time, other companies can produce the drug generically and sell it for a lower price. In 2010 American pharmaceutical companies had an unprecedented number of medications go generic. This was referred to as the “patent cliff.” In total, patents on drugs worth $12 billion expired in 2011 and in 2012 the figure was closer to $30 billion (DeRuiter & Holston, 2012). Many companies release metabolite compounds at the end of such patent cycles like desvenlafaxine/Prestiq is a metabolite of venlafaxine/Effexor (Wegman, 2009). The result is that clients with no insurance and little income will likely be able to afford a generic drug as opposed to one that has not yet “gone generic.” For example, in 2000 a common wholesale price for a nongeneric SSRI was approximately $150 for a 30-day supply. By contrast, the same supply of generic Elavil (amitriptyline) was approximately $5. Of course, now most SSRI drugs are available in generic form and are often the drug of first choice because of their safety profile. It is logical to imagine that after several newer antidepressant compounds become available in less expensive generic formulations, the use of TCAs will continue to decrease. That is what is happening in the early 21st century with exceptions of treatment resistant symptoms (Pitchot, Scantamburlo, & Ansseau, 2011). The following case demonstrates how TCA medication played an important role in the treatment of one client.

The Case of Rita

Rita, 31, sought counseling for several years in the late 1980s for generalized sadness, some hopelessness, lack of energy, great worry, a loss of a genuine sense of pleasure, and a recurrent sense of loneliness. Although she went to several mental health professionals during this period, not one suggested assessment for depression. Rita experienced almost no relief, as evidenced by her therapist shopping. She complained to her few friends, “They are all good listeners, but I don't feel I'm getting any help. Maybe that's just my lot in life.” About this time she stopped all therapy and began a very aggressive program of exercise and vitamin therapy. Also, she began to see a massage therapist for body massage twice a month and she began to meditate every morning. She felt some relief and improvement, but those feelings were short-lived. In November of the same year she became despondent with great personal anguish, had plaguing suicidal thoughts, and isolated herself from friends and family. Living single, she told one friend, “I might as well not live, no one will ever love me and I'm not lovable.” After a terrible period of two weeks, one of her friends took her to a local emergency room. There the attending physician diagnosed MDD; prescribed imipramine/Tofranil, which is a TCA as well as one of the most commonly used antidepressants at that time; and referred her to a female psychiatrist for follow-up. Gradually Rita improved. She followed up three times with the psychiatrist and continued on imipramine as prescribed for six months.

In the middle of this six-month period, Rita met a man whom she began to date. Rita quickly became attached, which seemed to frighten her companion and he abruptly ended the brief relationship. This termination triggered a severe suicidal depression in Rita, and she slit her wrists. Her landlord found her, and she was rushed to a local hospital and admitted to the psychiatric ward. After two weeks in the hospital, the treating team noted almost no improvement in Rita. She remained on suicidal precaution (being monitored closely for suicidal ideation), and she was sleeping poorly. The team decided to titrate her off the imipramine and began a course of nortriptyline/Pamelor, a different type of TCA, as soon as possible. The team also introduced a low dosage of diazepam/Valium, an anxiolytic, to address her sleep and anxiety problems.

Rita was hospitalized for nine weeks, and the medication change and the milieu of in-patient therapies assisted her recovery. After discharge, Rita remained on diazepam/Valium for an additional two months and on nortriptyline/Pamelor for an additional 15 months. She also began treatment with a skilled licensed counselor who was very knowledgeable about psychopharmacology. Rita remained in therapy until two months after titrating off nortriptyline/Pamelor. Five years later she remained stable, with no recurrence of her major depressive episode with an attempted suicide.

Most of Rita's treatment was in the medical model realm through the introduction of TCAs. It was not uncommon during the 1970s, when Rita received treatment, for psychiatrists to try different TCAs with a patient who demonstrated little response with one type. Also, it was not uncommon to add an anxiolytic in conjunction with a TCA to address symptoms of anxiety and sleeplessness. It is clear from the case material that Rita's earlier attempts with psychotherapy, in the psychological realm, were very unsuccessful and the therapists seemed naive to the importance of medication assessment because of Rita's chronic symptoms. We believe Rita's recovery after discharge resulted from careful interventions in both the medical model and psychological perspectives.

Review Questions

• How can monitoring vegetative symptoms give you a sense of the client's response to antidepressants?

• What are the primary mechanisms of action for MAOIs and TCAs?

• What are the primary side effects of MAOIs and TCAs?

SECTION FIVE: SECOND GENERATION ANTIDEPRESSANTS: SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Learning Objectives

• Understand the benefits and potential risks of SSRI medications.

• Be able to describe the primary mechanism of action in SSRIs and how it relates to the neurotrophic/plasticity theory of antidepressant action.

• Understand the controversy over SSRI-related violence and who is at risk.

Although we noted that TCA derivatives were sometimes referred to as “second-generation” antidepressants, the label more accurately belongs with the SSRIs (Olver, Burrows, & Norman, 2001). We begin the story returning to some historical high points.

A Bit More History

We noted in the beginning of this chapter that the amine theory was expanded to include the effects of serotonin on mood. This opened up a line of research looking at the effects on depression of drugs that made more serotonin available in the central nervous system. The first such agent trazodone/Desyrel had been released in 1981, but because of a rare but problematic side effect (priapism—prolonged and painful erection in males), it failed to gain widespread use although it is still used at lower doses as a sleep aid. In the early 1970s, a research team at Eli Lilly (Byron Malloy, David Wong, & Ray Fuller) had synthesized an agent labeled LY86032. Healy (1997) notes that the team created the compound in a series of ”moon-lighting experiments” and finally decided it was an inhibitor of serotonin reuptake. Following their discovery, they conducted several meetings to explore uses for the new compound. Ironically, when someone first suggested that the drug be tested as an antidepressant, the response was that it would not likely be useful in treating depression and that there was not much of a market for antidepressants anyway (Coppen & Healy, 1996).

Because serotonin is widely distributed in the body, any agent that affects its action is likely to have numerous effects. Research teams initially decided that fluoxetine/Prozac might be an antihypertensive agent, partially because in the 1970s the antihypertensive market was larger than the antidepressant market. In 1981, Marie Asberg and Lil Traskman (1981) demonstrated that serotonin metabolites were significantly decreased in the cerebrospinal fluid of suicidally depressed people. This led to speculation about the role of serotonin in depression. According to Healy (1997), this development and the ever expanding antidepressant market of the early 1980s led to clinical trials of fluoxetine/Prozac as an antidepressant, and the first evidence to support this hypothesis became available in 1985. Fluoxetine/Prozac was licensed in the United States in 1987. Several other compounds were made available at this time, including SmithKline and Beecham's paroxetine/Paxil. Paroxetine/Paxil hit the U.S. market in 1993, delayed by SmithKline and Beecham's skepticism about the market. In an effort to distinguish its compound, SmithKline and Beecham created the category SSRI, and the label “stuck” as the category in which all similar agents were grouped.

The SSRIs seemed to have treatment effects similar to those of TCAs with different side effects. It should be noted here that efficacy of all classes of antidepressants appear to be generally equal but some people respond better to one than another. Meta-analytic studies that suggested there were consistent differences in efficacy across compounds have been criticized for serious methodological problems (Del Ra et al., 2013).

Interestingly, whereas TCAs are molecularly similar across compounds, SSRIs are remarkably different in chemical structure. SSRI effects across the range of 5-HT receptor systems also vary. Thus, whereas Schatzberg and Nemeroff (1998) noted that if patients don't respond to one TCA it is unlikely they will respond to another, the situation is quite different with SSRIs and physicians may try patients on several agents before finding one that provides optimal symptom relief.

As Kramer (1993) has noted, no drug in the history of psychiatry has received more positive and negative attention than fluoxetine/Prozac. At the height of its popularity, sales of the drug topped $1.2 billion annually in the United States alone. This success, as has been the pattern, led to a plethora of SSRI agents being released in a short period of time. The SSRI compounds, and their general dosage range, are listed in  Table 5.8 .

TABLE 5.8 Examples of SSRI Antidepressants and Common Daily Dosage Ranges

Generic Name	Brand Name	Common Daily Dosage Range
Citalopram	Celexa	20–40 mg
Escitalopram oxalate	Lexapro	10–20 mg
Fluoxetine	Prozac	10–60 mg
Fluvoxamine	Luvox	50–250 mg
Paroxetine	Paxil	10–40 mg
Sertraline	Zoloft	50–200 mg

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Mechanism of Action

As already noted, although SSRIs are classed together many clients may have very different reactions to the drugs. This is one reason we provide no charts on when certain clients should get particular drugs: There is no database of knowledge from which to create such a chart. Whereas fluoxetine/Prozac may work for one client, another may respond only to citalopram/Celexa. A strictly medical model perspective offers no explanation for this, and although biological differences in client nervous systems may someday be found to underlie the phenomenon, we believe an integrative research approach to the problem may also yield useful hypotheses. A great deal of research has been done on SSRIs, and many authors now note that although more data on the TCAs are available, the SSRIs are really the drugs of first choice for depression. This is due in large part to a less severe profile of side effects and the difficulty of overdosing on the drugs. As Stahl (2000) explained, taking a two-week supply of a TCA would be lethal to many clients, whereas SSRIs rarely cause death in overdose unless combined with other agents (Fitzgerald, & Bronstein, 2013). In fact, McKenzie and McFarland (2007) examined trends in antidepressant overdoses. They found a dramatic rise in the United States in antidepressant overdoses between 1983 and 2003. These are not reported as fatalities because the drugs involved were mostly SSRI antidepressants. They noted that had TCAs been used, it would have tripled the death rate from overdose. One exception is citalopram/Celexa as it is more dangerous than other SSRIs because it causes QTc prolongation (Flanagan, 2008). While we will discuss this in great detail in  Chapter Seven , suffice to say here that the QTc interval is the measure of time between the start of what is called a “Q” wave and the end of what is called a “T” wave in the heart's electrical cycle. If this interval gets too long cardiac problems and even death can result.

As the name selective serotonin reuptake inhibitor suggests, the primary mechanism of action is the inhibition of reuptake of serotonin back into the neuron. However, researchers have learned over the past decade that a great deal more is going on than this. Once taken, the drug inhibits the reuptake of serotonin so more serotonin molecules are near the cell body area. Whereas researchers used to think that the increase was immediate, in the synapses it appears that the increase is first felt near the dendrites on the cell body, and scientists currently believe this increase produces many of the side effects. Over time, the increase of serotonin in this area causes the autoreceptors to decrease in number (to down-regulate) as well as to become desensitized. Recall that autoreceptors are specialized receptors that, when triggered, signal the cell to decrease the production of neurotransmitter. So if SSRI medications cause the downregulation of autoreceptors, it stands to reason the cell will produce more serotonin than it normally would. Researchers believe this information is communicated to the cell's nucleus, where the genome (via signaling pathways) sends out instructions to cause these same receptors to become less sensitive over time. Note that this hypothesis regarding genetic expression still requires more research. In addition, if medications do affect gene expression researchers need to investigate whether nonpharmacologic elements may also affect gene expression in the same manner.

Scientists now believe that as well as downregulating, the postsynaptic neurons also desensitize over time in the same way as autoreceptors on the presynaptic neuron do. This is a ripple effect, or what Stahl calls a cascade effect, wherein SSRIs affect the brain.

Common Side Effects

Another advantage to SSRI antidepressants is that, unlike TCAs, they have far fewer anticholinergic or antihistaminic side effects. The side effects listed in  Table 5.9  are due almost exclusively to the selective serotonin reuptake inhibition. There are many serotonin receptor systems throughout the central and peripheral nervous systems, and SSRIs can significantly affect them. Also there are multiple serotonin receptor systems and different SSRI compounds have different effects across these families.

TABLE 5.9 Common SSRI Side Effects

Headache

Nausea

Nervousness

Diarrhea

Insomnia

Weight gain

Sexual dysfunction

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These side effects often decrease or cease after therapeutic effects take hold, with the exception of sexual dysfunction. As we stated earlier in the chapter, SSRIs have a variety of on-label and off-label uses. Currently, different SSRIs have on-label uses approved for Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia previous to DSM-5), Social Anxiety Disorder (Social Phobia prior to DSM-5), Post-Traumatic Stress Disorder, and Obsessive-Compulsive Disorder. Off-label uses have included Panic Disorder, Generalized Anxiety Disorder, premature ejaculation, migraine headaches (as prophylactic), diabetic neuropathy, fibromyalgia, and neurocardiogenic syncope (Stone, Viera, & Parman, 2003). In 2013, the FDA approved the marketing of a low dose of paroxetine/Paxil (repackaged under the commercial name Brisdelle) as a nonhormonal treatment for menopausal symptoms (Toftegard, Voigt, Rosenberg, & Gogenur, 2013). This has caused concern because paroxetine/Paxil is one drug that has a weak estrogenic effect that could promote the growth of breast tumors in women because 70% of breast cancers in women are estrogen-sensitive (Healy, 2014).

Antidepressant-Induced Sexual Dysfunction

A particularly troubling side effect for many people is antidepressant-induced sexual dysfunction (AISD). This has been a problem for many clients taking a wide range of antidepressants, and the earliest documentation of it dates back to the early 1960s (Healy, 1997). Initially researchers found it hard to determine how much of the problem was due to the drugs and how much to the depression, because decreased libido is one of the vegetative signs of depression. George Beaumont (1973), who published one of the first papers on the topic, noticed that clients treated with clomipramine/Anafranil, a TCA with stronger effects on serotonin, had delayed orgasm. Beaumont learned that varying the client's dosage could somewhat control the problem. Also in the case of clomipramine/Anafranil, an orgasm rebound apparently could result when the drug was discontinued. Healy (1997) recounts the story of a nun who experienced three days of spontaneous orgasms when withdrawing from clomipramine/Anafranil.

With serotonin-related AISD, apparently the drug's stimulation of serotonin receptors in the spinal cord can inhibit the spinal reflexes, orgasm, and ejaculation (Stahl, 2000). Although early market research with SSRIs reported that approximately 4% of patients taking them would experience this side effect, Healy (1997) states that the number is now confirmed to be well over 50% and may be higher. There are multiple approaches to treating this side effect, and it is worth discussing, because this problem is often why clients stop taking the medication. From the psychological perspective, it is important that counselors tune into clients' comfort in discussing sexual issues. Many clients are uncomfortable with the topic, and this seems to have contributed to under-reporting of the side effect when SSRIs were first released. It is above all important to communicate to clients that prescribing professionals can do many things to decrease or ameliorate this side effect, including switching the client to another medication, supplementing the SSRI with a second medication, or altering the dosage.

The only antidepressant not associated with some sexual dysfunction is bupropion/Wellbutrin (Demyttenaere & Jaspers, 2008) and in studies exploring AISD mirtazapine/Remeron was a distant second correlated with AISD about 30% of the time (Segraves & Balon, 2013). In a largescale examination of interventions for AISD, females seemed to respond well to augmentation with high doses of bupropion/Wellbutrin where males more often responded to augmentation with sildenafil/Viagra and tadalafil/Cialis (Taylor et al., 2013).

Do Antidepressants Induce Dependence?

The simple answer to the politically delicate question “Do antidepressants induce dependence?” is yes. We are deliberately using the word “dependence” rather than “addiction,” because colloquial overuse of the latter has attached a great deal of emotional baggage to it. This baggage has rendered it almost meaningless except when one wants to elicit strong emotional reactions from readers. We prefer the construct of dependence, defined as a physical tolerance produced by repeated administration of a drug and a concomitant withdrawal syndrome (Stahl, 2000). Given this definition of dependence, we can state that SSRI antidepressants can induce what seem to be tolerance and dependence. As Advokat, Comaty, and Julien (2014) stated, “a discontinuation occurs in perhaps 60% of SSRI-treated patients following abrupt cessation of drug intake … onset of the syndrome is usually within a few days and persists perhaps 3 to 4 weeks” (pp. 406–407).  Table 5.10  lists a more complete list of discontinuation syndrome symptoms.

TABLE 5.10 Symptoms of Serotonin Withdrawal

Lethargy

Fatigue

Gastrointestinal disturbance (nausea, vomiting, diarrhea)

Paresthesias (numbness or tingling in extremities)

Insomnia

Agitation/anxiety

© Cengage Learning®

Schatzberg, Cole, and DeBattista (1997) offered the first definition of what they called “serotonin reuptake inhibitor discontinuation syndrome.” They noted that the syndrome typically consisted of physical and psychological symptoms. Their list of physical symptoms include disequilibrium; gastrointestinal symptoms such as nausea, vomiting, and diarrhea; flulike symptoms including lethargy, fatigue, and chills; sensory disturbances such as paresthesia; and sleep disturbances such as insomnia. Their list of psychological symptoms may include anxiety, agitation, and crying spells. Using the acronym “FINISH” Advokat et al. (2014) list discontinuation syndrome symptoms as Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances, and Hyperarousal. One important distinction between dependence on SSRI antidepressants and dependence on a drug that, for example, induces a “high” or euphoria (such as heroin) is that it appears a person who has developed physiological dependence on an SSRI antidepressant does not experience a “craving” for the drug as does someone dependent on heroin (or other opioids). This is why there is little abuse potential for antidepressants and no real “street value” for the drugs.

Another type of dependence is psychological dependence. In this syndrome, a person comes to believe he or she cannot function without a particular drug. In such cases we would say the person in question is psychologically dependent on the drug. Although there may not be physiological tolerance and withdrawal, psychological dependence can be every bit as difficult to deal with as physical dependence. Certainly a client could develop psychological dependence on SSRI antidepressants (or any medication, for that matter). Prescribing professionals and mental health professionals must help clients understand their relationship to the medication. It is important for clients to understand what the medication can do for them, and what they must do for themselves. In our opinion, the people least likely to develop psychological dependence on antidepressants are those who undergo counseling while they are taking the medication. In the counseling relationship, clients learn to differentiate their role from the role played by medications.

PSYCHOLOGICAL AND CULTURAL ISSUES WITH SSRIS

In the late 1980s and early 1990s, a backlash arose against SSRIs in general and Prozac in particular. We briefly review this episode here, because it was the first public outcry about possible dangers of antidepressants. These issues still come up in dialogue with clients and there are some serious concerns about using SSRIs with children and adolescents. The concern at the center of the backlash was whether SSRIs and other antidepressants could in fact instill violent, suicidal behaviors in people. The Church of Scientology launched the attack against Prozac in 1989. It should be clearly understood that Scientology holds as a doctrine a model of the mind falsified many times over and because of this misguided model, Scientologists believe contemporary mental health interventions to be useless and even harmful (e.g., the idea that your brain records everything that happens to you even if you are unconscious and forms “engrams” that can disturb you psychologically. We know of course that this is not true.). Psychiatry is at the top of the list for Scientologists in what the group calls the evils of mental health treatment (Church of Scientology, 1994).

Scientology's main ammunition in the initial attack on antidepressants appeared to be a 1990 (February) American Journal of Psychiatry article (Teicher, Glod, & Cole, 1990) reporting that after two to seven weeks on Prozac, six patients became preoccupied with obsessive, violent suicidal thoughts. These patients had not been responsive to other drugs, but four of the six were also on other medications. Although this was a small sample of cases, the authors were concerned because, as they wrote, “None of these patients had ever experienced a similar state during treatment with any other psychotropic drug” (p. 207).

Because some links appear between serotonin and aggression, there was concern that Prozac might trigger aggression or even sociopathy. Scientologists cited the case of Joseph Wesbecker, who in 1989 attacked his coworkers with an assault rifle, killing 8, wounding 12, and then killing himself. Scientologists blamed Prozac; however, the case history and witnesses indicate that he had a history of violent preoccupation before taking Prozac. At the time (1991), the FDA announced that Prozac and other antidepressants do not cause suicide or violent behavior and actually tend to reduce them. Although Scientology's claims about antidepressants (and psychotropic medications in general) are not all substantiated, their concerns should not be completely discarded. It is interesting that in 2004 the FDA issued a public warning about possible connections between adolescent suicides and SSRI medication. Scientologists must be given credit for questioning some of the word magic from extreme proponents of the medical model perspective. The FDA has required that SSRI antidepressants come with a warning on the label (called a “black box warning,” because the warning is situated in a black box on the label) that SSRIs can sometimes spur suicidal behavior in children and adolescents (Neergaard, 2004). The warning states that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric” (quoted in Healy, Herxheimer, & Menkes, 2007, p. 18).

In clinical trials, aggression and violence are coded under the term “hostility.” This includes homicide, homicidal acts, homicidal ideation, aggressive events, suicide, and conduct disorders. In trials on paroxetine/Paxil, there were 60 events from a sample of 9219 subjects. In the placebo condition, there were 20 events from a sample of 6455 subjects. In healthy volunteer trials, there were 3 hostile events in 271 volunteers taking paroxetine and none in the 138 taking placebo (Healy et al., 2007). Kauffman (2009) reports even more startling data noting that in a controlled trial of paroxetine/Paxil 75% of subjects had an adverse effect, 21% experienced a severe adverse effect and 13% (one in eight) committed a suicidal act. Part of the discrepancy in data is that not all studies get reported. In 53 healthy volunteer studies on sertraline/Zoloft, the results of only 14 were reported. In the unreported trials, there were high dropout rates due to side effects like akathisia (motor restlessness) (Kauffman, 2009) and akathisia is hypothesized to be related to hostile behavior (Healy et al., 2007).

The problem is not limited to SSRI antidepressants. In pediatric trials of venlafaxine/Effexor (a NE and 5-HT reuptake inhibitor discussed below) 2% of children dropped out because of hostility—more than twice the dropout rate in the placebo group (Kuslak, 2003). Healy et al. (2007) noted that this issue will continue to cause problems not just in treatment but what the legal ramifications are between medication and violence. This is all the more problematic because we now have evidence that the “. trial designs were devised by SSRI makers to prevent reports of suicides, by eliminating subjects with the slightest trace of suicidal tendencies” (Kauffman, 2009, p. 7).

When Eli Lilly denied links of suicidal behavior to the drug fluoxetine/Prozac, they cited a sponsored meta-analysis in the British Medical Journal. This study included only 3067 patients of the 26,000 in clinical trials and some of these had been rejected by the FDA in the United States. Also, “… no mention was made that Lilly had had benzodiazepines co-prescribed to minimize the agitation that had been recognized with fluoxetine/Prozac alone” (Kauffman, 2009, p. 9).

Cases Involving SSRI Medication

In the following two cases, SSRI medication proved helpful, but not a panacea. We recommend an exercise with these cases. In both cases, assign elements of the case to the four perspectives of our integrative model. This can increase your awareness of how medication can be a helpful, if only partial, component of treatment.

The Case of Linda

Linda, a 39-year-old Latina, came to therapy after a painful and difficult divorce. She had three children, ages 6, 8, and 11. Her concerns were focused on family survival; she had great worries about the children and feelings of worthlessness. The process of divorce was very difficult, and there were many terrible moments with her ex-husband, some of which the children witnessed. Linda quickly established a therapeutic relationship and began to put her life back together. Around the time of what would have been her 14th wedding anniversary, Linda showed signs of slipping into a clinical depression. After discussing these symptoms and changes with her therapist, she agreed to consult a psychiatrist, who recommended a course of treatment using sertraline/Zoloft.

Linda reluctantly agreed and began taking the medication. Her therapist was aware of the necessity of sertraline/Zoloft at this time for her and spoke to her in every session about its impact in her life. Linda experienced relatively few side effects, with some general nervousness at the beginning of treatment and a mild loss of sexual excitement, about which she talked in therapy. Linda's clinical symptoms lifted after four months and she was titrated off the sertraline/Zoloft.

Linda worked with her therapist for 17 months and made several changes to improve her life and inner attitude. The combining of talk therapy with psychiatric medication was crucial to the success of the overall treatment. Her therapist recognized Linda's serious depressive signs, referred her to a psychiatrist, and continued to see her during this period. Without the medication Linda's condition would likely have deteriorated, with little hope for progress in therapy. The success of this treatment depended on a well-trained therapist who, recognizing the severity of Linda's depression, referred her for medical evaluation in a timely and appropriate manner.

The Case of Jack

Jack, a 29-year-old single bisexual man, came to therapy ostensibly to sort out issues of great career ambivalence. Raised in a strict religious family, Jack lost his mother at age 20 and his father at 12. During his teenage years he was isolated, rebellious, and naive. He completed high school but never quite settled on college. After high school he had sustained heterosexual and homosexual relationships. He was brilliant, with an IQ over 155 and a great capacity to synthesize complex material. Recently, he had ended a five-year homosexual relationship, had made peace with an older sister who supported him, and had applied and been accepted to a prestigious East Coast college to study philosophy.

As the treatment unfolded, very complex material and conflicts entered into the work with Jack. He suffered greatly from the losses of both parents and seemed unable to grieve for them and move on. He expressed a great deal of excitement for female companionship, yet remained constantly disappointed in these relationships. In the transference he was meek and dependent, challenging and demanding, and rebellious and attacking. He sought to find from therapy quick-fix solutions to his historical problems and current dilemmas. He loved to philosophize and gossip. During moments of his greatest anguish and chaos, he identified with the antigovernment types of Montana who felt totally trapped by the rules of living in a democracy. About a year into the treatment he became seriously depressed and was referred to a psychiatrist who, after an evaluation, prescribed paroxetine/Paxil. Jack took the medication as ordered for about six months, and he reported relief from many of his depressive symptoms.

Gradually he then became disenchanted with the paroxetine/Paxil. He said he had all but lost his sexual drive and desire and wondered if the medication was a method to modify or control his radical thinking about some of the absurdities of American culture. At first it seemed he was expressing symptoms of paranoia, but when therapy explored the meanings, it appeared his feelings and meanings were rooted in a genuine disagreement with much of the fabric of American life. He identified with groups and cultures that deeply questioned the rules and values of Western culture. Jack's experiences were particularly poignant because of the many hateful reactions he encountered from society when he lived openly with his partner. Some of his agony was rooted in life experiences that were discriminatory and threatening. Although the medication was temporarily helpful, it could not address issues and conflicts he experienced as a result of internal group identifications. Understanding these dilemmas in his life allowed exploration of many alternative options for his present and future life choices. He gradually came off the paroxetine/Paxil in consultation with his psychiatrist.

In this case, we can see how a psychopharmacological intervention was helpful temporarily and that its limited effectiveness led to a deepened understanding of the client's struggles and therapeutic interventions. In this case, we see the paroxetine/Paxil as a bridge to more critical unfolding of Jack's psychic and political life.

Review Questions

• What are the benefits and risks of SSRI medications?

• What is the primary mechanism of SSRI medications and how does it relate to the neurotrophic/plasticity theory of antidepressant action?

• What is the controversy over SSRI-related violence and who is most at risk for this?

SECTION SIX: THIRD-GENERATION ANTIDEPRESSANTS

Learning Objectives

• Be able to describe how many third-generation antidepressants are really variations on existing compounds.

• Understand the mechanisms of action for third-generation antidepressants.

• Have a sense of the promises and pitfalls of ketamine as an antidepressant.

SSRIs constituted the second generation of antidepressants; there is now a third generation of antidepressants that includes drugs with diverse properties and that were chemically inspired by the development of the SSRIs (Olver et al., 2001). This category of drugs has a variety of actions that may include, but are not confined to, serotonin reuptake inhibition. Like the second-generation SSRIs, these drugs are supposed to have better side effect profiles and more safety than MAO Inhibitors and TCAs. However, despite much initial speculation that they might be more effective than SSRIs, they seem, at most, to be only equally effective and subject to the same “pooping out” problems as SSRIs.

TABLE 5.11 Current Third-Generation Antidepressants

Generic Name	Brand Name	Common Daily Dosage Range
Bupropion	Wellbutrin	200–450 mg daily
Remeron	Mirtazapine	15–45 mg daily
Venlafaxine	Effexor	75–375 mg daily
Reboxetine	Edronax, Vestra	4–8 mg daily
Duloxetine	Cymbalta	40–60 mg daily
Desvenlafaxine	Prestiq	50 mg once daily

© Cengage Learning®

The third-generation antidepressants include such drugs as bupropion/Wellbutrin, mirtazapine/Remeron, venlafaxine/Effexor, duloxetine/Cymbalta, and reboxetine/Edronax. In addition there is a new drug desvenlafaxine/Prestiq that is made from the metabolites of venlafaxine/Effexor. At the time of this writing, another third-generation antidepressant (nefazodone/Serzone) was taken off the market by manufacturer Bristol Myers Squibb because of rare but lethal side effects related to liver failure.  Table 5.11  summarizes the current third-generation antidepressants.

Bupropion/Wellbutrin: A Norepinephrine-Dopamine Reuptake Inhibitor

The mechanism of action for bupropion/Wellbutrin was unclear for some time. Although it at first seemed to have potent reuptake inhibition properties for NE and DA, the drug itself was actually a weak inhibitor of these reuptake processes. Researchers recently discovered that when taken into the body, the drug goes through an anabolic metabolism, which means that as the drug is metabolized, initially it becomes more potent. This is why psychopharmacologists sometimes call it a “prodrug,” meaning a drug that acts like a precursor and then becomes activated through the body's metabolic processes. From the psychological perspective, clients report that bupropion/Wellbutrin is somewhat stimulating and (from the medical model perspective) is not associated with AISD, which makes it an alternative for clients who are troubled by AISD. Some clients even report an increase in libido (though bupropion/Wellbutrin should not be thought of as an“aphrodisiac”). Interestingly, bupropion was initially marketed with two different brand names for two different purposes: Well-butrin as an antidepressant and Zyban as a smoking cessation aid. These distinctions are less relevant now that it is available in generic formulations. Bupropion/Wellbutrin seems to decrease the craving sensations associated with nicotine withdrawal (Warner & Shoaib, 2005).

Bupropion/Wellbutrin is available in an extended-release (XR) formulation that requires one dose per day. The dosage range for bupropion is from 150 to 450 mg daily. Side effects can include insomnia, gastrointestinal distress, and treatment-emergent hypertension. Bupropion/Wellbutrin has been shown to reduce the seizure threshold and is contraindicated for people who suffer from a seizure disorder, a head injury, or an eating disorder. Alcohol use is also contraindicated while taking bupropion, because it also lowers the seizure threshold. Overall bupropion compares favorably with other antidepressants (Maneeton, Maneeton, Eurviryanukul, & Srisurapanant, 2013) and may be preferable due to not causing weight gain or sexual dysfunction.

In 2012, the FDA recalled one 300 mg generic version of bupropion/Wellbutrin made by Watson pharmaceuticals. In testing the generic versions of four drug makers, Watson's version of the drug was not therapeutically equivalent to the brand name (FDA, 2013).

Mirtazapine/Remeron: A Serotonin-Norepinephrine Antagonist

Mirtazapine/Remeron is a drug that increases both serotonin (5-HT) and norepinephrine r (NE) release by blocking the appropriate autoreceptors (in this case the alpha-2 autoreceptors on both the NE and 5-HT neurons). Recall that autoreceptors help neurons regulate their output of whatever neurotransmitter the neurons happen to produce. Artificially blocking these with the mirtazapine/Remeron molecule so they cannot be naturally stimulated to give the slow-down signal the neuron is “fooled” into increasing its release of neurotransmitter. This increase then theoretically causes the same ripple effect in the central nervous system that we summarized in discussing the molecular/cellular theory of depression. Stahl (2000) offers the analogy that this mechanism of action is like “cutting the brake cable” (p. 251) and thus increasing neurotransmitter release. Mirtazapine/Remeron also blocks adrenergic receptors on terminal button of serotonin neurons. When these are blocked it causes the neurons to release more serotonin. Finally the increased release of serotonin stimulates 5-HT1 receptors while 5-HT2 and 5-HT3 receptors are blocked by mirtazapine/Remeron. Like all drugs, mirtazapine has side effects. It also blocks various serotonin and histamine receptors, resulting in sedation and weight gain. The typical dosage range for mirtazapine is 15 to 45 mg daily. It is also available in an orally dissolving “Soltab” formulation (Organon, 2003). Mirtazapine/Remeron compares favorably with SSRI antidepressants but seems to have better efficacy with mixed anxiety and depression (Kim et al., 2011).

VenlafaxineEffexor: A Serotonin-Norepinephrine Reuptake Inhibitor

Venlafaxine/Effexor has earned the label “dual reuptake inhibitor,” because it combines the SSRI mechanism of action with potent reuptake inhibition of norepinephrine. It is currently available in an extended-release formulation and can be taken once daily. Researchers consider this once-daily administration significantly reduces side effects. Stahl (2000) asks, “Are two antidepressant mechanisms better than one?” Because reality is complex, the answer is “It depends.” For some clients who have not responded to more specific, single-action agents (such as SSRIs), additional mechanisms of action can result in enhanced efficacy. From an integrative perspective we must note that the question presupposes a clear medical model etiology to depression, and this hypothesis has not been confirmed. Common side effects associated with venlafaxine/Effexor include gastrointestinal distress and insomnia. The common dosage range for venlafaxine/Effexor is 75 to 300 mg per day. A recent meta-analysis suggests that venlafaxine/Effexor is superior to SSRI antidepressants but has a significantly higher dropout rate due to adverse events (side effects) (de Silva & Hanwella, 2012).

DESVENLAFAXINE/PRESTIQ

In 2008, the FDA approved desvenlafaxine/Prestiq for the treatment of depression. It is designed from a metabolite of venlafaxine/Effexor and is a serotonin-norepinephrine reuptake inhibitor. Despite being a metabolite of venlafaxine, it appears desvenlafaxine has a different binding profile at both NE and 5-HT receptors. This leads to more adrenergic activity in desvenlafaxine which may account for the increase in cardiovascular side effects like heightened blood pressure. The parent compound (venlafaxine) only shows increased NE activity at higher doses but desvenlafaxine shows this at doses below the minimum therapeutic dose of 50 mg (Kamath & Handratta, 2008). Anything less than the minimum effective dose of 50 mg per day fails to show any difference from placebo (Liebowitz, Tourian, Huang, Mele, & for the Study 3362 Investigators, 2013; Rosenthal, Boyer, Vialet, Hwang, & Tourian, 2013). In comparisons between desvenlafaxine and its parent compound venlafaxine there appear to be few differences either in efficacy or tolerability that are significant enough to warrant a new drug. It has been suggested that desvenlafaxine was created and released about the same time as venlafaxine went generic and that this drug may be more about pharmaceutical profits (a “me too drug”) than about clinical utility (Sopko, Ehret, & Grgas, 2008).

Reboxetine/Edronax: A Selective Noradrenergic Reuptake Inhibitor

First recall that noradrenaline is synonymous with norepinephrine (the difference being that the latter term is derived from the Latin and the former from Greek). Thus, reboxetine/Edronax is a selective inhibitor of norepinephrine reuptake. You may think this sounds like a tricyclic antidepressant, and that is correct. The difference is that reboxetine/Edronax supposedly does not have the “dirty” quality of binding to histamine and acetylcholine receptors (which cause many of the side effects associated with the TCAs). As such, reboxetine/Edronax was supposed to be useful for patients who respond better to NE reuptake inhibition or as a complement to SSRI therapy where response has been partial. The initial efficacy of reboxetine/Edronax seemed to be equal to the TCAs and the SSRIs (Messer, Schmauss, & Lambert-Bauman, 2005).

Side effects may include tremor, agitation, and changes in heart rate and blood pressure. Stahl (2000) also describes a milder set of side effects, similar to TCA anticholinergic side effects (dry mouth, constipation, and urine retention). He noted that these effects are milder and shorter in duration, because they do not result from direct blockage of acetylcholine receptors. These effects are more a result of reboxetine's effects on the sympathetic and parasympathetic nervous systems, both of which are highly populated with norepinephrine receptors.

The problem turned out that reboxetine/Edronax does not seem to have efficacy for depression. It was never FDA approved for use in the United States, which is telling. More recently a meta-analysis published in the British Medical Journal (Eyding et al., 2010) revealed, once again, some very biased information from the company that produced reboxetine/Edronax. Reboxetine/Edronax was compared to SSRI and placebos across 13 clinical trials involving over 4000 patients. The maker of reboxetine/Edronax (Pfizer) never published data on 75% of those patients, which inflated the drug's effectiveness over placebo by 115% (Szalavitz, 2010). In 2007 the United States passed a law to make all data—positive and negative—from clinical trials on drugs regulated by the FDA public. What Eyding et al. (2010) found was that the partial presentation of data inflated the drug's effectiveness and greatly underestimated potential harm from adverse events. This particular drug highlights the important of access to positive and negative data as well as published and unpublished trials.

BRINTELLIX/VORTIOXETINE

Vortioxetine/Brintellix is being labeled an atypical antidepressant. It was FDA approved in late 2013 for MDD but there is much confusion over its mechanism of action; the maker (Takeda Pharmaceuticals) claims it is a 5-HT1d antagonist and a 5-HT1b partial agonist. It also binds on 5-HT1a, 5-HT3, 5-HT1d, and 5-HT7. The pharmacy information card (Takeda Pharmaceuticals, 2013) states with regard to the binding “the clinical relevance of this is unknown” and “the mechanism of the antidepressant effect of vortioxetine is not fully understood …” (p. 1). Gibb and Deeks stated that “vortioxetine is a bis-aryl-suphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation” (p. 135). Boulenger, Lundbeck, Loft, and Olsen (2014) concluded that the treatment has similar adverse effects as SSRI and SNRI; nausea, headache, diarrhea, dry mouth, and dizziness. They found it superior to placebo. Pearce and Murphy (2014) compared the significance of vortioxetine compared to other antidepressants and concluded “… vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatments” (p. 1542). Similarly, Dubovsky (2014) concluded that the “advantages of vortioxetine over existing antidepressants are not yet clear.”

MILNACIPRAN/SAVELLA

Milnacipran/Savella is a drug that blocks adrenergic and serotonergic reuptake and is FDA approved for the treatment of fibromyalgia. Fibromyalgia is characterized by pain and sensitivity to pressure (allodynia). It can also cause fatigue, stiffness, bowel and bladder problems, and numbness or tingling (Wolfe, 1989). There is some speculation that the genes responsible for fibromyalgia also play a role in Major Depressive Disorder (Buskila & Sarzi-Puttini, 2006). Kohno et al. (2012) noted that it is possible that Milnacipran/Savella blocks NMDA receptors in the spinal cord contribute to analgesia. This may be the case though only in combination with reuptake inhibition of monoamines.

Duloxetine/Cymbalta: A Newer Serotonin-Norepinephrine Reuptake Inhibitor

Duloxetine/Cymbalta is a serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2004 for depression, Generalized Anxiety Disorder, fibromyalgia, and some types of neuropathic pain (it was approved for generic versions in 2013). Duloxetine/Cymbalta seems to have a similar same side effect profile as do SSRI medications and is no more effective in alleviating depression than SSRI medications of venlafaxine/Effexor (Cipriani et al., 2012). When compared to escitalopram/Lexepro or venlafaxine/Effexor duloxetine dropout rates due to adverse events were higher.

In addition to the modest efficacy of antidepressants, another problem was confirmed in the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D) conducted in 2006 (Warden, Rush, Trivedi, Fava, & Wisniewski, 2007). This was the largest prospective, randomized treatment study at that time aimed at helping outpatients who had not had adequate benefit to their first antidepressant. Switching medications or trying to augment the medications the patients started on showed no significant differences in remission rates or times to remission. Participants who required increasing numbers of steps (adding, changing or augmenting medications) experienced great depressive symptoms and greater relapse rates (Warden et al., 2007). Thus it seems that we need a new direction for antidepressant research and novel agents that are perhaps even radically different from existing compounds. Ketamine may be just such an agent.

INTO THE FUTURE: KETAMINE

As early as 2000, researchers were learning that ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDA-R) antagonist, produced rapid and sustained antidepressant action in people suffering from severe depression that in many cases was treatment-resistant (Berman et al., 2000; Cornwell et al., 2012). These effects are immediate, last several days and appear to be linked to glutamatergic neuronal system as well as the mTOR signaling pathway discussed above (Naughton, Clarke, O'Leary, Cryan, & Dinan, 2014). Although some researchers feel there is evidence that the serotonin neuronal system is involved in the therapeutic response (Gigliucci et al., 2013) that is not yet clear. The evidence of therapeutic mechanism now seems focused on the glutamate system.

Glutamate is a major mediator of excitatory synaptic transmission in the human brain. It has important roles in synaptic plasticity, learning, and memory. Glutamate's possible role in depression was hypothesized in the late-20th century (Skolnick et al., 1996). The research had suggested that antagonizing NMDA receptors could be a viable treatment option in depressed clients. It took over 15 years of studies to validate this hypothesis.

Ketamine is an anesthetic agent for diagnostic and surgical procedures in humans and in veterinary medicine. It is perhaps better known as a drug of abuse called Special K on the streets. Ketamine can produce a dissociative state that many find pleasurable. Ironically this effect was pioneered by the son of the founder of Eli Lilly Pharmaceuticals, John Lilly (1996, 2006). John Lilly was trained in both neuroscience and psychoanalysis and he is best known as an explorer of altered states of consciousness. Working at the National Institute of Mental Health in the 1950s, Lilly wanted to isolate the brain from external stimuli. Toward this end, he invented the sensory deprivation tank, which was a dark, soundproof tank filled with body-temperature salt water in which subjects could float for hours (1956). In his own explorations with the tank he took doses of ketamine and claimed to experience what felt like out-of-body (OOB) experiences that took him to different levels of consciousness (Lilly, 1977, 1997).

As is often the case, any form of hallucinogenic experience is quickly labeled “psychotomimetic” by mainstream psychiatry (Browne & Lucki, 2013). Although politically incorrect to state, it may in fact be that the ketamine experience is an altered state that is not mimicking psychosis. Side effects include dizziness and perceptual disturbances but why these are supposedly “psychotomimetic” is not explained. Also listed among the “adverse effects” are euphoria and increased libido (Murrough, Perez, & Stern, 2013). We will let the reader judge if those should in any way qualify as adverse. Regardless the “adverse effects” reported returned to baseline within two hours of dosing. Although any drug that may induce altered states should be avoided by people with a vulnerability to mental disorders, there is growing evidence that drugs such as LSD, psilocybin, MDMA, and ketamine can be powerful therapeutic tools in the right hands and under the proper restrictions (Roberts & Winkleman, 2007). We will discuss this further in the upcoming chapter on the topic. One of the problems with ketamine as an antidepressant is that it must be given intravenously and the effects only seem to last a few days. For those reasons, it may do better to use it as a model for other drugs that can affect NMDA receptors in a similar manner but have therapeutic effects that last longer and are possible to get in an oral formulation.

The neurobiological mechanisms underlying the antidepressant actions of ketamine are more complicated than simple antagonism (blocking) of NMDA receptors. 30–40 minutes after administration of a low dose subjects experience dissociative effects. After this, antidepressant effects begin approximately 110 minutes into the experience and are sustained for up to seven days (Zarate, Singh, & Carlson, 2006). Ketamine seems to initiate a cascade or chain reaction of events that results in rapid response. These may include effects on NMDR receptors, BDNF translation, mTOR activation, increased synaptic proteins, and increased synaptic plasticity. It is surprising that the psychological effects of a dissociated state of wellbeing reported by so-called abusers of ketamine (Zarate et al., 2010) is not considered a therapeutic mechanism yet. Most recently attention has been given to BDNF. In a recent study, ketamine significantly increased markers of BDNF in subjects whose depression responded to ketamine treatment (Haile et al., 2014). Hopefully further research will clarify what else contributes to the therapeutic effects.

Review Questions

• In what way are third-generation antidepressants like venlafaxine/Effexor similar to SSRI and TCA compounds?

• Describe the primary mechanisms of action in bupropion/Wellbutrin, duloxetine/Cymbalta, and mirtazapine/Remeron.

• What are the potential gains and drawbacks of ketamine as an antidepressant?

SUMMARY POINTS ABOUT ANTIDEPRESSANTS

We end this section of the chapter with a few key points to communicate to clients about antidepressants. These are paraphrased from Julien, Advokat, and Comaty (2011):

• Onset of clinical action for all antidepressants may take from two to six weeks.

• Symptomatic improvement is usually most seen in physiological symptoms. Many other symptoms may respond only partially to the drugs.

• Although these medications may improve mood, they do not erase all sadness or one's ability to experience the full range of emotions.

• The best indication of medical response includes improved sleep, less daytime fatigue, and some improvement in emotional control, and mental clarity.

• There may be side effects, but these can often be managed by dosage adjustment, augmentation, or switching to another antidepressant.

• Length of treatment varies with the client. It takes four to eight weeks for symptoms to subside, and if you quit at this point the relapse rate can be as high as 80%. A general guideline is to continue for six months and then gradually decrease.

• SSRI antidepressants (and possibly other types) do induce a type of dependence. They do induce a tolerance effect that can result in a withdrawal syndrome, which can be pronounced if clients do not appropriately go off the medication under their doctor's supervision.

CASE OF JOSHUA

Joshua is a 36-year-old African American businessman who recently came to counseling because of many changes in his life, including sleeplessness, loss of energy, feelings of hopelessness, lack of concentration, and difficulties with his relationships at home and at work. After a three-session assessment, which included an evaluation of Joshua's thoughts and feelings, he reluctantly agreed to see a psychiatrist for an evaluation to determine his need for an antidepressant medication. The psychiatrist recommended that Joshua begin a course of treatment with fluoxetine/Prozac. A week later, he began taking the fluoxetine/Prozac while continuing weekly therapy with his counselor. Almost immediately Joshua complained of sleeplessness, irritability, and nervousness. His therapist encouraged him to give the fluoxetine/Prozac time, at least three weeks, which he did. However, the side effects did not subside. In fact, Joshua reported that they worsened.

Throughout this period, Joshua continued to attend his weekly sessions to talk both about his depression and his reaction to the medication. Both the counselor and Joshua felt that their work together deepened. After four weeks on the fluoxetine/Prozac, Joshua decided to talk over his problem with the psychiatrist. The counselor and Joshua prepared for this meeting, which went well, and as a result, Joshua was titrated off the Prozac. The psychiatrist prescribed a course of venlafaxine/Effexor, an SNRI for Joshua.

Joshua took the venlafaxine/Effexor as prescribed, and after about 25 days on the medication reported to his counselor that he was feeling better. It is clear from the medical model perspective that the fluoxetine/Prozac was not helping Joshua, and it was equally clear that venlafaxine/Effexor began to alleviate some of his symptoms. What is more difficult to ascertain is the impact of the emerging counseling relationship and how Joshua's growing trust in his counselor also contributed to his psychological relief. Joshua continued the venlafaxine/Effexor and the counseling for nine months and made almost a complete recovery. Although the technical aspects of this case are clear, it is most difficult to tease out the impact of the authentic counseling relationship on Joshua's movement back to health.

ANTIDEPRESSANTS IN OLDER CLIENTS

Depression in elderly people is thought to be underreported (Satlin & Wasserman, 1997). Elderly people compose 12% of the population and account for approximately 20% of all suicides. Men account for 81% of suicides in those 65 and older. Risk factors for later life depression include female gender, unmarried status, stressful life events, lack of social support, and concurrent medical illness.

Satlin and Wasserman (1997) have noted that the literature is an imperfect guide to pharmacologic treatment of the elderly for several reasons.

• Published antidepressant trials use clients 55 to 65, whereas antidepressants are being prescribed for people considerably older.

• Participants in studies are atypical in that they are often free from medical illness. Although this makes it easier to see the relationship of the drug under study to the symptoms, it does not mirror the reality that many older clients with depression have complicating medical conditions.

• Most studies include only those clients with moderate depression.

• Therapeutic response is measured only by the decline on depression scales, thus many people who showed “therapeutic response” have significant residual symptoms that continue to interfere with quality of life.

• With elderly clients it is important to screen for substance abuse, current nonpsychotropic medications, and general medical conditions. SSRIs are primary drugs of choice, starting at half-dose. Julien (2001) advises prescribers to start with a lower dose and titrate slowly. In addition, apparently bupropion and venlafaxine are promising treatments. Low doses of stimulant medication have also been used to improve mild dysphoric states (Satlin & Wasserman, 1997). We devote  Chapter Thirteen  to an overview of geriatric psychiatry.

SECTION SEVEN: FOCUS ON PSYCHOLOGICAL, CULTURAL, AND SOCIAL PERSPECTIVES

Learning Objectives

• Understand why it is important to talk to clients about how they feel about taking antidepressants.

• Be able to describe the placebo problem and the difference between active and inert placebos.

• Be able to discuss some nonpharmacologic treatments for depression.

In this section, we return to exploring antidepressants through psychological, cultural, and social perspectives—several issues concerning antidepressants that are rarely mentioned in standard psychopharmacology texts. As we noted in the cases for this chapter, the various quadrants offer us important perspective on these issues.

PSYCHOLOGICAL PERSPECTIVES

What does it mean to someone to take an antidepressant? As with many things in life, the meaning varies from person to person. Researchers working from the medical model perspective have tried to determine whether a given depressive episode was biological or psychological in etiology (Stahl, 2000). From an integrative perspective, this does not go far enough, because in the psychological realm alone many variations of psychological responses to stress or trauma can be delineated. John Teasdale (Teasdale, Segal, & Williams, 1999; Teasdale et al., 2000) hypothesized that even if biological mechanisms in some people allowed sadness to slide into depression, these same people could learn to stop that series of events through psychological, nonpharmacologic means. Using a variation of awareness meditation (described in  Chapter Three ) Teasdale was able to help clients disidentify from their thoughts to the point where they could preclude depressive episodes that likely would otherwise have followed periods of normal stress or sadness.

Another perspective regarding the variety of psychological experiences of depression views the subjective experience of depression in relation to a client's level of development. Human development can progress far beyond the stage of having a healthy ego. Most people have the capacity for growth beyond the levels of healthy ego development (Alexander & Langer, 1990). This further development is referred to as “transpersonal,” meaning “going beyond” or “including and transcending” the personal (Walsh & Vaughan, 1980). On the personal level of development, the subjective experience of depression is qualitatively different from that on the transpersonal level. Moving from personal to transpersonal frequently includes an existential component wherein the person feels a sense of meaninglessness and horror when confronted with the existential givens of the world (aging, illness, death, human cruelty). After passing such a developmental milestone, people who have stabilized ego functioning may experience the world without benefit of the filters the ego puts in place. This experience calls on such people to develop a deeper and broader philosophy or “big picture” in order to continue living and growing. Sometimes the spiritual personages considered saints in both Eastern and Western traditions report an experience called “dark night of the senses,” which qualitatively resembles anhedonia (a loss of joy or pleasure in all things). The dark night of the senses is a period of desolation where one no longer finds joy in life. Rather, one confronts the stark pain inherent in human existence and seeks a way to deal with that pain. Far from being a chemical imbalance of the brain, such a state is frequently a prelude to a more expanded state of spiritual understanding. We realize that in a society that values materialistic explanations, it is hard enough to accept various psychological theories for things such as depression, let alone to consider a worldview that, for lack of a better term, is spiritual in nature. Yet an integrative exploration of any topic must be broad enough to include a place for such worldviews. With these worldviews come technologies such as meditation that have rich potential for treating symptoms such as those seen in depressed clients.

DIFFERENT PERSPECTIVES ON THE PLACEBO PROBLEM

Placebo responses are common, according to researchers such as Fisher and Greenberg (1997) and practitioners such as Colbert (2002). These professionals begin by claiming that the evidence of efficacy of counseling and psychotherapy (from the psychological perspective) is not given equal weight with the evidence supporting pharmacologic interventions (medical model perspective). They then note that although medical research on psychotropic medication is lavishly funded by the pharmaceutical companies, research on counseling and psychotherapy struggles, because it has far fewer resources (when was the last commercial you saw for counseling?). Finally, many have claimed that many research results from the medical model perspective that do not distinguish between placebo and drug never get published and are not as accessible to the public as the published studies that support the efficacy of the drugs over placebo.

For example, Khan, Leventhal, Khan, and Brown (2002) demonstrated that in over 50% of the trials on antidepressants in the FDA database, researchers found no significant difference between active placebo and the drug being tested. Many of these studies are never published in peer-reviewed journals, because they are less likely to be published than studies that showed significant differences between placebo and drug. Another scenario is that when pharmaceutical companies sponsor studies, they may include clauses that allow them to “hold” results for a period of time before releasing them back to the researchers, who may then try to publish them. Bodenheimer (2000) has documented cases where companies prevented important research findings from being published because the results were not favorable regarding the compound being tested.

From the cultural perspective, one question is how far the culture of the pharmaceutical industry may go in protecting its interests. Although more research needs to be done regarding client responses to placebos (Naudet et al., 2013), it is unlikely the companies themselves would carry out such research. Government is more likely to fund it with tax dollars targeted for such research, but again, how will politicians who receive financial support from pharmaceutical companies view such research?

Pomerantz (2003) offers another perspective on antidepressants and placebo effects. Summarizing prescription trends, he notes that spending for antidepressants increased 600% during the 1990s and that in 2000 alone over $7 billion was spent on SSRI medications. He then cites studies from the United States and Italy suggesting that a significant percentage of clients stop taking the SSRIs after one or two months. He reminds us that off-label uses for SSRI antidepressants keep growing despite little evidence to support such uses. This practice includes using SSRIs for mild depression, for which SSRIs are no more effective than placebo in many studies. Pomerantz contends that in cases where SSRIs are being used off label, this use is akin to using them as active placebos. Because most clients feel something on beginning the medication, they assume something is working to help them, without realizing they are just feeling drug effects that may be unrelated to their problem. Because Streator and Moss (1997) have demonstrated that large numbers of patients are taking SSRIs for off-label uses, Pomerantz concluded this is simply very expensive (wastefully so) placebo therapy.

OTHER TREATMENTS FOR DEPRESSION

You can see that the systematic use of RCTs and the standardization of categorical psychiatry rely predominantly on the medical model perspective. Despite the dominance of the medical model perspective, many people seek out alternative and/or complementary treatments (herbs, and so forth), which we discuss more thoroughly in  Chapter Ten . One battle in mental health treatment is between the proponents of the psychological perspective, who point to successful psychosocial treatments for mood and anxiety disorders, and proponents strictly adhering to the medical model perspective, which reduces mental disorders to biochemical entities ignoring their social, cultural, and personal meaning. More studies are now showing the efficacy of the psychosocial methods. Two studies have even documented through brain scans that the neurological changes attributed to antidepressants also occur with psychotherapy (Brody et al., 2001; Martin, Martin, Rai, Richardson, & Royall, 2001).

Nevertheless, U.S. trends show an increased number of people given medication for depression, a decreased number receiving counseling or psychotherapy, and a lowered percentage of treatment costs covered by insurance (Olfson et al., 2002). In addition to the standard psychosocial interventions, an increasing number of studies show that exercise is effective in alleviating symptoms of depression (Babyak et al., 2000; Leppamaki, Partonen, Hurme, Haukka, & Lonnqvist, 2002; Salmon, 2001), as are yoga postures and breathing exercises (Jorm, Christensen, Griffiths, & Rodgers, 2002; Nyer et al., 2013; Ray et al., 2001). There is also a growing literature on nutrition and depression (Recheneberg & Humphries, 2013). Continued research on these nonpharmacologic treatment options is important. The case of Alex illustrates some problems when doctors may prescribe potential drugs of abuse ostensibly for depression.

A PROBLEM CASE: THE CASE OF ALEX

Alex, age 27, has been treated for his depression with dextroamphetamine/Adderall for the past five years. Recently, his psychiatrist lost his license to practice for prescribing addictive medications to patients who then sold the drugs on the street. Criminal charges against him are pending. When mental health professionals attempted to refer Alex to another psychiatrist, he indicated that he would only go to one that would give him dextroamphetamine/Adderall for his depression and withdrawal. No psychiatrist in the community would agree to that drug for Alex. After several months of suffering, Alex agreed to see a psychiatrist who recommended a course of bupropion/Wellbutrin for him. The psychiatrist cautioned about the dangers of long-term use of dextroamphetamine/Adderall and explained the potential proactive effects of bupropion. After a long discussion/argument, Alex agreed to give the bupropion/Wellbutrin a try. Six months later the psychiatrist added 50 mg of sertraline to the bupropion. In the last five to six years, psychiatrists have found this combination to be very effective with long-term depression. Alex continues to refuse to attend counseling for his depression.

Questions About the Case of Alex

1. Discuss the impact of Adderall on depression. Why did Alex refuse to switch medications?

2. What do you do when the patient/client attempts to control the treatment?

3. Do you believe Alex will ever try counseling? Why? or Why not?

When to Recommend Medication Evaluation

For mental health therapists, all these considerations raise the question “When should I recommend a medication evaluation?” As the cases in this chapter illustrate, antidepressant medication ideally provides a chemical window of opportunity for clients to gather the energy for making changes through counseling and psychotherapy. When to recommend this “window of opportunity” depends primarily on client factors: in particular, the severity of the depression and the associated risks to the client (or others) such as suicidal thinking or failing to meet caregiving responsibilities. Ideally, the counselor can develop some alliance with the client and work through the question with him or her. Clients who resist the idea of medication can use this resistance to apply themselves to counseling. Clients at risk for harming themselves or others by omission or commission require a more aggressive intervention to stabilize them.

The Culture of Pharmaceutical Companies: Are Newer Antidepressants Medical Innovations or “One-Trick Ponies”?

The issue of whether the newer antidepressants are just “one-trick ponies” relates directly to the culture of pharmaceutical companies and the legal-economic aspects of drug development in the United States. When pharmaceutical companies find a mechanism of action that seems effective, they focus research on finding as many permutations of that mechanism as possible. There are likely several reasons for doing so. Certainly one is that by fully exploiting the mechanism they may break through to advances that will help clients. The other reason may be less noble and more related to the amount of time and money it takes to really develop new compounds. Consider the FDA regulations we discussed in  Chapter Four . There we noted that the FDA requires companies to show through randomized, double-blind, placebo-controlled studies that their medication treats the symptoms of some disorder. These regulations are objectively built into this society through the authority of the FDA and related laws passed by state and federal legislators. Given these structures, it costs millions of dollars just to begin the long journey toward FDA approval. This increases the probability that once a single company has cleared part of the path to FDA approval, other companies will follow in that wake.

Recall that the first company to break SSRIs into the market was Eli Lilly, with fluoxetine/Prozac, and that after this, numerous other companies spent a great deal of money putting similar and equally effective SSRI compounds on the market (fluvoxamine/Luvox, sertraline/Zoloft, paroxetine/Paxil, citalopram/Celexa, escitalopram/Lexapro, etc.). These compounds were similar but different enough to garner FDA approval and be able to compete in the marketplace. The National Institute for Health Care Management (NIHCM) (2002) reported that approximately two-thirds of the medications the FDA approved in the 1990s were merely modified versions of existing drugs. Only 15% were for drugs containing new active ingredients.

Companies often seek to extend their patent rights over an existing compound either by bringing out a slightly different version of the compound or by seeking FDA approval for a new use for the existing compound. About a year before its patent ran out for fluoxetine/Prozac, Eli Lilly brought out fluoxetine under a new name (Sarafem) and received FDA approval for its use for PreMenstrual Dysphoric Disorder (PDD). This is curious, because the latter was technically not a DSM category at the time and only a condition for which further research was needed. It has been included in the Depressive Disorders in DSM-5.

At the same time, rival companies are constantly seeking ways to bring out generic versions of compounds other companies have patented. For example, in 1998, Apotex Corporation filed for approval of a generic form of paroxetine/Paxil. Paroxetine/Paxil was worth $2.1 billion in 2001, and the company with the patent rights (GlaxoSmithKline) sued Apotex for patent infringement. In 2003, a court ruled in favor of Apotex and GlaxoSmithKline stock fell sharply (Sipkoff, 2003). The companies filed an agreement in settlement in 2007 but as of 2012 there were still court cases dragging on as appeals are filed and as both companies assert the other was not abiding by the settlement. Critics thus question whether enough energy is going into the study of new compounds or whether pharmaceutical companies are relying on “one-trick ponies” for guaranteed profits, and such ponies tend to pay off a great deal. So what begins as serendipity, the possibility that a drug may have other uses with varied disorders, becomes a corporate strategy to fully support a new diagnostic category without the necessary research.

These issues have been summarized as the Matthew effect (Merton, 1968) and the Luke effect (Healy, 1997). Both paraphrase quotations from the biblical texts bearing these proper names. Merton summarized the Matthew effect as “To him who has, more shall be given, and from him who has not, even more shall be taken away.” He noted that the survival of ideas depends on how effective they are. In addition, Healy (1997) added that whose interests the ideas coincide with and the degree to which they have commercial application for brand name recognition also influence how much effort and energy is put into them. Thus, SSRIs in general and the outdated theories about why they work (for example, the “chemical imbalance” theory) garner a great deal of support and name recognition, and any company with a similar compound can “jump on the bandwagon” for an increased probability of success. Conversely, Healy noted that this effect may reduce the chance that different (and thus financially riskier) ideas will not get funded by pharmaceutical companies.

Based on this logic, Healy proposed the Luke effect, which followed the biblical parable that when a sower sows seed, some will fall on thorny ground and wither, some will fall on fertile ground and be choked by weeds, and some will fall on fertile ground and flourish. Thus, the nowoutdated metaphor of “chemical imbalance” provides fertile ground on which to sow the seeds of compounds that work like others that correct this hypothetical “imbalance.” Healy concludes, “This parable ends with an exhortation to those who have ears to listen, which I will argue is what drug companies do very successfully, as part of the business of bringing the development of their compounds to fruition” (p. 180).

We want to emphasize that we are not raising these issues to condemn pharmaceutical companies for seeking to make profits. Again from the social perspective, the principles of the free market and how those principles are implemented through laws are an integrative part of our society. This does not mean, however, that they should evade inspection, commentary, and a system of checks and balances.

CHAPTER EIGHT Mood Stabilizers

Bipolar I Disorder (BPI) is an incapacitating, severe mental illness that affects approximately 1% of the population (APA, 2013). It usually has its onset in adulthood and early onset is age 13. Despite this, there has been an epidemic of misdiagnosing children who act out as having Bipolar I Disorder. In an effort to stem the tide of misdiagnoses, the American Psychiatric Association (APA) included an untested, new diagnosis in DSM-5. It is called Disruptive Mood Dysregulation Disorder and deals with acting out, aggressive behavior, and tantrums that are developmentally abnormal as defined by the criteria. The consensus now is that for a child to be diagnosed with Bipolar I Disorder she or he must show evidence of sustained, inappropriate euphoria and grandiosity. We discuss this further in  Chapter Nine  but the context of mood stabilizers is changing radically and we hope, in this chapter, to not just introduce you to the medications that are grouped under the mood stabilizer category, but also help you understand the rapidly changing context of diagnosing and treating Bipolar I Disorder.

This chapter is divided into eight sections. The first explores the curious history of the phrase mood stabilizer and discusses what an effective mood stabilizer should do. The second section covers an overview of Bipolar I Disorder and its symptoms. Section Three provides some history on how some of the medications in use were discovered and developed. Section Four focuses on lithium, the first drug used specifically for Bipolar I Disorder or what used to be called Manic-Depressive Illness. Section Five discusses anticonvulsants used to treat Bipolar I Disorder. Section Six covers newer treatments like lamotrigine/Lamictal. Section Seven takes us back to the atypical antipsychotics and details their use in Bipolar I Disorder. Finally Section Eight discusses cultural and social issues related to mood stabilizers.

SECTION ONE: MOOD MISNOMERS

Learning Objectives

• Understand the history of the phrase “mood stabilization.”

• Be able to state what makes a drug a good mood stabilizer.

The very phrase “mood stabilization” is curious. Webster's New Universal Unabridged Dictionary (1989) notes that a stabilizer makes or holds things stable. That is simple enough, but the very nature of mood in us human beings is rarely stable. In fact, our range of affect and the manner in which we express it may be one of the hallmarks of being (or becoming) human. Clinically speaking, “normal” mood is referred to as a state of “ euthymia .” This word, however, has two slightly different meanings. The more clinical meaning of euthymia is a state that is neither manic nor depressed. Simple enough—perhaps too simple where human beings are concerned. A more important meaning of “euthymia” is rooted in the etymology of the word (almost never referred to by mental health clinicians). The original Greek meaning of euthymia is being “tranquil or joyous.” Eu- is a Greek prefix meaning “good or well,” and thymus refers to “mind.” Unfortunately, clinicians typically restrict the word euthymic to the shallower, clinical meaning, of “neither manic nor depressed.” Perhaps we would better serve clients if we aimed for the original meaning. Imagine what mental health delivery would be like if joy and tranquility were viewed as desirable goals for clients! As philosopher Alan Watts (1973) noted, mental health clinicians seem to be suspicious of things such as joy and prefer that consensual reality be defined as the frame of mind one has going to work on Monday morning. Be that as it may, mood stabilization is the practice of introducing pharmacologic agents that keep clients' moods within parameters clinically described as “normal” or “euthymic.” The psychotropic agents used to do this are called  mood stabilizers .

The phrase “mood stabilizer” was first used in 1985 by Guy Chouinard who suggested that combining estrogen and progesterone may create a mood stabilizer (Healy, 2008). The phrase mood stabilizer did not come into use until the mid-1990s and it was not a phrase scientifically gleaned from years of painstaking research on how certain drugs affected patients. No, it was pressed into use by Abbott Laboratories marketing their newly patented Depakote/valproic acid (Healy, 2013). Depakote was approved for the manic phase of Bipolar I Disorder in 1995 but, as Healy (2013) points out, this is not surprising because any sedating drug will produce a change in people suffering from mania. At the time there were relatively few manic patients and many sedatives on the market. Abbott's license did not allow them to claim Depakote would stop mood swings or act as a prophylactic. They dealt with this by emphasizing the ambiguous phrase “mood stabilization” in their marketing of Depakote. It was ambiguous enough to be the perfect marketing term. Even psychiatry began using it and admitting that as a field, psychiatry did not really know what it meant (Sobo, 1999). There were no peer-reviewed papers on “mood stabilizers” in 1990 and over 100 in 2000 (Healy, 2013).

Regrettably, as you will see, these so-called mood-stabilizing agents rarely bring clients the deeper experience of euthymia, described by the ancient Greeks as tranquil or joyous. In this society, suspicion of joy is perhaps reflected in the severe restriction of access to those drugs that actually seem to induce joy. More often, clients taking mood stabilizers report feeling constricted mood, something even less than the normal fluctuations of mood. Clinically, such clients are described as being neither manic nor depressed, but many tell us this is not a pleasant state. What does it mean to feel neither manic nor depressed? Describing a state by what it is not [called the via negativa or apophatic (without images) in the spiritual logic of St. Thomas of Aquinas] usually fails to give a clear picture of what the state really is. We suspect that the clinical meaning of euthymia is perhaps more word magic retreated to by exhausted clinicians who simply want to say, “The client is neither manic nor depressed.” So we are somewhat back where we started.

In an effort to operationalize for readers the mysterious phrase “mood stabilizer,” we use the parameters set by clinical logic and draw on the work of Schou (1997) and Keck (Interactive Medical Networks, 2001). Schou noted that a mood stabilizer should have far-reaching effects. Ideally, it should show efficacy for relieving manic episodes and depressive episodes, and as a prophylactic treatment, for preventing any further severe mood symptoms. Keck agreed, noting that mood stabilizers should (1) show efficacy in an acute manic phase, (2) show such efficacy in one stage of Bipolar illness without exacerbating another stage, and (3) show some efficacy for mood, psychotic, and cognitive symptoms. Keck also added that mood stabilizers should show some efficacy as a prophylactic (Interactive Medical Networks, 2001). The key to these definitions is that an ideal mood stabilizer does more than simply calm a person suffering from mania. That calming could easily be accomplished with one of the benzodiazepines described in  Chapter Six  or one of the neuroleptics described in  Chapter Seven ; however, the neuroleptic would have little impact on the depressive symptoms or as a prophylactic.

Clinically, the words used to describe mood disorders are important for understanding mood stabilizers. We all need to understand the terms bequeathed to us from DSM-IV to describe mood symptoms that may require mood stabilization. Although DSM-5 has changed “Mood Disorders” to two separate categories (Depressive and Bipolar Disorder), this exercise is still useful.  Figure 8.1  offers the metaphor of a pendulum to illustrate these concepts.

FIGURE 8.1 The Pendulum Metaphor of Mood Disorders

As you can see in  Figure 8.1 , euthymia is at the pendulum's center, implying a “centered” state, meaning normal. In the figure, elevated mood is shown as movement to the right of euthymia and depressed mood is shown as movement toward the left of euthymia. Mood elevated above normal is not described as pathology in DSM even when it reaches hypomanic levels. Hypomanic episodes were new in DSM-IV (American Psychiatric Association, 1994), have been retained in DSM-5 (APA, 2013) and remain difficult to diagnose. The primary difficulties lie in confirming the symptoms and in the fact that hypomanic symptoms eventually shade into manic symptoms. No “hard and fast” line separates them. Hypomanic episodes are described in terms exactly similar to manic episodes, except they are of shorter duration and less severe. As the pendulum of mood moves further to right toward elevated mood, the next descriptor is “manic episode.” This is mood so elevated that it is “sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others” (American Psychiatric Association, 2013, p. 124). In the direction of depressed mood, there is a low-grade depression spectrum referred to in DSM first as Persistent Depressive Disorder (previously Dysthymia in DSM-IV) and finally Major Depression, described in  Chapter Five .  Figure 8.1  includes arrows, spanning the range of a client's mood, that correspond to DSM criteria for particular disorders. Mood stabilization comes into play in Cyclothymia (fluctuations between hypomania and persistent depressive disorder), Bipolar II Disorder (fluctuations between major depression and hypomania), and Bipolar I Disorder (fluctuations between major depression and mania).

We are primarily concerned in this chapter with medications used to treat Bipolar I Disorder, colloquially known as “manic-depressive illness.” Although so-called mood stabilizers are used to treat Schizoaffective Disorder, Bipolar II Disorder, Borderline Personality Disorder, and Cyclothymia, these uses are not yet systematic, the literature is inconsistent, and mood stabilization focuses on manic symptoms (Delgado & Gelenberg, 2001). We cover lithium and several anticonvulsant medications, some of which have demonstrated efficacy for treating Bipolar I Disorder and others that are still under study. We also discuss atypical antipsychotic medications, as well as a new, hybrid medication combining olanzapine/Zyprexa with fluoxetine/Prozac (brand name Symbyax). Because there are so many brand names and formulations of lithium (e.g., Lithobid, Eskalith, Lithonate), we will depart from our generic/Brand name presentation in this case and simply refer to it as “lithium.” We will do the same when discussing valproic acid and use the term V alproate.

Note that the literature on medications for Bipolar I Disorder often use “mood stabilizer” as synonymous with “antimanic.” We use the phrase “mood stabilizer.” It is also important to note that the so-called mood-stabilizing medications described in this chapter are increasingly being used in an attempt to control aggressive behavior, particularly in children and adolescents (Viesselman, 1999). We discuss this use as well as the fact that little research supports this practice in the next chapter.

Review Questions

• What is your reaction to the origin of the phrase “mood stabilizer?”

• What qualities make a drug a good mood stabilizer?

SECTION TWO: BIPOLAR I DISORDER

Learning Objectives

• Be able to understand the challenges in identifying the etiology and proper treatment of Bipolar I Disorder.

• Know the spectrum of symptoms as well as the challenge of the specifiers “mixed episode” and “rapid cycling.”

As noted, Bipolar I Disorder is predominantly characterized by symptoms that meet the criteria for major depression and symptoms that meet the criteria for mania. The estimated  lifetime prevalence  fluctuates between 0.4 and 1.6% of the adult population (Kessler et al., 1994). In DSM-5, there are new categories replacing what were Mood Disorders in DSM-IV . One such category is Bipolar and Related Disorders that includes Bipolar I, Bipolar II, and Cyclothymia.

Prevalence estimates are very difficult to come by, and some practices used to justify them are questionable. In Ohio in 2003, a psychiatrist on a cable-access news program stated that the incidence of Bipolar I Disorder is significantly higher than currently believed. To support this assertion, he cited some survey research (Hirschfeld et al., 2003). He did not say that the survey in question was extrapolating diagnoses from a 10-item questionnaire (which is not clinically ethical), that the 10-item questionnaire had only fair validity, and that 10 of the 11 authors received substantial financial support from pharmaceutical companies. This was hardly a good citation of a supposedly objective, scientific study. Our point is that most viewers may not have even bothered to look up the study to which the speaker was referring and might believe him simply because he was a psychiatrist.

Estimates have sometimes been made for how many people are thought to suffer from Bipolar I, II, and Cyclothymia. These estimates are about 4% of the population (Advokat, Comaty, & Julien, 2014) but that is not an appropriate practice. In preparation for the release of the DSM-5, some advocated that all these disorders should be placed on a continuum called Bipolar Spectrum Disorder (Akiskal & Banazzi, 2006; Ghaemi, Ko, & Goodwin, 2002; Paris, 2009). In DSM-5, Bipolar and Related Disorders were given their own category but it is NOT a spectrum. The concern with the spectrum idea was the possibility that clients who showed symptoms of irritation or inattention (especially children and adolescents) would get mis-diagnosed under the bipolar spectrum umbrella with Bipolar I Disorder (Baroni, Lunsford, Luckenbaugh, Toubin, & Leibenluft, 2009; Paris, 2009). And it should be added that the DSM-IV Task Force rejected the idea of childhood Bipolar Disorder because there was not enough evidence (Frances, 2013). Although some researchers (Alloy et al., 2012; Walsh, Royal, Bronw, Barrantes-Vidal, & Kwapil, 2012) have explored what they call a “soft” Bipolar Spectrum, currently Bipolar I, Bipolar II, and Cyclothymia should be conceived of as discrete disorders rather than thinking of Cyclothymia or Bipolar II as leading to Bipolar I or diagnosing subthreshold symptoms.

The mean age of onset for Bipolar I Disorder is 18 (Weissman, Bruce, Leaf, Florio, & Holzer, 1991). The American Psychiatric Association (2013) describes Bipolar I Disorder as a long-term illness with a variable course. The association estimates that 90% of clients who suffer a single manic episode repeat the experience. The majority of manic episodes (60 to 70%) occur immediately before or after an episode of major depression (American Psychiatric Association, 2013). Most patients seek treatment for depression and may be misdiagnosed with unipolar depression for years (Angst et al., 2011). There are several specifiers for the disorder (that used to be subtypes in DSM-IV ), mixed episode and rapid cycling being the most difficult to treat. Mixed episode is when the person has both symptoms of depression and mania. Rapid cycling is when the person has four or more episodes (manic or depressive) in a 12-month period. In addition, 60% of people suffering from Bipolar I Disorder have comorbid substance use issues and substance use is correlated with a greater risk of switching from depressive symptoms to manic symptoms (Ostacher et al., 2010).

Scientists do not know what causes Bipolar I Disorder. This is surely dismaying to the clients who suffer its symptoms, but the truth is, the well-intentioned theorists who share a strong medical model perspective tend to theorize exclusively from this perspective. Although a great deal of attention has been placed on heritability, this focus has not provided clues as to the etiology of Bipolar I Disorder other than giving people the luxury of speculating that it may be genetic. From an integrative perspective, this hypothesis is not terribly useful. It might be just as useful to say that the disorder “appears karmic.” Some promising developments are occurring in molecular psychiatry, but more work needs to be done before a coherent theory can be articulated (Manji, Moore, Rajkowska, & Chen, 2000). Despite the ignorance about etiology, as with Schizophrenia, the spectrum of symptom presentation in Bipolar I Disorder requires comment.

Symptoms in Bipolar I Disorder

Bipolar I Disorder is unique in that symptoms manifest heterogeneously, which influences treatment (Pacchiarotti et al., 2013). About half of all clients suffering from Bipolar I Disorder have psychotic symptoms and these clients respond less well to some treatments, lithium in particular (Bowden, 1998). Most clients suffering from Bipolar I Disorder return to adequate functioning between episodes (approximately 80%); however, many require continued pharmacologic interventions to avoid future episodes. As with Schizophrenia, clients with Bipolar I Disorder are at a greater risk for suicide: the completion rate is 10 times that of the general population (Advokat et al., 2014).

Researchers estimate that 35 to 50% of clients who do stay on medication are likely to suffer relapse despite medication compliance (Advokat et al., 2014). Many clinicians assume that patients stabilized will continue on the medication indefinitely. There is some evidence in favor of slowly titrated withdrawal in patients who have made therapeutically based life changes and seem able to manage their illness. We say more about this later when we explore the disorder from various perspectives.

Review Questions

• Why is treating Bipolar I Disorder so difficult?

• What specifiers are harder yet to treat effectively and why do you think that is?

SECTION THREE: SOME HISTORY ON MOOD STABILIZERS

Learning Objectives

• Be able to describe some of the accidental events that went into the discovery of lithium.

In the 19th century, a popular theory called uric acid diathesis was a dominant concept in medicine used to explain the etiology of disorders as diverse as manic-depressive illness and cardiac problems (Healy, 2002). As Barlow and Durand (2002) have noted, “diathesis” means vulnerability (as in the diathesis–stress model of psychopathology), in this case, vulnerability to the effects of the uric acid on one's system. Uric acid is a breakdown product of urea, which is a compound, found in urine as a result of protein metabolism.

In the 19th century, as today, theories followed the technologies available to test them. The ability to peer inside neurons is followed by theories of mental disorders that hypothesize intraneuronal (and interneuronal) causes, as you saw in our  Chapter Five  discussion of depression (remember the molecular/cellular theory of depression?). In the 19th century, chemical analysis was the newest technology of that time, so researchers used it to investigate substances eliminated from the body and then proposed theories about disorders, based on the analysis. Although the uric acid diathesis theories are now recognized as no more accurate than the chemical imbalance theories of depression, they did provide a starting point for research that led to lithium being used for Bipolar I Disorder.

Uric acid was also found to be a major constituent in kidney stones and gout. Gout is a painful inflammation of the joints, caused by uric acid in salt form settling in joints. In the 19th century, gout was also linked to disturbances in mood (although these surely could have been side effects of the unpleasant experience of having gout). In 1817, a new element called lithium had been discovered. Lithium is a light, positively charged metal ion that has been used therapeutically in a number of ways for almost 200 years. Researchers realized that lithium dissolved kidney stones, so perhaps it would be useful for other disorders related to uric acid. From a period spanning 1840 to 1870, Alexander Ure and Alfred Garrod began experimenting with lithium as a treatment for disorders believed related to uric acid (Lenox & Manji, 1998).

As Healy (2002) documents, the effects of lithium on  urates  gave rise to an industry in lithium-laced products. Although many readers may know that Coca-Cola at one time had coca leaf extract as one of its ingredients, you may be surprised to know that 7-Up came on the market as a lithium-containing beverage. Spring waters containing lithium were carried by spas and were supposed to induce a sense of well-being, and lithium was even used as a salt substitute for patients with heart problems. As early as 1870, the Danish neurologist Carl Lange (co-creator of the James-Lange theory of emotions) found that lithium had therapeutic effects in clients with manic-depressive illness. In the United States, William Hammond gave lithium to patients with mood disorders and also reported positive results (Healy, 2002). One problem with lithium, however, is that in large enough doses it can be toxic, and there were some fatalities from these enthusiastic additive uses of the substance. This, coupled with the decline of the uric acid diathesis hypothesis of illness, contributed to the FDA removing lithium from the market in 1949. Ironically, this same year a little-known psychiatrist from Australia was about to put lithium “back on the map.”

Developments Down Under

John Cade was a psychiatrist and state hospital superintendent in Australia in the mid 20th century. Under the influence of the uric acid diathesis theory, Cade hypothesized that a toxin that entered the brain caused mania. He further asserted that this toxin could be detected in urine. He proposed injecting uric acid from manic patients into guinea pigs, thinking that if the hypothetical toxin were active, it would induce manic activity in the guinea pigs. Alas, uric acid is highly toxic and the first guinea pigs died. He then decided to dissolve the acid by mixing it with a metal to form a soluble salt. After failing with a number of metals, he found lithium ideal for his mixture. He then injected the dissolved mixture of uric acid and lithium into the guinea pigs, and they responded not with mania but lethargy. Cade thought the lethargy was a calming effect and eventually tried injecting just lithium into the guinea pigs. It had the same effect (in actuality, the lithium did not calm the guinea pigs, it just made them sick). At any rate, although this was not at all what he had expected to find, Cade (1949) concluded that lithium might have some effects on mood (calming what he called “psychotic excitement”), and he proposed to test it in humans, including himself (Snyder, 1996). Although Cade had some success using lithium in manic patients, several of his patients died from its toxicity (Healy, 2002).

Although some give Cade all the credit for discovering lithium (Snyder, 1996), others (Healy, 2002) cite the important contributions of Morgens Schou, a Danish researcher. Schou (1978) did the first randomized, controlled trials that demonstrated the efficacy of lithium. Although Cade had some success, it was anecdotal and not based on standard trials. Schou's research confirmed the usefulness of the compound and led to standards for safe dosage levels. Note that there is still no theoretical basis for lithium's use. As Snyder (1996) concludes, “One of the fascinations of the discovery process is that we often find the right answer by looking in the wrong place” (p. 119).

As noted, lithium was taken off the market in 1949(the same year it appeared to have efficacy for manic-depressive illness) and was not reapproved by the FDA for psychiatric use until 1970. Some think part of the reason for this time lag was that because lithium is a naturally occurring element, no pharmaceutical company could get a patent on it, thus limiting its profitability. The toxicity of lithium was surely another reason for the caution in approval. The early deaths related to lithium were all caused by lithium-induced cardiac problems. Researchers now think these cases were all cases of lithium toxicity, but when monitored and given in appropriate doses, the cardiac side effects of lithium are typically minor (Tilkian, Schroeder, Kao, & Hultgren, 1976). As we outline later, lithium therapy must be closely monitored, because the therapeutic dose is very close to the toxic dose. The only FDA-approved use of lithium is for mood stabilization.

Review Questions

• What are some of the accidental discoveries that went into figuring out lithium could be used to treat Bipolar I Disorder?

SECTION FOUR: LITHIUM: THE PROTOTYPICAL MOOD STABILIZER

Learning Objectives

• Be able to give an overview of at least four mechanisms of action of lithium and why we think they may help in Bipolar I Disorder.

• Be able to describe the categories of side effects from lithium.

• Know the profile of who is a good candidate for lithium.

As noted, lithium is a naturally occurring, positively charged alkali metal ion. Johan August Arfvedson in Stockholm, Sweden, discovered it in 1817. Its name derives from the Greek lithos, meaning “stone” because Arfvedson discovered it in a mineral source. It can be mixed with magnesium and aluminum to form metal alloys, is used in some glasses and batteries, and of course has use in psychopharmacology. It has been assumed that lithium has good efficacy in treating acute mania as well as being a prophylactic for both manic and depressive episodes (American Psychiatric Association, 2000a) and was the drug of first choice for Bipolar I Disorder. The problem is that in “real life,” many patients stop taking it because of its difficult side effect profile. Right now, anticonvulsants and atypical antipsychotics are more often the first drugs prescribed because clients do not want to be bothered with side effects and the blood testing necessary when taking lithium. Many still feel that lithium has the best efficacy in studies compared to other drugs and that it enhances the effects of antidepressants (Grof & Muller-Oerlinghausen, 2009). As usual, though, there are disagreements in the literature and the differences between what works in short-term studies versus what is necessary managing a chronic disorder are different things (Post, 2010). The evidence for lithium to treat bipolar depression is weaker than for its effectiveness in bipolar mania. Lithium does seem (when clients adhere to prescription) to have strong efficacy in maintenance of euthymia and prevention of relapse (Malhi, Tanious, Das, Coulston, & Berk, 2013).

Throughout the mid to late 20th century we had consistent support for the idea that long-term lithium therapy correlated with decreased suicide rates in clients suffering from Bipolar I Disorder (Goodwin & Ghaemi, 1999). Lithium may also have neuroprotective properties, which would mean that Bipolar I Disorder is progressive and/or degenerative and lithium protects neurons from the progression of the disorder. As with most hypotheses, more work needs to be done to confirm this one (Manji et al., 2000). Lithium is least effective in clients suffering from mixed episodes or rapid cycling of mood symptoms (Bowden, 1995). Lithium is typically available in capsules, tablets, slow-release tablets, and as lithium citrate syrup (Keck & McElroy, 2002). Common lithium formulations are listed in  Table 8.1 .

Peak plasma levels for lithium are reached by about three hours but lithium is not fat soluble and does not cross the blood–brain barrier easily. Because of this, the therapeutic dose can be close to the toxic dose which as you can imagine is problematic. Clients show an initial response within one week to one month of beginning lithium therapy. Because of this time lag and because clients suffering from manic symptoms may endanger themselves or others, additional medications may be used, including typical antipsychotics and benzodiazepines (Advokat et al., 2014). Once a client starts to show a response to lithium, symptoms usually diminish quickly. If lithium is discontinued abruptly during the manic phase of the illness, relapse may occur rapidly (Perry, Alexander, & Liskow, 2006). Lithium is not metabolized and is excreted unchanged by the kidneys which puts a strain on them. Thus, long-term lithium users should be screened regularly for markers indicating kidney damage (Rybakowski et al., 2012).

TABLE 8.1 Examples of Lithium Formulations

Generic	Brand Names	Formulation
Lithium citrate	Cibalith-S	Syrup
Lithium carbonate	Eskalith	Capsule
	Eskalith-CR	Scored tablet
	Lithobid	Tablet
	Lithotabs	Tablet
	Lithane	Gelatin capsule

© Cengage Learning®

As with all mental disorders, we do not know what causes Bipolar I Disorder. This makes finding an effective intervention challenging and severe mental disorders like BPI seem to be rooted in the brain, which makes things even more complicated as we are just beginning to realize how little we know about the brain. In placebo-controlled studies, approximately 60 to 80% of clients suffering from mania show some level of response to lithium over placebo. Some researchers (Grof & Alda, 2001; Grof, Alda, Grof, Fox, & Cameron, 1993) challenge this estimate and believe that the response rate is closer to 50%. Chen, Mehta, Aparasu, Patel, and Ochoa-Perez (2014) concluded that monotherapy with atypical antipsychotics was more effective and safer than monotherapy with mood stabilizers for adolescents. Because in many cases people are treated with multiple medications, it is harder to specify response rates to one. Grof (2006) has summarized research into a profile of patients who are good lithium responders. So, we might ask, what are the “symptoms” of a good lithium response? According to Grof, they include:

• Complete remission between episodes

• Depressive symptoms are more vegetative in nature (similar to what we said about depression in  Chapter 5 )

• The person does not meet criteria for rapid cycling or mixed episode specifiers

• No significant psychiatric comorbidity (but remember in some studies up to 60% of people with BPI meet criteria for substance use disorders)

• Episodic course in another family member

Another way to look at this is that combination therapy has become standard practice but even there it depends on the presentation of symptoms. For example, lithium seems most effective for enhancing the effects of antidepressants for refractory patients. Anticonvulsants plus lithium seem to provide better protection against relapse than just lithium (Leng et al., 2008). On the other hand, combination therapies that we seemed to think had efficacy in the first edition of this book, turned out not to. The most common practice was adding antidepressants to mood stabilizers, which Sachs et al. (2007) concluded did not improve response. Lithium treatment cannot occur until clients have several lab tests done, including checking sodium, calcium, and phosphorous levels, and an electrocardiogram, urinalysis, thyroid battery, and complete blood cell count.

Because the average duration of a manic episode is three months, plasma levels of lithium effective for the client should be maintained for three to six months afterward. If lithium is to be discontinued, Perry et al. (2006) recommend that the daily dosage be tapered by 25% each day over a period of four weeks. About half of patients stabilized successfully on lithium and then switched to placebo relapse within six months. There are stories of patients relapsing in a few days, but these are not from controlled studies and are rare.

Unlike antidepressants, there are more often significant statistical differences between lithium and placebo groups in participants with Bipolar I Disorder. Clearly something is happening, but what? To address that question, we begin by discussing the mechanisms of action of lithium.

Mechanisms of Action

The pharmacology of lithium is incredibly complex and a matter of ongoing speculation. Lithium affects different parts of the brain differently at different times when different doses are used. Lithium's effects extend to multiple neurotransmitters and second-messenger systems.

As all researchers point out, we are still uncertain of the key factors in lithium's effectiveness.  Table 8.2  outlines the mechanisms of action we know lithium exerts. Note that part of the complexity of lithium is due to the fact that it can affect the brain differently in different regions (e.g., increasing neurotransmitter release in some areas and decreasing release of the same neurotransmitter in other areas). These mechanisms are summarized from Malhi et al. (2013); Perry et al. (2006); and Schatzberg, Cole, and DeBattista (1997).

The best-studied effects of lithium are on serotonin, and these effects also demonstrate the complexity of lithium's pharmacodynamics. After short-term use (one to two weeks), lithium appears to increase serotonin synthesis by increasing tryptophan reuptake in synapses. After two to three weeks, it appears to enhance release of 5-HT from neurons in the parietal cortex and the hippocampus. Long-term taking of lithium seems to cause downregulation in 5-HT1 and 5-HT2 receptors. Again, how these effects may relate to mood is currently unknown.

Lithium's effects on norepinephrine (NE) are equally curious. Lithium appears to increase the rate of norepinephrine synthesis in some parts of the brain. It decreases excretion of norepinephrine metabolites in manic patients but increases excretion of norepinephrine metabolites in depressed patients. Lithium appears to block postsynaptic DA receptors, which seems to partly explain the controlling effects on mania and psychosis. There appears to be evidence that lithium affects the  G-proteins  in second-messenger systems. Apparently it inhibits some enzymes, in particular second-messenger systems, which in turn is believed to bring about some of the therapeutic effects.

TABLE 8.2 Mechanisms of Action of Lithium

Neurotransmitter System	Effects
Serotonin	Increase in tryptophan (precursor) uptake after short- and long-term treatment. General increases in serotonin levels. Increased release of serotonin in the hippocampus, hypothalamus, and parietal cortex. Serotonin receptor decreases in hippocampus. Long-term administration causes downregulation of 5-HT1 and 5-HT2 receptors.
Dopamine	Long-term administration diminishes neostriatal dopamine activity. May block the effects of highly sensitive DA receptors, thus decreasing the behaviors associated with DA stimulation.
Norepinephrine	Increases rate of synthesis of NE in some parts of the brain but decreases the synthesis in other parts. Decreases the excretion of NE metabolites in manic patients and increases the excretion of NE metabolites in depressed patients.
Second-messenger systems	Lithium appears to reduce the activity of second-messenger systems in undetermined ways.
Ionic effects	Lithium, being a positively charged metal ion, may have stabilizing effects on neurons in the CNS.
Inhibiting Intracellular Enzymes	Inhibition of glycogen synthase kinase-3 (GSK-3) increases Beta-catenin that stimulates axon growth and cell survival.
Neuroprotection	Antioxidant properties may protect brain from oxidative stress.

© 2015 Cengage Learning®

We know that in BPI, there are gray matter deficits, meaning, that compared to unaffected individuals and those who had brain scans after lithium treatment, people suffering from BPI seem to have reduced volume in the subgenual and anterior cingulate cortex as well as the prefrontal cortex. Some of these reductions are hypothesized to be the result of excitotoxicity caused by glutamate-induced stress. In patients (some but not all of course) who have responded to lithium treatment, these gray matter reductions decrease or vanish in subsequent brain scans positing a neuroprotective mechanism in lithium (Malhi et al., 2013).

If even after reviewing our brief description of lithium's mechanisms of action you are confused, you are not alone. Scientists do have molecular clues as to lithium's pharmacodynamics, but these clues do not help explain how it alters mood. From an integrative perspective, this is likely because mood cannot be explained in terms of brain chemistry alone. In fairness though, researchers have likely only seen the proverbial “tip of the iceberg” in terms of lithium's mechanisms of action, and continued research will likely yield a deeper understanding of its effects on brain chemistry.

Theories of Lithium Action

The short answer to the question “How does lithium work?” is “We don't know.” Because researchers do not really know what causes Bipolar I Disorder, it is hard to draw definitive conclusions as to how lithium corrects the disorder in people who respond to it as a treatment. Next, we briefly outline some medical model theories that have implications for psychosocial interventions as well.

Lithium and Neurotransmission

The Amine Theory Revisited

In  Chapter Five , we discussed the amine theory of depression, which in essence proposed that people whose nervous systems did not produce enough amines (specifically norepinephrine) become depressed. From here, it was a simple leap to propose that some people's nervous systems produce amines erratically, sometimes producing too many, and at other times producing too few. When the nervous system of such afflicted people produces too many amines, the result is manic mood. When the person's nervous system produces too few amines, the result is depression. This appeared to have limited support in that lithium is correlated with decreased norepinephrine metabolites in manic patients and increased NE metabolites in depressed patients. These data led researchers to conclude that lithium helped the body achieve some innate homeostasis (dare we say, “chemical imbalance?”) that had been lacking. Obviously, in light of how complex lithium's effects are, this chemical imbalance theory also turns out to be as oversimplistic and inadequate as is the chemical imbalance theory of depression.

Lithium's Ionic Impact on Neurotransmitter systems

That lithium is a positively charged metal ion may account for lithium's effects on the nervous system. As Preston, O'Neal, and Talaga (2002) note, “Since neurotransmitter production, release, and reuptake rely on various ions (sodium, calcium, potassium, and magnesium), lithium's ionic properties may affect neurotransmission-mediated depression and mania” (p. 187). This hypothesis is certainly plausible. As you saw in  Chapter Two , all neurons have ion channels that allow the passage of positively or negatively charged particles into the cell. We noted that an influx of positively charged ions (such as sodium) tends to excite cells and an influx of negatively charged ions (such as chloride) tends to inhibit or hyperpolarize cells. We will now cover hypothesized mechanisms of action for lithium using an algebra equation metaphor. Both the etiology of BPI and the actions of lithium involve multiple (maybe dozens) variables that could be said to resemble an algebra equation with many unknown variables. Each of these hypothesized mechanisms may play a part of the action of lithium and all may not be necessary to bring symptom relief in BPI. Until we know more about the etiology of BPI though, we don't know which equation variables we can dispense with.

Dopamine

Dopamine (DA) is an excitatory neurotransmitter that many researchers believe is an important variable in the equation in the symptoms of BPI and lithium's action. During mania, DA metabolites are increased in some but not all patients which may point to an increase in actual DA (Cousin, Butts, & Young, 2010). If DA transmission is elevated during mania then it may prompt a balancing (homeostatic) mechanism that could then cause depression. Animal models of lithium action show extracellular DA to decrease after the introduction of lithium. The postsynaptic actions of DA are mediated by G-protein receptors, which then stimulate second messenger systems like adenyl cyclase (AC) and cyclic adenosine monophosphate (cAMP). Research suggests that lithium also alters the function of these units in ways that may be neuroprotective.

Glutamate and NMDA Receptors

Glutamate (Glu) like DA is an excitatory neuro-transmitter. Michael, Erfurth, Ohrmann (2003) first hypothesized that glutamate was elevated in manic episodes. N-methyl-D-aspartate (NMDA) receptors, among other things, control many aspects of memory and plasticity. They also open ion channels that can increase sodium and calcium, positively charged ions that would increase cell firing. With chronic lithium administration, lithium binds to NMDA receptors and this causes downregulation of the NMDA receptors and enhanced Glu reuptake (Malhi et al., 2013).

GABA

GABA is an inhibitory neurotransmitter that plays crucial roles in modulating Glu and DA. Here again, we see the complexity of trying to understand the relationship between neurotransmitter families. Patients with BPI are thought to have diminished GABA transmission that then leads to increases in excitatory transmission via DA and Glu. This leads to excitotoxicity that in turn causes cell loss and perhaps accounts for the decreased brain structure volume in patients with BPI. Lithium increases the level of GABA in the plasma and spinal fluid of people and so supposedly it also increases it in the central nervous system.

Lithium's Effect on Second-Messenger Systems

In the late 1980s and early 1990s, researchers proposed that intraneuronal effects caused lithium's therapeutic effects. They specified second-messenger systems as a primary site where lithium exerted a powerful influence. In this theory, the lithium acts to modulate these systems, in some cases slowing them down and in others speeding them up (Avissar & Schreiber, 1989; Malhi et al., 2013; Weber, Saklad, & Kastenholz, 1992). Recall from  Chapter Two  that second-messenger systems may play a role in neuronal excitation and subsequent firing. In this theory, the slowing of the second-messenger systems may decrease cell firing and (theoretically) decrease manic symptoms. It now appears these may be only one of many effects that ultimately translate into therapeutic gains. Some of the second-messenger systems are responsible for the production of brain-derived neurotrophic factor (BDNF) that (recall from  Chapter Five ) acts as a brain cell nutrient repairing cells and stimulating neurogenesis. Lithium seems to enhance the production of BDNF in parts of the brain.

Lithium and Circadian Rhythms

As early as 1990, researchers have sought to explore the connection between Bipolar I Disorder and sleep–wake cycles that are part of our circadian rhythms (biologic cycles within the course of a day) (Goodwin & Jamison, 1990). This theory reflects the psychosocial intervention of optimizing sleep and setting regular patterns of sleep and wakefulness with clients suffering from Bipolar I Disorder. The circadian rhythm hypothesis of lithium's action derives from the fact that lithium slows the circadian rhythm in species ranging from plants to human beings (Lenox & Manji, 1998). Although studies with humans are hampered by several ethical limits that do not constrain animal models, it appears that lithium significantly slows and lengthens the circadian cycle. More recently, McCarthy et al. (2013) tied BPI disorder to those genes tied to the circadian cycle. Their research conclusions suggest that lithium enhanced the resynchronization of circadian rhythms and that may be one therapeutic mechanism in the equation of symptom relief.

Side Effects of Lithium

Approximately three-fourths of clients on lithium experience side effects (American Psychiatric Association, 2000b). The side effects are a primary reason for clients to stop taking the drug (Atack, 2000; Advokat et al., 2014). One problem is that the therapeutic dosage is often close to the toxic dosage, so the drug requires regular blood monitoring in clients. The side effects of lithium are summarized in  Table 8.3  and then described more fully in the text. The types and degrees of side effects clients will suffer are difficult to estimate. The literature on side effects has always given broad ranges of the percentage of patients complaining of adverse effects (35 to 93% according to Lenox and Manji, 1998)—so broad as to be not much help. Price and Heninger (1994) noted that the side effects increase as the serum levels of the drug increase. It is important to note that clients will have different numbers and degrees of side effects, and that lithium's difficult side effect profile is a main reason that continued research on different mood stabilizers is important. When the percentage is generally known, we have also listed in parentheses the proportion of clients thought to suffer from a given side effect. Data for  Table 8.3  are drawn from Lenox and Manji (1998); Perry et al. (2006); and Schatzberg et al. (1997).

CNS Side Effects of Lithium

The cognitive side effects of lithium may be the most troubling for clients but remain the least studied (Jamison & Akiskal, 1983; Lenox & Manji, 1998; Shaw, 1986). From the psychological perspective, clients say lithium decreases creativity and concentration and increases forgetfulness. Schatzberg et al. (1997) have noted that forgetfulness is one of the most common reasons given by clients who stop taking lithium. The few existing studies have produced conflicting data. Judd, Squire, Butters, Salmon, and Paller (1987) reported slowed rate of central information processing with short-term use of lithium. Some of these effects seem to diminish with long-term use, suggesting there is some accommodation to the effects. More research on this problem is warranted, and clinicians should monitor cognitive functioning in clients receiving lithium. Cognitive impairment can also be a sign of lithium toxicity.

TABLE 8.3 Side Effects of Lithium

Type of Effect	Description
CNS effects	Contradictory evidence of deleterious cognitive effects on concentration, memory, and creativity
	Seizures can occur as a result of lithium toxicity
Neuromuscular	Tremors at rest or although moving (4%–65%)
	Muscle weakness (40% in short-term treatment)
Gastrointestinal	Chronic nausea, diarrhea, occasional blood in stool
Endocrine	Weight gain (11 %–64%), Hypothyroidism (approx. 4%), Goiter (approx. 6%), Elevated thyroid-stimulating hormone (30%)
Renal	Polyuria/polydipsia (20%)
Dermatologic	Acne and rashes, Aggravation of psoriasis, Alopecia
Hematologic	Increase in white blood cells (75%–100%)
Teratogenic	Increased risk of Epstein's anomaly, a congenital heart defect characterized by displacement of the tricuspid valve
Sexual	Decreased libido in males and females, erectile dysfunction in males

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Neuromuscular Side Effects of Lithium

The most reported neuromuscular side effect of lithium is tremor. The tremor can occur while the client is at rest or moving. The incidence of tremor (like most estimates of side effects) is quite broad (4 to 65%) but the symptom is directly correlated with the client's lithium level. Emotional stress and stimulants such as caffeine can worsen the tremor. Although the tremor is reversible with discontinuation of the medication, it may also be controlled by lowering the lithium dosage or by administering a beta-blocking agent (such as that described in  Chapter Six ). Although the source of lithium-induced tremor is uncertain, it is not related to the extrapyramidal side effects caused by neuroleptics described in  Chapter Seven . Several studies have shown that medications used for EPS are ineffective with lithium-induced tremor. General muscle weakness is also a common neuromuscular side effect of lithium and is reported in about 70% of clients within the first two weeks of taking lithium. Again, this side effect is dose related and appears to resolve on its own after the first two or three weeks of lithium use.

Gastrointestinal Side Effects of Lithium

Gastrointestinal (GI) side effects can range from mild to severe, with milder effects that include bloating and slight abdominal pain and severe effects that include nausea and vomiting. It is important for clinicians to monitor these side effects closely, because they are also signs of lithium toxicity. Perry et al. (2006) noted that GI side effects frequently subside on their own and can be diminished if the medication is taken with food. Sometimes, the daily required dosage can be divided into more numerous, smaller portions. Although there are currently sustained-release formulations of lithium, studies indicate no real benefits in terms of side effect profile.

Endocrine Side Effects of Lithium

The most problematic endocrine-related side effect of lithium is weight gain. It has been clearly tied to lithium use and is another of the more common reasons that people stop taking lithium (Peselow, Dunner, Fieve, & Lautin, 1980). Weight gain is variable, ranging from about 7 to 60 pounds. Clients who are overweight to begin with seem to gain more weight while taking lithium. Also, the better the therapeutic response to lithium, the more weight the person typically gains (Perry et al., 2006). Although the reasons for the weight gain are not entirely clear, lithium does exert an insulin-like effect in lowering blood glucose levels and inducing hypoglycemia. This hypoglycemia then promotes eating and weight gain. Dietary regulation and exercise require close monitoring by a physician, because both can disrupt levels of lithium in the client's system. Lithium treatment may also disrupt thyroid functioning, most commonly through an increase in thyroid-stimulating hormone.

Renal Side Effects of Lithium

The most common renal side effects of lithium administration are polydipsia (chronic, excessive thirst) and polyuria (excessive urination). These effects occur in about 20% of clients on lithium. The polyuria is caused by lithium reducing the kidneys' ability to concentrate urine. Although these effects may wear off on their own, lowering the dosage or discontinuing the drug can relieve them. A more problematic (albeit rarer) side effect from lithium is inflammation of the renal tubules, blood vessels, and surrounding tissue (called interstitial nephritis). Although rare, it can cause renal scarring and destruction. Patients exposed to multiple periods of lithium toxicity are at greater risk for this disorder. These side effects have led to the recommendation that clients on lithium have kidney function checked every 6 to 12 months (Schatzberg et al., 1997).

Dermatologic Side Effects of Lithium

The dermatologic side effects of lithium include various rashes and outbreaks on the skin, aggravation of existing dermatologic conditions, and hair loss (alopecia). Cases of rashes, acne, or other outbreaks on the skin may resolve by themselves. Lowering the dosage frequently relieves them. Few studies have been done on hair loss and lithium treatment. Although more rare than other dermatologic problems, it seems associated with disrupted thyroid function. On discontinuation of the drug, hair loss stops and hair typically regrows. The mechanisms of action of these dermatologic side effects are at present unknown.

Sexual Side Effects of Lithium

Only a few studies have looked at incidence of sexual dysfunction related to lithium use. These and anecdotal clinical evidence suggest that lithium does interfere with sexual functioning. Note that hypersexuality is sometimes associated with mania, and for such clients, returning to baseline levels of sexuality may seem like impairment but that is only relative to the hypersexual state they experienced in manic episodes (Rojansky, Wang, & Halbreich, 1992). Under double-blind conditions, lithium has been reported to cause decreased libido as well as erectile failure (Vinarova, Uhlir, Stika, & Vinar, 1972).

Lithium Toxicity

As noted, the therapeutic dosage of lithium is frequently close to the toxic dosage. Prescribing professionals cannot know the correct dose in advance, because each person eliminates lithium at different rates. In addition, lithium is one of the few psycho-tropic medications that is not highly fat soluble. As a result, it has a more difficult time crossing the blood–brain barrier and requires higher concentrations in the blood to reach adequate concentrations in the central nervous system (Lickey & Gordon, 1991). Clients must have regular blood tests to ensure that their levels are within safe parameters.

The balance of lithium in a person's blood-stream is delicate. Many things can affect it, including physical and emotional stressors that alter sodium levels. For example, changes in diet and exercise can easily lower sodium levels, which in turn alter the plasma levels of lithium to the point where the person could suffer lithium toxicity. In some documented cases, medical illnesses seemed to tip the balance and bring about toxicity (Decina, Schlegel, & Fieve, 1987). Because the kidneys excrete lithium almost intact, any impairment of kidney functioning (such as mild dehydration, reduced salt intake, or dieting) can result in lithium toxicity.

The toxicity is of a type described as “excitotoxicity” (West, 1996). This means the brain's excitatory neurotransmitter systems become overstimulated and produce excess calcium (a positively charged ion) and free radicals and break down cell defenses. West and Melzer (1979) studied clients under severe psychological stress and found these clients were at higher risk for developing lithium toxicity. These authors were concerned that the ego disintegration typical of severe mental and emotional disorders actually functioned as a risk factor for lithium toxicity; ironically, it was ego disintegration that partially made people candidates for lithium. Also note that clients with a history of brain injury may have increased vulnerability to lithium toxicity (Moskowitz & Altshuler, 1991).

Lithium toxicity primarily affects the brain. The symptoms include confusion, slurred speech, loss of balance, tremor, GI upset, and possibly coma and death. Although some of these symptoms are side effects that are most likely to occur at the beginning of therapy, if they emerge in a client who has been on lithium for some time, the drug should be discontinued and immediate medical attention should be sought (Lickey & Gordon, 1991). There is no antidote to lithium poisoning, and the condition is usually treated by halting the drug administration and giving the client sodium-containing fluids. If the toxicity is serious enough, other medical interventions may be necessary (Paragas, 1984). Julien (2001) notes that complete recovery from lithium toxicity can take weeks to months, depending on the severity of the case.  Table 8.4  summarizes the signs of lithium toxicity.

TABLE 8.4 Signs of Lithium Toxicity

Nausea

Drowsiness

Confusion

Dizziness

Mental dullness

Slurred speech

Muscle twitches

Irregular heartbeat

Blurred vision

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Some authors (Sheean, 1991; West, 1996) feel that the dangers of lithium toxicity are minimized in the literature. Sheean (1991) estimated that 10% of lithium toxicity survivors suffer some permanent neurologic damage. Aronson and Reynolds (1992) recommend that clients have their blood checked as close as possible to 12 hours after the last dose. At this time, the drug absorption is complete and allows for the most consistent reading. Dennison, Clarkson, O'Mullane, and Cassidy (2011) noted that lithium toxicity occurred at the rate of about 6 cases per 100,000 clients in their sample from Cork County, Ireland. In many of those cases, the toxicity seemed to be the result of lithium interacting with other medications so polypharmacy must be closely monitored in patients taking lithium. Mental health clinicians often have to help clients organize schedules to make sure these tests are done consistently. Although lithium toxicity is a problematic side effect, the chances of developing it can be greatly reduced through conservative dosing strategies, care in combining lithium with other medications, regular blood monitoring, and educating clients and significant others about the core symptoms (Delva & Hawken, 2001).

Lithium and Aggression

An important footnote to lithium in the history of psychopharmacology is the work of Michael Sheard. He has conducted several studies exploring the effects of lithium on aggressive behavior (Sheard, 1971; Sheard, 1975; Sheard & Marini, 1978; Sheard, Marini, Bridges, & Wagner, 1976).

Sheard began his work on rodents, assuming that because serotonin was implicated in aggression and because lithium affected serotonin transmission,itmightaffectlevelsofaggressionin rodents. These initial studies seemed to indicate that lithium did decrease aggression, so he then treated prison inmates with lithium in a placebo-controlled study. Although lithium had no impact on nonviolent behaviors such as lying and stealing, it appeared to fully suppress serious assault in the inmates, as guards observed and documented. Sheard's conclusion was that only impulsive aggression was affected. More importantly, on discontinuation of lithium, the aggression returned. Sheard's work laid the basis for many different populations being treated with lithium for aggression. As we discuss in  Chapter Nine , children and adolescents are among those who receive lithium and other mood stabilizers for aggressive behavior and diagnoses like Conduct Disorder (Malone, Luebbert, Pena-Ariet, Biesecker, & Delaney, 1994)

Although lithium therapy is still an effective treatment for the symptoms of Bipolar Disorder (Baldessarini, Tondo, Hennen, & Viguera, 2002), that alone does not mean clients comply with lithium treatment. In addition, not all clients have a therapeutic response to lithium and need alternatives. After presenting some cases of clients taking lithium, we discuss those alternative treatments.

Lithium Cases

The following cases illustrate several different ways in which lithium has been used in mental health treatment.

The Case of William

Near the end of summer William, a 27-year-old, single construction worker, began to act very oddly and irrationally. He missed work or was often late. Coworkers noticed that he seemed “hyper” and silly, because he would toss tools, speak rapidly, and lose his train of thought. Friends recognized that William, an avid sports fan, was becoming obsessed with the owner of the local professional football team. William would talk at great lengths about his long conversations with this man and the inside advice he gave William just before each season. At present, he said the two of them were in intense discussions about strategies for the preseason games. One evening William's girlfriend, Sharon, called two of his best friends, a psychologist and attorney, to alert them of William's increasing bizarre behavior. She said he had invested most of his savings in what she believed was a scam to save dying children in Africa, was not sleeping, and had extreme mood swings she had never seen before. This evening she was afraid, because when he stormed out of her house, he told her he was going to walk on the center rail of the major highway at sunrise and he believed only the traffic driving west would be able to see him. He also believed this was the only way he could communicate with the sports owner about a disagreement they had had about a rookie on the team. She indicated she had never seen him like this, and she said she felt that William had slept little in recent weeks.

Eventually his two friends found William at the local YMCA, where he was being escorted out by police for creating a scene and using profanity with the manager. His friends spoke to the police, who released William to them. Over the next several hours, William talked with his friends about many grandiose plans, his paranoid fears, his worries that there wasn't enough time in a day, and his growing, spiteful hatred of the football team owner. Gradually, after long and circuitous arguments, William's two friends convinced him he needed medical help and took him to the emergency room of a local hospital. William was admitted and put on lithium carbonate 450 mg, three times a day, until he stabilized and was discharged. At the three- and six-month follow-up, William remained stable and his blood levels remained in the therapeutic range. Now, 10 years later, William has had only one, minor manic episode, which did not demand hospitalization. He no longer takes the lithium and leads a relatively normal life. He is now married, with three children, and continues to work in construction.

The Case of Lincoln

Lincoln is a 38-year-old trade laborer who has suffered from Bipolar I Disorder for 19 years. He has had to be restrained or arrested for 31 of his 32 hospitalizations. Lithium, supportive counseling, and case management have failed to manage his disorder. It is important to mention that the lithium worked well enough to stabilize Lincoln so that he could be discharged from the hospital, but even when taken as prescribed, it could not keep him from decompensating into a psychotic and manic state. In these states, Lincoln becomes menacing and violent. During his manic episodes, no one can talk to or reason with Lincoln, and he seems to become more agitated and grandiose when safety personnel or mental health staff attempt to reason with him, resulting in hospitalization and restraint.

On discharge, Lincoln could return to work for short periods of time, but eventually he would again begin to decompensate into a manic state. His psychiatrist recommended both case management and a counselor. Lincoln began a 10-year counseling regimen with the same counselor. The work was problematic and very difficult. It emerged that Lincoln was the oldest of seven children and that his domineering father was an alcoholic. As a child, Lincoln had sustained several beatings from his father, and yet as an adult he intermittently worked for him. The counselor could not predict when Lincoln would become manic and often found out about the episodes only after Lincoln was hospitalized. It appeared there was no way to break the cycle of Lincoln's hospitalizations, and he refused any other medications beside lithium and diazepam/Valium for his agitation. His severe Bipolar I Disorder with psychotic features and extreme manic states seemed impossible to control or manage.

During the 10th year of treatment, Lincoln recognized for the first time that he could self-admit to the hospital without the struggle of being either forcibly taken in or probated. This was a major breakthrough, and he externalized this decision by blaming the episode on his counselor when he spoke with the hospital staff. His counselor accepted this twist of events and worked with Lincoln to help him understand how this hospitalization was different from all the rest. Lincoln was never hospitalized again, except for the time he volunteered to participate in the Depakote/valproic acid studies at a local research hospital. During the study, Lincoln unfortunately got the placebo, and his mania went off the charts. He had to be put in isolation and administered both lithium and valproic acid/Depakote. This was also quite a learning experience for him.

When he returned to therapy, still on lithium and valproic acid/Depakote, Lincoln began to explore his family-of-origin issues, his current depressive feelings and enormous fear of them, and his desire to have a relationship with a woman. The combination of drugs seemed to stabilize Lincoln, and the counseling deepened his understanding of himself and his illness. He eventually married and managed to establish his own business, but he remains on his medication, is alert for side effects, and tries to cope with the anxiety and hyper states in his life.

Lincoln suffered tremendously from his Bipolar I illness, yet he managed to find the resilience to survive the numerous hospitalizations and connect with a counselor who maintained a tolerant, empathic, and focused relationship with him until he could begin to manage his illness in a more proactive way. In therapy, he explored intrapsychic issues and cultural examination of the impact of his Eastern European heritage. It is a miracle that Lincoln survived his illness and chaotic life. Both the combined drug therapy and the counseling facilitated Lincoln's improvement.

The Case of Kelly

Kelly is a 39-year-old, married, African American art teacher with no children. Over the holiday break, her husband noticed increased signs of agitation in Kelly, along with insomnia and heightened irritability. He also noticed that her daily activity increased dramatically and he could not keep up with everything she was trying to accomplish.

Kelly's state became so exaggerated that other family members became quite worried. Kelly would call members of her family at all hours of the night and try to enlist them in her ongoing activities. Finally, her husband had the good judgment to take Kelly to her family physician. She assessed Kelly briefly and referred her to a psychiatrist, whom she called immediately to alert her about Kelly's manic state. The psychiatrist evaluated Kelly the next day and recommended that she begin a course of lithium. She began on 450 mg daily and gradually increased to 1350 mg. The psychiatrist spoke with Kelly and her husband about lithium toxicity. Kelly returned to work and took the lithium as prescribed. She also had her blood levels checked regularly over the next several months. She never had a case manager or therapist.

In the seventh month, Kelly's husband began to notice a change in her skin, indicated by acne and rashes, one of the known side effects of lithium. Both he and Kelly noticed her continued drowsiness, frequent nausea, and mild dizziness. Kelly also complained of forgetfulness and mental dullness as she tried to remember her lessons for class. Most recently, she complained of blurred vision. She contacted her family physician, who immediately consulted with the psychiatrist who recognized the signs of lithium toxicity. He saw Kelly immediately, diagnosed toxicity from the signs, discontinued the lithium, and began sodium fluids. Even after this intervention, it took Kelly eight weeks to recover from the symptoms of lithium toxicity. She did not try another mood-stabilizing agent and tried to manage her rather moderate mood symptoms with diet, exercise, and meditation.

Review Questions

• What are four therapeutic effects of lithium and why do we think they help BPI disorder?

• What are the categories of side effects from lithium?

• What kind of client seems a good candidate for lithium?

SECTION FIVE: ANTICONVULSANTS AS MOOD STABILIZERS

Learning Objectives

• Understand the mechanisms of action that may be useful in using anticonvulsants to treat BPI.

• Understand the categories of side effects from anticonvulsants.

Anticonvulsant medications are used in treating Bipolar Disorder and appear to have some efficacy as antimanic agents. Researchers initially hypothesized that manic episodes resemble seizures in the sense that they “kindle,” or “catch fire,” just as fires “kindle” and then if enough kindling is present, the fire (manic episode) grows. For clients with seizure disorders, each episode seems to increase the probability of later episodes or to act as “kindling” for these later episodes. This was tied to reports about manic episodes, in that many clients who suffer from a manic episode are more likely to suffer from subsequent episodes. Thus, earlier episodes are said to somehow “kindle” the brain for other episodes. This theoretical similarity has been used as a justification for treating mania with anticonvulsants and birthed a line of research in which drugs that are approved as anticonvulsants seem to find their way into trials for treating Bipolar I Disorder. Since the first edition of this book, the support for the kindling theory has been inconsistent at best (Bender & Alloy, 2011). Some researchers have gone so far as to relabel the anticonvulsants “neuromodulators” when they are used to treat BPI (Advokat et al., 2014). Our position is to discard the kindling theory and to not add more labels to existing compounds. The search for the etiology and drug mechanisms to treat BPI are confusing enough without muddying the waters with unnecessary terms. As with schizophrenia, the most important thing with Bipolar I Disorder is research that will uncover the etiology, not more drugs and labels for existing drugs. The following anticonvulsant medications are used in treating Bipolar Disorder and mania.

Carbamazepine/Tegretol

Researchers developed carbamazepine/Tegretol in the late 1950s as an anticonvulsant medication with efficacy in treating epilepsy. Pharmaceutical companies introduced it to the European market in 1960. In the early 1960s, physicians believed carbamazepine/Tegretol had beneficial psychotropic effects in people taking it for epilepsy, and in the 1970s, Japanese researchers documented its effectiveness in manic-depressive illness (Keck & McElroy, 1998). This latter research was confirmed in the late 20th century in a doubleblind, crossover trial (Ballenger & Post, 1980). The FDA approved carbamazepine/Tegretol in 1974 as an antiepileptic drug for adults, in 1978 as an antiepileptic for children over 6 years of age, and finally in 1987 as an antiepileptic without age restriction. Carbamazepine/Tegretol comes in several liquid formulations (solutions, syrups) as well as slow-release and chewable formulations.

Mechanisms of Action in Carbamazepine/Tegretol

Table 8.5  summarizes the mechanisms of action for carbamazepine/Tegretol.

As you can see from  Table 8.5 , carbamazepine/Tegretol has many proposed mechanisms of action; however, researchers do not know which ones, or which combinations, account for carbamazepine/Tegretol's efficacy in clients suffering from Bipolar I Disorder (Keck & McElroy, 2002). Keck and McElroy (1998) and Mitchell and Malhi (2002) have proposed two basic mechanisms in carbamazepine/Tegretol that may influence the symptoms of Bipolar Disorder. The first is effects on ion channels to reduce the firing of neurons, and the second is effects on presynaptic and postsynaptic neurotransmission.

TABLE 8.5 Proposed Mechanisms of Action for Carbamazepine/Tegretol

Reduce neuronal firing through inhibition of sodium channels

Increased potassium conductance

Decreased glutamate release

Increase in adenosine receptors

Also alters neurotransmission mediated by NE, 5-HT, DA, GABA, Substance P, and aspartate

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Ion Channel Effects of Carbamazepine/Tegretol

Recall from  Chapter Two  that each neuron has ion channels that allow the influx of either positively charged or negatively charged ions. The influx of positively charged ions increases the likelihood of a cell firing, and the influx of negatively charged ions decreases the likelihood of the cell firing. Carbamazepine/Tegretol seems to reduce neuronal firing by binding to and deactivating sodium ion channels. Sodium is a positively charged ion, and when its ion channel is deactivated it cannot enter the neuron and exert its excitatory effects. Some studies in the late 20th century supported the notion that carbamazepine/Tegretol increases potassium conductance, which is strange because potassium is positively charged and that would seem to increase cell excitation (Post, Weiss, & Chuang, 1992). More recent research more often supports the idea that carbamazepine/Tegretol ultimately decreases potassium conductance because it decreases calcium entry, which is necessary for activating potassium channels (Thomas & Petrou, 2013).

These mechanisms occur shortly after a person takes the drug and account for carbamazepine/Tegretol's anticonvulsant properties. These mechanisms do not explain why it is an effective mood stabilizer, however, the mood-stabilizing effects usually do not appear for 10 to 14 days (Perry et al., 2006).

Carbamazepine/Tegretol's Effects on Neurotransmission

Carbamazepine/Tegretol has numerous effects on neurotransmission. It decreases glutamate release (recall from  Chapter Two  that glutamate is an excitatory neurotransmitter) and affects norepinephrine, dopamine, and adenosine. Adenosine was not covered in  Chapter Two  but is what is called a neuromodulator, which is similar to a neurotransmitter except that its actions are not limited to the synaptic cleft. Carbamazepine/Tegretol causes an increase in adenosine receptors, which overall, would have an inhibitory effect on the nervous system. As noted, knowledge of these mechanisms has not helped explain why carbamazepine/Tegretol has efficacy for manic-depressive symptoms.

Efficacy of Carbamazepine/Tegretol in Bipolar Disorder

Although the scant literature supports the efficacy of carbamazepine/Tegretol for manic-depressive symptoms, the drug does not appear as effective as once thought (Dardennes, Even, Bange, & Heim, 1995; Kleindienst & Greil, 2002). For patients who have never had a mood stabilizer, lithium outperforms carbamazepine/Tegretol (Hartong, Moleman, Hoogduin, Broekman, & Nolan, 2003). Although other researchers challenge this view, carbamazepine/Tegretol is listed as a second-line treatment for mania. Like lithium, response to carbamazepine/Tegretol is correlated to the dosage and many nonresponders have been on inadequate doses of the drug. Studies have also supported carbamazepine/Tegretol as a maintenance therapy for manic-depressive illness (Kishimoto, Ogura, Hazama, & Inoue, 1983). Many researchers believe that trials with appropriate methodologies and adequate samples would find carbamazepine/Tegretol equal to lithium in efficacy (Mitchell & Malhi, 2002).

TABLE 8.6 Common Side Effects Associated With Carbamazepine/Tegretol

Type	Description
Dermatologic	Rash that may foreshadow WBC problems
Endocrine	Hyponatremia (dangerous drop in sodium levels), Water intoxication
Gastrointestinal	Nausea, vomiting
Hematological	Leukopenia (elevated WBC count), Agranulocytosis (rare), Aplastic anemia (rare)
Hepatic	Elevated liver enzymes (20%)
Neurologic	Sedation/ataxia, dizziness, Dystonic reactions
Psychiatric	Delirium, hallucinations, Minimal cognitive impairment
Teratogenic	Associated with craniofacial defects and spina bifida

Side Effects of Carbamazepine/Tegretol

Table 8.6  summarizes the more common side effects associated with carbamazepine/Tegretol, according to Perry et al. (2006) and Schatzberg et al. (1997).

Dermatologic Side Effects of Carbamazepine/Tegretol

Within two weeks to five months of beginning carbamazepine/Tegretol, approximately 7% of users show general dermatologic problems such as rash or acne. Some data connect these dermatologic side effects to a more serious side effect of bone marrow suppression, particularly in children (Silverstein, Boxer, & Johnson, 1983). Another possible side effect is Stevens–Johnson syndrome, a rash involving the skin and mucous membranes. The lesions can include conjunctivitis as well as oral and genital lesions. Severe forms of the syndrome can include hepatitis and pneumonia and can be fatal. Once detected, this syndrome resolves when medication is discontinued. Recently, hypersensitivity to carbamazepine/Tegretrol has been linked to a family of genes referred to as human leukocyte antigen (HLA) (Tangamornsuksan, Chaiyakunapruk, Somkrua, Lohitnavy, & Tassaneeyakul, 2013). One particular allele of this family (HLA-B*1502) is correlated with Stevens–Johnson syndrome response to carbamazepine/Tegretol. This is one of those findings that moves the era of pharmacogenetics closer as now researchers recommend screening for this allele prior to treating a patient with carbamazepine/Tegretol (Amstutz et al., 2013).

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Endocrine Side Effects of Carbamazepine/Tegretol

Carbamazepine/Tegretol can cause sodium depletion (hyponatremia) as well as water intoxication (defined as too much water in the body). Although this occurs in only 5% of clients, hyponatremia can be fatal if not corrected. The symptoms of sodium depletion include headache, nausea, puffiness about the face, muscle weakness, and disorientation. Frequently lithium is combined with carbamazepine/Tegretol, and sodium depletion (as noted earlier) can in turn cause lithium toxicity.

Gastrointestinal Side Effects of Carbamazepine/Tegretol

The most commonly experienced GI side effects of carbamazepine/Tegretol are vomiting and nausea. If people experience these side effects, their dosage can be reduced to resolve the side effect. Frequently, clients experience this while the prescribing professional is titrating the dose upward. In that case, the prescribing professional usually slows the titration.

Hematologic Side Effects of Carbamazepine/Tegretol

Elevated white blood cell counts (leukopenia) are experienced in approximately 12% of adults and 7% of children taking carbamazepine/Tegretol. Symptoms include fever, sore throat, and ulcers in the mouth. Although the blood count should be monitored for problems, most blood counts return to baseline without intervention (Sedky & Lippmann, 2006). Patients with low counts should be monitored every two weeks for the first three months of medication treatment. If the count falls below a certain point (3000 per millimeter), the drug should be discontinued. This same problem exists with oxcarbazepine/Trileptal, which is a metabolite of carbamazepine/Tegretol (Milia et al., 2008). More problematic are agranulocytosis (drop in white blood cell counts) and aplastic anemia (failure of the bone marrow to produce white and red blood cells).

Hepatic Side Effects of Carbamazepine/Tegretol

The most common side effect related to the liver is an elevated level of liver enzymes that govern metabolism. This side effect occurs in about 20% of clients on carbamazepine/Tegretol and is generally thought benign. There are rare occurrences of liver toxicity, the majority of which occur in the first four weeks of treatment. Symptoms include fever, jaundice, rash, anorexia, and/or nausea. If liver toxicity occurs, the medication should be discontinued.

Neurologic Side Effects of Carbamazepine/Tegretol

Two of the most common side effects of taking carbamazepine in general are sedation and dizziness. These typically occur within the first few weeks of therapy. Some children on carbamazepine/Tegretol experience dystonic reactions in the first two to three weeks of treatment. This response is possibly due to dopamine antagonism. If carbamazepine/Tegretol is combined with lithium, about 12% of clients taking the combination risk neurotoxicity. Symptoms include confusion, disorientation, slurred speech, and problems with coordination.

Psychiatric Side Effects of Carbamazepine/Tegretol

No estimates exist on how many people experience psychiatric complications from carbamazepine/Tegretol, but the typical symptoms include delirium and hallucinations, insomnia, irritability, and mood lability. If these occur, the medication should be discontinued. There are also reports of some minimal cognitive impairment from carbamazepine/Tegretol; however, this impairment is not as great as is reported with lithium.

Teratogenic Side Effects of Carbamazepine/Tegretol

The use of carbamazepine/Tegretol in pregnant women has been associated with craniofacial defects, spina bifida (underdeveloped neural tube), underdeveloped fingernails, and developmental delays. Although some studies dispute these figures, there is not enough evidence to support safe use during pregnancy. Researchers recommend pregnant women avoid carbamazepine/Tegretol and valproic acid/Depakote (Werler et al., 2011).

OXCARBAZEPINE/TRILEPTAL

Oxcarbazepine/Trileptal can be thought of as a safer version of carbamazepine/Tegretol that may actually replace it in clinical practice (Advokat et al., 2014). It is carbamazepine/Tegretol with an oxygen molecule attached to one of its rings, which allows for an easier metabolism. It seems to have similar efficacy and side effects in treating BPI in adults but is not different from placebo in children and adolescents (Wagner et al., 2006).

THE CASE OF MOLLY

Molly is a 24-year-old single woman who has suffered from Bipolar I Disorder for over a year. She has had a great deal of difficulty on lithium, and her attending physician recognized that carbamazepine/Tegretol had just received FDA approval for use with Bipolar I Disorder in adults. He titrated Molly off the lithium and began a course of treatment on the carbamazepine/Tegretol. Over time, Molly noticed that her intermittent manic symptoms lessened while she was taking Tegretol, and she agreed to begin therapy to focus on issues surrounding her sexual orientation and great issues of anxiety and concern about “coming out” as a lesbian.

In this case, the carbamazepine/Tegretol served as an important alternative to lithium, and it stabilized Molly enough that she was able to explore other psychological issues in counseling. Another outcome of the counseling was that Molly was able to tolerate her depressive symptoms and link them to the losses she experienced in her life and to deep personal sadness. Molly remained on carbamazepine/Tegretol for six years and then successfully titrated off the psychotropic with minimal adverse effects. Molly's case is a good illustration of how psychotropic medication provides a window of opportunity for clients to explore intrapsychic issues.

THE CASE OF ROGER

Roger, a 32-year-old single male has suffered from a variety of mood and psychotic disorders over the past decade. Sometimes his chronic manic symptoms would intensify and Roger would become psychotic and have to be hospitalized. During these hospitalizations, Roger was given various diagnoses: He was variously diagnosed with Schizophrenia, Schizoaffective Disorder, Cyclothymia, and Bipolar I Disorder. He was treated with several medications, including lithium, perphenazine/Trilafon, loxapine/Loxitane, haloperidol/Haldol, and thiothixene/Navane. None of these medications seemed very helpful to Roger, and his case remained a mystery to his psychiatrist.

Recently, Roger was prescribed carbamazepine/Tegretol for his symptoms, and after three months he began to report some relief from his chronic manic symptoms. After six months on the drug, however, Roger began to experience continuous auditory and tactile hallucinations. He had never experienced either of these symptoms before, although the variety of his symptoms was extensive. After a careful assessment, his attending psychiatrist recognized that there was a very strong possibility that Roger was experiencing psychiatric side effects of the carbamazepine/Tegretol. The psychiatrist discontinued the medication, and after about five days the hallucinations disappeared.

Given the complexity and range of Roger's symptoms and diagnoses, it is remarkable that his psychiatrist was able to link his hallucinations to an adverse reaction to the carbamazepine/Tegretol rather than to new psychotic symptoms. This case is a good illustration of the importance of good medical care, particularly where multiple medications are involved.

VALPROIC ACID

Valproic acid is another anticonvulsant that is used as a mood stabilizer. There are several formulations of valproic acid with different names, including Divalproex, Depakene, Depacon, and Depakote. We use valproate because that is the most general term in use. Valproate was first synthesized as a sodium salt by George Carraz in 1962. Its initial use was as a solvent, and its anti-convulsant properties were not discovered until 1963. This discovery (like many in psychopharmacology) was made by accident: In France, researchers were mixing valproate (as a solvent) with other compounds thought to have anticonvulsant properties. The researchers soon discovered that the other compounds worked only when mixed with valproate and that only the valproate had anticonvulsant properties. It was tested and introduced as an anticonvulsant in Europe in 1967. Abbott Laboratories obtained a license for it as an anticonvulsant in 1983. In 1987 and again in 1991 Abbott was granted a patent and a new method to produce semisodium valproate, which differed from the original valproate by only one sodium ion. Abbott claimed it had a better gastrointestinal side effect profile. In 1995, Abbott won FDA approval for using valproate to treat acute manic episodes.

TABLE 8.7 Proposed Mechanisms of Action for Valproate

Inhibits sodium and calcium channels

Slows metabolism of GABA

Increases release of GABA

Inhibits reuptake of GABA

Unspecified effects on gene expression

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Mechanism of Action

Table 8.7  summarizes proposed mechanisms of action for valproate.

Valproic acid differs chemically from all other anticonvulsants and psychotropic compounds. Like carbamazepine/Tegretol and lithium, it has many mechanisms of action. Scientists do not know why it acts effectively as an anticonvulsant or as a mood stabilizer. One theory, summarized by Keck and McElroy (1998), is that valproate slows down metabolism of GABA by attaching to the enzyme that breaks down GABA (GABA transaminase). Second, it increases GABA by inhibiting its reuptake. Third, valproate may inhibit sodium channels hyperpolarizing neurons. Finally, valproate may affect gene expression in ways that are therapeutically beneficial but not yet understood (Oguchi-Katayama et al., 2013). Recall from  Chapter Two  that GABA serves an inhibitory function in the nervous system, so any agent that increases its presence would increase inhibition of the nervous system.

Efficacy of Valproate in Bipolar I Disorder and Aggression

Current data suggest that valproate is as effective as lithium in treating acute mania and may be more effective than lithium in mixed-state or rapid-cycling subtypes of Bipolar I (Bowden et al., 1994; Freeman, Clothier, Pazzaglia, Lessem, & Swann, 1992; Mitchell & Malhi, 2002). Schatzberg et al. (1997) have noted that open trials indicate that valproate is also effective as a prophylactic. The antimanic effects of valproate begin within 7 to 14 days of a patient beginning the medication. It is currently being used in both children and adults (Wagner et al., 2002).

Some support exists for the notion that valproate is better tolerated than lithium. French researchers Lambert and Venaud (1992) noted in their study that valproate decreased aggression in animal models, may increase cognitive functions in humans (as opposed to the impairment of cognitive function associated with lithium), and may provide “awakening” effects on personality. An example would be a client whose emotional flattening and avolition improve after being put on valproate. Perry et al. (2006) make the point that in comparing valproate to lithium, it is important to separate the participants in various studies into those who have taken lithium and responded, those who have taken it and not responded, and those who have never taken it. This would give us more accurate information on how valproate compares to lithium, but many researchers do not give the participants' lithium history. It appears that valproate is also useful in reducing aggression and irritability in people suffering from personality disorders. Like lithium, it also seems useful in treating reactive/affective/defensive/impulsive (RADI) aggression (Padhy et al., 2011).

Side Effects of Valproate

Table 8.8  outlines the most common side effects of valproate. Note that the percentage of clients who suffer from a given side effect varies, as does the reported percentage of side effects, depending on which source you consult.

Cardiovascular Side Effects of Valproate

Edema is a condition characterized by swelling of body parts, particularly the limbs. Pitting edema is when pressure applied to the swelled area leaves a pit for some time after the pressure is released. This is caused by excess fluid under the skin and in the tissue outside the blood vessels. The condition is caused by excess salt in the system, and the valproate in some manner seems to disrupt the balance of salt in the system. Although this side effect is relatively rare, clients should know how to recognize it and report it to the doctor if it occurs.

TABLE 8.8 Common Side Effects Associated With Valproate

Type	Description
Cardiovascular	Pitting edema
Dermatologic	Transient alopecia
Endocrinologic	Weight gain
Gastrointestinal	Anorexia
	Nausea, indigestion, Vomiting, Transient diarrhea
Hematologic	Neutropenia (low count of a particular white blood cell) Thrombocytopenia (low platelet count)
Hepatic	Increase in hepatic enzymes, Hepatotoxicity
Neurologic	Sedation, Fatigue, Confusion, Headache
Teratogenic	Neural tube defects, Craniofacial defects

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Dermatologic Side Effects of Valproate

The transient alopecia (hair loss) that is a side effect of valproate is similar to that seen with lithium. The hair tends to regrow when the drug is discontinued and may regrow even if the drug is continued. Obviously, most clients find this distressing enough to discontinue medication.

Endocrinologic Side Effects of Valproate

Weight gain and increased appetite are common side effects of valproate. Perry et al. (2006) note that although dietary counseling may be recommended, caloric restriction may not solve the problem. Although it is hard to determine which clients suffer from this side effect and how much they gain, all clients should have baseline weight measured before beginning valproate therapy.

Gastrointestinal Side Effects of Valproate

This category of side effects of valproate has the broadest range. It is the second most common set of side effects attributed to valproate. Although many clients suffer from gastrointestinal side effects, researchers really do not understand the mechanisms of action. Both Perry et al. (2006) and Schatzberg et al. (1997) have emphasized that often these side effects can be alleviated by changing the formulation of valproate used. In addition, an over-the-counter histamine blocker such as Pepcid can also provide relief.

Hematologic Side Effects of Valproate

Platelet dysfunction (thrombocytopenia) can be a problem for clients on valproate. The symptoms include easy bruising or bleeding. Platelet levels can be checked, and if the counts are low, the prescribing professional can lower the dose or try a different medication. Another problem in this category is neutropenia, which is a low count of a particular type of white blood cell. Again, if this occurs, the drug dosage can be decreased or the medication discontinued.

Hepatic Side Effects of Valproate

The most common hepatic side effect from valproate is elevated levels of liver enzymes. This side effect, which seems benign, occurs in almost half the participants taking valproate in some studies. A more serious although rare problem is hepatotoxicity. This may be fatal and can be detected through tests of liver functioning. Symptoms of hepatotoxicity include lethargy, vomiting, anorexia, and weakness.

Neurologic Side Effects of Valproate

Sedation is the most common neurologic side effect of valproate. Less commonly, clients may experience headache, fatigue, and confusion. Small studies have also reported onset of hand tremor within one month of beginning treatment.

Teratogenic Side Effects of Valproate

Like carbamazepine/Tegretol, valproate is associated with increased risk of neural tube defects and craniofacial defects in infants of mothers taking valproate.

As can be seen from the side effect descriptions of lithium, carbamazepine/Tegretol, and valproate, there are some very unpleasant side effects associated with all these drugs. Although they all show efficacy to some extent in treating the symptoms of Bipolar I Disorder, many clients will not take them because of the side effect profiles. In addition, the truth is that scientists still do not understand why any of these medications are effective against the symptoms of Bipolar I and aggression. For these and many other reasons, the search continues for better mood stabilizers.

THE CASE OF JOSÉ

José is a 15-year-old Latino student who was placed in a Severe Emotionally Disturbed (SED) classroom for his aggressive and acting-out behavior. José had beaten up several boys and one girl over the past three years, and one of the boys had to be hospitalized for head injuries. After a recent fight, one of José's teachers noticed that José became very tired, even though he was the violent and uncontrolled aggressor. He slept in the dispensary for over an hour, and when he woke up he seemed very dazed and disoriented. The teacher consulted with the school psychologist, who was aware of many studies and efforts to administer mood stabilizers to aggressive youth. The psychologist also wondered if José might be experiencing some sort of atypical seizure disorder. As a result, the intervention teams met with the mother (his parents were divorced) and recommended a psychiatric consult for José.

José was referred to a psychiatrist who had an excellent reputation for treating children and adolescents. After a careful evaluation of José that included a complete neurological evaluation, he recommended that José begin a combined psychotropic medication treatment of lithium and carbamazepine/Tegretol for his atypical seizure disorder and extremely aggressive behavior.

The intervention team included an explanation of this pharmacologic treatment in their staff meetings, and they monitored the administration of both drugs while José was at school. This therapy, along with milieu support, greatly reduced José's outbursts and his aggressive behavior. In fact, over the next 18 months he only threatened, but did not assault, one student.

THE CASE OF BEVERLY

Beverly, age 67, is a widow of 17 years who has suffered from Schizoaffective Disorder for over 17 years. Her psychiatrist had tried to manage her extreme manic episodes with both lithium and carbamazepine, with only marginal effectiveness. Over time, Beverly had several side effect problems with lithium, including tremors, weight gain, goiter problems, severe rashes, and muscle weakness. Carbamazepine/Tegretol was ineffective in managing her manic episodes, which often necessitated that Beverly be hospitalized for long periods.

Beverly was not responsive to counseling, because she lacked insight and seemed to blame all her problems on either her husband's death or bad luck. She did connect with a female case manager, who helped her with daily living and survival skills, medication management, and support with her loneliness. The case manager was very knowledgeable about psychotropic medications, and she wondered if Depakote/valproic acid might be helpful to Beverly. She not only brought her idea to the attention of the staff psychiatrist but also spoke with Beverly about the medication. Beverly began a course of treatment on Depakote/valproic acid, and her manic episodes and symptoms diminished significantly. She was hospitalized once for a brief period over the next four years, and she had minimal side effects on the Depakote.

In this case, the knowledge, experience, and diligence of the mental health professional helped the client and alerted the psychiatrist to an alternative medication. This decision addressed Beverly's extreme suffering from her manic symptoms and the side effects. When counselors are well educated about psychopharmacology, they can competently assist both the client and the attending physician.

Review Questions

• What are the mechanisms of action that may be useful in using anticonvulsants to treat BPI?

• What sorts of side effects do anticonvulsants have?

SECTION SIX: NEWER ANTICONVULSANTS AS MOOD STABILIZERS

Learning Objectives

• Understand the hypothesized therapeutic effects of using these agents on BPI disorder.

• Know what some of the more dangerous side effects are.

Ever since valproate first showed promise as a treatment for Bipolar I Disorder, the search has continued for new mood stabilizers. Most drugs approved as anticonvulsants were considered for efficacy as mood stabilizers. Newer anticonvulsants may hold promise as mood-stabilizing agents, but they must be thoroughly researched, because their structures, effects, and side effects are heterogeneous (Calabrese, Shelton, Rapport, & Kimmel, 2002). Although research has just begun on these agents, the following sections summarize what we know about them so far.  Table 8.9  lists newer anticonvulsant agents being researched for efficacy in treating Bipolar I Disorder.

Lamotrigine/Lamictal

The FDA approved Lamotrigine/Lamictal as an anticonvulsant in 1994. Since that time, researchers have been studying its efficacy in treating Bipolar I Disorder, making it the most studied of the newer anticonvulsants (Yatham et al., 2002). Macdonald and Young (2002) had hoped that in terms of its efficacy, lamotrigine/Lamictal would be promising but the study results since then have been disappointing and inconsistent. Lamotrigine/Lamictal has shown some initial efficacy in preventing relapse in BPI but is not useful for acute mania or depression (Advokat et al., 2014).

TABLE 8.9 Newer Anticonvulsants Being Investigated for Efficacy in Treating Bipolar I Disorder

Generic Name	Brand Name
Oxcarbazepine	Trileptal
Lamotrigine	Lamictal
Topiramate	Topamax
Gabapentin	Neurontin

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Mechanism of Action of Lamotrigine/Lamictal

Although lamotrigine/Lamictal is still under study, research to date has identified several mechanisms of action. The drug seems to stabilize neuronal membranes by blocking sodium, calcium, and potassium ion channels. Lamotrigine/Lamictal also inhibits release of glutamate in the hippocampus. Recall from  Chapter Two  that glutamate is an excitatory neurotransmitter. Thus, inhibiting glutamate would generally tend to inhibit the neurons in those areas of the brain. This may result in an overall decrease in excitability in the brain that accounts at least for its anticonvulsive properties.

Side Effects of Lamotrigine/Lamictal

Table 8.10  summarizes the side effects so far known from taking lamotrigine/Lamictal. Unlike the other side effect tables in this chapter, these are not listed by category, on which more research is needed.

Probably the most serious side effect in  Table 8.10  is the rash, which could be related to Stevens–Johnson syndrome, an immune-complex-mediated hypersensitivity disorder where the epidermis separates from the dermis and that may be fatal (which we discussed above in the section on carbamazepine/Tegretol). Children and adolescents are more susceptible to this so lamotrigine is not indicated for anyone under the age of 16 (Kazeem et al., 2009). Clients taking lamotrigine/Lamictal who notice a rash should contact their doctor immediately. In addition to these, some psychiatric side effects have been reported, including depression, confusion, irritability, and mania (Asghar, 2002; Ferrier, 1998).

TABLE 8.10 Side Effects of Lamotrigine/Lamictal

Side Effect	Percentage Reporting
Dizziness	38%
Headache	29
Double vision	28
Unsteadiness	22
Nausea	19
Blurred vision	16
Sleepiness	14
Rash	10
Vomiting	10

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Preliminary Conclusions About Lamotrigine/Lamictal for Bipolar I Disorder

Although there have been some positive reports on lamotrigine/Lamictal, its use in treating Bipolar Disorder may lie in using it as an adjunct to complement other agents such as lithium. Lamotrigine/Lamictal seems to have the most impact on unipolar depression, typically being significantly more effective than placebo. It is also useful for preventing future depressive episodes. Although it has not yet shown efficacy in treating acute mania, it may be a useful complement for unipolar depression (Calabrese et al., 1999). As Hurley (2002) noted, lamotrigine/Lamictal costs two to four times as much as lithium and when this is considered along with lamotrigine/Lamictal's adverse effects and efficacy, it does not seem like a strong contender as a mood stabilizer.

Topiramate/Topamax

Topiramate/Topamax is a new anticonvulsant that has shown some promise in open trials for treating Bipolar I Disorder. Although initial studies seemed to indicate that weight loss was a side effect (Marcotte, 1998), recent analyses indicate that any lost weight is regained after 12 to 18 months of therapy (Gordon & Price, 1999). At this point, it appears that topiramate/Topamax may serve as a useful adjunct to more traditional mood stabilizers in treatment-resistant cases (Chengappa, Gershon, & Levine, 2001; Letmaier, Schreinzer, Wolf, & Kasper, 2001). Topiramate/Topamax alone is no better than placebo for the treatment of mania (Kushner, Khan, Lane, & Olson, 2006).

Gabapentin/Neurontin

Gabapentin/Neurontin was introduced to the United States in 1993 as an anticonvulsant. In addition, it has been used off label for a variety of disorders, including BPI Disorder, impulsive behaviors, anxiety disorders, substance use disorders, and chronic pain. Some of these uses have proven quite problematic, and we return to this issue later. Gabapentin/Neurontin is designed to mimic the effects of GABA in the central nervous system (and is hence referred to as a GABA analog). Although initial trials proved promising (Stanton, Keck, & McElroy, 1997), later controlled studies and meta-analyses have found gabapentin/Neurontin no more effective than placebo (Frye et al., 2000; Maidment, 2001; Pande, Crockatt, Janney, Worth, & Tsaroucha, 2000). Gabapentin may yet show efficacy for agitation in psychiatric patients (Megna, Devitt, Sauro, & Mantosh, 2001), but thus far it has not sufficiently demonstrated antimanic properties. At the time of this writing, a great deal of controversy surrounds gabapentin/Neurontin and criminal fraud in its off-label uses that we explain shortly.

One of the more promising groups of agents are the newer antipsychotics covered in  Chapter Seven . We now review the use of these in treating Bipolar I Disorder and finish the section by giving overviews of newer agents that may yet rise to prominence as useful compounds.

Review Questions

• What are some of the mechanisms of action for lamotrigine and topiramate?

• What are some potentially dangerous side effects of these drugs?

SECTION SEVEN: ATYPICAL ANTIPSYCHOTICS AS MOOD STABILIZERS

Learning Objectives

• Understand what the hypothesized mechanisms of action are for using atypical antipsychotics for BPI.

• Know the side effects and how they relate to the side effects of lithium and anticonvulsants.

Throughout the book, we have written about the lack of accuracy in the DSM categories and in the psychotropic drug categories. For example, we noted that drugs categorized as antidepressants seem to have efficacy for a variety of disorders. So are they really “antidepressants” proper? The same problem crops up when we consider the use of atypical antipsychotics for Bipolar I Disorder. Olanzapine/Zyprexa was approved in 2000 for treating Bipolar I Disorder. Although the dosing is somewhat higher for Bipolar I Disorder than for Schizophrenia, current evidence suggests that olanzapine/Zyprexa may also be useful in the long-term treatment of Bipolar I Disorder and is at least as effective as lithium (Berk, Ichim, & Brook, 1999). In a large, randomized, clinical trial, Tohen et al. (2002) concluded that olanzapine/Zyprexa was more effective than valproate in treating acute mania over a three-week period. More recently, Derry (2007) examined five trials of treating BPI with atypical antipsychotics and found they were better than placebo. Derry felt the antipsychotics had efficacy in treating both phases of the disorder, but more recent research by Singh, Chen and Canuso (2012) contradicts this and implies they only have efficacy for the manic stage. They did produce weight gain. The other consistent finding seems to be that even when symptoms are in remission, patients on atypical antipsychotics for BPI have significantly poorer quality of life ratings than those in the control group. Yen et al. (2008) believed that adverse effects from the medications was a big part of this.

Current research is also looking at risperidone's/Risperdal's role in treating mania. Because these medications must be used at higher doses than those used for treating schizophrenia, there is an increased risk of tardive dyskinesia. It also seems that atypical antipsychotics, although showing promise for treating mania, may induce depression in some clients with BPI Disorder (Yatham, 2002). The most attractive feature of the atypical antipsychotics is the possibility that they would be better tolerated in terms of side effects than any of the mood stabilizers discussed so far. Although not associated with side effects such as hair loss, they are associated with weight gain, sedation, and the increased risk of diabetes (in some cases) that may be equally problematic for some clients (McIntyre, 2002).

One of the newer uses of atypical antipsychotics is as complements for another mood stabilizer (Kafantaris, Coletti, Dicker, Padula, & Kane, 2001). Delbello, Schwiers, Rosenberg, and Strakowski (2002) outlined a course of treatment for adolescents diagnosed with Bipolar I Disorder, complementing valproate with quetiapine/Seroquel. The study found that the combination therapy was more effective than valproate alone. Likewise, Weizman and Weizman (2001) concluded that the atypicals had promise both alone and when used in addition to other mood stabilizers, although these authors point readers to the debate on whether or not the atypical antipsychotics have significant advantages in terms of side effects.

Review Questions

• What are the hypothesized mechanisms of action for using atypical antipsychotics to treat BPI?

• How do you think the side effect profiles compare between atypicals, anticonvulsants, and lithium?

GENERAL CONCLUSIONS ON MOOD STABILIZERS

Although we have yet to explore mood stabilizers through the other perspectives of the integrative model, we can draw some conclusions from the medical model summary of these drugs covered thus far. First, as we noted at the beginning of the chapter, the very notion of mood stabilization is as illusive as the etiology of Bipolar I Disorder. All the medications discussed in this chapter were originally developed to treat other conditions, and their effects on mood states were accidentally discovered. Researchers really need to understand the etiology of Bipolar I Disorder and the action mechanisms of the effective drugs before they can move forward to designing drugs and other treatments specifically to treat Bipolar I Disorder. The inclusion of the phrase “and other treatments” implies that causes of Bipolar I Disorder may in fact not be limited to biological ones. From an integrative perspective, looking at psychological and even spiritual aspects of the disorder may help therapists radically redirect treatment efforts. Finally, it is becoming clear that the most difficult aspect of mood stabilization is the prophylactic one. Mitchell and Malhi (2002) noted that one large problem with researching this area is that clients eligible for the trials usually suffer from less severe forms of the disorder. This makes the clinical trial easier to carry out but decreases the generalizability in the field.

SECTION SEVEN: ISSUES FROM OTHER PERSPECTIVES

In this section, we explore some of the many issues surrounding mood stabilizers that frequently are not covered in psychopharmacology books. From an integrative perspective, there are numerous non-pharmacologic issues that, if engaged, could have profound implications for treatment.

Psychological Issues

Bipolar Illness and Creativity

Several of our students have asked whether there is a significant connection between Bipolar I Disorder and creativity. Jamison (1989) conducted a study with an admittedly small number of participants that supported the notion that clients who identified themselves as artists seemed to have a higher incidence of manic-depressive illness. Jamison (1993a, 1993b) revisits this study with several other case studies that seem to support the hypothesis. At the time she noted that medical model theorists resist this connection; however, much current work supports it as accepted now by the medical community (Ricciardiello & Fonaro, 2013). In a family study with 300,000 people, Kyaga et al. (2011) found that people with BPI and healthy siblings of people with BPI and Schizophrenia were over-represented in the creative professions. One difficult question is how treatments may stifle creativity, raising the question as to whether the treatment is worse than the disorder. The case of Robert illustrates this situation.

The Case of Robert

Robert worked as a visual artist, suffered severe mood swings, and met the criteria for Bipolar I Disorder. When he was depressed, he described himself as being in a liminal state between life and death. In this liminal state, he claimed to “peer across the narrow vale” that separated the living and the dead. In peering across that valley, Robert felt overwhelmed by the immensity of both the horrors and beauty of being alive; he became acutely aware of the needless cruelty that human beings inflict on one another. His conclusion was that most people were suicidal and expressed their suicidality outwardly in cruel actions. In such periods, he frequently contemplated suicide, and the only thing that stopped him was a profound conviction that suicide did not bring about the cessation of consciousness that, in these states, Robert so desperately desired. As a practicing Wiccan, Robert believed souls would continue to deal with the same problems in the afterlife that they faced in this life, so suicide would not be “an easy out.” Robert's practice of Wicca also led him to see his own alienation from mainstream society as an illness of the society more than his illness. To cope, Robert drank and abused opioids until he could create a buffer of numbness between himself and the terrors and pain of the world.

When Robert was in a manic mood, his creative output was indeed amazing. He was able to capture on canvas the rapture he could feel in contemplating the beauty of life as well as the desolation that so frequently overtook him. He could often work for days and even weeks on little or no sleep. Robert's manic episodes usually ended in a more restrictive setting as he would take his paintings out to museums and offer them to personnel there for display. His insistence and manner usually resulted in law enforcement officers being called and transporting Robert to an inpatient facility. Although certainly disruptive, Robert never threatened or hurt anyone.

After his third manic episode, Robert was stabilized and agreed to try lithium therapy. He suffered from forgetfulness, weight gain, sexual dysfunction, and hand tremors. Although the forgetfulness and hand tremor interfered with his painting, he said it was his total lack of mood that he found unacceptable. He said in essence that the medication took away all feeling and passion from his mind. He said it reminded him of the “zombie powder” used in voodoo ceremonies in the B-grade horror movies he watched. In addition, Robert found the regular blood testing uncomfortable and disruptive to his life. He discontinued lithium under his doctor's care after three months. The doctor then tried treating Robert with divalproex, with similar results.

Robert eventually stopped all medical treatments for his condition and chose instead to return to his previous lifestyle. Family members twice tried to have him involuntarily committed but were unsuccessful. Robert stated that if his condition were going to kill him at least he would be able to function as an artist until death. While on medication, he was not an inconvenience to society, he said, but neither was he fully alive. In his last therapy session, Robert said he did not expect his therapist or most people to understand, because most people hated life and hated to see anyone truly living the mystery of it. When told by family that his lifestyle was a risk to his well-being, he was fond of quoting the saying, “The candle that burns twice as bright burns half as long.”

Again, from an integrative perspective there is much to reflect on in Robert's story. Do people have a right to live as they wish even if that lifestyle may cause them impairment and distress and possibly shorten their life? Is Robert really any different from other people who engage in unhealthy behaviors (such as smoking, fighting, creating unnecessary anger and stress for themselves and others)? Certainly it would be ideal if a medication existed that his doctor could have used to treat Robert without the severe side effects on his creativity, but this has never been an ideal world.

Robert's story also brings in the spiritual aspects of life. Although many adherents to positivism and the medical model perspective abhor the mere mention of the word, if spirituality reflects a person's ultimate concerns in life then Robert's spirituality was an important component of his story. From an integrative perspective, clients' spirituality is as important as the medications they are taking and the cultural/social context in which they find themselves.

Compliance with Mood Stabilization Therapy

Cases such as Robert's raise the issue of compliance with mood stabilizer therapy. One of our clients said to us, “I don't like taking lithium, but I seem to always get in trouble when I don't take it.” This client—let's call him Jack, for convenience—was suffering some fairly severe side effects from lithium in the early 1990s but had failed to respond to carbamazepine/Tegretol. Weight gain and forgetfulness particularly bothered Jack. In addition, Jack, like Robert, deeply disliked having blood drawn and found the regular blood testing very difficult to comply with. On one occasion he went on a drinking binge, almost winding up in the emergency room. He recovered from that but became deeply depressed over his situation. Twice the doctor had titrated Jack off lithium, and twice he relapsed within 18 months. The relapses were crushing blows to his sense of self-efficacy, and he began to refer to himself as a “chemical cripple.”

Compliance can be a difficult challenge for clients who are taking lithium. Studies on compliance show that about half the clients who begin lithium therapy stop taking the drug against medical advice. This also holds true for other mood stabilizers such as carbamazepine/Tegretol and valproate. Predictors regarding who is likely to be noncompliant include clients with histories of noncompliance, clients with denial regarding the severity of their illness, and the length of time the client has been on the mood stabilizer (the longer, the less compliant) (Scott & Pope, 2002). Most clients stop taking the medication because of the side effects, and it is not hard to understand why (Silverstone & Romans, 1996). As we see later, numerous medications may be as effective as lithium in treating Bipolar I Disorder, and mental health clinicians need to be prepared to advocate for their clients should lithium be unacceptable to the client. Although some clients can manage their symptoms without medication, many may require long-term or even lifelong pharmacologic intervention. For these people, the dangers of going off medication include not only relapse but also a significantly increased risk for suicide (Baldessarini, Tondo, & Hennen, 1999).

We have also found from the psychological perspective that clients tend to miss the “high” associated with manic states. There is no simple solution to this other than to establish a good therapeutic alliance with the client and, early in the relationship, to construct a history of the client's symptoms, making sure you discuss the symptoms that were most troubling for the client. When the client misses the manic states, it is important to balance what may be an idealization of these past states with the reality of the problems they caused the client. This dialogue must take place within a trusting relationship. Family therapy and support can also help clients face difficult existential issues. The bottom line, though, is that it is not the mental health clinician's job to “talk the client into” staying on medications. If the client cannot come to this decision autonomously, then clinicians need to explore alternatives to lithium therapy.

SECTION EIGHT: ISSUES FROM THE CULTURAL AND SOCIAL PERSPECTIVES

It is not rocket science to notice some oddities about aggression in U.S. society in general. The author Kurt Vonnegut (1991) has pondered aggression in the United States and what it means that we live in a time when killing is a leading entertainment form. Although many scholarly works support this description (Shifrin, 1998), we recommend instead that readers check their local cable listings. Other estimates indicate that many categories of violent crime have increased between the 1980s and 1990s, and this may continue into this 21st century (Goldstein & Conoley, 1998). The linguist and activist Noam Chomsky (2002) has noted that U.S. society has a history of violent imperialist policies requiring that citizens be distracted to other things (such as forms of violent entertainment). When you pair this aspect of U.S. society with the rates of psychotropic medication use, you may begin to wonder if perhaps everyone needs something to “take the edge off.”

In  Chapter Nine , we discuss the controversy that surrounds diagnosing younger and younger children with Bipolar I Disorder. At this point, though, we want to examine from an integrative perspective the connection between the violent nature of U.S. society and the use of “mood-stabilizing” medications. We have already noted that more and more mood stabilizers are being prescribed off label to treat children who engage in aggressive/violent behaviors, but we question if this is really treating the cause of the behaviors. The American Academy of Pediatrics (Shifrin, 1998) has summarized the literature that has concluded that viewing violence on television does influence the aggressive behaviors of children. Nevertheless, few studies look at how much violence children are exposed to who are also being treated with mood stabilizers for violent medication.

From an integrative perspective, we would do well to examine any correlation between viewing such violence on television or in video games and being on mood-stabilizing medication. Further, as we document in  Chapter Nine , resources are decreasingly available for psychosocial interventions with children who have suffered or witnessed violence. Psychosocial interventions help children make meaning out of these horrible experiences, and the meaning they make has everything to do with how well they function after the event (Garbarino, 1998).

Although in U.S. society we discourage and punish some forms of aggression, others are blatantly rewarded. A good example is marketing strategies. Marketers frequently use martial vocabulary speaking of “conquering” a market, “exploiting” a competitor's weakness, or “destroying” the competition. The culture of marketing takes on special meaning in the pharmaceutical industry and, as we noted earlier, requires special monitoring.

The lawsuit discussed below, regarding the anticonvulsant gabapentin (Neurontin), illustrates some of the problems of aggressive marketing.

The Gabapentin Controversy: Corruption in Corporate Culture

As we noted earlier, studies from the medical model have not supported gabapentin as having efficacy in treating Bipolar I Disorder. Yet the drug continues to be prescribed off label. One such prescription became the center of this mess. This story was reported on National Public Radio on January 16, 2003 (Prakash, 2003). Although drug companies must follow rules in promoting medications to physicians, there are also ways around these rules. The case in question deals with a 16-year-old who committed suicide while under the care of his doctor, ostensibly for Bipolar I Disorder. The doctor was treating the teenager with gabapentin/Neurontin, although the young man said it was not helping. The patient's statements make sense in light of a review of the literature that does not support gabapentin as having efficacy for Bipolar I Disorder.

What has come to light and became the center of a criminal fraud lawsuit is that the drug's manufacturer (Warner-Lambert, a subdivision of Parke-Davis) was accused of illegally marketing the drug for unapproved uses. The basic strategy was that the company encouraged the off-label use of gabapentin/Neurontin by directing money at influential doctors, who then wrote favorable reports for medical journals about gabapentin's efficacy in Bipolar I Disorder. By also talking about such findings at meetings of professional organizations, drug companies create “buzz” about the possible uses and increase the probability of increased off-label experimentation by others in the field. The “loophole” is that a company cannot market a drug for off-label uses but can “educate” doctors about those uses.

Parke-Davis contracted with a company called Medical Education Systems in Philadelphia, paying MES $160,000 to develop 12 scientific papers to “support epilepsy education.” In actuality, three of these papers were on gabapentin/Neurontin and Bipolar I Disorder. The documents indicate that Parke-Davis made sure the articles printed what it wanted included, preapproved the authors and topics, and even chose the journals to which they would be submitted. According to the NPR story, some of the papers may have been entirely written by MES ghost-writers. The NPR reporter interviewed a former editor-in-chief of the New England Journal of Medicine, who stated that this arrangement is not unusual and that pharmaceutical companies often hire medical education companies to write such papers and then pay prominent physicians to basically sign the paper.

In another story, Prakash (2002) documented that Warner-Lambert/Parke-Davis planned the strategy to promote gabapentin for unapproved uses and that a company committee formulated the strategy. This strategy was enacted after the company determined in 1995 that clinical trials would be too expensive and take too long. The fear was that by the time the clinical trials were completed, the patent on gabapentin would have expired, and competitors would flood the market with generic formulations of the compound. The lawsuit involving Parke-Davis'sWarner-Lambert division (recently acquired by Pfizer) maintained that this strategy was illegal. In addition, Warner-Lambert withheld one study from publication that concluded gabapentin was less effective than placebo for treating Bipolar I Disorder. The question arises, to what extent did the illegal strategy contribute to the physician prescribing gabapentin for the young man who committed suicide?

We are aware that we are writing this at a time when corporate scandal has been prominent in the headlines, first with the Enron scandal and then the WorldCom story. We feel the gabapentin story describes an extension of the immoral practices that seem to be such a large part of the U.S. corporate culture. Any integrative view of psychopharmacology must take this corporate culture into account when considering the impact of pharmaceuticals on the person. Any mental health clinician operating in the United States must consider these perspectives when treating clients taking psychotropic medication. Ideally, clinicians can get the client's agreement to monitor prescriptions for off-label uses of medications and when necessary, advocate for the client. As noted, the pharmaceutical company Pfizer acquired the Warner-Lambert division of Parke-Davis and was held responsible for the subdivision's activities between 1996 and 2000.

Pfizer pleaded guilty to criminal fraud and agreed to pay $240 million in criminal fines (the second-largest ever in health care fraud) and an additional $152 million in civil fines to be shared among state and federal Medicare agencies (Journal News.com, 2004). Perhaps the most difficult thing to comprehend is that this fine was a fraction of the money made through the off-label uses of gabapentin. Time magazine (2004) estimated that gabapentin/Neurontin made Pfizer $2.7 billion in 2003 and that 90% of that figure was from off-label uses. This would mean that almost $2.25 billion was made in off-label uses, making the $430 million in fines a proverbial “drop in the bucket.”

Ingersoll, Bauer, and Burns (2004) have explored the role of advocacy in light of possible corruption in the corporate culture of the pharmaceutical industry. These authors recommend the following steps. First, mental health clinicians must know how to read and evaluate research. In an ideal world this would be enough, but in the real world clinicians must also work to understand how papers come to be published and whether the trial was conducted by a neutral party or a vested interest (including the pharmaceutical company itself). Clinicians need to know how well psychological treatments work and advocate with their professional organizations to focus on this material in professional journals and conferences. In addition, clinicians need to know the limits of diagnostic categories and that they are not descriptions of diseases capable of a single allopathic treatment but rather clusters of symptoms occurring together that can help guide treatment. Finally, mental health clinicians should consider advocating for regulatory oversight of pharmaceutical marketing to preclude dishonest or misdirected marketing efforts.

The Role of the Law in Pharmaceutical Company Regulation

Certainly, the gabapentin/Neurontin suicide described in the last section has components that should be addressed from the social perspective. First and foremost are the laws that allow companies to use loopholes such as the ones described. All too often there is an assumption that if something is not against the law, there is no problem. This of course ignores the rich history of unjust laws in our, as well as other, societies as well as discriminant enactment and adjudication. What protection does the individual citizen have when competing with vested power interests such as pharmaceutical companies that have the power to speak directly to elected representatives who supposedly represent us all? Here oversight—supervision—becomes an issue. Although many say that government oversight of corporations is already too great in this country, this is hard to believe when you look at scandals such as those involving Enron, WorldCom, and now Pfizer. If anything, these scandals point to the need for further oversight and for internal checks and balances on the government regulatory agencies and courts, as well as legislation, and on media and advertising.

The Social Costs of Bipolar Disorder

Another social issue that needs to be considered concerns the social costs of Bipolar Disorder as well as the costs of treatment. An interesting study by Wyatt, Henter, and Jamison (2001) looked at the social costs of the disorder and then tried to estimate the amount society saved by using lithium. Reporting that the estimated social cost of manic-depressive illness in 1991 was roughly $45 billion, these authors noted that by comparing the actual social costs and the projected costs had lithium never been introduced, they could estimate how much money was saved. Recall that the FDA did not approve lithium for manic-depressive illness until 1970, so estimated social costs from that year in 1991 dollars may be considered an estimate of typical social costs prior to lithium's approval.

These authors concluded that in terms of direct social costs, lithium appeared to save approximately $8 billion a year, or a total of over $170 billion. These direct costs included inpatient and outpatient care and research dollars. In addition, the authors sought indexes of indirect costs and estimated that introducing lithium saved society approximately $155 billion. Indirect social costs included factors such as lost productivity of wage earners, homemakers, and caregivers as well as the unhappiness and waste of those people who languished in institutions or of those who, without lithium, may have committed suicide. Although many complex variables cannot be represented adequately in such studies, it is safe to assume that although not a perfect treatment, lithium has worked well enough for enough individuals to effect substantial savings in the social costs of treating manic-depressive disorders. The unaddressed issues in large-scale “guesstimates” about “costs to society” include general questions about the relative health of the society and the pointed question: If the society were healthier, would the need for intrusive interventions such as lithium treatment remain the same?

CONCLUSION

We hope this chapter on mood stabilizers has at least increased the complexity with which readers think about the issue. In many ways, the topic is like the mythic Hydra, with each problem representing a head. Once one head is cut off, several more arise in its place. Probably, until scientists can more clearly outline the etiology of manic-depressive illness, clinicians will continue to approach treatment in a “hit-or-miss” fashion. Although newer research on the human genome may accelerate the quest for the “perfect” medication, research must also continue examining the most effective psychosocial treatments for clients who take medications as well as for those who choose not to.

SUMMARY

Bipolar I Disorder is a serious and, in many ways, mysterious mental/emotional disorder. Although there are medications that help people suffering from the disorder, researchers are still unclear as to how the disorder develops and how to discern which medications will work best for individual clients. Although the drugs to treat Bipolar I Disorder are referred to as mood stabilizers, this is an inexact term. The oldest mood stabilizer is lithium, although researchers are not clear exactly how it exerts its therapeutic effects. Although lithium is still in use, not all clients respond well to it and many must try other medications. Alternatives to lithium include carbamazepine/Tegretol and valproic acid. Both of these compounds have proven efficacy for treating Bipolar I Disorder. There are several new drugs that the jury is still out on including oxcarbazepine, lamotrigine/Lamictal, and topiramate/Topamax. As with antidepressants, pharmaceutical companies must be closely monitored in the claims they make for mood stabilizers, as the gabapentin/Neurontin controversy illustrates. Because so little is known about the etiology of Bipolar I Disorder, it is important to take an integrative view of efficacy claims made by pharmaceutical companies.