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CHAPTER SEVEN Antipsychotic Medications The Evolution of Treatment

Many readers may begin this chapter with some familiarity with antipsychotic medications. Others may think antipsychotic medications or the research related to them has not affected their lives. These latter readers may be wrong. Have you ever taken a prescription antihistamine such as Seldane or Allegra? Perhaps got over motion sickness with a compound that included promethazine? If so, your life has been affected by research into antipsychotics. As with so many other areas of research in psychotropic medication, antipsychotics and theories about their use have been developed through combined scientific effort, clinical research, market-driven agendas, and serendipity. Let's look at some history to introduce this topic. The primary source for the following is Healy (2002).

THE CURRENT IMPACT OF ANTIPSYCHOTICS

In a video designed for psychiatrists (Novartis Pharmaceuticals, 1998), a young man suffering from treatment-resistant schizophrenia is shown in an inpatient setting. Although his psychotic symptoms are temporarily under control, he is so incapacitated by medication side effects that he can barely walk across a small room. His movements are jerky contractions of muscle groups that he can hardly control. Anyone who has treated clients taking conventional antipsychotic medications knows that this young man is living a worst-case scenario in which the treatment is worse than the disorder being treated. The video progresses, showing the young man at monthly intervals as he is slowly weaned off the medications causing the side effects, and gradually titrated onto a new medication (clozapine). With each passing month, we see that the young man's psychotic symptoms remain under control but that he is gradually regaining control of his body. In the final video frame, we see the same young man enjoying a game of basketball and apparently having no problems with movement or symptoms of psychosis.

This was one of the first videos promoting what we describe later as an atypical antipsychotic, and at the time of their development most of us believed that clozapine and drugs modeled after its molecular structure launched another revolution in psychopharmacology. It was hoped that (as was hoped in the SSRI revolution in antidepressants) the new antipsychotics would change the way psychotic disorders are treated as well as the quality of life that patients can expect during treatment. As we will see, although newer agents do work better for some but not all people with schizophrenia, the newer agents have problematic side effects similar in impact (if different in quality) as the older agents. Also, the claims that newer medications worked better than the older ones now seem to be untrue ( Jones et al., 2006; Lieberman et al., 2005).

This chapter is divided into seven sections. The first is an overview of schizophrenia and the spectrum of symptoms being treated. The second focuses on theories of neuroleptic antipsychotic action. Section Three is an overview of the side effects of first generation, neuroleptic medications. Section Four is an introduction to the first atypical antipsychotic, clozapine/Clozaril. Section Five covers the rest of the drugs modeled on clozapine called serotonin-dopamine antagonists. Section Six looks at newer compounds and theories of how to create more effective antipsychotics. The final section looks at psychological, cultural, and social issues relevant to antipsychotic medications.

SECTION ONE: SCHIZOPHRENIA

Learning Objectives

• Have a sense of the complexity of theories of etiology for schizophrenia.

• Be able to discuss why the name “schizophrenia” is not terribly useful.

• Understand positive symptoms, primary negative symptoms and secondary negative symptoms.

Schizophrenia “… definitely involves genetic factors the precise genes and gene-environment interactions are yet to be clarified” (Keshavan, Tandon, & Nasrallah, 2013, p. 4). As Stober et al. (2009) concluded, “the phenotypic complexity, together with the multifarious nature of the ‘group’ of ‘schizophrenic psychoses’ limits our ability to form a simple and logical biologically based hypothesis of the disease group” (p. 129). Schizophrenia shares many heritable factors with Bipolar I disorder, suggesting there may be an underlying genetic basis for both disorders that runs on a continuum. At the more severe end of the continuum, the person is afflicted with schizophrenia; at the less severe end (if it is fair to use that phrase in regard to any of these disorders), the person is afflicted with Bipolar I Disorder (McIntosh et al., 2006). Ultimately, though, schizophrenia is a disorder with a heterogeneous presentation involving multiple genes that may each have relatively small effects. Etiological factors also include differences in brain structures (Hartberg et al., 2011), white matter or the glial cells in the brain (Frances, 2013), and neurochemical variables (although nothing as simple as dopamine imbalance as was believed in the mid to late 20th century). Prevalence among adults is thought to be between 1 and 1.5% of the adult population (American Psychiatric Association, 2013). Keshavan (2013) has advocated eliminating the name “Schizophrenia” because it conveys an inaccurate characterization of the symptoms, has acquired a negative connotation (like “lunacy”), and belies what we are learning neurobiologically about the disorder. Keshavan et al. (2013) have suggested an acronym “CONCORD,” which stands for “youth onset conative, cognitive and reality distortion” (p. 1). As Keshavan notes, we do not take lightly renaming a disorder but the label of “schizophrenia” seems to be obsolete.

One of the most distressing aspects of schizophrenia is that it seems to be correlated with premature death. Even more disturbing is that we still have to discern if this is related to the disorder, the medications people with the disorder take, or both. Joukamaa and colleagues (2006) did a 17-year follow up of 99 people with schizophrenia. Of the 99, 39 died in that 17 years. Adjusted for age and sex and other diseases, the risk for premature death was significantly higher than expected. The deaths also increased as the number of neuroleptics taken increased. Even though we have agents to treat the symptoms of schizophrenia, as noted above, they do not really differ much from one another in general effectiveness and what is needed is that we understand the mechanisms underlying the illness and its progression. Until we can accomplish this, we will remain stuck in symptom management (Kane & Correll, 2010).

The Spectrum of Symptoms in Schizophrenia

In DSM-5 (APA, 2013), the category Schizophrenia and Other Psychotic Disorders of DSM-IV has been changed to Schizophrenia Spectrum and Other Psychotic Disorders. Many aspects of the DSM-5 were designed to reflect the International Classification of Mental and Behavioural Disorders (ICD-10) (WHO, 1992), which includes Schizotypal Personality Disorder under the Schizophrenia heading. So in DSM-5, the spectrum of disorders also contains a spectrum of symptoms. The spectrum of symptoms in schizophrenia includes both positive and negative symptoms. This concept derives from the work of the 19th-century neurologist John Hughlings Jackson.  Positive symptoms  of schizophrenia are things the client experiences but likely should not be experiencing, such as  hallucinations ,  illusions ,  delusions , and  paranoia . Clients with positive symptoms usually lack insight into the sense outsiders have that these experiences are not real or normal and frequently cannot distinguish between them and the consensual reality shared by most others.

Negative symptoms  of schizophrenia are deficits in the client's functioning expressed as things like  anhedonia  (lack of pleasure in life), isolation, withdrawal, flat or restricted affect, and reduced motivation. These negative symptoms severely affect quality of life for afflicted clients and can be exacerbated by certain antipsychotic medications clients are given to control the positive symptoms. In addition to the positive and negative symptoms, clients suffering from schizophrenia experience conceptual disorganization, which used to be called ”  thought disorder .” This disorganization can range from concrete thinking to severe  loose associations  and  word salad . These symptoms may also severely reduce clients’ quality of life (Thaker & Tamminga, 2001). From an integrative perspective, all these symptoms need to be addressed. Although pharmacological interventions are the first line of treatment for schizophrenia, it is also important to include psychosocial and educational components (American Psychiatric Association, 2000a).

Gelman (1999) divides the history of medicating psychotic disorders into four periods. The first period encompasses the 1950s and 1960s and began with the appearance of chlorpromazine (Thorazine). In this period, the mechanisms of action for chlorpromazine were not known, and although many people believed this drug would usher in an age of deinstitutionalization, others felt it would likely just make hospital wards more manageable.

The second period begins in the early 1960s with the emphasis (begun in the Kennedy administration) of community care versus hospital care. At this time, the National Institute of Mental Health was labeling antipsychotics “ antischizophrenic .” At this time, psychological explanations for mental disorders were dropped in favor of medical model theories. Some writers at the time (Swazy, 1974) even posited that chlorpromazine was a “ magic bullet ” for schizophrenia (which it never was). This second period ends in the 1980s with the disappearance of such overly optimistic views. By the 1970s, clinicians accepted that neuroleptics could produce “alarming side effects, non-profound benefits in most cases, and no benefit at all in many” (Gelman, 1999, p. 7).

The third period, encompassing the 1980s and early 1990s, found many clinicians still clinging to the vague medical model notion of a chemical imbalance as causing schizophrenia despite the theory being increasingly falsified. Although researchers and clinicians began to understand schizophrenia as a complex, overdetermined disorder, many psychiatrists continued to follow the chemical imbalance theory (old habits die hard and it is easier to feign certainty than to live in ambiguity). Research during this period birthed the atypical antipsychotics, and for many psychiatrists these drugs seemed to continue to support the chemical imbalance theory, although they operate very differently from the neuroleptics that actually spawned the theory. Neuroleptics block dopamine-2 (D2) receptors whereas the atypicals block mostly serotonin receptors and some D2 receptors but not as many as neuroleptics. That these drugs that massively block serotonin receptors work as well as neuroleptics that block D2 receptors calls into question how schizophrenia could possibly be just a dopamine imbalance.

The fourth and current period began in the mid-1990s and continues to the present. This period is marked by new imaging technology that allows neurologists and psychopharmacologists to more closely examine the brain and the effects of medications on the brain. During this period, researchers will likely continue to construct newer theories to account for the action of antipsychotic medications.

Review Questions

• What are some of the variables currently considered as important to the etiology of schizophrenia?

• Why is the label “schizophrenia” inaccurate and what could replace it?

• Describe positive symptoms, primary negative symptoms, and secondary negative symptoms.

SECTION TWO: THEORIES OF NEUROLEPTIC ACTION FROM THE MEDICAL MODEL PERSPECTIVE

Learning Objectives

• Understand the dopamine hypothesis of schizophrenia and how it has been falsified.

• Be able to describe the primary dopamine tracts in the brain and how neuroleptic medications are thought to work.

• Know the four classes of extrapyramidal side effects (EPS).

• Know two classes of medications regularly used to treat EPS.

In this section, we outline the mechanism of action in typical antipsychotics (neuroleptics), detail their common side effects, and discuss how to deal with side effects. It is interesting that neuroleptics, and chlorpromazine/Thorazine in particular, were widely used before their mechanisms of action were isolated. As you are now aware, this is not unusual in the history of psychopharmacology, and the neuroleptics were being used on a global scale before their mechanisms of action were identified.

The Dopamine Hypothesis of Schizophrenia

The  dopamine hypothesis of schizophrenia  (the first “chemical imbalance” theory for the disorder) actually was formulated in the 1960s but had no impact on the field of psychiatry until the 1970s. The hypothesis proposed that schizophrenia was caused by an undefined problem in dopamine transmission. The hypothesis grew out of the realization that chlorpromazine/Thorazine and haloperidol/Haldol both seemed to interrupt dopamine transmission and decrease the symptoms of schizophrenia. Equally, abuse of amphetamine drugs that stimulate dopamine can cause symptoms indistinguishable from schizophrenia in some but not all people. As you may recall from Chapter Five, this is similar to the  amine hypothesis of depression . It posits a simple (too simple) cause-and-effect relationship from observations of medical trials. As in other cases, though, the reality is far more complex, and emotional defense of the simple dopamine hypothesis today carries the same authority as emotional proclamations espoused by the Flat Earth Society.

So how was the dopamine hypothesis developed, and what relevance has it for mental health clinicians? Since the early administration of chlorpromazine/Thorazine, researchers had noted that the drug caused symptoms similar to those in Parkinson's disease (so named for James Parkinson, who outlined the symptoms in 1812). Carlsson and Lindqvist (1963) proposed the first variation on the dopamine hypothesis, but remember that at the time people knew little about neurotransmitters and nothing at all about neurotransmitter receptors. Arvid Carlsson discovered dopamine in the central nervous system, where, researchers learned, dopamine was also a precursor to norepinephrine. Studies with reserpine/Serpalan demonstrated that it depleted norepinephrine and serotonin from the brain, but when these neurotransmitters were replaced they did not counter the effects of the reserpine/Serpalan. Carlsson and his colleagues, hot off their discovery that dopamine was also present in the brain, assumed that dopamine too was depleted by reserpine and discovered that giving research animals a precursor for dopamine (levodopa/Carbidopa) did in fact reverse the effects of reserpine/Serpalan. Thus was born the first variation of the dopamine hypothesis—that psychoses were somehow related to deficiencies in dopamine.

The first response to this theory was that it did not make sense, because chlorpromazine/Thorazine did not empty the presynaptic neuron of dopamine (recall that researchers had not yet learned about receptors). Carlsson and Lindqvist (1963) demonstrated that chlorpromazine/Thorazine and haloperidol/Haldol acted on the postsynaptic neurons. Only after Solomon Snyder and Candace Pert confirmed the presence of receptors could researchers make the conceptual leap linking the effects of chlorpromazine/Thorazine to dopamine receptors. Snyder, Banerjee, Yamanura, and Greenberg (1974) also demonstrated that there were many dopamine receptors, and subsequent research showed that antipsychotic drugs had a particular affinity for binding at the dopamine-2 (D2) receptor. This paved the way for the inordinate focus on receptors in today's pharmacologic research. Researchers concluded that neuroleptic drugs such as chlorpromazine/Thorazine and haloperidol/Haldol blocked the D2 receptors, preventing dopamine from binding at those receptors and exerting an effect. Thus, decreasing dopamine activity in this manner lessened symptoms of schizophrenia in many patients. When researchers assumed that people suffering from Parkinson's disease were suffering from decreased dopamine activity, this hypothesis further explained why people taking neuroleptics might suffer Parkinsonian side effects. Although the drug they were taking, not Parkinson's disease, had disrupted their dopamine transmission, the result was the same.

This variation of the dopamine hypothesis was supported by observations of amphetamine users as well. Researchers had long known that heavy amphetamine users could develop symptoms similar to those seen in schizophrenia. Because amphetamines were later shown to increase dopamine in the synaptic cleft, it made sense that if problems in dopamine transmission could cause schizophrenia, drugs that artificially increased dopamine levels might cause symptoms similar to those of schizophrenia, just as decreased levels of dopamine would cause symptoms similar to those of Parkinson's disease.

To summarize: It is now clear that neuroleptics (also called typical antipsychotics) bind to a subfamily of dopamine receptors called the D2 receptors. Here the drugs act as  antagonists , meaning they block the receptor but exert no effect. They merely block dopamine molecules from binding. The dopamine molecules would exert an effect if they could bind, but they are prevented from doing so as long as the person is taking a neuroleptic medication. The dopamine hypothesis was a mainstay for understanding drug treatment for schizophrenia until the 1990s.

The following two cases illustrate both (1) the use of neuroleptics to treat disorders in the spectrum of schizophrenia and (2) the reliance on the dopamine hypothesis as the cornerstone for treating schizophrenia until the early 1990s. This approach met with both success and failure, showing that the dopamine hypothesis was too simplistic. Despite warnings from researchers such as Solomon Snyder and Arvid Carlsson that the hypothesis was merely a correlation and should not be mistaken for a cause-and-effect relationship, by the 1970s the dopamine hypothesis of schizophrenia was quite popular. It is still espoused by some clinicians with great certainty today and that is an error because we also know that agents that block serotonin receptors and glutamate receptors can decrease psychotic symptoms in some but not all people. The serotonin hypothesis was developed by observing that drugs with strong serotonergic agonism like lysergic acid diethylamide (LSD) can cause psychotic-like hallucinations in some but not all users (and these are actually usually visual unlike most psychotic hallucinations) and (as noted above) newer antipsychotics massively block serotonin and decrease psychotic symptoms in some but not all people. Finally, the glutamate hypothesis is that excessive release of excitatory neurotransmitters like glutamate and acetylcholine causes deterioration in the frontal cortex that causes the symptoms of schizophrenia. As Advokat, Comaty, and Julien (2014) conclude “… none of these models completely explains nor exactly mimics the phenotypic presentation of behaviors associated with schizophrenia” (p. 340).

THE CASE OF COLIN

Colin, a 27-year-old father of four, began to notice that he experienced strange thoughts, maybe voices, during his workday. His wife noticed that he was more agitated and tense at home, even impatient with the children. In his work as a media specialist at a major university, Colin had a range of responsibilities linked to a very tight schedule. His schedule had become all but impossible with the layoff of his assistant and he was under the most pressure he had ever been under in his career. His immediate supervisor noticed his growing disorganization at work and a gradual deterioration of his performance. Colin insisted he was receiving messages that preoccupied his mind and distracted him from his daily routine. He became frightened and paranoid, and said people were out to destroy him. He stopped sleeping and eating, and believed his food was poisoned. Finally his wife called the emergency room and was advised to bring Colin in as soon as possible. He resisted her efforts, but finally agreed to go when his best friend insisted he should to demonstrate to the world that he was not insane.

Colin was hospitalized for 18 days and prescribed 24 mg of a typical antipsychotic called thiothixene/Navane. Colin also participated in group and art therapy during his hospitalization. On release, Colin continued the thiothixene/Navane (reduced to 12 mg a day) and began individual and couples therapy at a mental health center. Colin continued both therapies for several years, stopping the thiothixene/Navane after nine months. Ten years after his hospitalization, Colin remains relatively stable both at work and at home, leading an active and productive life. Colin was never hospitalized again, nor did he decompensate to such a state that he needed to go back on thiothixene/Navane or into the hospital. This episode occurred in the early 1980s, and the diagnosis at the time was Brief Reactive Psychosis (what DSM-5 would label Brief Psychotic Disorder).

Colin's case also illustrates several of the perspectives we have discussed in this book. He suffered from a brief but serious cognitive impairment that included hearing voices, losing some contact with reality, and becoming paranoid. From the medical model perspective, Colin had psychotic symptoms and was hospitalized for them. The neuroleptic, thiothixene/Navane, was very helpful, and Colin never developed any serious side effects. It is important to note that six months after his recovery, Colin found a different position with more promotion potential and less stress. As usual though, the medical model perspective provides only part of the story. From the psychological perspective, Colin experienced enormous pressure to earn more money for his growing family at the same time he learned of his parents’ divorce. He also learned there was little promotion potential for him at work, and he began to sense a growing stress with his wife. Culturally, Colin, as a second-generation Irishman to the United States, was ashamed of the dramatic nature of his psychological disorder and his need to take a psychotropic medication. The influence of his family's rigid interpretation of Catholic dogma made Colin ashamed to share this experience with others. In addition, Colin felt a covert stigmatization at work from his immediate supervisor, who was Japanese and who failed to grasp the seriousness of Colin's illness and to be empathic toward him during his recovery. His supervisor also had a work ethic that seemed to view an enormous workload as a source of pride rather than the burden Colin felt it was.

Therapy was invaluable to Colin as he focused on some personal issues that bothered him and also worked on many of the difficulties in his marriage. Throughout the therapy, Colin became alert to the signs that indicated that he could become ill again and, as of this writing, he has had no further serious problems.

THE CASE OF ETHEL

For many years, Ethel suffered from what DSM-IV called Undifferentiated Schizophrenia accompanied with many negative symptoms. Ethel's psychiatrist had prescribed 600 mg of chlorpromazine/Thorazine daily. Because Ethel was single and lived alone, it was very difficult for her case manager to assess how compliant she was with her medication, including her benztropine/Cogentin (taken to treat side effects from her chlorpromazine/Thorazine). Over a period of two years, Ethel had to be hospitalized six times, for periods ranging from eight days to four weeks, because she was unable to function or care for herself. Eventually, the pattern became clear: Ethel would stop taking her chlorpromazine/Thorazine and gradually retreat into a nonfunctioning catatonic state. During her last hospitalization, the treatment team recommended haloperidol/Haldol by injection on a monthly basis to assist her with compliance. This strategy altered Ethel's response to her illness. Although it remained essential for her to take her benztropine/Cogentin orally, getting an injection once a month at the mental health center ended her cycle of hospitalizations, seemed to ease her negative symptoms, and allowed her to participate in group activities sponsored by the center.

Neuroleptic therapy by injection was a strategy implemented for noncompliant patients before the advent of the atypical antipsychotics. This intervention was only partially successful, because many clients remained resistant to treatment with all neuroleptics and/or suffered such serious side effects that neuroleptic treatment became a burden.

Side Effects of Neuroleptic Medication

Perhaps one of the greatest influences for the development of newer antipsychotic medications was the side effects of the neuroleptic medications. Table 7.1 lists the most common neuroleptic drugs still in use today. Note that all these drugs are associated in different degrees with the difficult side effects we describe next.

To fully understand the side effects of neuroleptic antipsychotic medications, we must look at four primary dopamine pathways in the brain that are affected by these medications. Table 7.2 summarizes these pathways, and then we discuss each.

TABLE 7.1 Examples of Neuroleptic (Typical) Antipsychotics

TABLE 7.2 Four Primary Dopamine Pathways in the Brain

Name	Location
Mesolimbic pathway	Projects from the ventral tegmental area of the brain to the limbic system. Plays a role in emotional behavior.
Mesocortical pathway	Projects from the ventral tegmental area of the brain all the way to the cerebral cortex. Plays a role in cognition.
Nigrostriatal pathway	Projects from the substantia nigra of the brain stem to the basal ganglia and is part of the extrapyramidal nervous system.
Tuberoinfundibular pathway	Projects from the hypothalamus to the pituitary and governs prolactin release.

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The Four Primary Dopamine Pathways in the Brain

The Mesolimbic Pathway

Without dispute, the mesolimbic pathway is most clearly associated with the positive symptoms of schizophrenia. Stahl (2013) has noted that the auditory hallucinations, delusions, and even thought disorder symptoms of schizophrenia have been correlated with this pathway. Stahl has suggested that perhaps the dopamine hypothesis of schizophrenia should be renamed the “mesolimbic dopamine hypothesis of positive psychotic symptoms” (p. 374), because that more accurately describes the correlation between neuroleptic medications acting at this brain site and decreased symptoms. Obviously one problem in medicating clients with schizophrenia is that the effects of the medications (at least to date) cannot be isolated to this one dopamine pathway.

The Mesocortical Pathway

The mesocortical pathway is related to cognition, but its role (if any) in the symptoms of schizophrenia is undetermined. It does appear that the blockade of the dopamine-2 receptors in this pathway by neuroleptic medications causes an emotional blunting (sometimes referred to as flat affect) and cognitive problems that look like thought disorder. This has sometimes been called neuroleptic-induced deficit syndrome (Stahl, 2013). Neuroleptic-induced deficit syndrome is particularly problematic, because it mirrors the negative symptoms of schizophrenia that we discussed at the beginning of this chapter. Part of the ongoing debate is whether neuroleptic medications acting on this pathway actually exacerbate the negative symptoms of schizophrenia and in turn degrade the client's quality of life. Further, if clients have pronounced negative symptoms before receiving neuroleptic medication, such medications may make the symptoms worse.

The Nigrostriatal Dopamine Pathway

The nigrostriatal dopamine pathway as part of the extrapyramidal nervous system governs motor movements. Any deficiency of dopamine in this pathway causes a movement disorder. Parkinson's disease is caused by a deficiency of dopamine in this pathway, in turn caused by degeneration of dopamine neurons in the pathway. What we describe later as extrapyramidal symptoms are the Parkinsonian side effects that result when neuroleptic medications block dopamine receptors in this pathway and cause movement disorders. One of the more serious disorders is tardive dyskinesia, or late-appearing abnormal movement. Although the effects of neuroleptics on this pathway and thus movement confirmed initial hypotheses about the role played by dopamine in their mechanism of action, such effects have also confirmed fears that for some clients the treatment may be as difficult to live with as the symptoms.

The Tuberoinfundibular or Hypothalamic Pathway

Ironically, the physically shortest dopamine tract we will discuss has the longest name. The tuberoinfundibular pathway (also called the hypothalamic pathway) is much shorter than the previous three and, as noted in Table 7.2, controls the prolactin levels that normally rise in breast-feeding women. The firing of dopamine neurons in this pathway inhibits the release of prolactin, precluding lactation. When a woman is pregnant, part of the hormonal changes she experiences include inhibition of these neurons. This inhibition increases prolactin release so the woman can lactate to feed her child after birth. Herein lie more problematic side effects from neuroleptic medications. When the medications artificially inhibit the dopamine neurons in this pathway by blocking DA receptors, the result is an unintended increase of prolactin and symptoms such as galactorrhea (breast secretion) and amenorrhea (cessation of menses) in females as well as development of female secondary sex characteristics in males. Clients of both genders may also experience sexual dysfunction.

Given this overview of important pathways affected by neuroleptic medications, you can surmise the basic problem. As we noted, the only antipsychotic actions from these medications result from their blockage of D2 receptors in the mesolimbic pathway. The blocking of D2 receptors in the remaining three pathways result in undesirable side effects. In addition, neuroleptics are “dirty” drugs, meaning that they not only block dopamine receptors but also may block histamine, acetylcholine, and adrenergic receptors. These properties also result in undesirable side effects. Having introduced the different ways in which side effects can occur from neuroleptic medication, let's now look more closely at the primary side effects of these medications. Please note that this discussion of the topic is not exhaustive and does not include rare side effects. These descriptions should give clinicians a sense of what clients may expect and what to listen for as clients describe effects they are experiencing.

Allergic Reactions to Neuroleptics

Allergic reactions to neuroleptics occur in approximately 7% of patients and usually manifest between two weeks and two months of treatment. The primary symptom is a rash on the face, neck, upper chest, or extremities. The rash (local or general) results in red pimples accompanied by a burning or stinging sensation. These are usually treated with  antihistamines  or, in more severe cases, steroids (Malhotra, Litman, & Pickar, 1993).

Anticholinergic Effects of Neuroleptics

As the name implies, anticholinergic effects of neuroleptics result from the neuroleptic medication blocking acetylcholine receptors in both the peripheral and the central nervous systems. The secondary results are called  autonomic side effects  because of their impact on the autonomic nervous system. The primary CNS side effect related to anticholinergic action is  delirium . The peripheral effects of anticholinergic action are described later. Note that all these side effects may be exacerbated if the client is also taking an anticholinergic agent with the neuroleptic. We explain the rationale for using these agents later, when we address extrapyramidal symptoms.

Blurred Vision

The anticholinergic action of neuroleptics can paralyze the ciliary muscle in the pupil of the eye, causing difficulty in focusing on objects within a close field of vision. Sometimes prescribers lower the dosage temporarily or recommend reading glasses to provide relief (Perry, Alexander, & Liskow, 2006). We have found that although not all clients experience this (or any other side effect), those who do often prefer to have the doctor change their medication (and honestly who can blame them?).

Dry Mouth

Dry mouth can be particularly bothersome for clients, depending on the strength of the effect. Both the antihistaminic and anticholinergic effects of neuroleptics cause dry mouth. Many clients can obtain relief with sugarless gum or candy, but many clients find it necessary to carry a drinking bottle with them at all times. Our clients often preferred sweetened, caffeinated soft drinks, which, combined with other poor dietary habits, exacerbated the weight gain associated with the antihistaminic effects of neuroleptics.

Constipation

Constipation can be seriously aggravated by neuroleptic medication, although it may resolve as the client adjusts to the medication. Routine use of laxatives is to be discouraged (Perry et al., 2006). Malhotra and colleagues (1993) noted that in severe cases, constipation can progress into fatal intestinal dilation or paralytic ileus. Paralytic ileus can result in death through intestinal obstruction. Although this is rare, clients need regular checkups with regard to intestinal functioning.

Urinary Retention

Urinary retention may be noticed two to four weeks from beginning the neuroleptic regimen. According to Perry and colleagues (2006), blocking the acetylcholine neurons affects the detrusor muscle that governs the flow of urine. Although the effect is dose related, acute urinary retention is a sign for the prescribing professional to consider another medication as it can lead to kidney problems and bladder or urinary tract infections.

Withdrawal Reactions

Although neuroleptic medications are not drugs of abuse per se, regular and long-term use can induce tolerance, which can lead to withdrawal reactions if medications are discontinued abruptly. The symptoms usually begin two or three days after discontinuation and include headache, nausea, vomiting, diarrhea, and insomnia. Any client who has taken a neuroleptic for at least one month should have the medication tapered off if it is to be discontinued. Perry et al. (2006) recommend at least a one-week period (inpatient) or a two-week period (outpatient) where the dosage is titrated down before the drug is discontinued. Although it is more associated with the atypical antipsychotics, hypersalivation can also occur in people taking neuroleptics. Essali and colleagues (2013) have noted that this is an understudied phenomenon and although they believe anticholinergic drugs may be helpful, more research is necessary.

Cardiovascular Side Effects from Neuroleptics

As with some of the antidepressants we discussed in Chapter Five, neuroleptics can cause orthostatic hypotension, which is due to the antiadrenergic effects of these drugs. This effect inhibits the normal constriction of blood vessels associated with postural change, resulting in the lightheadedness and dizziness characteristic of orthostatic hypotension (Malhotra et al., 1993). This side effect usually begins within the first few hours or days of treatment and is more pronounced when the neuroleptic has been administered  parenterally  (by injection). In most cases, clients can easily manage this by standing up slowly and by elevating their feet when lying down. In cases where clients have complained about this effect, lowering the medication dose has also been effective as long as the therapeutic effects are not diminished to the point that symptoms begin to interfere with the client's life again. Clients on neuroleptics may also experience electrocardiogram changes, which are of debatable clinical significance. Although case reports exist of lethal cardiovascular events in people taking neuroleptics, they have not been linked to the neuroleptic medication per se.

Dermatological Side Effects from Neuroleptics

Perhaps the most common dermatologic side effect is photosensitivity. This sensitivity to sunlight occurs in approximately 3% of clients taking neuroleptic medications. Most cases are related to chlorpromazine/Thorazine, but all clients on neuroleptics should limit their exposure to the sun and should use sunscreen and protective clothing. Approximately 1% of clients on neuroleptics develop a bluish pigmentation in their skin. This rare effect depends on the neuroleptic used, dosage, and extent of exposure to sunlight. These disorders are thought to be much less frequent today because use of neuroleptics has decreased and lower doses are used (Perry et al., 2006).

Endocrinological Side Effects of Neuroleptic Medications

Neuroleptics can cause hormonal side effects partly because of their impact on dopamine transmission in the tuberoinfundibular pathway, described earlier. As mentioned, galactorrhea and amenorrhea can occur in females. It is important to note that breast enlargement and engorgement can occur in both males and females (Sullivan & Lukoff, 1990). Elevated prolactin levels may subside within two to three days of discontinuing treatment of oral antipsychotics, but in some cases this may take weeks or months (Perry et al., 2006). In addition, clients may experience polydipsia (excessive thirst and water drinking) or a deficiency of sodium in the blood (hyponatremia).

Weight Gain

Studies done in the 1970s correlated weight gain with neuroleptic medications. The average gain was approximately 13 pounds. Weight gain is tied to the antihistaminic properties of the neuroleptics, as is drowsiness and sedation (Advokat et al., 2014), but it can be exacerbated by poor choices like sugary drinks to ease side effects like dry mouth. Perry et al. (2006) caution that although weight gain may be a property of neuroleptic medications, it may also be due to a combination of factors such as the medication, a sedentary lifestyle, and poor diet habits. Although these authors encourage clinicians to monitor patients’ weight, they remind us that under no circumstances should clients use amphetamine-based appetite suppressants, because of the connection between dopamine stimulation and exacerbated symptoms.

Extrapyramidal Symptoms Caused by Neuroleptic Medication

As you may recall from our discussion of the nigrostriatal dopamine pathway in the brain, neuroleptic medications block the dopamine-2 receptors in this pathway and cause movement disorders. These EPSs, can range from mild to severe, and may have early or late onset. For most clients, these symptoms are problematic and are one reason that many psychiatrists believe newer, atypical antipsychotics should be the first line of treatment.

Early-Onset Extrapyramidal Symptoms

Estimates of early-onset EPSs fluctuate wildly, ranging between 2 and 95% of clients taking neuroleptics (Lavin & Rifkin, 1992).  Dystonias  or  dystonic reactions  occur in 2 to 10% of clients on neuroleptic medications. The onset is sudden (1 to 3 days after neuroleptic medication is taken) and consists of involuntary contractions of possibly any striated muscle group. The most common dystonic reactions are in the muscles of the head and face, producing tics, facial grimacing, or spasms. The reactions are possible with all neuroleptics but are less likely with the piperazine phenothiazines (e.g., fluphenazine/Prolixin) (see Table 7.1). Although these side effects often cease without treatment, they can be easily treated with Benadryl or benztropine/Cogentin, an anticholinergic agent. The etiology of dystonic reactions is not known.

The term akathisia refers to a subjective experience of motor restlessness, a condition that is much more difficult to treat than dystonic reactions. In our clinical work with clients, the psychological experience of this particular side effect can be profound. Clients report feeling that they cannot sit still, and they tap their foot/feet, pace back and forth, shake their hands, or rock back and forth when standing. Observed behaviorally, they are always in constant motion. The incidence of akathisia in studies ranges from 21 to 75% (Perry et al., 2006). The majority of clients who develop akathisia experience symptoms within about two months. Schatzberg et al. (1997) note that sometimes akathisia has been misdiagnosed as psychotic agitation. Obviously, this misdiagnosis may lead doctors to increase the dosage of the very compound causing the problem.

One sign from which to discern the difference between psychotic agitation and akathisia is the degree of psychological contact the client can make. It is important that someone who has a therapeutic alliance with the client talk to him or her about the symptoms. Most clients suffering from akathisia can, to some extent, describe the symptoms and differentiate them from psychotic symptoms they have experienced in the past. Schatzberg and colleagues note that asking the client whether the restlessness is “a muscle feeling or a head feeling” (p. 145) often helps differentiate akathisia (the muscle feeling) from anxiety that may accompany agitation (the head feeling). These authors consider that to assume akathisia over agitation is to err on the side of caution. Doctors may treat akathisia with a benzodiazepine, an anti-Parkinsonian agent such as benztropine/Cogentin, or even a beta-blocker such as propranolol/Inderal. Although some clients may not even be aware of their akathisia, the symptoms greatly distress others. Furthermore, sometimes agents used to treat akathisia exacerbate the sedation the client experiences, making such treatment problematic.

Parkinsonism is a set of side effects that manifest as muscular rigidity, slowed movement, tremors (usually in the hands), or  bradykinesia  (fatigue when performing repetitive motion). The tremors may occur at rest or while in motion and may include the mouth, chin, and lips. Clients with Parkinsonism appear depressed, but it is important to differentiate this from actual depression. The incidence ranges in studies from 2 to 56% of clients taking neuroleptics. Again it depends on the neuroleptic used, the dosage, and the individual's response to it. Parkinsonism is typically treated with anticholinergic agents (such as benztropine/Cogentin). There is debate as to whether or not all neuroleptics should be given with an anti-Parkinsonian agent (Stanilla & Simpson, 1995). Advocates claim that doing so precludes the appearance of many extrapyramidal symptoms, and opponents claim the neuroleptics are toxic enough without adding a second agent if not needed.

Late-Onset Extrapyramidal Symptoms

Two identified late-onset EPSs are similar to the early-onset symptoms and differ only in the time it takes them to manifest. Frequently these are called tardive syndromes, meaning delayed-onset, abnormal, and involuntary movement disorders (Fernandez & Friedman, 2003). Bear in mind that the word tardive means “late appearing”; thus, tardive dystonia and tardive akathisia are the same as dystonic reactions and akathisia as described earlier, but with a much later onset (sometimes after a patient has taken the neuroleptic for years). Although there is no developed literature regarding these two late-onset EPSs, there is a great deal of literature on tardive dyskinesia.

Tardive dyskinesia is a late-appearing abnormal movement of the mouth, lips, and tongue that may be accompanied by involuntary twitching and jerking of muscles (choreic movement). The primary differential diagnoses include Huntington's chorea and other disorders that affect the basal ganglia (Casey, 1993). The most common symptoms are sucking and smacking lip movements, lateral movements of the jaw, and puffing of cheeks with tongue-thrusting motions (Perry et al., 2006). Tardive dyskinesia affects on average 15 to 20% of clients on neuroleptics, although gender (7:1 male-to-female ratio), age, diagnosis, dosage, and duration of neuroleptic regimen all seem to play a role. Perry and colleagues (2006) noted, tardive dyskinesia is seen in approximately 5–10% of patients being treated with neuroleptics who are over 40 years of age but can also occur in up to 80% of elderly patients. In general, people with schizophrenia (likely due to the drugs they are taking) have a 31 times higher chance of developing tardive dyskinesia than those in the general population (Merrill, Lyon, & Matiaco, 2013).

There are several theories of etiology for tardive dyskinesia, including hypersensitivity to dopamine, imbalances between the dopamine and acetylcholine systems, GABA dysfunction, and excitotoxicity. Most recently, a theory has been proposed that oxidative stress and resulting structural abnormalities are the key factors in people who develop tardive dyskinesia (Kulkarni & Naidu, 2003). At present, there is no one accepted theory.

Tardive dyskinesia is unpredictable. Although a six-month regimen of neuroleptics is generally considered safe, some patients develop tardive dyskinesia after only a few weeks of taking neuroleptics. When clients show signs of tardive dyskinesia and the neuroleptic is discontinued, often the symptoms vanish within weeks to months. Tardive dyskinesia appears irreversible in some cases, whereas in others it may only remit years after the neuroleptic is discontinued. Schatzberg et al. (1997) noted that about 25% of their clients developed dyskinesia when the neuroleptic was tapered off or stopped. Dyskinesia develops in some individuals who have never been exposed to neuroleptics (Merril et al., 2013). Schatzberg and colleagues (1997) state there is no single effective or standard treatment for tardive dyskinesia and clinicians should consider the risks and benefits of extended treatment with neuroleptics in patients likely to be kept on the medication more than a few months.

Schatzberg and colleagues (1997) conclude that “this issue must be discussed with the patient and his or her family unless there are defensible clinical reasons for not doing so” (p.151). From our clinical experience, the only reasons for not discussing this with clients and/or family members is if a client's symptoms preclude making psychological contact and the family members are clearly judged to be incapable of acting, or unwilling to act, in the client's best interest. Although most of the newer atypical antipsychotics are not associated with tardive dyskinesia, there is still a risk with some like risperidone/Risperdal. It appears that the incidence of tardive dyskinesia in the newer antipsychotics is substantially lower than in the neuroleptics (Dolder & Jeste, 2003; Friedman, 2003; Lykouras, Agelopoulos, & Tzavellas, 2002).

Neuroleptic Malignant Syndrome

Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening complication of neuroleptic medications. Although rates of occurrence are low, they should be noted. Approximately 1% of all psychiatric admissions may have this response to standard neuroleptic medications. Hyperthermia, severe extrapyramidal symptoms, and autonomic disturbances characterize NMS. Caroff and Mann (1993) have noted that the onset may occur within an hour to two months after the first dose of the neuroleptic. In most cases, the clients show signs within a week. Once NMS begins, it progresses rapidly over a one- to three-day period. If the medication is discontinued in time, most cases resolve within a month. Fatalities from NMS are rare, because use of neuroleptics has decreased and the syndrome is detected early.

Agents to Treat Extrapyramidal Side Effects

Anti-Parkinsonian agents are used for treating early-onset extrapyramidal symptoms. Recall that these side effects result from neuroleptic-induced blockade of dopamine receptors in the nigrostriatal pathway that cause decreased dopamine transmission. Table 7.3 lists drugs commonly used to treat EPSs. More recently, experimental studies have been conducted to examine calcium channel blockers (e.g., diltiazem/Cardizem, nifedipine/Procardia, nimodipine/Nimotop, and verapamil/Veralan) as agents to treat EPSs but more research is needed (Essali, Deirawan, Soares-Weiser, Adams, 2011).

Looking at Table 7.3, readers may sense the paradox of all the agents listed. As for the dopaminergic agent (amantadine), you may ask, “If neuroleptics are decreasing dopamine transmission, won't the addition of a dopamine agonist worsen symptoms?” Similarly, you may look at all the anticholinergic agents and wonder, “If neuroleptics cause anticholinergic symptoms, won't adding an anticholinergic agent worsen these side effects?” Both are good questions. To understand why any of these agents may be given to a client taking neuroleptic medication for psychotic symptoms, it is first important to understand something we discussed in Chapter Two, the delicate balance of neurotransmission and the ripple effect of how impact on one neurotransmitter system eventually influences others.

Recall that although most neurons produce only one type of neurotransmitter, most neurons have receptors for multiple neurotransmitters. When we clinicians interfere with neurotransmission by introducing an agent such as a neuroleptic, we set in motion a ripple effect that can upset the function and balance of many other systems. One of these is the cholinergic system. It seems the neurons that make acetylcholine depend on dopamine transmission. If we interfere with dopamine transmission, we disrupt acetylcholine transmission as well. Thus, one theory about extrapyramidal symptoms is that they result from disruption in balance between dopamine neurons and acetylcholine neurons. Therefore, two ways to restore balance logically present themselves. The first is to decrease the acetylcholine transmission so it “evenly matches” the dopamine transmission. That is done with anticholinergic agents. The second solution is to boost dopamine transmission so it more evenly matches acetylcholine transmission. The obvious challenge here is not to increase it in an area or in a way that exacerbates the psychotic symptoms that were the problem in the first place.

TABLE 7.3 Drugs Commonly Used to Treat Extrapyramidal Side Effects

Both solutions to addressing EPSs have their problems. Although amantadine/Symmetrel does in fact diminish dystonia, akathisia, and Parkinsonism more effectively than placebo, it also causes orthostatic hypotension, skin rashes, and GI disturbance and can exacerbate psychotic symptoms or induce agitation. Similarly, anticholinergic agents effectively treat dystonia, akathisia, and Parkinsonism, but can cause allergic reactions (rash or dermatitis), increase heart rate, exacerbate all anticholinergic side effects listed earlier for neuroleptics, cause urinary retention, impair memory, and may induce confusion and/or delirium. Although helpful with EPSs, clearly neither type of agent is a panacea, and prescribing professionals must carefully balance the intended therapeutic effects with the emergence or exacerbation of side effects.

Table 7.4 describes the rational prescribing practice recommended by Perry et al. (2006).

The following two cases address some of the complex side effect issues linked to neuroleptics and potential dependency issues related to some anticholinergics.

TABLE 7.4 Rational Prescribing Practice for Treating Extrapyramidal Symptoms

First, try lowering the dose of the neuroleptic or switch the client to an atypical antipsychotic.

Generally speaking, anticholinergics should not be routinely added as prophylactics when a client is prescribed neuroleptic medication.

Every three months reassess a client who is prescribed medication for EPSs, because not all clients need long-term treatment with these agents.

If a client does not respond to one agent, try another, because responses differ person to person.

There is no support for combining anticholinergic agents.

© Cengage Learning®

THE CASE OF TEANA

Teana, a 37-year-old divorced biracial mother of three, suffered from Schizoaffective Disorder and polysubstance dependence. Most recently, her presenting symptoms seemed more like the positive symptoms of schizophrenia than those of a manic profile. The psychiatrist was acutely aware of Teana's polysubstance dependence. Both Teana and her case manager vouched for the fact that Teana was attending Narcotics Anonymous (NA) and was not currently using any drugs of abuse. The psychiatrist reluctantly prescribed fluphenazine/Prolixin 20 mg daily, accompanied by the anticholinergic benztropine/Cogentin 2 mg daily.

About a month later, Teana scheduled an appointment with the psychiatrist, indicating that it was an emergency. Both the psychiatrist and case manager were puzzled, because she had enough medication for 90 days. In the waiting room, another case manager overheard Teana talking about what a “sweet” high she got from that “cognitive stuff” and that she was totally out and needed more. The case manager alerted the psychiatrist, who took Teana off the benztropine/Cogentin and substituted a dopaminergic, amantadine/Symmetrel. Teana was upset and acted out both in the physician's office and in the waiting room, and she went back to using for a time. Eventually, she returned to her drug treatment and accepted the amantadine/Symmetrel in place of the benztropine/Cogentin.

THE CASE OF MAURICE

Maurice, a 39-year-old, single, auto assembly-line worker, became acutely psychotic at work. He spoke in a “language” that could not be understood, and he appeared delusional and paranoid. He was hospitalized for seven weeks and released on 30 mg of trifluoperazine/Stelazine daily. Maurice could not return to work, and three months after being released from the hospital he was evicted from his apartment. He had been homeless and on the streets for over four months when he was accepted by a Christian house of hospitality, which offered to house him and monitor his medication. Over time, Maurice changed from the positive symptoms of Schizophrenia to an array of negative symptoms. He became withdrawn, isolated, and detached, with slurred speech and impaired movement. The monk who was in charge of the house noticed that he seemed fatigued, that his hands trembled constantly, and that his movements were rigid and very slow. He called the mental health center to alert them to these changes in Maurice, and the psychiatrist saw him the following week. The case manager also had reported that Maurice had seemed more withdrawn lately. The psychiatrist evaluated Maurice, found he was suffering from Parkinsonism, and treated him with benztropine/Cogentin, an anticholinergic.

Maurice's symptoms improved gradually, but he never returned to any previous level of functioning. He remained in a state of isolation with minimal Parkinsonian symptoms, but with little hope of improving the quality of his life. We lost track of Maurice when he was recommended for clozapine/Thoarazine in 2000. He had already been on neuroleptics for 13 years.

Uses and Efficacy of Neuroleptic Medications

Thus far, you are likely aware that the neuroleptics we have described have several drawbacks. Despite persistent and troublesome side effects, how well do these traditional agents really work? As we noted while summarizing the history of neuroleptics, compared to no medication at all they were a breakthrough. The questions remain, though, what is the efficacy today for neuroleptics? For what disorders are clinicians likely to see them employed? Pies (2005) has emphasized that the main indication for any antipsychotic is, of course, for psychosis. He noted that although it is not necessarily inappropriate to use an antipsychotic for a nonpsychotic disorder, antipsychotics are often misused for other conditions, such as agitation.

Certainly this is where the “practice” of medicine comes in and doctors must make clinically informed judgments to the best of their ability. At the same time, mental health clinicians should be aware of the difference between common and uncommon uses for neuroleptics. Table 7.5 lists common uses of antipsychotics outlined by Pies (2005) and Stahl (2013).

And what about efficacy? As you learned in Chapter Five, many antidepressants fare no better than placebo in controlled trials, making the question of efficacy an important one to explore in great depth. All the available neuroleptic (typical) antipsychotics have conclusively been shown to be more effective than placebo in reducing the positive symptoms of schizophrenia. The positive symptoms are typically the target symptoms, because they are the most disruptive to the client and others in the client's life. However, negative symptoms do not respond well (if at all) to neuroleptics (Kane & Marder, 1993).

TABLE 7.5 Common Uses for Neuroleptic Medications

Schizophrenia

Schizophreniform Disorder

Brief Psychotic Disorder

Schizoaffective Disorder

Major Depression with Psychotic Features

Psychosis secondary to cocaine intoxication

Manic states

Dementia related to various causes/disorders

Noncompliant client in an acute setting where fast onset of action is desired

Noncompliant client needing intramuscular formulations

Tics associated with Tourette's syndrome

Severe cases of Obsessive-Compulsive Disorder

Agitated State of PTSD

© Cengage Learning®

The most recent large-scale studies we have are the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (Lieberman et al., 2005) and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS1) (Jones et al., 2006).

Although some clients may respond within hours to days of receiving a neuroleptic, an adequate trial should be at least four weeks, and maximum improvement in symptoms is expected to occur within the first six months of therapy. Although evidence suggests that early antipsychotic treatment in recently diagnosed clients improves long-term outcomes, over two to three years, the relapse rates of even those with a diagnosis of first-time psychosis are in the 60 to 90% range (Szymanksi, Cannon, Gallagher, Erwin, & Gur, 1996). Table 7.6 summarizes strategies outlined by Perry et al. (2006) for clients who do not respond to neuroleptics or who respond only partially.

Clearly, although they offer some relief from the symptoms of psychosis, neuroleptics carry side effects so severe that many clients are not motivated to comply with medication regimens. Interestingly though, clients drop out of treatment with the older neuroleptics at about the same rate as the newer serotonin-dopamine antagonists (Zyprexa/olanzapine; Risperdal/risperidone) (Advokat et al., 2014). The only drug that may still be better for treatment-resistant cases is Clozaril/clozapine and it is to that drug that we turn next. A final note: neuroleptics may have uses outside of psychiatry. Advokat et al. (2014) noted that the neuroleptic thioridazine/Mellarill can kill an antibiotic resistant bacteria called Staphylococcus. It does so by removing glycine from the cell wall thus weakening it and allowing the antibiotics to then move in for the kill. So who knows how many other useful functions these drugs may have even if we eventually stop using them to treat schizophrenia?

TABLE 7.6 Strategies for Clients Taking Neuroleptics Who Partially Respond or Do Not Respond

Continue the same neuroleptic at the same dose.

Increase the dose of the current neuroleptic.

Switch to a different class of neuroleptic.

Add another medication to the neuroleptic.

Switch to an atypical (second-generation) antipsychotic.

© Cengage Learning®

Review Questions

• What is the dopamine hypothesis of schizophrenia and how has it been falsified?

• What are the four primary dopamine tracts in the brain and how are they affected by neuroleptic medications?

• What are the four classes of EPS?

• What are two classes of medication to treat EPS?

SECTION FOUR: CLOZARIL: THE PROTOTYPE FOR ATYPICAL ANTIPSYCHOTICS

Learning Objectives

• Be able to describe what makes the atypical antipsychotics atypical.

• Give a general summary of the mechanisms of action and side effects for clozapine.

• Understand potential drug-drug interactions that may be dangerous for people taking clozapine.

There were two early attempts to develop antipsychotics that were structurally different from the neuroleptics. Molindone/Moban was a structurally unique molecule in that it resembled the neurotransmitter serotonin. Despite this similarity, its binding properties resemble neuroleptics in the affinity for dopamine receptors. Although its use is less frequently associated with tardive dyskinesia, it seems to induce many of the same early-onset EPSs of the neuroleptics. Its efficacy is similar to that of haloperidol/Haldol, and these similarities lead researchers to group it with the neuroleptics. Loxapine/Loxitane is structurally more related to serotonergic antipsychotics (such as clozapine/Clozaril) than a neuroleptic, but it too functions more like a neuroleptic than like anything else. Loxapine/Loxitane binds to both dopamine and serotonin receptors but has many of the same side effect problems as the neuroleptics.

THE CASE OF BONNIE

Bonnie experienced her first psychotic episode when she was 17 years old. Bonnie's mother had been institutionalized off and on for 18 years, diagnosed with Schizophrenia. Her father left Bonnie and her mother when Bonnie was only 2 years old, and she had no siblings. Bonnie had been diagnosed with Schizophrenia, Disorganized subtype (under DSM-IV criteria. In DSM-5 all subtypes of schizophrenia have been eliminated). She suffered from delusions, magical thinking, and bizarre behavior such as storing feces in Mason jars under her bed, believing they would turn to gold if stored long enough. Bonnie would masturbate openly with little concern for where she was and would only say, “The voices are fucking me.”

Bonnie showed marked negative symptoms and conceptual disorganization. These became substantially worse when she was treated with neuroleptic medication. When Bonnie was referred to the partial hospitalization program (PHP), she was 28 years old. She had three children of her own with three different men but had lost custody because of her inability to care for them. She was not allowed visits with them in their foster home because her bizarre behavior upset them. On first coming to the PHP from an inpatient unit, Bonnie was taking 500 mg of chlorpromazine/Thorazine daily as well as 6 mg of benztropine/Cogentin. This medication produced pronounced EPSs and worsened her anhedonia and social withdrawal. Over the course of two years, the psychiatrist at the PHP switched Bonnie's medication four times (constantly adjusting dosages), trying to maximize the therapeutic benefits and minimize the side effects. The best combination seemed to be haloperidol/Haldol (20 mg daily) and benztropine/Cogentin (2 mg daily). This “best” combination, the doctor reluctantly agreed, allowed Bonnie to reside in a maximum-supervision group home and attend (but rarely participate in) PHP programming. Apparently, Bonnie was in for a life living on the fringes of society.

In 1990, we became aware of a new drug called clozapine/Clozaril and a patient management program sponsored by Novartis Pharmaceuticals. As a person suffering from treatment-resistant Schizophrenia with pronounced negative symptoms, Bonnie was an ideal candidate for the program. Further, her Social Security disability benefits covered the costs of the medication. The program was rigorous, including weekly blood draws to check Bonnie for potentially lethal side effects (described later). After several months, Bonnie was titrated off her haloperidol/Haldol and benztropine/Cogentin and titrated onto clozapine/Clozaril. Although she experienced many of clozapine's/Clozaril's side effects (weight gain, excessive salivation, GI upset), these seemed acceptable compared to what she had experienced on the neuroleptic.

Further, several months into treatment the PHP staff noticed a pronounced change in Bonnie. One day as she was coming to the PHP to have her blood drawn, a staff member greeted her, joking that she looked as if she had just gotten up. Bonnie, who had rarely responded with more than one- or two-syllable answers, turned to the staff member and said, “Yes, as you can see I am quite tired.” This marked a dramatic decrease in Bonnie's negative symptoms. She began to participate in groups and to engage in conversations with other clients about day-to-day activities. Further, she became more independent in the group home and moved to a moderate-supervision setting. Perhaps the most rewarding aspect of her case was that she improved to the point that she was allowed to (and could enjoy) biannual visits with her children, who lived about an hour away. Certainly Bonnie did not fully recover from Schizophrenia, but the clozapine/Clozaril brought about a diminishment of symptoms that greatly improved her quality of life. At last check, Bonnie was still stable and tolerating the clozapine/Clozaril therapy.

A NEW ERA

As we have noted, the discovery of antipsychotic drugs in 1950 was a breakthrough in treating mental illness. Lieberman (1997) noted that the magnitude of this advance in psychiatry has been compared to the discovery of insulin for diabetes, antibiotics for infectious disease, and anticonvulsants for epilepsy. At the same time, almost a half-century's experience with these compounds has made clinicians and consumers painfully aware of their limitations. According to Essali, Haasan, Li, and Rathbone (2009), 25–33% of patients treated with neuroleptics are treatment-resistant. Even when patients respond, Lieberman (1997) noted that almost 50% of patients respond only partially to treatment. And, as you have seen, the therapeutic effects of the neuroleptics predominantly reduce the positive symptoms; neuroleptics are less beneficial for the negative symptoms and conceptual disorganization. Finally, the therapeutic effects of neuroleptics come with a great number of side effects. It is important to note; however, that paying attention to clients’ subjective distress over these side effects helps doctors titrate medications and clients participate in treatment (Taira, Hashimoto, Takamatsu, & Maeda, 2006).

Lieberman drew the metaphor that after 40 years of wandering in the proverbial pharmacological wilderness (1950 to 1990), many researchers and clients thought the introduction of clozapine/Clozaril was the gateway to a “promised land.” Alas, though it brought improved treatments to some clients, the horizon of the true “promised land” will continue to recede from sight until the etiology of schizophrenia is understood.

Although clozapine/Clozaril was actually synthesized in 1959, it took 30 years before it was released for use in the United States. What makes clozapine/Clozapine atypical? First, the majority of its binding action takes place at serotonin sites rather than dopamine receptors. Second, it alleviates psychotic symptoms while causing significantly fewer extrapyramidal side effects. Third, it is a more effective antipsychotic agent than conventional neuroleptics. Finally, clozapine/Clozaril has an impact on both the negative and the positive symptoms of schizophrenia. Melzer (1993) noted that clozapine/Clozaril is very effective in treating a set of symptoms we have been referring to as conceptual disorganization (Lencz, Smith, Auther, Correll, & Cornblatt, 2003). Haloperidol/Haldol has typically been the neuroleptic baseline against which all other antipsychotic drugs are tested. In numerous studies, clozapine/Clozaril was more effective than haloperidol/Haldol (Wahlbeck, Cheine, Essali, & Adams, 1999). More recently, the CATIE research indicated that clozapine/Clozaril is still better than other serotonindopamine antagonists after failure on a first agent (Lieberman et al., 2005).

Placebo Versus Active Control Trials

Before exploring the atypical antipsychotic medications, we want to briefly note an important difference in the way newer antipsychotic medications are tested. In the introduction to Part Two and in Chapter Five, we covered the problem of placebo response, particularly with regard to antidepressant medications. In tests of newer medications designed to help people suffering from psychotic symptoms, an ethical problem arises with placebo-controlled trials. First, placebo responses from people suffering psychotic disorders have historically been very small in number, which raises the ethical concern of testing new medications against placebo. If a person is suffering from psychotic symptoms, it simply is not ethical to withhold treatment from the person for the purposes of having the person in a placebo control group. Therefore, new antipsychotics are frequently tested against the older neuroleptic medications. Such active control trials (Fleischhacker et al., 2003) are more designed to test the medication's side effect profile than to test efficacy against placebo. For the most part, the newer antipsychotics (with the exception of clozapine/Clozaril) work just as well as haloperidol/Haldol but have a more favorable side effect profile.

Mechanisms of Action

How does clozapine/Clozaril work? Whereas we noted the mechanism of action in neuroleptics focused on the blocking of dopamine receptors, clozapine/Clozaril is one of the most complicated drugs on the market. Researchers have found it has noteworthy interactions with at least nine neurotransmitter receptors. Six of the nine receptors are dopamine or serotonin receptors. Researchers currently do not know which of these receptors (or which combination of receptors) accounts or account for the antipsychotic effects. Table 7.7 details the mechanisms of action of clozapine.

Reviewing Table 7.7, perhaps the most striking thing you note is that the primary mechanism of action is strong serotonin antagonism and weak dopamine antagonism. Recall that all the neuroleptics worked by powerful dopamine antagonism, particularly at the D2 receptor. As far as clozapine/Clozaril goes, although the overall effects on dopamine are weak, those effects are more pronounced on the D1 receptor than the D2 receptor. Without having to understand the biochemistry involved, you can draw the significant conclusions: (1) This compound is more effective in treating schizophrenia than neuroleptics that rely solely on D2 antagonism, and (2) this result weakens any interpretation of the dopamine hypothesis of schizophrenia that ties symptoms to dopamine transmission. On the other hand, it was recently postulated that clozapine/Clozaril exerts antipsychotic action by transiently occupying D2 receptors as opposed to the prolonged occupation of receptors seen in neuroleptics (Seeman, 2014).

The most that can be said is that by significantly interfering with dopamine transmission, neuroleptics can attenuate the positive symptoms of schizophrenia. There have also been some more recent papers suggesting that clozapine/Clozaril acts as an antagonist at glutaminergic NMDA receptors (Schwieler, Engberg, & Erhardt, 2004). This makes sense because some current studies are looking to NMDA antagonists to treat both schizophrenia and Bipolar I Disorder ( Javitt, 2010). Schatzberg et al. (1997) remind us that clozapine/Clozaril, although an exciting development, is not a panacea. They warn, “The drug does have problems and dangers, it does not work for everyone, and patients who are helped substantially may still be far from well” ( p. 157). With those cautions in mind, we turn now to the side effects of clozapine/Clozaril.

TABLE 7.7 Mechanisms of Action of Clozapine

Receptor	Action	Strength of Action
Dopamine 4	Antagonist (blocks receptor, most DA antagonism here)	Weak
Dopamine 1	Antagonist (blocks receptor)	Weak
Dopamine 2	Antagonist (blocks receptor)	Weak
Dopamine 3	Antagonist (blocks receptor)	Weak
5-HT2	Antagonist (blocks receptor)	Strong
5-HT2C	Antagonist (blocks receptor)	Strong
5-HT3	Antagonist (blocks receptor)	Strong
Histamine	Antagonist (blocks receptor)	Unknown
Ach	Antagonist (blocks receptor)	Unknown
Adrenergic	Antagonist (blocks receptor)	Unknown

© Cengage Learning®

Clozapine/Clozaril Side Effects

We cover the more common side effects of clozapine/Clozaril here. Those seeking a more elaborate discussion, including rare side effects, should see Perry et al. (2006) or Pies (2005).

Agranulocytosis

The most potentially dangerous side effect of clozapine/Clozaril is agranulocytosis. This hematologic (related to blood-performing organs) side effect causes white blood cell (WBC) count to drop dramatically in about 1.2% of treated patients. In a sense, this problem is related to the normal functioning of the immune system. In such cases, the clozapine/Clozaril molecule attaches to the white blood cells, which the body then mistakenly interprets as foreign substances and discards. Mounting evidence suggests that people who develop agranulocytosis have a genetic predisposition to it. After clozapine has been around for more than one generation of clients to receive it, researchers will likely know more about this disposition. Approximately half of the clients quit taking clozapine/Clozaril because of this hematological side effect (Davis, Fuller, Strauss, Konicki, & Jaskiw, 2013).

The first reports of agranulocytosis came from Finland in 1975, where 13 trial subjects had the reaction and 8 died from resulting secondary infection. Of the 73 agranulocytosis cases reported in the United States, 84% occurred in the first 3 months of treatment, 12% between 3 and 6 months, and the remaining 4% after 6 months. So the longer clients tolerate the drug, the less likely they are to develop agranulocytosis (Pisciotta, 1992). Clients must be monitored closely, though, and the manufacturer (Novartis Pharmaceuticals) mandates a weekly white blood cell count for the first six weeks. If all goes well, the monitoring is every four weeks. This mandate is based on the hope that the white blood cell decrease is gradual and that therefore advance warning is possible. All patients must be cleared through a national registry (the Clozaril Patient Management System, at http://www.dozapineregistry.com/faq.aspx.), and the doctor and pharmacy are responsible for making blood counts as long as the patient is on the medication. Most patients stay on between 200 and 350 mg per day. Despite these precautions, 12 fatalities had occurred by 1994, with 5 of these people dying despite drug discontinuation. A baseline white blood cell count must be obtained before the first dose is given, and the cell count must be 3500/mm or higher. If the WBC falls below 3000, clozapine/Clozaril should be discontinued and never given again. The client should also be admitted to a hospital for observation. Table 7.8 lists the side effects of clozapine/Clozaril, drawn from Perry et al. (2006).

TABLE 7.8 Common Side Effects of Clozapine

Type	Side Effect	Proposed Cause
Hematologic	Agranulocytosis	Potentially lethal drop in white blood cell count related to drug binding to white blood cells and immune system response
Autonomic	Constipation Hypersalivation Nausea/vomiting Syncope	Likely caused by anticholinergic and antiadrenergic properties
Cardiovascular	Hypertension Hypotension ECG changes	Possibly caused by antiadrenergic properties
Metabolic	Weight gain	Possibly caused by antihistaminic and antiserotonergic properties
Neurologic	Delirium Seizures	Rarer effect caused by anticholinergic properties Mechanism not known
Psychiatric	OC symptoms	Possibly caused by antiserotonergic properties
Sexual dysfunction	Anorgasmia Impotence Priapism Decreased libido	Possibly caused by antiadrenergic or anticholinergic properties
Other CNS effects	Problems with temperature regulation	Mechanism not known

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A final note, more recently (Shuman, Trgoboff, Demler, & Opler, 2014) several studies have been reviewed that point to certain drug classes, in combination with clozapine/Clozaril, increase the chance of hematological adverse side effects. Autonomic agents like asthma medications, anti-infective agents like antiviral medications or antibiotics, protonpump inhibitors that decrease gastric acid and other drugs for the gastrointestinal system are all correlated with an increase in hematological side effects.

Although nonmedical mental health professionals do not prescribe medications, it is important that they know of these potential adverse effects so they can advocate for the client if necessary. Clozapine/Clozaril is still the least prescribed atypical antipsychotic because of all the blood monitoring that is necessary.

Autonomic Side Effects of Clozapine

Autonomic side effects result from the antiadrenergic and anticholinergic actions of clozapine/Clozaril. These include constipation, hypersalivation, nausea/vomiting, and syncope (fainting or passing out). For some clients, the constipation may be severe. Dosage reduction, increased exercise, and increased fluid intake may alleviate the problem. Hypersalivation is a still unexplained side effect that a significant percentage of clients experience (Hodge & Jespersen, 2008; Perry et al., 2006). This typically manifests as excessive drooling at night but may include gagging. Although this decreases over the first two to three months, it will likely persist at some level. Clinicians have treated this with anticholinergic medications and some patients have sought out Chinese herbal medicines but there is no consensus on how to treat this (Essali et al., 2013). Other clinicians try to help clients adjust by sleeping with a towel on their pillow. This latter solution was in fact preferred in the case of Bonnie, given earlier. Although Bonnie was bothered by the salivation, she did not want to take any additional medications—and who could blame her?

Nausea and vomiting may occur after weeks or months of treatment, because there are large numbers of serotonin receptors in the gut that the drug affects, but the exact etiology is still unclear. Taking the medicine with food may help some clients. Syncope is a transient loss of muscle tone that may be localized or more general leading to unconsciousness. It appears dosage related, and reducing dosage may solve the problem.

Cardiovascular Side Effects

Cardiovascular side effects may range from hypertension to hypotension and tachycardia. Hypotension is more often reported (11 to 13% of clients) than hypertension (4% of clients). Although dosage reduction may alleviate both symptoms, tolerance to the hypotensive side effects usually develops within a month (Perry et al., 2006). As for tachycardia, the client may experience an increase in heart rate of 20 to 25 beats per minute. Onset is usually within a week of starting clozapine/Clozaril, and although the symptom may decrease, it rarely abates completely. Although other atypical antipsychotics can cause QTc interval problems, clozapine does not seem to be among them (Grande, Pons, Baeza, Torras, & Bernardo, 2011). The QTc interval is the measure of the time between the start of the “Q” wave and the end of the “T” wave in the heart's electrical cycle (the “c” stands for “correction”). This represents electrical depolarization and repolarization of the ventricles. A lengthened QTc interval is a marker for torsades de pointes (ventricular tachycardia) that can cause sudden death. We will say more about this below in discussing other atypicals.

Metabolic

The most problematic metabolic side effect is weight gain, with clients gaining between 9 and 25 pounds on average. This is problematic to both patients and doctors as the weight gain can then lead to the onset of type II diabetes (Hodge & Jespersen, 2008). Males gain more weight than females and the weight gain seems to happen in three stages suggesting different underlying neural mechanisms (Pai, Deng, Vella, Castle, & Huang, 2012). The first stage is an initial period from baseline to 3 months, the second a steady increase between 3 and 18 months and the third a plateau after this point (Pai et al., 2012). The side effect is thought to be due to antihistaminic and antiserotonergic mechanisms of action in clozapine. In a retrospective analysis of weight gain across several different atypical antipsychotics, Wirshing et al. (1999) concluded that weight gain associated with clozapine/Clozaril tended to be most persistent. In the case described earlier, Bonnie gained a total of 30 pounds over two years of clozapine/Clozaril treatment. She was close to her ideal weight at the start of treatment, and this side effect troubled her. She did not want to discontinue the medication, although.

Neurological Side Effects

Of the neurological side effects in Table 7.8, the one of greatest concern is seizures. Grand mal seizures can occur in patients on high dosages. The maximum dosage is 900 mg a day. Approximately 5% of clients receiving between 600 and 900 mg suffer from seizures, about 3% of those receiving dosages between 300 and 600 mg develop seizures, and some 1% of those receiving up to 300 mg develop seizures (Perry et al., 2006). If seizures occur, discontinue clozapine/Clozaril until the patient has a normal neurological exam. If the neurological exam is normal, clozapine/Clozaril can be reintroduced at 50% the original dose. Sometimes anticonvulsant medication can be used with clozapine to preclude further seizures.

Extrapyramidal Side Effects

As noted, clozapine/Clozaril is associated with a low incidence of severe EPSs. Approximately 3% of clients experience muscular rigidity or tremor, and approximately 6% develop akathisia. There have been no reports of dystonias or late-onset EPSs.

In general, Damkier, Lublin and Taylor (2011) wrote that optimizing clozapine/Clozaril treatment, in addition to watching for the adverse events described here, requires the following:

• Working together with the patient and the family to monitor therapeutic and side effects

• Keeping plasma levels above 350–420 ng/mL in a period of at least 12 weeks to gauge responsiveness

• Augmenting clozapine/Clozaril with Lamictal/lamotrigene, ECT, or another antipsychotic if the response is partial

• Diminishing side effects by reducing the dose when possible

• If reducing the dosage relieves side effects but interferes with main effects try adding another antipsychotic medication

Review Questions

• Given that clozapine/Clozaril is the first “atypical antipsychotic,” what is it that makes it “atypical” compared to neuroleptics?

• What are the primary mechanisms of action and side effects of clozapine/Clozaril?

• Which side effect is potentially lethal and how is it monitored?

• What are potential drug-drug interactions that may be dangerous for people taking clozapine/Clozaril?

SECTION FIVE: THE SEROTONIN/DOPAMINE ANTAGONISTS

Learning Objectives

• Understand what the differences are between the different SDAs. Are they unique or are they “me too” drugs?

• Know what the common side effects are across the SDAs.

• Understand the problem with QTc intervals and why Serlect/sertindole was taken off the market.

Despite its side effects, clozapine/Clozaril shifted the momentum of antipsychotic research. Starting with the introduction of chlorpromazine/Thorazine in 1952 and the dopamine hypothesis of schizophrenia, there was little research on how to treat clients who did not respond to neuroleptic medication (Lopez-Munoz, Alamo, Rubio, & Cuenca, 2004). The creation and introduction of clozapine ushered in a new research direction in antipsychotics. Whereas researchers up to this point had focused on antihistamines and dopamine antagonists, clozapine/Clozaril raised a new possibility, which was that some combination of serotonin balanced against dopamine antagonism would have an antipsychotic effect. Further, this approach held much more promise for impacting both positive and negative symptoms. Serotonin dopamine antagonists (SDAs) have been developed in the hopes of maximizing therapeutic benefits. Since clozapine's/Clozaril's U.S. release in 1989, several drugs have been developed that to differing degrees are intended to balance serotonin against dopamine antagonism. SDAs are atypical antipsychotics patterned after clozapine/Clozaril.

Another way to view this mechanism is by looking at relative percentages of antagonism of various receptors (Stahl, 2013). With therapeutic doses of neuroleptic agents, 70 to 90% of D2 receptors are blocked with little (if any) blockage of serotonin receptors. With therapeutic doses of clozapine, only 30 to 60% of D2 receptors are blocked, whereas 85 to 90% of serotonin receptors are blocked. SDAs fall midway on the range, with 30 to 50% of D2 receptors blocked and 60% of 5-HT receptors blocked. As noted above, it is still assumed that some D2 blockage is necessary to get an anti-psychotic effect but it can be transitory blocking rather than longer term blocking.

The primary goal for side effects has been to eradicate the risk of agranulocytosis. Many new atypical medications have been developed that are “clozapine/Clozaril-like” without causing agranulocytosis. Note that although these agents appear generally just as effective as neuroleptics, they are not as effective as clozapine/Clozaril. Although many clients prefer the side effect profiles of the newer drugs, others seem to prefer the neuroleptics ( Jones et al., 2006; Lieberman et al., 2005). Table 7.9 lists the SDA antipsychotics.

The Specter of Side Effects

Before exploring the individual SDA compounds, we want to emphasize that the primary problems driving this research were the lack of EPSs in clozapine/Clozaril and the presence of agranulocytosis in clozapine/Clozaril. The underlying theme of these forces was legal liability. With this liability in mind, apparently the most problematic side effect with the SDAs is related to a cardiac process called the Q Tc interval. The QTc interval is the length of time the heart's natural pacemaker (the sinuatrial node) ventricles need to electrically discharge and repolarize. The sinuatrial node is impulse-generating tissue and prolonging its QTc interval can cause cardiac arrhythmia, including a potentially serious condition called torsades de pointes (TdP) and sudden death. The antihistamine Terfenadine/Seldane had a similar effect and was therefore taken off the market. This effect also caused drug regulation authorities in the United Kingdom and United States to pull the SDA sertindole (sertindole/Serlect) off the market between 1999 and 2001. After postmarket analyses it was relaunched in Europe in 2005, a move the FDA strongly disagreed with (Pae, 2013).

TABLE 7.9 Atypical (Second Generation) Antipsychotics

Generic Name	Brand Name	Date Released
Risperidone	Risperdal	1994
Risperidone Consta	Risperdal	2003
Risperidone M-Tab	Risperdal M-Tab	2003
Olanzapine	Zyprexa	1996
Olanzapine & fluoxetine	Symbyax	2006
Paliperidone	Invega	2009
Paliperidone	Invega Sustenna	2009
asenapine	Saphris	2009
Sertindole	Serlect	1997
Quetiapine	Seroquel	1998
Ziprasidone	Geodon	2001
Ziprasidone Intra Muscular	Geodon	2002
Amisulpride	Solian (in Europe)	1997
iloperidone	Fanapt	2009
Lurasidone	Latuda	2010
Aripiprazole	Abilify	2002

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Healy (2002) notes that many other antipsychotics, including neuroleptics, have this side effect, which came to light when Paul Leber of the FDA had experts testify on both sides of the argument. Presently the drugs with the most profound effects on QTc interval are contraindicated in patients with cardiac conditions, but as with all newer drugs, only time will tell how significant this potential side effect is. It is also important to understand that other drugs may contribute to QTc prolongation and that these medications are contraindicated with sertindole (Table 7.10). The side effect is also present to a lesser degree in neuroleptics, antide-pressants, stimulants, and anxiolytics (Advokat et al., 2014). Mental health clinicians should check with prescribing professionals for more information about drug–drug interactions related to QTc prolongation. An overview of QTc can be found at http://www.sads.org/, a website devoted to sudden arrhythmia death syndromes.

In addition to the problems with QTc prolongation, atypical antipsychotics are now clearly linked to an increased risk for type 2 diabetes and other metabolic problems (Lebovitz, 2003). People taking certain atypical antipsychotics (clozapine/Clozaril, olanzapine/Zyprexa, and quetiapine/Seroquel but not risperidone/Risperdal) are almost 15% more likely to develop adult-onset (type 2) diabetes than those taking neuroleptics (Newcomer, 2005). The American Diabetes Association and the America Psychiatric Association have recommended clients on these medications have blood drawn and tested for insulin resistance every 6–12 months. Liberty, Todder, Umansky, and Harman-Boehm (2004); Lindenmayer and Patel (1999); and Goldstein et al. (1999) noted that the use of atypical agents is associated with increased risk of diabetes and diabetic  ketoacidosis  in adults. Koller, Cross, and Schneider (2004) have reported the same problem in pediatric populations. Liberty et al. (2004) and Lebovitz (2003) recommend screening patients for risks associated with the disorder prior to putting them on an atypical antipsychotic regimen, and then monitoring them closely. In September 2003, the FDA requested that manufacturers of atypical antipsychotics update their product information labeling to contain additional information about diabetes and hypoglycemia.

TABLE 7.10 Common Side Effects Associated With Sertindole

Type	Description	Percentage of Patients
Autonomic	Dry mouth, decreased ejaculatory volume	Unknown
Cardiovascular	Prolonged QTc interval	Unknown
	Hypotension, dizziness	Unknown
Hematologic	None noted at this point
Hepatic	None noted at this point
Metabolic	Weight gain of 5% body weight	Unknown
	May be associated with increased risk of diabetes
Endocrinologic	Minor, short-term prolactin increase	Unknown
Gastrointestinal	None noted at this point
Neurologic	None noted at this point
Respiratory	Rhinitis (nasal congestion)	Unknown

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Currently researchers are trying to sort out how much increased risk users of atypical antipsychotics may have for developing diabetes or hyperglycemia and what the mechanisms of this risk may be. It is also important to sort out this risk from the increased incidence of diabetes and hyperglycemia in the general population (Brown University Psychopharmacology Update, 2003). One study comparing the risk in olanzapine/Zyprexa versus risperidone/Risperdal found that cases of patients on olanzapine/Zyprexa seem associated with significantly higher risk of medication-related diabetes (Fuller, Shermock, Secic, & Grogg, 2003). Alas, whereas researchers once believed that moving from neuroleptic antipsychotic medications to atypical antipsychotic medications resulted in fewer medical complications and higher quality of client life, that conclusion seems ill-founded (Abidi & Bhaskara, 2003).

Risperidone/Risperdal

Risperidone/Risperdal was the second atypical or second generation antipsychotic introduced in 1994. It was called a “novel” antipsychotic (Perry et al., 2006) because at low doses it does not cause EPSs but does at higher doses. This reversal arises because its dopamine antagonism is far greater than that ofclozapine/Clozaril. On the positive side, it is not associated with agranulocytosis. There is a long-acting, injectable formulation of risperidone/Risperdal (Resperdal Consta) now and the oral formulation is now generic. The injectable, long-acting form of risperidone/Risperdal appears efficacious and well tolerated (Kane et al., 2003). Compared to clozapine/Clozaril, risperidone/Risperdal seems slightly less effective, although these studies also show mixed results (Perry et al., 2006). Stahl (2013) notes that risperidone/Risperdal has a far simpler pharmacologic profile than clozapine/Clozaril but still seems to decrease positive and negative symptoms.

There are some EPSs with risperidone/Risperdal, particularly at higher doses. Although risperidone/Risperdal does not block histamine or acetylcholine receptors, some weight gain is still associated with it but only about half as much as other second generation antipsychotics like olanzapine/Zyprexa and quetiapine/Seroquel. Because the SDA side effects can vary we include tables of the side effects for each SDA. Table 7.11 summarizes the side effects associated with risperidone/Risperdal. An active metabolite of risperidone (9-hydroxy-risperidone) was synthesized and approved in 2006 as paliperidone/Invega. It is more effective than placebo and (not surprisingly) has a side effect profile similar to risperidone/Risperdal. In 2009, the FDA approved a parenteral formulation of paliperidone/Invega called Invega Sustaenna/paliperidone palmitate for the treatment of acute schizophrenia and for treatment in the maintenance phase. Risperidone/Risperdal is also approved for the maintenance phase of Bipolar I Disorder as a monotherapy or an adjunctive therapy to lithium/Lithobid or valproate/Divalproex. It is also indicated for treating irritability in individuals diagnosed with Autism.

Olanzapine/Zyprexa

Olanzapine/Zyprexa was approved in 1996. It has on-label approval to treat schizophrenia bipolar disorder with mixed or manic specifiers as well as the maintenance phase of Bipolar I Disorder.

When compared in clinical trials, olanzapine/Zyprexa performs as well as haloperidol/Haldol without EPS but with weight gain. As doses increase so does the blockade of D2 receptors. We do not yet have much data comparing olanzapine/Zyprexa with clozapine/Clozaril. Olanzapine/Zyprexa has a chemical structure similar to clozapine but is different from both clozapine/Clozaril and risperidone/Risperdal. This unique structure differs enough from both the latter compounds as to have neither agranulocytosis nor short-term EPSs associated with it. There is a very low incidence of tardive dyskinesia with long-term use. Olanzapine/Zyprexa is not as sedating as clozapine/Clozaril but is associated with weight gain. A parenteral formulation of olanzapine (Zyprexa Relprevv) was approved in 2009. There is a post-injection delirium/sedation syndrome (PDSS) so patients must be under observation for three hours after injection and have someone with them when they leave the facility where they got the injection (Advokat et al., 2014). Table 7.12 outlines the common side effects for olanzapine.

TABLE 7.11 Common Side Effects Associated With Risperidone

Type	Description	Percentage of Patients
Autonomic	None noted
Cardiovascular	Prolonged QTc interval	Unknown
	Hypotension, dizziness	10%
Hematologic	None noted, no agranulocytosis
Hepatic	None noted, no monitoring necessary
Metabolic	Weight gain of 7% body weight	18%
	Increased risk of diabetes
Endocrinologic	Increased prolactin levels	Unknown
Gastrointestinal	Nausea	18%
Neurological	Agitation/anxiety	58%
Early-onset EPS	Dose related
Tardive dyskinesia	Dose related
Neuroleptic malignant syndrome	2 cases noted by 1997
Respiratory	Rhinitis (nasal congestion)	Approx. 9%
Other	Headache	16%
	Insomnia	54–58%
	Sedation	Approx. 9%

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Quetiapine/Seroquel

Quetiapine/Seroquel has a chemical structure similar to clozapine/Clozaril but has some atypical advantages. First, it appears to be associated with no prolactin increases nor EPSs. It is approved for use in the maintenance treatment of schizophrenia, the manic phase of bipolar disorder and can but used adjunctively in major depressive disorder and Bipolar I disorder. As with other SDAs, the goal with quetiapine/Seroquel was to have the therapeutic effects of clozapine/Clozaril without the agranulocytosis. At this point quetiapine/Seroquel is not associated with agranulocytosis. It has a half-life of about seven hours, which may necessitate dosing two to three times a day. In 2007, extended release versions of quetiapine/Seroquel were approved. Table 7.13 details the side effect profile for quetiapine/Seroquel. It should be noted that Advokat et al. (2014) commented that quetiapine/Seroquel has been used inappropriately to promote sleep in settings like prisons and we have seen this in many foster care homes. This drug also can disrupt the QTc interval so should only be used under the closest supervision. Others have criticized quetiapine/Seroquel as a largely “me too” drug (Prescrier International, 2011) because in two large-scale meta-analyses, it has not shown therapeutic advantage over other treatments.

TABLE 7.12 Common Side Effects Associated With Olanzapine

Type	Description	Percentage of Patients
Autonomic	Constipation, dry mouth	Approx. 8%
Cardiovascular	Minor changes in blood pressure	Unknown
Hematologic	None noted, no agranulocytosis
Hepatic	Minor changes in enzyme levels	Unknown
Metabolic	Weight gain	Unknown
	Increased risk of diabetes
Endocrinologic	Increased prolactin levels	Unknown
Neurologic	Early-onset EPS	Dose related
Tardive dyskinesia	Unknown
Neuroleptic malignant syndrome	No cases known
Other	Sedation	26%

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TABLE 7.13 Common Side Effects Associated With Quetiapine

Type	Description	Percentage of Patients
Autonomic	Constipation, dry mouth	Approx. 6%
Cardiovascular	Prolonged QTc interval	None noted
	Dizziness	Approx. 7%
	Orthostatic hypotension	Approx. 6%
	Tachycardia	Approx. 4%
Hematologic	None noted at this point
Hepatic	None noted at this point
Metabolic	Weight gain	None noted
Endocrinologic	Prolactin increase	Rare
Gastrointestinal	Dyspepsia	Approx. 4%
Neurologic	None noted at this point
Respiratory	Rhinitis (nasal congestion)	Unknown
Other	Sedation	18%
	Priapism	Rare

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Ziprasidone/Geodon

Ziprasidone/Geodon is the sixth atypical antipsychotic to be released. It was initially slated for release with the brand name of Zeldox but the FDA felt there were too many new drugs with brand names that began with “z,” so it was released as Geodon. Like all other SDAs, ziprasidone/Geodon blocks a combination of dopamine and serotonin receptors. Unlike the other SDAs, ziprasidone/Geodon is an agonist of a particular serotonin receptor (the 5-HT1a receptor), giving it a buspirone/BuSpar-like action. Some feel this may make the drug useful for depressive symptoms as well (Dunner, 2007). As with the other SDAs, the most common side effects of ziprasidone/Geodon are sedation, nausea, constipation and/or diarrhea, dizziness, restlessness, respiratory congestion, and some uncontrollable movements such as tremor and shuffling. As with several other drugs in this category, clients need to be monitored for prolongation of QTc interval (Rivas-Vasquez, 2001). Ziprasidone/Geodon seems to induce less weight gain than olanzapine/Zyprexa but also does not seem as efficacious (Grooten et al., 2009). Ziprasidone/Geodon is also available in parenteral formulations beginning in 2003. Ziprasidone/Geodon is also associated with QTc interval prolongation. The following case demonstrates the effective use of ziprasidone/Geodon after a long and complex history with neuroleptics and their side effects.

THE CASE OF MELANIE

Melanie, a 16-year-old high school sophomore, was referred to a psychiatrist because she developed psychotic symptoms. She was very disorganized and suffered from visual, olfactory, and auditory hallucinations. She was first put on 25 mg of chlorpromazine/Thorazine, and she experienced an array of side effects, including severe postural hypotension. Melanie was taken off the chlorpromazine/Thorazine, and thiridazine/Mellaril at 25 mg was attempted, with the same result. Even with benztropine/Cogentin, Melanie developed severe postural hypotension. This prevented her from working and going to school, because she was very lightheaded and fainted frequently. Therefore her psychiatrist switched her to first trifluoperazine/Stelazine and then haliperodol/Haldol, and with both Melanie developed akathisia with restlessness and pacing. She felt as if she was “crawling out of her skin.” These side effects persisted even with trihexiphenidyl/Artane to combat this movement disorder.

After many trials she and her psychiatrist found she could tolerate perphenazine/Trilofon at 4 to 8 mg and up to her eventual stabilizing dose of 16 mg. Melanie stayed on the perphenazine/Trilafon for many years, with very good results. Her psychiatrist noted that during this time her organization improved. Although her course fluctuated, she was able to graduate from college, marry, and have a child while on the perphenazine/Trilafon; the child was born healthy. She became an effective K-6 teacher and mothered her child well. Later, she developed a severe tardive dystonia that affected her neck and back muscles, and she suffered incapacitating back spasms that hot baths or massages could not assuage. Gradually, she was taken off the only neuroleptic that helped her, perphenzine/Trilafon, which she had taken for 17 years.

After careful consideration and evaluation, her psychiatrist now put Melanie on quetiapine/Seroquel 400 mg, but she experienced a very serious relapse. This was her first psychotic break in over a decade, so for the time Melanie was put back on perphenzine/Trilafon and the dystonia (which never fully went away) worsened. Her psychiatrist also tried the SDAs risperidone/Risperdal and olanzapine/Zyprexa but both were too sedating. Then in June 2001 Melanie began a course of treatment with ziprasidone/Geodon, with great success. Her tardive dystonia is improving and although she cannot risk going off the medication to have another baby, Melanie is learning to cope with this limited sense of choice. Melanie had no drowsiness on ziprasidone/Geodon. Finally, she told her psychiatrist that her feelings were back and she was learning how to love.

This case reflects the efforts of a diligent and determined psychiatrist and a courageous patient. They addressed each medication and side effect dilemma as it arose and sought to provide options from among both the neuroleptic and the serotonin-dopamine antipsychotics. Issues from several perspectives were certainly addressed during the course of treatment. The most significant factor was that the quality of Melanie's life improved.

Review Questions

• What are the main differences between the different SDAs?

• What are the common side effects of the nonclozapine/Clozaril SDAs?

• What is QTc prolongation and why was sertindole/Serlect taken off the market?

SECTION SIX: NEWER AGENTS

Learning Objectives

• Understand how the newer agents compare to the atypical antipsychotics.

• Be able to critically examine adjunctive therapies like adding aripiprazole/Abilify to antidepressants.

Amisulpride/Solian

At the time of this writing, amisulpride/Solian is available in Europe and Australia. It is classified an atypical antipsychotic but is not an SDA. It is a specific antagonist for D2 and D3 receptors. At between 400 and 800 mg a day, amisulpride/Solian appears effective in treating schizophrenia but dosing has been a poor predictor of response with the drug (Bowskill, Patel, Handley, & Flanagan, 2012). Amisulpride/Solian is unique in that it has high specificity for blocking D2 and D3 receptors in the limbic system but not in other are as such as the basal ganglia. At low doses it blocks autoreceptors, but at high doses it shows postsynaptic antagonism. This increases DA action in the limbic system at low doses and decreases DA action at high doses. The combination seems to result in low EPSs. In low doses, it also seems to alleviate depression and dysthymia but would not be subject to the same types of abuse as other dopaminergic compounds (such as amphetamines) (Danion, Rein, Fleurot, & the Amisulpride Study Group, 1999; McKeage & Plosker, 2004). In controlled studies, amisulpride has been associated with the following side effects: insomnia, anxiety, and agitation (5 to 10% of clients); sedation, constipation, nausea, vomiting, and dry mouth (2% of patients); and weight gain, acute dystonia, tardive dyskinesia, hypotension, and QTc prolongation. Amisulpride/Solian has also been associated with increased prolactin release. Researchers have recently concluded that amisulpride/Solian is equal in efficacy to risperidone/Risperdal and may surpass it in subsequent studies (Sechter et al., 2002). Researchers have tried treating fibromyalgia with amisulpride/Solian but it was poorly tolerated by study participants (Rico-Villademoros et al., 2012). As with any new drug, only time will tell whether this drug is contributing anything new or improved.

Lurasidone/Latuda

Lurasidone/Latuda was approved to treat schizophrenia in 2009 and bipolar depression in 2013 (Belmaker, 2014; Loebel et al., 2014). Lurasidone/Latuda is an antagonist of 5-HT2a, 5-HT7, 5-HT1a and D2 receptors (Awad et al., 2014). In many trials it is superior to placebo and as effective as olanzapine/Zyprexa. In other studies patients switched from their current antipsychotic to lurasidone showed improvements in self-reported health status (Awad et al., 2014). Side effects include some EPSs (Parkinsonism and akathisia), sedation, agitation and some nausea. It does not appear to affect QTc intervals.

Iloperidone/Fanapt

Iloperidone/Fanapt was approved in 2009 for the treatment of schizophrenia. It is considered a second-generation atypical antipsychotic whose primary mechanism of action is 5-HT2a and D2 antagonism (Weiden, 2012). It has greater binding capacity at the 5-HT2a receptor than the D2 receptor. It can cause mild QTc disruption and weight gain although it seems to produce lower EPS than haloperidol/Haldol or risperidone/Risperdal (Dargani & Malhotra, 2014). In a “switch study” conducted by Weiden et al. (2014), there were no significant differences in efficacy or safety/tolerability between iloperidone/Fanapt, risperidone/Risperdal, olanzapine/Zyprexa, and aripiprazole/Abilify (Rado & Janicak, 2014). Arif and Mitchell (2014) also noted that iloperidone/Fanapt lacks a clear benefit over other drugs for schizophrenia. Although early trials produced only modest results, later trials that used slower initial dosing found iloperidone/Fanapt to be equal to other non-clozapine/Clozaril antipsychotics (Rado & Janicak, 2014).

Asenapine/Saphris

Asenapine/Saphris was approved for the treatment of schizophrenia and manic or mixed specifiers for Bipolar I Disorder in 2009. It also was approved in 2010 as an adjunct to lithium or valproate for Bipolar I Disorder. It comes in a unique formulation of dissolving tabs that require no eating or drinking for 10 minutes after putting the tab in the mouth. The mechanism of action involves more receptors than most antipsychotics (other than clozapine/Clozaril). Advokat et al. (2014) note that it is chemically similar to the antidepressant mirtazapine/Remeron. It binds antagonistically to D1, D2, D3, D4, and D5 receptors, 5-HT2a, 5-HT2c, 5-HT1a, alpha-1 and H1 (histamine) receptors. According to Cortese, Bressan, Castle, and Mosolov (2013) asenapine/Saphris is effective in treating the positive symptoms of schizophrenia in acute situations and has  prophylactic  value. The most common side effects include dizziness, akathisia, and sedation. It is associated with weight gain but better than olanzapine/Zyprexa in this area (Kemp et al., 2014). In two 3-week trials, asenapine/Saphris was reported to lead to improvements in self-reported health-related quality of life (Michalak, Guiraud-Diawara, & Sapin, 2014). It should be noted that other studies from countries outside the United States are emerging in the literature suggesting that while all atypical antipsychotics may decrease psychotic symptoms, they may be correlated with a decreased quality of life due to adverse effects that limit mobility as well as socioeconomic factors (de Araujo et al., 2014).

Aripiprazole/Abilify

Aripiprazole/Abilify is an antipsychotic that may open up yet another approach to treating the symptoms of schizophrenia. It has FDA approval for treating schizophrenia, the maintenance phase of Bipolar I Disorder, as an adjunctive treatment for depression, and for irritability associated with Autism Spectrum Disorders. It is sometimes said to be the first third-generation antipsychotic (neuroleptics being the first generation and atypicals being the second). It was approved in 2002 and presents us with yet another set of mechanisms of action. It appears to be a potent partial agonist of D2 receptors, a partial agonist of 5-HT1a receptors, and an antagonist of 5-HT2a receptors (Dhillon, 2012). These studies indicate that it is better than haloperidol/Haldol at treating positive and negative symptoms as well as having fewer side effects. Bristol-Myers Squibb filed a regulatory application with the FDA, and the drug was approved in November2002 (Barclay, 2002). Aripiprazole/Abilify is available in oral and parenteral formulations. In 2007, the FDA approved aripiprazole as an “add-on” drug for depression (Rosen, 2007).

Stahl (quoted in Manisses Corporation, 2002) stated that aripiprazole/Abilify belongs to a class of drugs called dopamine system stabilizers although we would contend that until the dopamine system has conclusively proven to be “unstable” in patients with schizophrenia or Bipolar I Disorder, the phrase dopamine system stabilizer may be more marketing than clinical reality. Aripiprazole/Abilify seems to have a decent side effect profile, and does not seem to cause QTc prolongation but can cause weight gain, tardive dyskinesia, neuroleptic malignant syndrome and hyperglycemia (prescribing information at http://www.drugs.com/pro/abilify.xhtml). In 2007, aripiprazole was approved as an adjunctive treatment for depression in adults if the antidepressant did not seem to be working. This was based on two studies that lasted six weeks with 743 patients whose depression had not lifted despite the fact they were taking an antidepressant (Hellerstein et al., 2008; Nelson et al., 2010).

This particular use of aripiprazole/Abilify seems odd to us. First of all to use a powerful, expensive antipsychotic drug with possibly serious side effects for nonpsychotic depression does not make sense in a risk–benefit analysis. Why not increase the anti-depressant dose, add another antidepressant or change antidepressants altogether (Reidbord, 2009)? This points to pharmacoeconomic gains more than therapeutic gains. Antipsychotic drugs are increasingly being used for mild mood disorders and insomnia. We should be rightfully alarmed that prescriptions for antipsychotics increased from 28 million in 2001 to 54 million in 2008. Also, the use of these drugs for off-label indications doubled between 1995 and 2008. It is probably no coincidence that money pharmaceutical companies spent advertising antipsychotics increased from $1.3 billion in 2007 to $2.24 billion in 2010 (Friedman, 2012). From an integrative perspective this adjunctive practice seems highly questionable.

Review Questions

• How do newer agents like aripiprazole compare to the atypical antipsychotics like olanzapine?

• What are some problems in the risk-benefit analysis of adjunctive therapies like adding aripiprazole/Abilify to antidepressants.

SECTION SEVEN: FOCUS ON OTHER PERSPECTIVES

Learning Objectives

• Practice empathizing with the experience of people suffering from schizophrenia.

• Understand how stigma interferes with medication adherence.

• Be able to discuss how advocacy is even more important based on what we know about pharmacoeconomics.

PSYCHOLOGICAL CONSIDERATIONS

What is it like to experience psychotic symptoms? One of our clients told us that to suffer from schizophrenia was to suffer from interminable boredom. This client knew what it felt like to be intellectually and interpersonally engaged and knew what her symptoms were robbing her of. Her treatment with olanzapine/Zyprexa was an important part of her recovery, and her psychotherapy was another crucial component. Another client spoke of his experience in terms of stark terror. He was plagued by voices he felt sure were demonic in origin, and he was convinced his very soul would not survive his ordeal. For this client, a series of seven antipsychotic medications were tried, with only minimal success. Counseling with an ego-strengthening focus helped this client retain some quality of life. We note these narratives because we have encountered clinicians who thought people with psychotic disorders could not benefit from counseling or psychotherapy. Quite to the contrary, such clients are unlikely to improve much if only treated with medication.

Sayre (2000) examined clients’ perceptions of their symptoms. Their perceptions fell into five distinct themes, summarized in Table 7.14.

Regardless of the extent to which one agrees with the ultimate truth of each conclusion, each theme obviously opens a gateway for counseling and psychotherapy. When a client with psychotic symptoms can make psychological contact, it is crucial that a trained therapist begin establishing a relationship with the person so that when able to use it, that person has access to therapy that will help him or her through the psychological realm. The type of therapy employed will vary with the developmental level of the client. Many clients with psychotic disorders are struggling with establishing adequate ego functioning, and counseling them should focus on ego-strengthening techniques. Some clients who have adequate ego functioning may be struggling with transpersonal development. These clients are likely a minority, but they do exist, and several clinicians have offered guidelines for working with them (Grof, 1998, 2000; Lukoff, Lu, & Turner, 1996).

TABLE 7.14 How Clients Understand Their Symptoms, by Theme

Theme	My symptoms are …
Disease	… the result of a brain disease
Psychology	… related to my personality and behaviors
Crisis	… the result of a trauma or crisis
Ordination	… a sign of significance or special power
Punishment	… a punishment for past behavior

© Cengage Learning®

In addition Seeman and Seeman (2012) reviewed publications in three databases between 2001 and 2012 looking for studies about clients’ attitudes toward taking medication. They found about 60 studies relevant to their goal of understanding these attitudes. Themes extracted from these papers fell into three main themes. The first was control by medication and of medication where many felt under the control of the medication and wanted more control over their medication regimen. The second theme was a sense of dependence on the medication and prescriber. This was often a negative attitude as they felt it restricted their lives. Finally, the third theme was stigma from using antipsychotic medication. Non-medical mental health therapists need to listen for such theme as they relate to adherence.

Lauriello, Lenroot, and Bustillo (2003) provided an overview ofsome of the counseling approaches that have shown success with clients suffering from schizophrenia. Although the studies reviewed did not favor psychodynamic approaches, they found that personal therapy, cognitive behavioral therapy, social skills training, and family therapy all had some support in the literature. In addition to vocational and job coaching, these treatments are an important part of an overall treatment plan and have been shown to decrease the number of hospitalizations that clients experience (Bichsell, 2001; Fenton & McGlashon, 1997).

In the spirit of an integrative approach, it is also important to note that clients who have significant improvements on atypical antipsychotics may also suffer psychological sequelae. Weiden, Aquila, and Standard (1996) point to clients experiencing “awakenings” phenomena, in which their improvement allows them to be more in touch with their losses and psychological pain. Weiden et al. (1996) concluded that the long-term psychological issues many clients must deal with include changes in self-image, sexuality, and intimacy concerns. That such researchers are addressing these issues alongside medication management is encouraging and leads us to our discussion of counseling and psychotherapy with clients who are suffering from schizophrenia.

Dealing With Ambivalence About Taking Medication

Clinicians encounter many clients who are ambivalent about taking medication that is going to cause them severe side effects. Even though the newer medications hold promise for allowing clients to regain a great deal of functioning, there is no getting around the side effects of weight gain, potentially fatal blood disorders, the risk of diabetes, and annoying side effects such as hypersalivation. The most important thing (as in any form of counseling or psychotherapy) is the quality of the therapeutic alliance. Counselors who have a good relationship with the client and client's family (or caregivers) know the client's personality, the client's http://www.dozapineregistry.com/faq.aspxvalues,and the client's degree of insight and the extent to which symptoms are impairing their ability to function.

Although not a unitary concept, insight assessment is possible and to a large extent depends on the qualities of the therapeutic alliance just listed. Insight includes awareness of the illness, relabeling of symptoms and treatment compliance (Chan et al., 2014; Konstantakopoulos et al., 2014) and is highly correlated with cognitive functioning (Ouzir, Azorin, Adida, Boussaoud, & Battas, 2012). We are also learning that although only a minority of people with schizophrenia act out violently, the more insight the client has the more easily clinicians can predict (and head off) violent outbursts (Ekinci & Ekinci, 2013). David and Kemp (1997) summarized five psychological barriers to insight. The first two are psychopathology and cognitive deficits. Both interfere with the abstract reasoning processes that are necessary to have a sense of how others are experiencing you. If these deficits are a result of symptoms and medication reduces the symptoms, then after the deficits have been addressed clinicians can work with the client. The third and fourth barriers to insight are ego defense mechanisms and aspects of personality. Assuming the client can make psychological contact, these can be handled within the context of the therapeutic relationship. The last barrier to insight is culturally and socially determined attitudes, which may be intricately woven together with ego defenses and aspects of personality. Ideally, an integrative assessment will take these social and cultural attitudes into account. When consciously acknowledged by the clinician, they can be worked with in the counseling relationship.

Issues from the Cultural Perspective

The Culture of Stigma

Perhaps the most prominent issue from the cultural perspective is stigma (Seeman & Seeman, 2012). The idea of suffering from a mental/emotional disorder still carries the belief, shared by many, that the afflicted person is somehow “defective,” not equal to others in the eyes of society, and, in some cases, even being justly punished by whatever god there may be. Although the United States and other countries have made strides in addressing this through education, advocacy, and community action, stigma still persists (Corrigan et al., 2000; Penn & Corrigan, 2002; Schreiber & Hartrick, 2002). In our brief historical outline of the antipsychotics, you saw how when the first neuroleptics were leading to deinstitutionalization of recovering clients, towns lobbied hospitals with petitions to keep the recovering people behind hospital walls (Healy, 2002).

In some societies a stigma is equally associated with the use of psychotropic medications. Jorm (2000) detailed a study in which many people expressed negative beliefs about medication for mental health disorders, although they favored medication for physical disorders. As we have argued in this book, a healthy skepticism about what medications can and cannot provide is important; however, negative beliefs about medication can also develop into negative beliefs about people who choose to take such medications. This is where mental health clinicians can intervene with advocacy and education. It should be noted that a recent study also commented on stigmatization of individuals receiving psychotherapy. The perspectives of mental health consumers reflected in the study is that they are portrayed particularly negatively in the media. The researcher in this case felt that this stigma may prevent people from seeking help in the first place (Ben-Porath, 2002).

The issue of stigma is particularly pronounced in severe disorders such as schizophrenia. Positive and negative symptoms of schizophrenia severely decrease clients’ quality of life by decreasing their social interactions or the receptivity of others to interacting with them. Add the severe extrapyramidal side effects associated with neuroleptic medications, and the problem is unnecessarily compounded. We say “unnecessarily” because more and more clinicians are advocating the atypical antipsychotics as a first line of treatment. It is important for mental health clinicians to participate in this advocacy. Assuming a client is willing to take a medication to deal with the life-disrupting symptoms of schizophrenia, that client deserves every opportunity to be given the most effective agent with the fewest side effects. At this point, clozapine/Clozaril is still reserved for treatment-refractory clients, because of the risk of agranulocytosis. However, the SDAs (olanzapine/Zyprexa in particular) may be excellent first-line medical treatments for schizophrenia (Psychlink, 1998). As most clinicians are aware, the lives of many people with schizophrenia have been so disrupted by their symptoms that they frequently lack financial resources such as health insurance. Many of these clients receive Medicaid or Social Security disability. Therefore, those responsible for paying for treatment may balk at the cost. Advocacy must be directed to these payers, which takes us next to the social issues.

Social Issues

Pharmacoeconomics

Perhaps the most important obstacle to the widespread adoption of atypical antipsychotics is cost. Pharmacoeconomics is an area of which mental health clinicians need to be aware (van Luijn, 2012). Ernst et al. (2000) found that physicians often do not know the cost of generic and brand name medications. Even when they do know the cost of generic versus brand name, some studies show it does not affect prescribing habits (Polinski et al., 2008) especially when prescribers have negative views of the generics (Shrank et al., 2011). Bearing in mind that over a 12-year period a new drug may cost $400 million to $500 million to bring to market, the costs of newer agents are going to be substantially more than older ones. Brand-label atypical antipsychotics cost approximately eight times what similar generic drugs cost. In 2014 in the United States, a 30-day supply of olanzapine costs approximately $392 and a 30-day supply of generic olanzapine/Zyprexa is $12. A 30-day supply of clozapine is approximately $300 whereas generic clozapine/Clozaril is $34. There are always questions though about the equivalence of generic compounds (Lam, Ereshefsky, Toney, & Gonzales, 2001).

In the United States, the decisions about what drugs to use for Medicaid patients are made by state formulary boards, pharmacy committees, or state medical directors and pharmacy directors. In a 1998 video symposium (Psychlink, 1998), pharmacologist Larry Ereshefsky and psychiatrists Bill Glazer and Jay Fawver reviewed a protocol for lobbying state officials, which can be useful to mental health professionals. Depending on the regulatory agency and personnel involved, clinicians cannot assume that audiences for advocacy know about the symptoms of schizophrenia and so are advised to consider the following steps when advocating for atypical antipsychotics to be routinely available to indigent clients. This protocol can also be helpful in educating the public about the long-term benefits of allowing clients access to the atypical antipsychotics. One of the problems we run into is that high-cost medications are frequently targets of cost-containment.

Although only 1.1% of the population is thought to suffer from schizophrenia, 30% of those patients are on Medicaid. Since they were first introduced in the 1990s atypical antipsychotics have become the first line of treatment and accounted for 15% of all Medicaid spending in 2005. Since then Medicaid programs and Medicare Part D prescription programs require prior approval or some other restriction for at least one antipsychotic (Seabury et al., 2014). Because of the vulnerable nature of these patients disruption of medication routine can have adverse consequences. Seabury et al. (2014) estimated that restrictive formulary policies in 24 states studied resulted in a 2% point increase in the prison population due to more mentally ill people being arrested. This increased the nationwide prison population by 9920 prisoners and $362 in costs.

When advocating for formulary fairness, make sure the parties involved (whether a formulary board or the lay public) understand the positive and negative symptoms of schizophrenia. Next, explain the mechanism of D2 blockade and the severe side effects associated with it. A discussion of compliance is important, because many clients go off neuroleptic medications to avoid the severe side effects. Clinicians should then discuss how the newer atypical antipsychotics are more complex drugs than the neuroleptics, with multiple mechanisms of action. These more complex molecules are associated with better outcomes. It is also important to emphasize that each atypical is structurally different from the others, to preclude the assumption that one atypical is just as good as any other. Much like antibiotics, some clients respond to one atypical and not to another, so it is important that prescribing professionals have access to all of them.

Efficacy and Compliance

As we have documented here, the atypical antipsychotics appear to have at least equal efficacy on the overall symptoms and seem better tolerated than neuroleptics. Although the initial excitement over the atypicals was somewhat euphoric, more recent studies note that it may be time to tone down that excitement (Volavka et al., 2002). Still, clozapine/Clozaril and the SDAs seem to have better side effect profiles than do the neuroleptics and are at least as good as the neuroleptics at addressing the symptoms of schizophrenia. Although clinicians hoped as recently as 1998 that the atypicals would clearly improve quality of life and decrease suicidality, these hopes have yet to be consistently confirmed (Sernyak, Desai, Stolar, & Rosenheck, 2001). As far as compliance goes, clients do seem more likely to continue taking clozapine/Clozaril as opposed to haloperidol/Haldol, because clozapine/Clozaril offers greater symptom relief and reduced side effects (Rosenheck et al., 2000).

Whom Do We Trust?

A final note is called for as we end this long journey through the world of antipsychotic medications. Readers are likely aware that many issues remain unresolved about just how good the newer, atypical antipsychotics are. One variable that continues to play a role from an integrative perspective is the economic power of pharmaceutical companies. It is interesting that many of the initial studies that were optimistic about the revolution atypicals could bring about were funded by pharmaceutical companies and were short-term studies. One of the latest studies that suggests the initial response to the atypicals was too enthusiastic was sponsored by the National Institute of Mental Health, with only moderate funding from the pharmaceutical industry. We hope that through such independent, large-scale, long-term studies, the truth will be easier to pursue. Healy (2002) documented how Eli Lilly Pharmaceuticals recruited well-known figures from psychiatry beginning in the 1970s to conduct research and write papers. He connected this effort to meta-analyses on drug efficacy that have been written entirely by people on the pharmaceutical company payroll. One example is the meta-analysis on fluoxetine/Prozac that appeared in the British Medical Journal (Beasley et al., 1991), supposedly refuting the connection between fluoxetine/Prozac (a Lilly product) and suicide. It stated, “Until then, papers written solely by company personnel would never have been published in a leading journal like the British Medical Journal. This article cracked the dam that had separated the academic and commercial universities” (p. 263). That crack in the dam has unleashed a flood and we ask, where is that flood leading us?

More recently many pharmaceutical companies are paying increasingly expensive fines for things like unlawful marketing practices. In the first edition of this book, the largest criminal fraud settlement was when the Warner Lambert division of Parke Davis Pharmaceuticals paid $479 million for criminal fraud in promoting the off-label use of gabapentin/Neurotin for adolescents diagnosed with Bipolar I Disorder. In 2013 Johnson & Johnson agreed to pay $2 billion for unlawful marketing of risperidone/Risperdal and paliperidone/Invega. Johnson & Johnson's Janssen unit settled claims that marketed risperidone for children and the elderly without approval and that it paid kickbacks to physicians and to Omnicare Inc., the largest pharmacy for nursing homes (Bloomberg News, 2013). In addition Abbott Laboratories paid $1.5 billion to resolve criminal and civil investigations of the off-label use of valproic acid/Depakote (United States Department of Justice, 2012). Lawsuits such as these are actually leading some pharmaceutical companies to close their neuroscience divisions (Greenberg, 2013).

CHAPTER TWELVE Drug-Assisted Psychotherapy By Ingmar Gorman

Learning Objectives

• To understand the psychological effects of 3, 4-methylenedioxy-N-methylamphetamine (MDMA) and psilocybin.

• To understand how the psychological effects of MDMA and psilocybin may be used psychotherapeutically.

• Be able to describe “set and setting” and to be able to articulate the importance of these factors.

• Be able to discuss the psychotherapeutic approach used in conjunction with MDMA-assisted psychotherapy for Post-Traumatic Stress Disorder (PTSD).

• Be able to describe the risks associated with the use of MDMA or psilocybin.

INTRODUCTION

Drug-assisted psychotherapy is defined by the use of a pharmacological substance's acute psychological and physiological effects to catalyze and enhance psychotherapy. This chapter will cover various substances used in drug-assisted psychotherapy, the psychopathologies being currently investigated in clinical trials, future avenues of research, and the benefits it may hold for people who are confronted with psychiatric illness. Although these studies are often associated with decades past, there is a current resurgence of research in the United States supported by modern psychotherapeutic and psychopharmacological understandings.

In this chapter, we will focus primarily on clinical research with the classical hallucinogen psilocybin (the compound found in magic mushrooms) and the empathogen 3, 4-methylenedioxy-N-methylamphetamine (MDMA). Other pharmacological agents such as lysergic acid diethylamide (LSD) and ibogaine will also be mentioned. Yet, a whole host of substances including the class of dissociatives, cannabis, peyote, ayahuasca, and others are worthy of further research but beyond the scope of the current chapter.

WHAT DO PSILOCYBIN AND MDMA DO?

The entactogen MDMA and the hallucinogen psilocybin belong to different classes of substances, and although distinct in their effects, they share a propensity to bring about an acute “altered” or “nonordinary” psychological state. We can understand this alteration to refer to changes in our thoughts (cognitions), emotions (mood), and incoming sensory information (perception). An example of a day-to-day alteration in one's state is when a calm person becomes angry. Anger is associated with physiological changes such as increased perspiration, changes in facial expression, and other body lan-guage. When angry, a person is likely to appraise risks more optimistically and, in interpersonal contexts, blame others for his or her circumstances (Cox & Harrison, 2008).

“Non-ordinary” states are distinct in that they are alterations in psychological states which are uncommon or rare (Barušs & American Psychological Association, 2003). Examples of such states include sensations of oneness with the external world, profound feelings of well-being, or sacredness. However, delineating the effects of these substances by their frequency of occurrence is not entirely sufficient.

Another way to conceptualize similarities in the states induced by MDMA and psilocybin is to focus on their ability to increase the intensity of one's cognitions, emotions, and perceptions. In this way, Grof, Hofmann, and Weil (2008) have described hallucinogens as nonspecific amplifiers, which interact with the psychological factors and social context of the individual taking the substance. In other words, psilocybin can intensify how a person feels at a given moment, making the person sensitive to changes in his or her physical and social environment. For example, someone under the influence of psilocybin in an enclosed poorly lit room may begin to experience anxiety or claustrophobia, but after the window shades are opened to a view of a sunlit forest, the person may feel a profound alleviation of anxiety and a flooding feeling of well-being.

Describing these substances as catalysts of nonordinary states or as nonspecific amplifiers helps convey a sense of how varied the specific effects of these substances can be. To speak of changes in thought, emotion, and perception is nearly equivalent to speaking about changes in human experience generally. Although these definitions are limited, these terms help convey the difficulty in pinpointing the exact psychological effect of these substances.

HALLUCINOGEN TERMINOLOGY OVER TIME

The challenge of describing the effects of these substances is clearly reflected in the varied terminology that has emerged to label them over the course of time. The terms chosen often reflect the theoretical orientation of those originating the label. One of the earliest of such labels was “phantastica,” coined in 1924 by the first person to discover the active alkaloid in the peyote cactus (Lewin, 1998).

With the discovery of lysergic acid diethylamide's (LSD's) psychoactivity in 1943, other terms entered the lexicon. These included: “psycholytic” translated as “soul dissolving” or “mind dissolving” introduced by Sandison in the 1960s, “psychedelic” translated as “soul manifesting” or “mind manifesting” introduced by Osmond in 1957 (Murray, 2003), and “psychody-sleptic” emphasizing impairment of psychological function, and similar to “psychotomimetic” translated as “mimicking psychosis.” “Oneirophrenica” or “oneirogen” emphasized dreamlike states as coined by Turner (1964), and “entheogen” (god-manifesting) emphasized the use of these substances strictly in a religious or spiritual context as coined by Ruck, Bigwood, Staples, Ott, and Wasson (1979).

Of these terms, “hallucinogen” is most dominant in the scientific field today, which emphasizes the hallucinatory effects of these drugs. This is considered to be a misnomer by many in the hallucinogen research world, as outright hallucinations are very rare. However, the utility of using the term “hallucinogen,” aside from tradition, is that it can be used in reference to “classical hallucinogens.” Classical hallucinogens can be further subdivided into tryptamines (e.g., psilocybin), ergolines (e.g., lysergic acid diethylamide), and phenethylamines (e.g., mescaline). In this chapter, hallucinogen and psychedelic will be used interchangeably, and will serve as a reference to the classical hallucinogens strictly.

THE SUBJECTIVE EFFECTS OF PSILOCYBIN

In their book, Stafford and Golightly (1967) describe the onset of hallucinogens as being associated with anxiety and suspense. These sensations are described as “weird” and “difficult to describe” by participants; however, these feelings often pass an hour after administration. Typical effects of psilocybin and other classical hallucinogens, include somatic symptoms (e.g., dizziness, nausea, drowsiness), perceptual symptoms (e.g., altered colors, sharpened sense of hearing), and psychological symptoms (changes in mood, distorted sense of time, dreamlike feelings, depersonalization) (Jacobs, 1984).

To better understand what happens with psilocybin after onset, we can briefly examine some recent research from the field. A study examining the mystical-like experiences of healthy humans who had been administered psilocybin found significant differences between psilocybin and placebo on a number of measures (Griffiths, Richards, McCann, & Jesse, 2006). Using a self-report instrument that captures elements of alteration in consciousness, such as positive shifts in consciousness or anxiety of losing control (Dittrich, 1998), participants reported feelings of oceanic boundlessness, dread of ego dissolution, and visionary restructualization. On another similar measure in the same study, participants reported feelings of internal unity, external unity, sacredness, noetic quality, transcendence of time and space, deeply felt positive mood, and ineffability.

Vollenweider and Kometer (2010) present quantitative data of the subjective effects of psilocybin using the five-dimensional altered states of consciousness rating scale (Dittrich, Lamparter, & Maurer, 2006). The intensity of the subjective responses was found to be dose-dependent and included elementary visual alterations, audio—visual synesthesia, vivid imagery, changes in meaning of percepts, experience of unity, and blissful states. Effects also included sensations of disembodiment and impaired control and cognition.

It is important to highlight that not everyone will experience the same exact effects, and variations in these effects may be partly explained by additional factors such as “set” and “setting,” which will be explained later in this chapter. After these acute effects subside, usually after 4–6 hours, it is hypothesized that there are persistent effects such as a decrease in existential fear, feelings of well-being, improved mood, and an increase in healthier behaviors (anecdotally referred to as “afterglow”). These persistent effects are thought to be associated with therapeutic utility; however, they are currently not well understood or empirically verified.

THE SUBJECTIVE EFFECTS OF MDMA

The subjective effects of MDMA are commonly reported to include a sense of well-being, elevated mood, euphoria, a feeling of closeness with others, and increased sociability (Stevens, 2009). MDMA is not a hallucinogen, but rather classified as an empathogen or entactogen, emphasizing the emotional and social effects of the substance. However, individuals may experience psychological phenomena similar to those that occur under the influence of hallucinogens.

In a controlled study, Liechti, Gamma, and Vollenweider (2001) found significant differences between MDMA and placebo on positive mood, visual hallucinations or pseudohallucinations, synesthesia, changed meaning of percepts, facilitated recollection or imagination, and altered perception of space and time. These effects were not always positive and included mania-like experience, anxious derealization, thought disorder, and fears of loss of thought or body control. On another measure used in the study (Liechti et al., 2001), self-confidence, heightened mood, apprehension—anxiety, thought-fulness—contemplativeness, extroversion, dazed state, sensitivity, and emotional excitation were elevated.

Within the context of therapy, MDMA has been reported to decrease fearfulness, while allowing for a clear-headed and alert state of consciousness (Greer & Tolbert, 1986; Mithoefer, Wagner, Mithoefer, Jerome, & Doblin, 2011). However, the complete picture of the subjective experience of MDMA is complex. Although the effects of MDMA are largely predictable and consistent across users, there is variability in the amount of anxiety (particularly the fear of loss of control) individuals may experience. Liechti et al. (2001) found increases in anxiety or no substantial decrease in anxiety, whereas others (Cami et al., 2000) have found sedation-like subjective effects in some participants.

CLINICAL RESEARCH WITH PSILOCYBIN AND MDMA

A Note About Psychoactive Biota Use Among Indigenous People

This chapter focuses entirely on psychiatric research from the 20th century onward. Such a discussion excludes a wealth of knowledge accumulated by indigenous cultures over many centuries. It would be an injustice to not acknowledge the historical and cultural antecedents to current research. Many of the pharmacological agents under investigation today were first used within indigenous contexts for religious and healing purposes. These include: psilocybin, ayahuasca, peyote, iboga, and others. It is, however, beyond the scope of the current chapter to include findings from anthropology, ethno-botony, ethnopharmacology, sociology, literature, and other important fields pertaining to indigenous and ancient plant use. If the reader is interested in additional resources on these topics, an excellent start would be “Plants of the Gods” by Schultes, Hoffman, and Rätsch (2001) or “Psychedelics Encyclopedia” by Stafford (1992).

A Short History of MDMA

Unlike psilocybin, there are no plants that contain MDMA and it is thus produced by laboratory synthesis. The plant sassafras does contain safrole, which is an oily liquid used as a precursor in the production of MDMA. Due to the complexity of its production, MDMA does not have an extensive history of human use. It has been misreported that MDMA was first synthesized in 1914 as an appetite suppressant. However, an investigation by Freudenmann, Öxler, and Bernschneider-Reif (2006) found no support for this claim when investigating Merck's historical archive in Darmstadt, Germany. Freudenmann et al. (2006) located a patent for MDMA dating back to 1912 with additional documentation highlighting a search for a new type of blood clotting agent. And although MDMA was resynthesized in 1927 and 1959, there was no evidence for human testing until 1960.

It wasn't until the mid-1970s that MDMA was rediscovered by the biochemist Alexander Shulgin (who died as this edition of the book was going to press), who observed that the substance can evoke “an easily controlled altered state of consciousness with emotional and sensual overtones, and with little hallucinatory effect” (Shulgin & Nichols, 1978, p. 77). Shulgin proceeded to introduce psychiatrists and psychologists to the drug, who found the substance to be an exceptional psychotherapeutic adjunct. Although no randomized clinical data were gathered from this period of underground therapy, it has been estimated that thousands of sessions took place throughout the decade. Some estimates indicate that up to 500,000 doses were administered in a psychotherapeutic setting within North America during its period of legality (Stolaroff & Multidisciplinary Association for Psychedelic Studies, 2004). It was said that the drug was exceptional in its utility to facilitate couples counseling.

THE NATURE OF EARLY DRUG-ASSISTED PSYCHOTHERAPY RESEARCH

When discussing the potential clinical benefits of drug-assisted psychotherapy, it is essential to properly contextualize current research of these substances. The current clinical studies using psilocybin and MDMA are in early stages of investigation. This means that small sample sizes are used to evaluate efficacy. Efficacy can be understood as a treatment providing positive results in a controlled research trial. Efficacy does not equate to effectiveness, which refers to finding positive therapeutic results in routine care outside the controlled experimental setting. It is therefore very important to highlight that none of the treatments discussed in this chapter have been evaluated for effectiveness. There is however early evidence supporting the efficacy of these treatments.

Small sample studies, such as some of those included in this chapter, are vulnerable to a Type I error and expectancy effects. A Type I error is the incorrect rejection of a true null hypothesis. In other words, it is the incorrect conclusion that a treatment should provide symptom relief, when it may not. An expectancy effect occurs when a participant or researcher expects a given result (symptom improvement) and this affects the outcome of the study (participant reports fewer symptoms). The issue with classical hallucinogen research from the 1960s and 1970s is that many early studies suffered from such flawed research designs. Although current research still encounters these issues, more modern research methodologies are allowing for increased confidence in the measured effects.

SET AND SETTING

We discussed how psilocybin and MDMA may be thought of as nonspecific amplifiers; substances that strengthen or intensify a person's thoughts, feelings, and perceptions, throughout the duration of the substance's effect. We have also briefly mentioned how these effects interact with a person's psycho-logical, social, and physical context. Because these factors can influence a person's experience on the substance, guidelines for facilitating sessions with these drugs have evolved over the past 50 years, formally beginning with “set and setting” (Leary, Litwin, & Metzner, 1963).

“Set” can be understood as the current state of mind of the person taking the substance. This can include their personal psychological, social, and spiritual history and the context of the intoxication (intention or expectation of the drug's effect). “Setting” pertains to the environment or external factors, which include sounds, the appearance of the room, time of day, and so on. This is particularly significant when contrasting the therapist's office and a concert hall, where recreational use may occur. In addition to “set and setting,” we may think of “cast” as the presence of other persons who accompany the individual under the acute effect of the drug. It is hypothesized that clinicians' and researchers' interaction with the individual before, during, and after the administration of the psychedelic is of particular importance. Clinicians will be familiar with this as the therapeutic alliance (Lambert, 2004), a topic which will be expanded on further in the chapter.

Empirical studies have attempted to examine the psychological factors (set) that may influence or predict the quality of a person's experience with psilocybin. A person's recent emotional excitability or their openness to experience has been shown to predict the positive or negative valence of a response to psilocybin (Studerus, Gamma, Kometer, & Vollenweider, 2012). And although clinical research has been able to measure consistent effects (e.g., Griffiths et al., 2006; Hasler, Grimberg, Benz, Huber, & Vollenweider, 2004), it is difficult to predict with absolute accuracy how an individual will respond to psilocybin.

It is thought that through proper screening, preparation, dosage, and the maintenance of a supportive setting, some of the variables that contribute to a negative response (“bad trips”) can be controlled. However, it has also been hypothesized that an over-emphasis on controlling a person's experiencecan contribute to negative responses as well. Drug-assisted psychotherapy has adapted to this dialectic by including an element of nondirectedness, to allow the participant greater agency in their experience when under the acute effects of the drugs. More will be mentioned on this topic in the “Psychotherapeutic Methods of Action” section of this chapter.

Due to the significance of “set, setting, and cast,” Johnson, Richards, and Griffiths (2008) published a seminal article titled “Human Hallucinogen Research: Guidelines for Safety,” which outlines a set of safeguards against factors that may contribute to an overwhelmingly distressing experience. Johnson et al. (2008) re-emphasized the importance of atrustingrelationship between the participant or patient and the therapists, preparing the participant for what the psychedelic experience may entail, and a safe setting. In addition to these factors, we must not forget about the dose administered. Research has shown that psilocybin has an optimal dose range for inducing mystical-like experiences, which when exceeded, increases the likelihood of an anxious response (Griffiths et al., 2006).

PSILOCYBIN-ASSISTED PSYCHOTHERAPY IN BRIEF

Psilocybin occurs in various species of mushrooms and after ingestion is metabolized into psilocin, a serotonin receptor agonist (Presti & Nichols, 2006). In clinical research, psilocybin is given in doses ranging from 10 to 30 mg/kg, with effects including the aforementioned changes in perception, cognition, and affect. The duration of these effects often lasts between four and six hours. Psilocybin has a very low physiological toxicity profile, with no organ damage or negative neuropsychological effects (Gable, 1993; Halpern & Pope, 1999; Hasler et al., 2004; Nichols, 2004; Strassman, 1984). However, as with other hallucinogens, there may be complications for individuals with a family history of psychosis.

The clinical application of psilocybin has focused on its utility in the treatment of anxiety related to cancer. A person diagnosed with cancer will often face physical, emotional, and existential challenges. Being confronted with the possibility of an untimely death can induce hopelessness, anxiety, depression, and these feelings can persist even after successful cancer treatment. Persons living with a cancer diagnosis often live with dread over the feeling of imminent death and may experience restlessness, fatigue, problems concentrating, and an inability to live their life to the fullest. It is thought that a mystical-like experience with psilocybin may help patients better understand their condition so that they may experience less anxiety.

The three institutions associated with this research are Habor-UCLA, New York University, and Johns Hopkins University. The study at Habor-UCLA has been completed and published (Grob et al., 2011), whereas the two remaining studies are ongoing. In a within-subject, double-blind, placebo-controlled study, researchers administered psilocybin to 12 sub-jects with advanced-stage cancer diagnosed with acute stress disorder, generalized anxiety disorder, anxiety disorder due to cancer, or adjustment disorder with anxiety. The study found significant decreases in depressive symptoms at six-month follow-up and significant decreases in trait anxiety scores at one month to six months post treatment. However, state anxiety scores demonstrated a nonsignificant increase at six months post treatment, with the authors speculating the deteriorating medical condition of the participants as being a factor.

MDMA-ASSISTED PSYCHOTHERAPY FOR POST-TRAUMATIC STRESS DISORDER

Post-Traumatic Stress Disorder (PTSD) is marked by intrusive symptoms such as nightmares, or distress on exposure to trauma-related cues; avoidance, characterized by efforts to avoid thoughts or reminders of the traumatic event; negative cognitions and mood, such as negative beliefs about the self and feelings of detachment from others; and alterations in arousal, characterized by difficulties falling asleep, outbursts of anger, difficulty in concentrating, and hypervigilance.

PTSD has often been shown to be a chronic illness, with patients receiving treatment experiencing symptoms for an average duration of 36 months, patients not receiving treatment experiencing symptoms for 64 months, and more than one-third of patients never fully recovering from PTSD (Kessler, Chiu, Demler, & Walters, 2005).

The reported lifetime prevalence of PTSD is approximately 8% in the United States (American Psychiatric Association, 2013a). Incidence among U.S. soldiers involved in the current Iraq War is estimated to be as high as 18%, with estimates of 75,000 to 225,000 soldiers suffering from PTSD. In 2004, the U.S. Veterans Administration spent $4.3 billion on PTSD disability for veterans who were mostly from the Vietnam War (MAPS, 2009).

The First Randomized Controlled Pilot Study

The first randomized controlled pilot study with MDMA to treat chronic, treatment-resistant PTSD was completed by Mithoefer et al. (2011). Participants in the study were enrolled only if they received a score of 50 on the Clinician-Administered PTSD Scale, a clinician-administered measure of PTSD (Weathers, Keane, & Davidson, 2001) and had at least one unsuccessful treatment with an SSRI and at least one unsuccessful treatment with psychotherapy. The participants included in the study suffered from chronic PTSD with an average duration estimated at over 19 years. Fifteen of the 20 participants had been previously prescribed an average of 4 different psychiatric drugs, and 15 had completed more than one course of psychotherapy (Mithoefer et al., 2011).

Individuals excluded from the study included those who did not suffer from a crime or combat-related traumatic event and women who were pregnant, nursing, or who were not taking birth control. Individuals with a history of psychotic, bipolar, dissociative identity, an eating disorder with purging, or borderline personality disorder were also excluded from the study. A list of contraindicative medical complications was excluded, along with anyone who met the criteria for substance abuse or dependency, or anyone who had prior use with “ecstasy” more than five times or anytime within the preceding six months of the study (Mithoefer et al., 2011).

The CAPS served as the primary outcome measure, with efficacy measured via subsequent assessments after MDMA-assisted psychotherapy. In addition to the CAPS, the Impact of Events Scale-Revised (IES-R), a measure of psychological response to stress, and the Symptom Checklist 90-Revised (SCL-90-R), a measure of psychiatric symptom categories, were administered. Also, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Paced Auditory Serial Addition Task (PASAT), and the Rey-Osterreith Complex Figure (RCFT) were used to assess potential neurocognitive changes (Mithoefer et al., 2011).

In the blinded segment of the study, participants underwent two experimental sessions with MDMA or placebo. First, physiological and psychological measures were taken, which were then followed by two 90-minute sessions with therapists. The participants then underwent their first MDMA session followed by a 90-minute therapy session the next morning. Psychological measures were administered four days after the experimental session, followed by three 90-minute therapy sessions for integration approximately once a week. Following the last integration session, one more experimental session with MDMA took place and the preceding stages were repeated. At the end of this process, psychological measures were once again assessed (Mithoefer et al., 2011). After the primary evaluation, the blind was broken for each participant. Participants assigned to the placebo control condition could enroll in an open-label crossover arm. All, save one of the eight participants in this condition, went on to enroll in the crossover arm with the active drug.

In the study, a clinical response was defined as a minimum of a 30% reduction in baseline CAPS total severity score. Ten of the 12 participants demonstrated such a reduction after MDMA treatment, whereas 2 of the 8 participants showed such a response in the placebo group. In addition, seven of the eight participants in the placebo control group who had chosen to partake in the crossover arm of the MDMA-assisted therapy, and all seven demonstrated a clinical response. Mithoefer et al. (2011, p. 10) also note that “all three subjects who reported being unable to work due to PTSD were able to return to work.” No serious side effects took place and the neurophysiological and cognitive measures did not measure any impairment in functioning as resulting from the MDMA-assisted therapy.

Long-Term Follow-Up Study

A long-term follow-up (LTFU) evaluating the outcomes of the aforementioned was completed to assess the durability of these improvements (Mithoefer et al., 2013). The follow-up assessment was administered on an average of 45.4 months after the study's final MDMA session. Of the 16 participants who completed the CAPS, no statistically significant differences were found between the CAPS score at follow-up and the CAPS score obtained at the final end point for each individual prior to LTFU. However, two of these participants relapsed with a CAPS score above 50, indicating moderate-to-severe PTSD symptoms. The 19 participants who completed a questionnaire designed to assess perceived harms and benefits of the study indicated experiencing some benefit and did not report any harm. An open-label proof-of-principle study has been completed to test the use of an additional MDMA-assisted psychotherapy session to treat the participants who relapsed in the previous clinical trial. The participants have been treated and follow-up interviews are currently taking place.

HEALTHY VOLUNTEER RESEARCH

This textbook focuses on the use of psychopharmacology in the treatment of psychiatric disorders; yet, this chapter would not be complete without the inclusion of studies with healthy volunteers. Psychopathology is thought of as a condition in which illness must be extracted or removed from a person. Attention is rarely paid to the possibility of using psychopharmacology to prevent psychopathology or as a means to enhance the well-being of individuals not diagnosed with a psychiatric disorder.

Griffiths et al. (2006) published results of a doubleblind study that reliably produced mystical-like experiences in a sample of 36 healthy volunteers. At two-month follow-up, participants reported having sustained positive changes in attitudes and behaviors, which was corroborated by two preselected community observers familiar with the participants. The participants attributed these changes to the mystical-like experience, which was reported to have substantial personal and spiritual significance. A 14-month follow-up study was conducted in which 58% of the volunteers rated the psilocybin experience as one of the top five most personally meaningful, and 57% reported it to be one of the top five most spiritually significant experiences of their lives (Griffiths, Richards, Johnson, McCann, & Jesse, 2008). Griffiths et al. (2011) found the positive changes in attitude and behavior to persist at 14-month follow-up. Commonly reported positive changes included better relationships with friends and family, increased physical and psychological self-care, and increased spiritual practice. The benefit reported by volunteers was related to the sequence of psilocybin doses they received. Participants who received ascending doses of psilocybin had more sustained positive changes in attitudes and behaviors than participants in the descending dosage condition.

In another recently published study (MacLean, Johnson, & Griffiths, 2011), researchers found evidence of personality change as a consequence of psilocybin administration in healthy adults. Measuring changes in the five broad domains of personality (also known as the Big Five), Maclean and colleagues found a significant increase in the domain of Openness. This personality change remained significantly altered in participants one year after the psychedelic experience in those participants who had a mystical experience. The construct of Openness consists of six facets: fantasy, aesthetics, feelings, ideas, values, and actions. It can generally be thought of as open-mindedness to new ideas and experiences.

Another extensive area of research in healthy humans pertains to understanding the basic neuro-psychological, cognitive, and behavioral effects of MDMA and hallucinogens. A very large contribution in this regard has been made by Franz Vollenweider (Vollenweider & Kometer, 2010). Other important figures contributing to this research include: Baggott (Baggott, Coyle, Erowid, Erowid, & Robertson, 2011), Bedi (Bedi, Hyman, & de Wit, 2010), Carhart-Harris (Carhart-Harris et al., 2012), Dumont (Dumont et al., 2009), Gouzoulis-Mayfrank (Gouzoulis-Mayfrank & Daumann, 2006), and Kuypers and Ramaekers (Kuypers & Ramaekers, 2007).

THE USE OF MDMA AND HALLUCINOGENS IN CLINICAL TRAINING

It is suggested by some researchers that it is important for therapists who will be working with participants under the influence of psychedelics to have familiarity with nonordinary psychological states. The manual for MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder (MAPS, 2013a) includes the therapist's comfort with “intense emotional experience and its expression,” “first-hand validation of and trust in the intelligence of the therapeutic process as it arises from an individual's psyche,” as it helps “familiarize therapists with the terrain … of non-ordinary states,”“help therapists to identify features of the experience that might be most helpful,” allows the therapist “to be comfortable supporting people during times when the process is difficult and unsettling,” and “provides the therapist with intrapersonal working knowledge of the integration process” (MAPS, 2013a). Such experience also alludes to the practice of psychotherapists to undergo therapy of their own to understand the psychotherapeutic process in themselves and others.

In a 40-year follow-up study, of the 20 psychotherapists interviewed, who conducted drug-assisted psychotherapy during the 1950s and 1960s with LSD, all showed high levels of agreement when asked whether their experiences with autointoxication, conducted during their training, were a valuable didactic experience for their work as psychotherapists (Winkler & Csémy, 2014). Similar findings have been established in the case of MDMA, where one study found that of the 20 psychiatrists interviewed with personal histories of MDMA, 85% had reported an increased ability to interact with others, 80% reported decreased defensiveness, 65% reported decreased fear, 60% decreased sense of separation from others, 50% increased awareness of emotions, and 50% reported decreased aggression (Liester, Grob, Bravo, & Walsh, 1992). It is important to emphasize that this does not suggest that therapists “need to have” prior experience with these substances, but that research suggests that it may have benefits.

To aid therapists in their understanding of the MDMA-induced state, a study has been approved in which therapists will receive MDMA as part of their training in MDMA-assisted psychotherapy (MAPS, 2009). The purpose is to “provide an in-depth understanding of how to maximize the therapeutic effects of MDMA-assisted psychotherapy,” and “allow participants to better draw distinctions between common, self-limiting side effects of MDMA-assisted psychotherapy and those effects that require intervention” (MAPS, 2009, p. 7).

In a recent interview, Dr. Herb Kleber (White, 2013) discussed how in the late 1960s, he was interested in comparing therapists who had personal experiences with LSD to those who did not. There were anecdotal reports that therapists with the LSD experience had better outcomes in group therapy than those who did not. Dr. Kleber began the study but had to close the study prematurely due to Sandoz recalling the LSD after its widespread recreational use. In the interview, Dr. Kleber states, “… in general, most of the people did not seem to change very much. I was not terribly impressed with the outcome of the study.” However, this research was never completed and therefore, no empirical evidence exists to support an interpretation.

MECHANISMS OF ACTION

Potential Mechanisms of Action in Psilocybin-Assisted Psychotherapy

Classical hallucinogens are also known as serotonergic hallucinogens as they act as 5-HT2A receptor agonists. This activation is necessary but not sufficient in the explanation of hallucinogens' effects (Nichols, 2004). Yet, their action is far more complex, causing alterations in glutamatergic, dopaminergic, and serotonergic transmission. Studies conducted by researchers in Zurich found that most of the subjective effects of psilocybin were attenuated by drug that inactivates 5-HT2A receptors (Carter et al., 2005). The evidence for contribution of dopaminergic receptors is weaker but the research in this area is incomplete. Recent neuro-scientific advances have allowed for the neurobio-logical correlates of psychedelic states to be better understood.

Desynchronization of oscillatory rhythms in the posterior cingulate cortex (PCC) has been found to be one of the mechanisms associated with the subjective psychedelic experience with psilocybin (Muthukumaraswamy et al., 2013). The cerebral cortex is composed of interconnected neurons that make up networks that allow the brain to function. When these neurons fire in a particular pattern, brain waves may be observed using an electroencephalogram (EEG). Desynchronization is when this synchronization decreases. The function of the PCC is complex and unclear, but it is associated with the procession of emotion, memory, and is a central node in the default mode network (DMN). The DMN is a network of brain regions that are active when a person is not focused on the outside world and the brain is restfully awake.

A recent study using fMRI found evidence for the association between subjective effects of psilocybin and decreased connectivity and activity in the key connection hubs (thalamus, anterior and posterior cingulate cortex, medial prefrontal cortex), which enabled a state of unconstrained cognition (Carhart-Harris et al., 2012). These hubs are central to communication and integration across the brain, and thus play an important role in a diverse set of cognitive functions. In the past, it was thought that psychedelics increase brain activity, leading to their subjective psychological effects. This research shows evidence of the contrary.

Aldous Huxley and Huxley (1977) theorized that the brain functions as a reducing valve, acting to filter out unnecessary information and external stimuli, so we are not overwhelmed. The work of Dr. Carhart-Harris and colleagues indicates that psychedelics initiate a decrease in brain activity in areas responsible for constraining our sensory experience and our subjective experience of self-consciousness. As a result of this decrease, these senses are less constrained.

There is much more to learn about the neurobiological underpinnings of the psychedelic state. For a more detailed description of the effects of psychedelics, please see Vollenweider and Kometer (2010) and Nichols (2004).

Potential Mechanisms of Action in MDMA for PTSD

The psychopharmacological profile of MDMA is complex. It is associated with the release of serotonin, norepinephrine, and dopamine, and can act directly on adrenaline and serotonin receptors, and elevate vasopressin (Cami et al., 2000). The most common effects of MDMA include stimulant effects (cardiovascular, autonomic, and perceptual).

MDMA is relatively short acting (lasting four to six hours) and has been reported to facilitate introspection, interest and capability for intimacy, temporary freedom from anxiety, and emotional openness (Greer & Tolbert, 1986). The symptoms of increased and uncontrolled fear response and avoidance in PTSD can both be hurdles in the ther-apeutic process. Psychotherapies for PTSD such as cognitive-behavioral therapy involve the recall of traumatic memories, their updating, and integration (Ehlers & Clark, 2000).

The reduction of a fear response induced by MDMA may facilitate the revisiting of traumatic experiences during psychotherapy without associated emotional numbing (Mithoefer et al., 2011). Another proposed model is that MDMA increases the window of tolerability for engaging with trauma-related thoughts, memories, and feelings. The drug may deepen emotions, empathy, and contribute to a “clearer perspective of the trauma as a past event with a heightened awareness of the support and safety that exist in the present” (Gorman 2013a, p. 3).

Another mechanism of action implicated in MDMA-assisted therapy may be linked to changes in neurobiological abnormalities, particularly in the amygdala and ventral/medial prefrontal cortex, which has been hypothesized to result from PTSD. MDMA has been associated with increased blood in the ventromedial front and occipital cortex, and decreases in the left amygdala (Gamma et al., 2000).

The Psychotherapy in MDMA-Assisted Psychotherapy

The psychotherapy provided in clinical trials of MDMA-assisted psychotherapy for PTSD is a multifaceted integration of various treatment modalities. The following section outlines several components of the psychotherapy and how it may interact with the acute effects of MDMA. Although not comprehensive, these psychotherapy processes and techni-ques are considered to be key aspects of the treatment (Mithoefer, 2013).

One of the earliest goals at the beginning of MDMA-assisted psychotherapy is the establishment of the therapeutic alliance (Mithoefer, 2013). This alliance or relationship between the therapist and client has been one of the most consistent psychotherapy factors to be associated with therapeutic outcome (Lambert, 2004). In the case of persons living with PTSD, the alliance can be of particular importance due to the impact interpersonal trauma and shame may have on developing trust. Therapeutic alliance is developed in MDMA-assisted psychotherapy through introductory sessions with the therapists prior to MDMA administration. It may be further supported by the effects of MDMA.

This hormone oxytocin is thought to be affiliated with the establishment of trust and the facilitation of bonding in humans, and has been hypothesized to be a component of MDMA's psychophysiological effect. This is supported by indirect evidence showing levels of oxytocin to be elevated in the blood of healthy volunteers who had been administered MDMA and to be positively correlated with the prosocial effects of the drug (Dumont et al., 2009; Hysek et al., 2013). In this way, oxytocin may facilitate the establishment of the therapeutic alliance (Johansen & Krebs, 2009). However, conclusive evidence is yet to be collected.

The highly affective nature of PTSD symptoms and the content of trauma itself can present a challenge to establishing an alliance, and if left unaddressed, can impede the therapeutic process. Cloitre, Stovall-McClough, Miranda, and Chemtob (2004) found negative affect management to mediate the relationship between the therapeutic alliance and treatment outcome. In other words, the relationship between the patient and therapist is more likely to lead to better results if the patient is able to manage the negative feelings he or she experiences. In the case of MDMA-assisted psychotherapy, the pharmacological intervention can be thought of as a way of enhancing negative affect management. It allows the person to engage with traumatic content without a heightened fear response or dissociation, and within a highly supportive environment.

The potential for MDMA to manage negative affect is supported by preliminary neurobiological evidence. Extensive studies into the neurobiology of PTSD have found symptoms such as intrusive memories and hyperarousal to be associated with decreased hippocampal and medial prefrontal cortex signaling and increased amygdala activity (Ravindran & Stein, 2009). In contrast, healthy volunteers who were acutely administered MDMA showed decreased activity in the left amygdala, which is associated with fearful associations and memories (Gamma et al., 2000). A recent study by Carhart-Harris et al. (2014) found that the decrease in amygdala activity was associated with self-reported intensity of MDMA effects. The potential for MDMA to dampen an overactive amygdala remains a tentative hypothesis, which is currently being evaluated empirically in an fMRI substudy examining persons living with PTSD before and after MDMA-assisted psychotherapy treatment (MAPS, 2014).

In clinical studies for PTSD, participants are administered MDMA on only 2 or 3 occasions out of approximately 12 psychotherapy sessions. During these sessions, it is possible that the participants may experience increased anxiety and strong affective states. To support participants during these experiences, mindful diaphragmatic breathing techniques are taught prior to drug administration, which are similar to the relaxation exercises used in other psychotherapies such as Cognitive Behavioral Therapy (CBT) and Prolonged Exposure (PE).

MDMA-assisted psychotherapy shares other similarities to PE, Cognitive Processing Therapy (CPT), and Eye Movement Desensitization and Reprocessing (EMDR). This includes an emphasis on the importance of directive preparation sessions, which includes the establishment of the aforementioned therapeutic alliance, psychoeducation about PTSD, socialization to the treatment model, and preparing the participant for the process and consequences of exposure to traumatic material.

What makes MDMA-assisted psychotherapy distinct from the aforementioned treatments is an emphasis on the therapist's largely nondirective stance after the preparation sessions. A nondirective approach allows the participant to direct the pace and direction of the therapy session. This is done so that the participant can bring up traumatic content when optimally prepared to do so. To maintain an exposure component in MDMA-assisted psychotherapy, in cases where the partici-pant avoids discussing the trauma entirely, the participant and therapist prior to the drug administration, have informally agreed that the therapist can bring up the traumatic content at a later point during treatment if needed. However, therapists in the current clinical studies have noted that participants discuss the trauma spontaneously, without the need for prompting by the therapist, in almost all (nearly 100) MDMA sessions.

A nondirective approach allows for several additional advantages. Participants may elect to discuss traumatic content not initially conceptualized in the case formulation. These experiences may be associated with intense shame or guilt, which the participant may not have been willing to share during intake. Providing the participant greater agency allows for unexpected, yet potentially important therapeutic content to surface.

Habituation to anxiety, fear, or other affective responses associated with the traumatic content is not the goal or process emphasized in MDMA-assisted psychotherapy. Rather, in MDMA-assisted psychotherapy, emphasis is placed on emotional connection, increased clarity into traumatic memories and a sense of mastery over the process and recall of traumatic events. Habituation can be understood as a form of learning, a consequence of repeated exposure, in which a person shows a decreased response to a stimulus. In the case of PTSD, this may be a repeated exposure to a traumatic event, with the aim of reducing a fear response and avoidance of stimuli associated with the event.

Part of the trauma processing relates to cognitive restructuring in which negative thoughts, beliefs, and distortions are challenged in a nondirective way to help the participant understand the meaning of their trauma. When a traumatic experience is reflected upon without psychophysiological dysregulation, aided by the MDMA, the traumatic memories can be safely recontextualized with the support of the therapist.

Perhaps the most central aspect of MDMA-assisted psychotherapy, particularly in the sessions in which the participant is under the effects of the MDMA, is the emphasis on the participant's inward focus. This is done with the participant closing his or her eyes and listening to appropriate music. As a consequence, the participant leads much of the therapy, with the therapists facilitating the participant's process. It is not assumed the therapist is the expert, but rather that the patient, with the help of the MDMA, will engage in the therapeutic process at least partially independently. In relation to cognitive restructuring, the participant may come to understand his or her trauma with a greater sense of agency and self-efficacy. In a traumatic event, the victim encounters powerlessness and helplessness over the situation. Allowing the person to regain some sense of power and control in MDMA-assisted psychotherapy is a reversal of this circumstance. In this situation, the therapists offer guidance and support when needed or requested.

The active role of the therapist becomes more prevalent during integration sessions. Participants discuss the content of the MDMA sessions, their reactions to it, and discuss the insights gained. The therapist must make clear to the participant that the process catalyzed by the MDMA session will continue for several weeks and participants are encouraged to discuss any distress that may arise. “Integration involves the ability to access and apply to daily life the lessons, insights, changes in perception, awareness of bodily sensations, and anything else that has been revealed during the MDMA sessions (MAPS, 2013a).” There are at least three integrative meetings planned after each MDMA-assisted psychotherapy session in which to address the sessions. Participants are also encouraged to use forms of self-expression, such as journaling or drawing, to confront or integrate material from the sessions. They also have option to view recordings of their sessions, though they are not required to do so.

IS IT THE DRUG, THE PSYCHOTHERAPY, OR BOTH?

Now that we have covered both MDMA- and psilocybin-assisted psychotherapy, we can begin to address a central question in this form of treatment. When drug-assisted psychotherapy successfully treats a patient, is it an effect of the substance, the psychotherapy, or the combination of the two. The importance of the therapist cannot be underestimated, as he or she can assist in the optimization of the aforementioned set and setting, assist in preparation before the substance is administered, and help with the integration of the experience afterward.

In his article, Bogenschutz (2013) succinctly describes the unique methodological issues encountered in clinical trials using psychedelics, and it is likely that these extend to MDMA as well. Psychedelics have both acute psychoactive effects and hypothesized persistent effects that last longer than the acute drug response. Bogenschutz (2013) highlights that the therapeutic brain changes induced may be dependent on the subjective experience of the patient. Unlike other psychopharmacological medications, the set and setting of the patient will impact the experience on the medication, which is hypothesized to impact the treatment outcome. Thus, a combination of psychotherapy and medication effect is being measured. This can be problematic because clinical trials focus on isolating variables, so that specific mechanisms of either drug or psychotherapy can be defined. We will address these questions by using two clinical illustrations.

CLINICAL EFFECT WITHOUT PSYCHOTHERAPY

Sewell, Halpern, and Pope (2006) interviewed individuals experiencing cluster headaches who had used psilocybin or LSD to treat their condition. Cluster headaches are chronic, occurring as regular attacks during a cluster period, and then subside into a remission period. The pain experienced in this neurological disorder is severe (rated as 11 out of 10 on pain scales), typically felt on one side of the head or around the eye (Nesbitt & Goadsby, 2012). The results of the interviews conducted by Sewell et al. (2006) indicated that individuals who used LSD and psilocybin to terminate cluster periods, required less than three doses to do so, and in doses that were subhallucinogenic (did not produce profound changes in cognition and perception). Several years later, it was found that the nonhallucinogenic 2-bromo-lysergic acid diethylamide (2-Bromo-LSD) could produce similar results as psilocybin or LSD. Although cluster headaches are not a psychiatric condition, this case illustrates how the psychedelic experience is not always necessary for treatment.

In 2006, a pilot study was published on the safety, tolerability, and efficacy of psilocybin in the treatment of OCD (Moreno, Wiegand, Taitano, & Delgado, 2006). Although treatments such as Cognitive-Behavior Therapy and other pharmacotherapy exist for OCD (Stein, Ipser, Baldwin, & Bandelow, 2007), the investigators sought to study anecdotal reports suggesting psilocybin may relieve symptoms of OCD. After treatment with psilocybin, symptoms of OCD decreased by 23 to 100%, with improvement lasting beyond 24 hours post administration. In these studies, no formal psychotherapy was provided, although some participants reported the psychedelic experience to be psychologically and spiritually enriching. The reduction in symptoms after the acute effects of psilocybin brings us back to the question of mechanism of action. To this date, there has been no follow-up to this research. It is thus unknown whether the therapeutic effect of the psilocybin treatment was only pharmacologically mediated or a combination of pharmacologically and psychotherapeutically mediated.

BETWEEN PSYCHOPHARMACOLOGY AND PSYCHOTHERAPY

Ibogaine is not a classical hallucinogen, but shares some hallucinogen qualities. Ibogaine is referred to here as it sits in the center of the dialectic between pharmacological and psychotherapeutic action. The psychoactive effects of the substance have been described as introspective and dreamlike, with alterations in consciousness lasting beyond 20 hours. The experience has been characterized as unpleasant, with effects including ataxia and vomiting, making it potentially unattractive as a substance for recreational use (Brown, 2013). Mash (2010) provided an analysis of ibogaine experiences and identified the following themes reported by study participants: new insight (86.7%), need to become sober/abstinent now (68.3%), cleansed/healed/reborn (50%), second chance at life (40%), increased self-confidence (33.3%), and impending self-destruction if drug use continued (18.3%).

Unlike the other serotonergic hallucinogens, ibogaine also acts as an NDMA receptor antagonist and an agonist of the k-opioid receptor set (Glick & Maisonneuve, 1998). These properties may lend it to be of particular use in the treatment of addiction to a wide range of drugs including opiates, stimulants, nicotine, and alcohol (Brown, 2013). However, as other researchers have noted (Alper, Lotsof, Frenken, Luciano, & Bastiaans, 1999), there is a lack of systematic clinical research with ibogaine.

The therapeutic profile of ibogaine for substance-use disorder has been reported to include alleviation of withdrawal (Alper, Lotsof, & Kaplan, 2008; Alper et al., 1999) and cravings (Mash et al., 2000). These findings are supported by accumulated preclinical research with lab animals (Alper, 2001). These properties observed in lab rodents suggest a pharmacological rather than psychological mechanism of action. Thus, the psychedelic effects of ibogaine can be viewed as side effects (Carnicella, He, Yowell, Glick, & Ron, 2010). Undergoing a 20-hour experience with profound changes to cognition and perception is not practical if a similar effect can be achieved otherwise.

Two compounds related to ibogaine, noribogaine and 18-Methoxycoronaridine (18-MC), have been developed, which have demonstrated the antiaddictive profile of ibogaine in rodents, but are theorized to have fewer hallucinogenic side effects. Of these two, a preclinical study indicated noribogaine to be more effective in decreasing alcohol self-administration in rats (Carnicella et al., 2010). There have been no human trials at this point.

If a nonhallucinogenic analogue is developed with the same antiaddictive properties, would studies demonstrate the same treatment outcome as ibogaine? This empirical question brings us back to our discussion of mechanism of action. Treatment outcome, particularly in addiction, is supported not only by the removal of cravings and withdrawal symptoms, but by other psychological, social, and cultural factors. The hallucinogenic experience may increase confidence, readiness to change, greater understanding in motivations for use, and psychospiritual resources that may prevent relapse. It remains unanswered whether the hallucinogenic component of ibogaine contributes to efficacy. Yet, the length and the unpleasant quality of the ibogaine experience may be a barrier to those seeking treatment, suggesting that 18-MC or noribogaine may be more useful treatment tools.

To conclude this section, we see that in the case of cluster headaches, the purely pharmacological action of LSD and psilocybin was responsible for a therapeutic effect. In the study using psilocybin to treat persons living with OCD, no psychotherapy was provided, and clinical improvement was established, albeit for a short period of time. Whether the therapeutic effect on OCD could be prolonged with combination of psychotherapy remains uninvestigated. Finally, we discussed the antiaddictive properties of ibogaine and how both the psychological and pharmaceutical effects of the substance may contribute to recovery.

RISKS VERSUS BENEFITS

Safety of Psilocybin and other Classical Hallucinogens

The classical hallucinogens are considered to be physiologically safe and do not show the same dependency issues as other drugs associated with substance-use disorders. There is no evidence that these substances are toxic to any mammalian body organ and no deaths as a direct consequence of classical hallucinogens have been recorded. However, fatal accidents have occurred while under the influence of hallucinogens in uncontrolled settings by recreational users. The safety of classical hallucinogens is supported by a recent study by Krebs and Johansen (2013), who examined data from a U.S. national health survey to examine 130,000 participants of which 22,000 had taken a classical hallucinogen at some point in their lives. After controlling for risk factors, the study found no association between increased rates of psychiatric problems and psychedelic use. Counter to expectation, weak associations were found between the use of certain psychedelics and lower rates of mental health problems. It is important to note that these findings may be a result of chance and that these findings are not causal due to the retrospective nature of the research.

It is also important to take into consideration previous research which has found increased incidence of negative responses to hallucinogens in individuals with a family history of schizophrenia (Anastasopoulos & Photiades, 1962). There is a lack of firm empirical evidence demonstrating a direct causal link between the use of the classical hallucinogens and schizophrenia in humans. However, the common consensus is that hallucinogens may bring about a latent psychosis in individuals who are predisposed (e.g., genetically vulnerable) to schizophrenia. Participants who have such personal or family histories are excluded from studies using MDMA or hallucinogens.

Contraindications to hallucinogen administration include combining hallucinogens with a monoamine oxidase inhibitor (MAOI) or as previously mentioned, administering a hallucinogen to an individual with a family history of schizophrenia or other psychotic disorders. It is also important to state that the substances used in approved research trials in the United States have been synthesized with the oversight of multiple governing bodies, including the Drug Enforcement Agency. Individuals who seek out these substances off the black market run the risk of obtaining impure syntheses and potentially adulterated substances. In these circumstances, the possible negative consequences to a person's physical and psychological health cannot be underestimated.

Safety of MDMA

The greatest risk with MDMA pertains to cardiovascular issues associated with increased blood pressure and heart rate. Individuals with a serious cardiovascular condition are at risk when ingesting MDMA. These physiological changes are known to be predictable effects and are thus a serious concern for a vulnerable population. This issue is heightened in recreational settings, where the purity of the substance is in question or where users are overexerting themselves.

As with other pharmacological substances, there are dangers associated with MDMA's use in illegal contexts. Black market MDMA, commonly sold in tablets as ecstasy or in powder form as molly, may include other substances, contaminants, and adulterants, and thus, their interaction and effects on the body can be unpredictable. Use in uncontrolled settings only compounds these dangers. Prolonged dancing in poorly ventilated spaces after the ingestion of MDMA has been linked to hyperthermic reactions leading to medical complications and in some cases, death. However, excessive hydration associated with MDMA use can provoke severe hyponatremia induced by the syndrome of inappropriate antidiuretic hormone secretion. The greatest risk is in premenopausal women (Rosenson, Smollin, Sporer, Blanc, & Olson, 2007). The first fatalities associated with MDMA were related to severe pre-existing cardiac or respiratory disease. Cerebrovascular events have been reported as well, including stroke and subarachnoid hemorrhage, effects also reported after psychostimulant use (Gledhill, Moore, Bell, & Henry, 1993; Henry, Jeffreys, & Dawling, 1992). However, when considering the prevalence of illicit ecstasy use, the report of a serious adverse event is rare.

These dangers can be avoided within the context of therapy, as the use of pure MDMA can be assured, patients with medical contraindications can be excluded, and an appropriate environment can be provided. However, other potential dangers may still exist. Research with nonhuman animals has detected a reduction in brain serotonin after high, repeated doses of MDMA (Baumann, Wang, & Rothman, 2007). There are consistent findings of impaired memory in people reporting repeated, heavy use of ecstasy and other drugs (Reneman et al., 2006). To date, there has been only one prospective comparison of memory and serotonin uptake sites in people who later did or did not use ecstasy, finding difficulties in verbal memory but no changes in uptake sites (Schilt et al., 2007). A comparison of people with PTSD who received either placebo or MDMA failed to detect significant differences in performance on measures of cognitive function (Mithoefer et al., 2011). A comprehensive review of research on the neurotoxic effects of MDMA has been completed by Rogers et al. (2009).

Dependency

Data suggest that MDMA possesses an abuse potential that is greater than the classical hallucinogens but not as strong as stimulants such as cocaine and methamphetamine. Studies have shown that animals will self-administer MDMA, although they will not work as hard to obtain MDMA as they would for methamphetamine or cocaine (Fantegrossi, 2006; Wang & Woolverton, 2006). Substance abuse is also low in representative samples (Lieb, Schuetz, Pfister, von Sydow, & Wittchen, 2002; von Sydow, Lieb, Pfister, Höfler, & Wittchen, 2002).

In the United States, 12% of high school seniors have admitted to trying MDMA at least once, with this number being twice as high according to research at undergraduate universities (Ruiz, Strain, & Langrod, 2007). In a study cited by MAPS (2006), of a sample of 74 drug-naïve participants, who received MDMA in a research setting, “none of the participants expressed any interest in taking MDMA as a recreational drug” (Liechti et al., 2001). This may be indicative of how intentions associated with use may be linked to abuse.

Risks Associated with Psychotherapeutic Use

Short-term side effects of MDMA administration include trismus (lockjaw), bruxism (teeth grinding), restlessness, anxiety, decreased appetite, tachycardia, palpitations, dry mouth, insomnia, difficulty concentrating, and impaired balance (Liechti et al., 2001; Peroutka, Newman, & Harris, 1988). MDMA may temporarily reduce immune functioning for two to three days, but this is likely to be below clinical significance and is similar to effects produced by other psychoactive drugs (Pacifici et al., 2000). Other side effects include mild alterations in perception and potential for complications due to comorbidity with substance abuse (MAPS, 2006). However, counterintuitively, preliminary data indicate that through addressing conditions that exacerbate it, MDMA may also be a potential adjunct in treating substance-use disorders (Jerome, Schuster, & Yazar-Klosinski, 2013). There is no evidence for lasting toxicity after MDMA administration in humans in Phase I studies utilizing 120-mg doses (Grob, Poland, Chang, & Ernst, 1996; Harris, Baggott, Mendelson, Mendelson, & Jones, 2002). This does not discount the possibility that neurotoxic effects may be occurring outside a controlled clinical context.

The Future of Psychedelic Research

As we have outlined in this chapter, current research into drug-assisted psychotherapy indicates preliminary clinical success. Although there is a need for more research with greater sample sizes, we may also begin to consider what future research questions may be posed.

The Future of MDMA Research

Grob and Danforth (MAPS, 2013b) will be launching a double-blind, placebo-controlled pilot study to assess the safety and feasibility of MDMA-assisted psychotherapy to treat social anxiety in adults on the autism spectrum. MDMA may be well suited to treat social anxiety as it produces decreases in fear and amygdalar responses to angry faces (Bedi, Phan, Angstadt, & de Wit, 2009). A recent study by Carhart-Harris et al. (2014) observed decreased communication between the medial temporal lobe and medial prefrontal cortex of healthy volunteers under the effects of MDMA while under fMRI. These changes in the limbic system are the opposite of what is observed in individuals who suffer from anxiety. Another rationale for the use of MDMA for social anxiety is the aforementioned elevation of oxytocin levels hypothesized to occur in the brain after MDMA administration. Increased levels of peripheral plasma oxytocin have been linked to prosocial feelings (Dumont et al., 2009).

Baggott (2013) proposes that a decrease in fear may be only a part of a more complex response to MDMA. In his research with healthy volunteers, participants were administered MDMA and completed a measure of authenticity. Those who received MDMA, compared to placebo, reported higher rates of authenticity operationalized as awareness and trusting of one's thoughts and feelings, acting in accordance with one's values, lack of interpretive distortions of self-relevant information, and acting with sincerity in relationship with close others. Thus, it may not be only a decrease in fear, but other psychological mechanisms that may lead to prosocial communicative behavior.

Another potentially promising application of MDMA is in the treatment of psychiatric conditions that exacerbate substance use disorders (Jerome et al., 2013). Currently, there are no published studies on the use of MDMA-assisted psychotherapy for this purpose. It is counter intuitive to use a drug that has the potential for abuse as a treatment for problematic substance use. However, MDMA may facilitate treatment by enhancing the psychotherapeutic process generally and more specifically by addressing psychological factors that contribute to substance misuse (Jerome et al., 2013). At this time, there are no studies being conducted to evaluate the feasibility of MDMA in the treatment of problematic substance use.

The Future of Psilocybin Research

Another novel area of study is the application of psilocybin as an adjunct to CBT for smoking cessation (Johnson, 2013). In this ongoing study, 50 participants with multiple unsuccessful quit attempts will receive the treatment. This consists of three psilocybin sessions, followed by eight weekly psychotherapy sessions to discuss the psilocybin experiences and provide support for smoking cessation. Although the study is yet to be completed, there are currently 12 of 50 participants who have been biologically confirmed as abstinent at 6 months post quit date. These biological markers include urinary nicotine and breath carbon monoxide levels.

There is renewed interest in the application of psilocybin in the treatment of addiction to alcohol. There is significant precedent for this research, as hundreds of articles were published focusing on LSD's potential to treat alcoholism in the 1960s. In a recent meta-analysis, T. S. Krebs & Johansen (2012) identified 546 participants in six randomized control trials published between 1966 and 1970. It was found that a single dose of LSD, accompanied with an alcohol treatment program, was associated with a decrease in problematic alcohol use at follow-up assessment, which ranged from 1 to 12 months after discharge from treatment programs. These effects were persistent at 3 months and 6 months, did not last at the 12-month period. Nonetheless, this is an impressive result for a single-dose treatment.

Bogenschutz (2013) is currently completing a small open-label pilot study examining the effects of psilocybin in 10 alcohol-dependent participants. The treatment provided uses two-dose sessions and incorporates Motivational Enhancement Therapy into 12 sessions over a 12-week period. Particular attention is paid to the role of spirituality in relation to the participant's alcohol use. It is hypothesized that the treatment will contribute to increases in motivation, self-efficacy, and spirituality, which are important factors in recovery from substance misuse. The study's primary outcome will be decreases in participant's drinking behavior. Once completed, it is likely that a study with a larger participant pool will be launched.

More generally, we can contrast the current paradigm for psychiatric treatment and the model of drug-assisted psychotherapy. Under the former paradigm, a person visits a psychiatrist, he or she is evaluated, and if deemed appropriate, he or she will be prescribed a medication. The person will then take the medicine daily, and is followed up with on a semiregular basis. The drug-assisted psychotherapy model, in contrast, requires a person to receive several sessions of psychotherapy in preparation for receiving the medicine. When ready, the person receives the drug in the context of a psychotherapy session, and then several integration psychotherapy sessions take place. Depending on the treatment, this cycle may repeat approximately one to three times. As such, this treatment may be considered a “brief therapy” with a psychopharma-cological agent as an adjunct.

The medicine or adjuvant is thought to be beneficial through a synergistic relationship with the psychotherapy provided. However, it remains unclear how exactly the medicine aids in the psychotherapeutic process. Further investigations into this area will allow researchers to improve the psy-chotherapy, to offer maximum potential benefit to the participant. How current (often competing) evidence-based psychotherapies will be compatible with these medicines is unknown. Will an existing psychotherapeutic model work best in conjunction with these substances or will a novel model of psychotherapy emerge? These questions will continue to be investigated as research in this field continues.

Legal Status of MDMA and the Classical Hallucinogens

The classical hallucinogens and MDMA are classified as Schedule-I controlled substances in the United States, meaning “the drug or other substance has a high potential for abuse,” “the drug or other substance has no currently accepted medical use in treatment in the United States,” and “there is a lack of accepted safety for use of the drug or other substance under medical supervision (Office of Diversion Control, 2012).” It is therefore important to note that research presented in this chapter has been conducted under legal clinical and preclinical contexts. All published research is reviewed and approved or cleared by ethics review and multiple regulatory authorities. Considering the medical and psychotherapeutic potential of these substances and the relative safety demonstrated in the clinical data presented here, questions regarding the validity of the aforementioned scheduling should be raised.