Addictions Case Study: Part 3 - Treatment Plan

(Ksir, 2021)

Ksir, C. C. (2021-05-01). Drugs, Society, and Human Behavior, 18th Edition

Chapter 8

Medication for Mental Disorders

Mental Disorders

The Medical Model

The use of the term mental disorder seems to imply a particular model for behavioral dysfunctions. The medical model has been criticized by both psychiatrists (who are medical doctors) and psychologists (who generally hold nonmedical doctorates such as a PhD or PsyD).

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According to this model, the afflicted person appears with a set of symptoms, and on the basis of these symptoms a diagnosis is made as to which disease the patient is suffering from. Once the disease is known, its cause can be determined and the patient provided with a cure. In general terms, the arguments for and against a medical model of mental illness are similar to those for and against a medical model of substance use disorder, presented in Chapter 2. For an infectious disease such as tuberculosis or syphilis, a set of symptoms suggests a particular disorder, but a specific diagnostic test for the presence of certain bacteria or antibodies is used to confirm the diagnosis, identify the cause, and clarify the treatment approach. Once the infection is cleared up, the disorder is cured.

For mental disorders, a set of behavioral symptoms is about all we have to define and diagnose the disorder. A person might be inactive, might not sleep or eat well, and not say much, and what little is said might be quite negative. This behavior might lead us to call the person depressed. Does that mean the person has a “disease” called depression, with a biological cause and a potential cure? Or does it really only give a description of how he or she is acting, in the same way that we might call someone “crabby,” “friendly,” or “nerdy”? The behaviors that we refer to as indicating depression are varied and probably have many different causes, most of them not known. And we are far from being able to prescribe a cure for depression that will be generally successful in eliminating these symptoms.

Despite these criticisms of the medical model, it still seems to guide much of the current thinking about mental disorders. The fact that psychoactive drugs can be effective in controlling symptoms, if not in curing disorders, has lent strength to supporters of the medical model. If chemicals can help alleviate an individual’s symptoms, a natural assumption might be that the original problem resulted from a chemical imbalance in the brain—and that measurements of chemicals in urine, blood, or cerebrospinal fluid could provide more specific and accurate diagnoses and give direction to efforts at drug therapy. Although a lot of people have searched for many years, so far we have no direct evidence for a chemical imbalance causing depression or schizophrenia or anxiety disorders. And, although drug therapy is the first-line treatment for most mental disorders, we don’t have a clear biological understanding of how the drugs work to reduce the symptoms of these disorders.

Classification of Mental Disorders

Because human behavior is so variable and because we do not know the causes of most mental disorders, classification of the mentally ill into diagnostic categories is difficult. Nevertheless, some basic divisions are widely used and important for understanding the uses of psychotherapeutic drugs. In 2013, the American Psychiatric Association published the fifth edition of its Diagnostic and Statistical Manual of Mental Disorders (referred to as the DSM-5).1 This manual provides criteria for classifying mental disorders into hundreds of specific diagnostic categories. Partly because this classification system has been adopted by major health insurance companies, its terms and definitions have become standard for all mental health professionals.

Anxiety is a normal and common human experience: Anticipation of potential threats and dangers often helps us avoid them. However, when these worries become unrealistic, resulting in chronic uneasiness, fear of impending doom, or bouts of terror or panic, they can interfere with the individual’s daily life. Physical symptoms may also be present, often associated with activation of the autonomic nervous system (e.g., flushed skin, dilated pupils, gastrointestinal problems, increased heart rate, or shortness of breath). The DSM-5 refers to these and other problems as anxiety disorders (see the DSM-5 box). Obsessive-compulsive disorder and posttraumatic stress disorder used to be included within this group, but the new manual gives each of these its own separate chapter.

Perhaps because these disorders all seem to have some form of anxiety associated with them, and perhaps because for many years psychiatrists classified benzodiazepines and other depressants as antianxiety drugs (see Chapter 7), we tend to think of anxiety not as a behavioral symptom but rather as an internal state that causes the disorders. That view fits well with the medical model, but we should guard against easy acceptance of the view that these disorders are caused by anxiety and that therefore we can treat them using antianxiety drugs. In recent years, psychiatrists have increasingly used selective reuptake inhibitors, classified as “antidepressants” to treat anxiety disorders.

Psychosis refers to a major disturbance of normal intellectual and social functioning in which there is loss of contact with reality. Not knowing the current date, hearing voices that aren’t there, and believing that you are Muhammad or Christ are some examples of this withdrawal from reality. Many people refer to psychosis as reflecting a primary disorder of thinking, as opposed to mood or emotion.

Psychotic behavior may be viewed as a group of symptoms that can have many possible causes. One important distinction is between the organic psychoses and the functional psychoses. An organic disorder is one that has a known physical cause. Psychosis can result from many things, including brain tumors or infections, metabolic or endocrine disorders, degenerative neurological diseases, and chronic alcohol use. Functional disorders are simply those for which there is no known or obvious physical cause. A person suffering from a chronic (long-lasting) psychotic condition for which there is no known cause will probably receive the diagnosis of schizophrenia. There is a popular misconception that schizophrenia means “split personality” or refers to individuals exhibiting multiple personalities. Instead, schizophrenia should probably be translated as shattered mind. See the DSM-5 box for the diagnostic criteria for schizophrenia.

Depressive disorders are characterized by feelings of sadness, emptiness, or irritability and can be accompanied by body and mental changes that impairs the individual’s ability to function. The quintessential condition in this category is major depressive disorder. Bipolar and related disorders, on the other hand, must involve at least one manic episode, perhaps alternating with periods of depression. See the DSM-5 box for diagnostic criteria for bipolar I disorder and major depressive disorder.

Individual human beings often don’t fit neatly into one of these diagnostic categories, and in many cases assigning a diagnosis and selecting a treatment are as much a matter of experience and art as they are of applying scientific descriptions. For example, it is common for people to experience symptoms of anxiety and depression at the same time, and different clinicians might view one or the other as the more important issue. Also, a person may be first seen when depressed, but a key issue is whether there might have been an unreported manic episode prior to the current problem.

Treatment of Mental Disorders

Before 1950

Over the centuries, patients diagnosed with mental disorders have been subjected to various kinds of treatment, depending on the views held at the time regarding the causes of mental illness. Because we are concerned with drug therapy, a good place to begin our history is in 1917, when a physical treatment was first demonstrated to be effective in serious mental disease. In those days, a great proportion of patients with psychosis were suffering from general paresis, a syphilitic infection of the nervous system. It was noticed that the fever associated with malaria often produced marked improvement, and so in 1917 “malaria therapy” was introduced in the treatment of general paresis. In the 1940s, this particular type of treatment was virtually eliminated when the antibiotic penicillin—which could cure syphilis—came widely available.

In the 1920s, wealthier patients could afford a course of “narcosis therapy,” in which barbiturates and other depressants were used to induce sleep for as long as a week or more. Another use for sedative drugs was in conjunction with psychotherapy: an intravenous dose of thiopental sodium, a rapid-acting barbiturate, would relax a person and produce more talking during psychotherapy (see Chapter 7). The theory was that such a reduction in inhibitions would enable the patient to express repressed thoughts; thus, the term truth serum came to be used for thiopental sodium and for scopolamine, an anticholinergic drug used similarly. Anyone who has ever listened to a person who has drunk a good bit of alcohol will tell you that although the talk might be less inhibited, it isn’t always more truthful. So-called truth serum apparently worked about as well.

In the 1930s, European physicians experimented with various chemicals to induce either a coma (insulin) or convulsions similar to epilepsy (camphor, Metrazol). At first this type of treatment was used in schizophrenia, and indeed the patients were calmer for at least a short while after the seizures were over. However, repeated treatments were problematic as the patients became quite agitated in the few minutes after the drug was administered and before the seizures began. In 1938, it was demonstrated that seizures could be induced by sending electrical current through the brain of an anesthetized patient, and so electroconvulsive therapy (ECT) replaced drug-induced seizures and came to be in widespread use in mental hospitals until the 1960s. While there proved to be no long-term benefits for schizophrenia, ECT turned out to be a rapid and effective way to reduce symptoms of depression. ECT is still used to treat severely depressed patients who do not respond to medication.3

By the 1950s, probably the major drug in use for severely disturbed patients in large mental hospitals was paraldehyde, a sedative (see Chapter 7). Although it produces little respiratory depression and therefore is safer than the barbiturates, the drug has a characteristic odor, which is still well remembered by those who worked in or visited the hospitals of that era. Sedation of severely disturbed patients by drugs that make them drowsy and slow them down has been referred to as the use of a “chemical straitjacket.”

Antipsychotics

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A number of people were involved in the discovery that a group of drugs called the phenothiazines had special properties when used with mental patients. Credit is usually given to a French surgeon, Henri Laborit, who first tested these compounds in conjunction with surgical anesthesia. He noted that the most effective of the phenothiazines, chlorpromazine, did not by itself induce drowsiness or a loss of consciousness, but it seemed to make the patients unconcerned about their upcoming surgery. He reasoned that this effect might reduce emotionality in psychiatric patients and encouraged his psychiatric colleagues to test the drug. The first report of these French trials of chlorpromazine in mental patients mentioned that not only were the patients calmed, but the drug also seemed to act on the psychotic process itself. This new type of drug action attracted a variety of names: In the United States, the drugs were generally called tranquilizers, which some now think is an unfortunate term that focuses on the calming action and seems to imply sedation. Another term used was neuroleptic, meaning “taking hold of the nervous system,” a term implying an increased amount of control. Although both of these terms are still in use, most medical texts now refer to this group of drugs as antipsychotics, reflecting their ability to reduce psychotic symptoms while producing less drowsiness and sedation than earlier drugs.

The tremendous impact of phenothiazine treatment on the management of hospitalized patients is clear from a 1955 statement by the director of the Delaware State Hospital:

We have now achieved . . . the reorganization of the management of disturbed patients. With rare exceptions, all restraints have been discontinued. The hydrotherapy department, formerly active on all admission services and routinely used on wards with disturbed patients, has ceased to be in operation. Maintenance EST (electroshock treatment) for disturbed patients has been discontinued. . . . There has been a record increase in participation by these patients in social and occupational activities.

These developments have vast sociological implications. I believe it is fair to state that pharmacology promises to accomplish what other measures have failed to bring about—the social emancipation of the mental hospital.4

Atypical Antipsychotic Drugs

In the years since 1950, many new phenothiazines were introduced and several completely new types of antipsychotic drugs have been discovered. Table 8.1 lists those in the U.S. market. We now refer to antipsychotic drugs as being either conventional antipsychotics (the phenothiazines and most of the other drug types introduced before the mid-1990s) or atypical (all antipsychotics introduced in the past 10 years are atypical antipsychotics). The atypical antipsychotics now dominate the market, with four of these drugs among the top 25 in psychiatric medication prescription sales in 2018.5

Mechanism of Antipsychotic Action

The first clue to the mechanism of action for antipsychotics was that virtually all of the phenothiazines and other conventional antipsychotics produce pseudoparkinsonism. Patients treated with these medications exhibit symptoms similar to Parkinson’s disease (tremors and muscular rigidity). Because Parkinson’s disease is known to be caused by a loss of dopamine neurons in the nigrostriatal dopamine pathway (see Chapter 4), scientists focused on the ability of antipsychotic drugs to block dopamine receptors. Although the conventional antipsychotics are generally fairly “dirty” drugs pharmacologically (they block other types of receptors as well), the doses required for the different drugs to produce antipsychotic effects do not correlate well with the ability of the different drugs to bind to any receptor except dopamine receptors (specifically, the D2 type of dopamine receptor). It is now well accepted that the initial effect of antipsychotic drugs is to block D2 dopamine receptors. However, this effect occurs with the first dose, but the antipsychotic effect of these drugs is not seen for at least 10 to 14 days (the “lag period”). Thus, the ultimate mechanism of antipsychotic action is some (as yet unknown) response of the nervous system to repeated administration of dopamine antagonists.

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When clozapine was introduced, it differed from the other antipsychotics in two interesting ways. First, it produced much less pseudoparkinsonism than the other drugs. Second, some patients who had failed to improve with the other antipsychotics showed improvement when treated with clozapine. Clozapine was very promising, but it unfortunately has a risk of producing a deadly suppression of white blood cell production. The drug was withdrawn from the market but then made available again as long as patients have periodic blood samples taken to monitor their white cells. Clozapine produces effects on a wide range of receptor types, but eventually it was determined that its unique properties were probably related to its ability to block both D2 dopamine and 5HT2A serotonin receptors. Risperidone, olanzepine, and the other atypical antipsychotics were developed with these two actions in mind, and none of the newer drugs carries the risk of suppressing white blood cell production. The atypical antipsychotics are sometimes referred to as serotonin-dopamine antagonists. Pseudoparkinsonism is reduced because of serotonin-dopamine interactions in the nigrostriatal pathway.

Side Effects of Antipsychotics

Allergic reactions might be noted, such as jaundice or skin rashes. Some patients exhibit photosensitivity, a tendency for the skin to darken and burn easily in sunlight. These reactions have a low incidence and usually decrease or disappear with a reduction in dosage. Agranulocytosis, low white blood cell count of unknown origin, can develop in the early stages of treatment. Because white blood cells are needed to fight infection, this disorder has a high mortality rate if not detected before a serious infection sets in. It is extremely rare with most of the antipsychotics other than clozapine.

The most common side effect of antipsychotic medication involves the nigrostriatal dopamine pathway (see Chapter 4). The major effects include a wide range of movement disorders from facial tics to symptoms that resemble those of Parkinson’s disease (tremors of the hands when they are at rest; muscular rigidity, including a masklike face; and a shuffling walk). As noted earlier, this pseudoparkinsonism is less of a problem with the newer atypical antipsychotics.

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Tardive dyskinesia is the most serious complication of antipsychotic drug treatment. Although first observed in the late 1950s, it was not viewed as a major problem until the mid-1970s, 20 years after these drugs were introduced. The term tardive dyskinesia means “late-appearing abnormal movements” and refers primarily to rhythmic, repetitive sucking and smacking movements of the lips; thrusting of the tongue in and out (“fly-catching”); and movements of the arms, toes, or fingers. The fact that this syndrome usually occurs only after years of antipsychotic drug treatment, and that the symptoms persist and sometimes increase when medication is stopped, raised the possibility of irreversible changes. The current belief is that tardive dyskinesia is the result of supersensitivity of the dopaminergic receptors. Although reversal of the symptoms is possible in most cases, the best treatment is prevention, which can be accomplished through early detection and an immediate lowering of the medication level.

Based on results from a large international three-year study, it now appears that treatment with conventional antipsychotics produces pseudoparkinsonism in about 30 percent of psychotic patients, with tardive dyskinesia appearing in about 10 percent. Several of the atypical antipsychotics, including clozapine, olanzepine, and quetiapine, are in a lower-risk group that produces about one-third as many of each of these important side effects.6

Significant weight gain has been seen with many of the newer atypical agents, along with increased blood lipids and other indications of a “metabolic syndrome” that is associated with increased risk for diabetes. This is a significant public health concern because so many patients are now receiving these medications.

Long-Term Effectiveness

It was mentioned earlier that drug dependence is not a problem with these antipsychotic agents. In fact, it has long been known that even patients who clearly benefit from their use tend to dislike the drugs and often stop taking them. The drug trials that demonstrate the benefits of antipsychotics typically last 6 or 8 weeks. This is a long enough time period to allow for some dosage adjustment and for the lag period for the antipsychotic effect to emerge, so these studies are optimal for the drug companies’ purpose—to show that their drug works better than a placebo. But patients typically take these drugs for long periods of time—in many cases, for the remainder of their lives. The National Institute of Mental Health funded a long-term study, that followed 1,400 patients with chronic schizophrenia taking four different atypical antipsychotics and one conventional antipsychotic for up to 18 months.7 The most surprising finding was that three-fourths of the patients quit taking the assigned medication before reaching 18 months of treatment. Some stopped because the drug did not appear to be helping and some stopped because the side effects became intolerable to them, but the biggest single reason for stopping was “patient’s decision.” In other words, in spite of short-term evidence of the efficacy of these drugs, their real-world effectiveness in treating chronic schizophrenia is considerably less than previously thought. The other surprising finding was that there was no clear evidence that the newer atypical agents worked any better than the conventional drugs, nor were there significant differences in extrapyramidal symptoms. A more recent meta-analysis of several long-term studies did report a slight advantage in relapse prevention for olanzepine, but the same drug caused greater weight gain.8

Antipsychotic Use in Children and the Elderly

Although almost all the research used to demonstrate the effectiveness of antipsychotic medications has been conducted on adults diagnosed with schizophrenia, once the drugs are marketed they can be prescribed for other populations and other uses. For example, in recent years there has been a large increase in the use of atypical antipsychotics in children, not only to treat psychotic disorders but also with diagnoses including ADHD and conduct disorder, for which they have not been approved. The reasoning seems to have been that because the newer drugs are less likely to produce the long-known and troublesome side effects of pseudoparkinsonism and tardive dyskinesia, they are “safer” than the older medications. However, several studies have now found an increased risk of both weight gain and metabolic changes combined with obesity, diabetes, and cardiovascular problems in children treated with the atypical antipsychotics.9

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Likewise, elderly patients have been treated with antipsychotic drugs for years, often to control behavioral problems such as emotional outbursts or inappropriate sexual acting out in institutionalized patients. In many cases, these patients are suffering from dementia, and their uncontrolled behavior is a problem for their families, the staff, and the other patients. Evidence of a significant increase in death risk from cardiovascular and other problems in elderly patients treated with the atypical antipsychotics led the FDA in 2008 to require a “black box” warning regarding the use of these drugs for behavior management in elderly patients with dementia.

Antidepressants

Monoamine Oxidase Inhibitors

In previous editions of this textbook, we stated that the discovery of “antidepressant medications” had its origins in the treatment of tuberculosis around the mid-1950s. In a sense, that’s correct, but it’s not the entire story. Long before 1950, a number of others drugs, including the stimulants cocaine and amphetamine, were used in the treatment of depression. Indeed, as we noted in Chapter 6, amphetamine is still used today as an adjunctive antidepression therapy, albeit in a limited fashion.

The notion that the 1950s ushered in the antidepressant drug era stems from a story of serendipity. In 1951, iproniazid was synthesized in the search for new anti-tuberculosis drugs. At the time, tuberculosis was a major public health problem and caused tens of thousands of deaths each year in the United States. Iproniazid proved to be not just an effective tuberculosis treatment but also a mood enhancer in some tuberculosis patients. Clinical reports on its use in tuberculosis hospitals emphasized that there was considerable elevation of mood in the patients receiving iproniazid. This fortuitous information spurred several research studies investigating the drug for its utility in treating depression. Results varied widely, with some patients improving and others not. Some even got worse. In spite of this reality, around 1955 some influential psychiatrists began prescribing iproniazid as an off-label treatment for depression, and others dutifully followed. Thus, iproniazid is often referred to as the first “official” antidepressant, even though it was never received FDA approval for that purpose.

Iproniazid is a monoamine oxidase (MAO) inhibitor, and its discovery opened up a new class of compounds for investigation. Although several MAO inhibitors have been introduced over the years, toxicity and side effects have limited their use and have reduced their number. Iproniazid was removed from sale in 1961 after being implicated in at least 54 fatalities. Currently four MAO inhibitors are in the U.S. market (see Table 8.2). A major limitation of the use of the MAO inhibitors is that they alter the normal metabolism of a dietary amino acid, tyramine, such that if an individual consumes foods with a high tyramine content while taking MAO inhibitors, a hypertensive (high blood pressure) crisis can result. Because aged cheeses are one source of tyramine, this is often referred to as the “cheese reaction.” A severe headache, palpitations, flushing of the skin, nausea, and vomiting are some symptoms of this reaction, which have in some cases ended in death from a stroke (cerebrovascular accident). Besides avoiding foods and beverages that contain tyramine (aged cheeses, Chianti wine, smoked or pickled fish, and many others), patients taking MAO inhibitors must also avoid sympathomimetic drugs, such as amphetamines, methylphenidate, and ephedrine.

MAO is an enzyme involved in the breakdown of serotonin, norepinephrine, and dopamine, and its inhibition results in increased availability of these neurotransmitters at the synapse. This was the first clue to the possible mechanism of antidepressant action.

Tricyclic Antidepressants

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Sometimes when you are looking for one thing, you find something entirely different. The MAO inhibitors were found among antituberculosis agents, and the phenothiazine antipsychotics were found while looking for a better antihistamine. The tricyclic antidepressants were found in a search for better phenothiazine antipsychotics. The basic phenothiazine structure consists of three rings, with various side chains for the different antipsychotic drugs. Imipramine resulted from a slight change in the middle of the three rings and was tested in 1958 on a group of patients. The drug had little effect on psychotic symptoms but improved the mood of depressed patients. This was the first tricyclic antidepressant, and many more have followed (see Table 8.2). Although these drugs are not effective in all patients, most controlled clinical trials do find that depressive episodes are less severe and resolve more quickly if the patients are treated with one of the tricyclic antidepressants than if they are given a placebo.

The first tricyclics were discovered to interfere with the reuptake into the terminal of the neurotransmitters norepinephrine, dopamine, and serotonin. This results in an increased availability of these neurotransmitters at the synapse. Because MAO inhibition also results in increased availability of the same neurotransmitters, there has been considerable speculation that the antidepressant actions of both classes of drugs result from increased synaptic availability of one or more of these neurotransmitters. One of the effective antidepressants, desipramine, was found to have a much greater effect on the reuptake of norepinephrine than on the reuptake of either dopamine or serotonin, so for a time most theories of antidepressant action focused on norepinephrine.

Selective Reuptake Inhibitors

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The introduction of fluoxetine (Prozac) in 1987 ushered in the era of the selective serotonin reuptake inhibitors (SSRIs). Trazodone had already been available and was known to have a greater effect on serotonin than on norepinephrine reuptake, calling the norepinephrine theory into question. Prozac soon became the most widely prescribed antidepressant drug ever marketed. Prozac is safer than the tricyclic antidepressants in that it is less likely to lead to overdose deaths, so physicians felt more confident about prescribing it. Despite some reports in the early 1990s of unusual violent or suicidal reactions, sales of Prozac continued at a high rate, and several other SSRIs were introduced by other companies. Drugs have also been developed that are reuptake inhibitors for both serotonin and norepinephrine. In that sense they are similar to the older tricyclics, but these newer drugs are more selective (have fewer other actions than the tricyclics) and are thus referred to as selective serotonin and norepinephrine reuptake inhibitors (SSNRIs). Effexor was the first of these, followed in 2004 by Cymbalta (see Table 8.2).

Add-On Medication

In 2007, the antipsychotic drug Abilify (aripiprazole) was approved by the FDA as an add-on treatment for those already taking antidepressant medication, because of some studies showing improvement in patients who had not responded to the antidepressant alone. Since then, Abilify has been one of the top-selling prescription drugs each year. In 2018, it was Number 4 on the list of best-selling psychiatric medications raking in $1.7 billion (see Table 8.3). Abilify’s patent ran out in 2014 and several generic versions hit the market starting in 2015. In response, Abilify’s Japanese manufacturer Otsuka submitted a similar drug, brexpiprazole (Rexulti), which received FDA approval in 2015. We can expect a major advertising push to shift new prescriptions to this newly approved drug.

The worldwide value of antidepressant sales is expected to exceed $15 billion by 2023. Sales of these drugs are driven not only by prescriptions written to combat depression, but also by their increasing use to treat generalized anxiety, obsessive-compulsive, and panic disorders.

Another factor that perhaps should influence prescribing practices is the question of just how effective antidepressant medications are in general. It had been noticed in an earlier, not widely read Internet journal article that the data submitted to the FDA for approval of the SSRIs often showed very small, or sometimes no, differences between the tested drug and placebo. Because the FDA requires the company to submit records of all studies, even the unsuccessful ones, analysis of the overall set of results seemed to indicate that the majority of the effectiveness produced by these drugs can be attributed to a placebo effect. A recent review of the research used to receive approval for the new antidepressant vortioxetine (Trintellix) pointed out a number of limitations in the results as well as in the FDA’s process for evaluating effectiveness.10 Overall, only about half of the 74 studies submitted to the FDA since 1987 in support of the new drug applications for 12 antidepressants found positive results in favor of the tested drug. The selective publication of only the positive findings means that practicing physicians who read the medical literature get an inflated picture of the overall effectiveness of this type of medication. At this point, the best evidence we have indicates that these antidepressant drugs are probably slightly better than placebos but are certainly not as effective overall as most people, including most physicians, have believed. However, if you are currently taking one of these medications yourself, please do not simply stop taking it abruptly. There are major withdrawal effects associated with abrupt cessation of most of these medications, so if you are trying to decide what to do about continued use, be sure to consult your physician.

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Mechanism of Antidepressant Action

It seems that most antidepressants work by increasing the availability of either norepinephrine or serotonin at their respective synapses. However, the antidepressant effect of MAO inhibitors, tricyclics, and SSRIs exhibits a “lag period”: The patient must take the drug for about 2 weeks before improvement is seen, even though the biochemical effects on MAO or on reuptake occur in a matter of minutes. Although it has been suggested that some patients might benefit more from one type than from another, experiments have so far failed to reveal any rational basis for choosing among the drugs in any individual case, and overall the effectiveness of the drug does not seem to depend on which of the neurotransmitters is more affected.

Current theories of the antidepressant action of these agents focus less on the initial biochemical effects of the drugs than on the reaction of the neurons to repeated drug exposure. As is the case with antipsychotics, we do not yet know the complete story of how long-term exposure to antidepressant drugs eventually improves the symptoms of depression. In addition to the MAO inhibitors, tricyclics, and selective reuptake inhibitors, drugs such as Spravato and Remeron act through different mechanisms. The fact that drugs with a wide variety of initial biochemical effects are all about equally effective (they reduce depressive symptoms for some people, but not for all) means it is possible that there is not a single biochemical mechanism to explain the effects of all these drugs.

Electroconvulsive Therapy

An effective, but controversial, treatment for depression is electroconvulsive shock therapy (ECT). For many, this procedure conjures up images of a time long passed, when large, state psychiatric institutions were staffed with individuals more obsessed with patients’ strict adherence to rules designed for conformity and submission than patients’ well-being. Nevertheless, ECT has been shown repeatedly to be more effective in relieving the symptoms of depression than placebo. Further, it has been demonstrated to be more effective than (or equal to) the most effective class of antidepressant drugs. One factor that makes ECT sometimes the treatment of choice is its more rapid effect than that found with current antidepressant drugs. Reversal of depression might not occur for 2 or 3 weeks with drug treatment, but with ECT results sometimes are noticed almost immediately. When there is a high risk of suicide, ECT is often considered necessary and it is possible to use both drug and ECT treatment simultaneously.3 However, one consistent troubling finding is that ECT causes memory impairments. Generally speaking, the greater the antidepressant effect, the more extensive the impairment. This drawback has generally limited ECT to patients suffering from severe depression whose symptoms have not responded to other therapies.

Mood Stabilizers

In the late 1940s, two medical uses were proposed for salts of the element lithium. In the United States, lithium chloride, which tastes much like sodium chloride (table salt), was introduced as a salt substitute for heart patients. However, above a certain level lithium is quite toxic, and because there was no control over the dose, many users became ill and several died. This scandal was so great in the minds of American physicians that a proposed beneficial use published in 1949 by an Australian, John Cade, produced little interest in this country.

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Cade had been experimenting with guinea pigs, examining the effects of lithium on urinary excretion of salts. Lithium appeared to have sedative properties in some of the animals, so he administered the compound to several disturbed patients. The manic patients all improved, whereas there seemed to be no effect on depressed or schizophrenic patients. This was followed up by several Danish studies in the 1950s and early 1960s, and it became increasingly apparent that the large majority of manic individuals showed dramatic remission of their symptoms after a lag period of a few days when treated with lithium carbonate or other salts.

Three factors slowed the acceptance of lithium in the United States. First was the salt-substitute poisonings, which gave lithium a bad reputation as a potentially lethal drug. Second, mania was not seen as a major problem in the United States. Manic patients feel energetic and have an unrealistically positive view of their own abilities, and such people are unlikely to seek treatment on their own. Also, patients who became quite manic and lost touch with reality would probably have been called schizophrenic in those days, perhaps at least partly because a treatment existed for schizophrenia. The antipsychotic drugs can control mania in most cases. The third and possibly most important factor is economic and relates to the way new drugs are introduced in the United States: by companies that hope to make a profit on them. Lithium is one of the basic chemical elements (Number 3 on the periodic chart) and its simple salts had been available for various purposes for many years, so it would be impossible for a drug company to receive an exclusive patent to sell lithium. A company generally must go to considerable expense to conduct the research necessary to demonstrate safety and effectiveness to the FDA. If one company had done this, as soon as the drug was approved any other company could also have sold lithium, and it would have been impossible for the first company to recoup its research investment. After several years of frustration, the weight of the academically conducted research and the clinical experience in Europe was such that several companies received approval to sell lithium in 1970.

Treatment with lithium requires 10 to 15 days before symptoms begin to change, and once again the ultimate mechanism for its action is not yet known. Lithium is both safe and toxic. It is safe because the blood level can be monitored routinely and the dose adjusted to ensure therapeutic, but not excessive, blood levels. Patients develop tolerances to the minor side effects of gastrointestinal disturbances and tremors. Excessively high levels in the blood cause confusion and loss of coordination, which can progress to coma, convulsions, and death if lithium is not stopped and appropriate treatment instituted.

Of primary importance in the therapeutic use of lithium is the realization that lithium acts as a mood-normalizing agent in individuals with bipolar illness. Lithium will prevent both manic and depressed mood swings. It has only moderate effects on unipolar depressions.

The biggest limitation to the usefulness of lithium is that patients simply do not like to take it and most will discontinue its use at some point. This high rate of noncompliance is the major reason why, although lithium is perhaps the single most effective psychotherapeutic agent available, alternative medications have been developed.

Table 8.4 shows that several other drugs also have been approved to treat bipolar disorder. Some such as the anticonvulsants—valproic acid, carbamazepine, and lamotrigine—may be particularly useful in people who might be susceptible to epileptic seizures. They are probably not quite as effective as lithium, but they have the advantage that monitoring of blood levels is not required. Also, as we stated earlier, some atypical antipsychotics are also used as mood stabilizers (to treat bipolar disorder). The mood-stabilizing anticonvulsants and antipsychotics are thought to be better accepted by patients than is lithium, but noncompliance is an issue with these drugs as well (perhaps not as much as with lithium). Patients with bipolar disorder who clearly improve while on medication but who relapse because they stop taking it may go through this cycle repeatedly, often with tragic consequences (suicide, arrest, homelessness).

Consequences of Drug Treatments for Mental Illness

The use of modern psychopharmaceuticals, which began in the mid-1950s in the United States, has affected the lives of millions of Americans who have been treated with them. But the availability of these effective medications has also brought about revolutionary changes in our society’s treatment of and relationship with our mentally ill citizens. Figure 8.1 depicts what happened to the population of our large mental hospitals from 1946 to 2014. These hospitals had grown larger and larger and held a total of over half a million people in the peak years of the early 1950s. The year in which chlorpromazine was introduced in the United States, 1955, was the last year in which the population of these hospitals increased. Since then the average population has continued to decline. The antipsychotics do not cure schizophrenia or other forms of psychosis, but they can control the symptoms to a great degree, allowing the patients to leave the hospital, live at home, and often earn a living. These drugs began the liberation of mental patients from hospitals, where many of them had previously stayed year after year, committed for an indefinite time.

The movement out of mental hospitals was accelerated by the 1963 Community Mental Health Act, which provided federal support to states to develop community-based mental health centers. The idea was to treat mental patients closer to home in a more natural environment, at lesser expense, and on an outpatient basis. The opportunity for such a program to work was greatly enhanced by the availability of the antipsychotics. The establishment of Medicare and Medicaid in 1965 moved thousands of elderly patients suffering from dementia out of mental hospitals and into nursing homes, further accelerating the decline in psychiatric hospital populations.

The mental health professions have been greatly affected by these drugs. The majority of psychiatrists in practice today spend less time doing psychotherapy than did their colleagues in the 1950s. In fact, for many psychiatrists the first issue is to establish an appropriate drug regimen, and only after the initial symptoms are controlled will they engage in much talk therapy. For some psychiatrists, the prescription pad has replaced the couch as their primary tool. This may be sensible in terms of overall cost effectiveness, but it has altered the doctor-patient relationship.

Along with the liberation of patients from hospitals and their return to the community came a concern for their civil rights. Indefinite commitment to a hospital was declared unconstitutional in 1975, and all states have since developed procedures to protect the rights of individual patients. Hearings are required before a person can be committed for treatment against his or her will, and it is usually necessary to demonstrate a clear and present danger to the patient’s own person or to others. Periodic reviews of the patient’s status are called for, and if at any time the immediate danger is not present, the patient must be released. No one would want to argue that mental patients should not have these rights, but the availability of psychoactive medications helps create difficult situations. A patient who is dangerously psychotic might be admitted for treatment and, after a few weeks on an antipsychotic drug, might be sufficiently in control to be allowed to leave the hospital. However, if the patient remains suspicious or simply doesn’t like to take the medication, he or she will eventually stop taking it and again become psychotic. Or patients might be released into the community, perhaps functioning with medication or perhaps not, too sick to really take care of themselves but not sick enough to present an immediate danger. Often, the eventual result is violation of a law, leading to imprisonment. In fact, more mentally ill persons are jailed each year than are admitted to state mental hospitals. About one-third of all homeless people in the United States have some form of serious mental illness. The plight of our homeless, rootless, mentally ill citizens has been the subject of magazine and television reports, and efforts are being made to change the way these people are treated.

Summary

· The medical model of mental illness has been widely criticized, yet psychotherapeutic drugs are often discussed in the context of this model.

· Diagnosis of mental disorders is difficult and controversial, but the DSM-5 provides a standard diagnostic approach for most purposes.

· The introduction of antipsychotics in the mid-1950s started a revolution in mental health care and increased interest in psychopharmacology.

· The antipsychotics reduce the symptoms of schizophrenia, but they often produce movement disorders, some of which resemble Parkinson’s disease. Atypical antipsychotics are now widely prescribed for a variety of disorders.

· The major groups of antidepressant drugs are the MAO inhibitors, the tricyclics, and the selective reuptake inhibitors.

· The selective reuptake inhibitors are a major source of revenue for the pharmaceutical industry.

· Lithium is useful in treating mania and in preventing mood swings in bipolar disorder.

· The number of people occupying beds in mental hospitals has declined since 1955, partly because psychotherapeutic drugs allow people to be released after shorter stays.

Review Questions

1. Give two examples of anxiety disorder.

2. Is schizophrenia a functional or an organic psychosis?

3. Besides sadness, what are some other indicators of a major depressive episode?

4. What type of drug is chlorpromazine, and where was it first tested on patients?

5. What is tardive dyskinesia, and how does it respond to a reduction in the dose of an antipsychotic drug?

6. Which type of drug was discovered while testing an antituberculosis agent?

7. How do the selective reuptake inhibitors differ from the older tricyclics in terms of their actions in the brain?

8. What were two of the three reasons it took so long for lithium to be available for use in the United States?

9. If clozapine is so dangerous, why is it prescribed at all?

10. Why was Prozac the most widely prescribed antidepressant drug ever marketed?