Biopsychology of Psychiatric Disorders PDF

HOOFDSTUK 2 This chapter is about the biopsychology of psychiatric disorders (disorders of psychological function sufficiently severe to require treatment). One of the main difficulties in studying or treating psychiatric disorders is that they are difficult to diagnose. The psychiatrist or clinical psychologist must first decide whether a patient’s psychological function is pathological or merely an extreme of normal human variation: For example, does a patient with a poor memory suffer from a pathological condition, or is he merely a healthy person with a poor memory? If a patient is judged to be suffering from a psychiatric disorder, then the particular disorder must be diagnosed. Because we cannot yet identify the specific brain pathology associated with various disorders, their diagnosis usually rests entirely on the patient’s symptom profile. Currently, the diagnosis is guided by the DSM-5 (the current edition of the Diagnostic and Statistical Manual of the American Psychiatric Association). There are two main difficulties in diagnosing particular psychiatric disorders: (1) patients suffering from the same disorder often display different symptoms, and (2) patients suffering from different disorders often display many of the same symptoms. Consequently, experts often disagree on the diagnosis of particular cases, and the guidelines provided by the DSM change with each new edition (see Blashfield et al., 2014). One purpose of this chapter is to help you understand why it is important to periodically revise the diagnosis of psychiatric disorders. This chapter begins with discussions of five sorts of psychiatric disorders: schizophrenia, depressive disorders, bipolar disorder, anxiety disorders, and Tourette’s disor-der. It ends with a description of how new psychotherapeutic drugs are developed and tested. Schizophrenia: The Case of Lena Lena’s mother was hospitalized with schizophrenia when Lena was 2. As a child, Lena displayed periods of hyperactivity; as an adolescent, she was viewed as odd. She enjoyed her classes and got good grades, but she had few friends. Shortly after their marriage, Lena’s husband noticed that Lena was becoming more withdrawn. She would sit for hours barely moving a muscle, often having lengthy discussions with nonexistent people. One day, Lena’s husband found her sitting on the floor in an odd posture staring into space. She was totally unresponsive. When he tried to move her, Lena displayed waxy flexibility—that is, she reacted like a mannequin, not resisting movement and holding her new position until she was moved again. She was diagnosed with schizophrenia with catatonia (schizophrenia characterized by long periods of immobility and waxy flexibility). In the hospital, Lena displayed a speech pattern exhibited by some individuals with schizophrenia: echolalia (vocalized rep-etition of some or all of what has just been heard). Doctor: How are you feeling today? Lena: I am feeling today, feeling the feelings today. Doctor: Are you still hearing the voices? Lena: Am I still hearing the voices, voices? What Is Schizophrenia? LO 2.1 Describe the positive and negative symptoms of schizophrenia, and provide specific examples of each. Schizophrenia Schizophrenia means “the splitting of psychic functions.” The term was coined in the early years of the 20th century to describe what was assumed at the time to be the primary symptom of the disorder: the breakdown of integration among emotion, thought, and action. Schizophrenia is considered to be a severe psychiatric disorder. It attacks about 1 percent of individuals of all races and cultural groups, typically beginning in adolescence or early adulthood (see Sikela & Quick, 2018). Schizophrenia occurs in many forms, but the case of Lena introduces you to some of its common features (Meyer & Salmon, 1988). The major difficulty in studying and treating schizophrenia is accurately defining it (see Bhati, 2013). Its symptoms are complex and diverse; they overlap greatly with those of other psychiatric disorders and frequently change during the progression of the disorder. Also, various neurological conditions (e.g., complex seizures) have symptoms that might suggest a diagnosis of schizophrenia. Because the current definition of schizophrenia overlaps with that of several different disorders, the DSM-5 prefers to use the label schizophrenia spectrum disorders to refer to schizophrenia and related disorders (see Bhati, 2013). The following are some symptoms of schizophrenia, although none of them appears in all cases. In an effort to categorize cases of schizophrenia so that they can be stud-ied and treated more effectively, it is common practice to consider positive symptoms (symptoms that seem to repre-sent an excess of typical function) separately from negative symptoms (symptoms that seem to represent a reduction or loss of typical function)—see Smigielski et al. (2020). Examples of positive symptoms include the following: Delusions. Delusions of being controlled (e.g., “Martians are making me steal”), delusions of persecution (e.g., “My mother is poisoning me”), or delusions of grandeur (e.g., “Steph Curry admires my jump shot”). Hallucinations. Imaginary voices making critical com-ments or telling patients what to do. Inappropriate affect. Reacting with an inappropriate emotional response to positive or negative events. Disorganized speech or thought. Illogical thinking, pecu-liar associations among ideas, belief in supernatural forces. Odd behavior. Talking in rhymes, difficulty performing everyday tasks. Examples of negative symptoms include the following: Affective flattening. Diminished emotional expression. Avolition. Reduction or absence of motivation. Catatonia. Remaining motionless, often in awkward positions for long periods. The frequent recurrence of any two of these symp-toms for 1 month is currently sufficient for the diagnosis of schizophrenia—provided that one of the symptoms is delusions, hallucinations, or disorganized speech. Discovery of the First Antipsychotic Drugs LO 2.2 Describe the discovery of the first two widely prescribed antipsychotic drugs. The first major breakthrough in the study of the biochemistry of schizophrenia was the accidental discovery in the early 1950s of the first antipsychotic drug (a drug that is meant to treat certain symptoms of schizophrenia and bipolar disorder), chlorpromazine. Chlorpromazine was developed by a French drug company as an antihistamine. Then, in 1950, a French surgeon noticed that chlorpromazine given prior to surgery to counteract swelling had a calming effect on some of his patients, and he suggested that it might have a calming effect on difficult-to-handle patients with psychosis (a loss of touch with reality). His suggestion triggered research that led to the discovery that chlorpromazine alleviates the symptoms of schizophrenia: Agitated patients with schizophrenia were calmed by chlorpromazine, and emotionally blunted patients with schizophrenia were activated by it. Don’t get the idea that chlorpromazine cures schizophrenia. It doesn’t. But it often reduces the severity of symptoms enough to allow institutionalized patients to be discharged. Shortly after the antipsychotic action of chlorpromazine was first documented, an American psychiatrist became 27 Biopsychology of Psychiatric Disorders 487 interested in reports that the snakeroot plant had long been used in India for the treatment of mental illness. He gave reserpine—the active ingredient of the snakeroot plant—to his patients with schizophrenia and confirmed its antipsy-chotic action. Reserpine is no longer used in the treatment of schizophrenia because it produces a dangerous decline in blood pressure at the doses needed for successful treatment. Although the chemical structures of chlorpromazine and reserpine are dissimilar, their antipsychotic effects are similar in two major respects. First, the antipsychotic effect of both drugs is manifested only after a patient has been medicated for 2 or 3 weeks. Second, the onset of this antipsychotic effect is usually associated with motor effects similar to the symptoms of Parkinson’s disease (e.g., muscular rigidity, a general decrease in voluntary movement). These similarities suggested to researchers that chlorpromazine and reserpine were acting through the same mechanism— one that was related to Parkinson’s disease. The Dopamine Theory of Schizophrenia LO 2.3 Describe the evolution of the dopamine theory of schizophrenia. The next major breakthrough in the study of schizophrenia came from research on Parkinson’s disease. In 1960, it was reported that the striatums (caudates plus putamens; see Figure 3.28) of persons with Parkinson’s disease had been depleted of dopamine (see Goetz, 2011). This finding suggested that a disruption of dopaminergic transmission might produce both Parkinson’s disease and the antipsychotic effects of chlorpromazine and reserpine. Thus was born the dopamine theory of schizophrenia—the theory that schizophrenia is caused by too much dopamine and, conversely, that antipsychotic drugs exert their effects by decreasing dopamine levels (see McCutcheon, Abi-Dargham, & Howes, 2019). Lending instant support to the dopamine theory of schizophrenia were two already well-established facts. First, the antipsychotic drug reserpine was known to deplete the brain of dopamine and other monoamines by breaking down the synaptic vesicles in which these neurotransmitters are stored. Second, drugs such as amphetamine and cocaine, which can trigger episodes that resemble schizophrenia in healthy users, were known to increase the extracellular levels of dopamine and other monoamines in the brain. An important step in the evolution of the dopamine theory of schizophrenia came in 1963, when Carlsson and Lindqvist assessed the effects of chlorpromazine on extra-cellular levels of dopamine and its metabolites (substances that are created by the breakdown of another substance in cells). Although they expected to find that chlorpromazine like reserpine, depletes the brain of dopamine, they didn’t. The extra-cellular levels of dopamine were unchanged by chlorpromazine, and the extracellular levels of its metabolites were increased. The researchers concluded that both chlorpromazine and reserpine antagonize transmission at dopa-mine synapses but that they do it in different ways: reserpine by depleting the brain of dopamine and chlorpromazine by binding to dopamine receptors. Carlsson and Lindqvist argued that chlorpromazine is a receptor blocker at dopamine synapses—that is, it binds to dopamine receptors without activating them and, in so doing, keeps dopamine from acti- vating them (see Figure 2.1). We now know that many psychoactive drugs are receptor blockers, but chlorpromazine was the first to be identified as such. Carlsson and Lindqvist fur- Figure 2.1 Chlorpromazine is a receptor blocker at dopamine synapses. Chlorpromazine was the first receptor blocker to be identified, and its discovery changed psychopharmacology. 1 Chlorpromazine binds to postsynaptic dopamine receptors; it does not activate them, and it blocks the ability of dopamine to activate them. Chlorpromazine Dopamine receptor 23 The blockage of dopamine receptors by chlorpromazine sends a feedback signal to the presynaptic neuron, which increases the release of dopamine. The feedback signal increases the release of dopamine, which is ther postulated that the lack of activity at postsynaptic dopamine receptors sent a feedback signal to the presynaptic cells that increased their release of dopamine, which was broken down in the synapses. This explained why dopaminergic activity was reduced while extracellular levels of dopamine stayed about the same and extracellular levels of its metabolites were increased. Carlsson and Lindqvist’s findings led to an important revi-sion of the dopamine theory of schizophrenia: Rather than high dopamine levels, the main factor in schizophrenia was presumed to be high levels of activity at dopamine receptors. In the mid- 1970s, Snyder and his colleagues (see Creese, Burt, & Snyder, 1976; Madras, 2013) assessed the degree to which the various antipsychotic drugs that had been developed by that time bind to dopamine recep-tors. First, they added radioactively labeled dopamine to samples of dopamine-receptor-rich neural membrane obtained from calf striatums. Then, they rinsed away the unbound dopamine molecules from the samples and mea-sured the amount of radioactivity left in them to obtain a measure of the number of dopamine receptors. Next, in other samples, they measured each drug’s ability to block the binding of radioactive dopamine to the sample; the assumption was that the drugs with a high affinity for dopamine receptors would leave fewer sites available for the dopamine. In general, they found that chlorpromazine broken down in the synapse, resulting in elevated levels of dopamine metabolites. Dopamine Dopamine metabolites and the other effective antipsychotic drugs had a high affinity for dopamine receptors, whereas ineffective antipsychotic drugs had a low affinity. There were, how-ever, several major exceptions, including haloperidol. Although haloperidol was one of the most potent anti-psychotic drugs of its day, it had a relatively low affinity for dopamine receptors. A solution to the haloperidol puzzle came with the discovery that dopamine binds to more than one dopa-mine receptor subtype—five have been identified (see Beaulieu, Espinoza, & Gainetdinov, 2015). It turns out that chlorpromazine and other antipsychotic drugs in the same chemical class (the phenothiazines) all bind effectively to both D1 and D2 receptors, whereas haloperidol and the other antipsychotic drugs in its chemical class (the butyro-phenones) all bind effectively to D2 receptors but not to D1 receptors. This discovery of the selective binding of butyro- phenones to D2 receptors led to an important revision in the dopamine theory of schizophrenia. It suggested that schizophrenia is caused by hyperactivity specifically at D2 receptors, rather than at dopamine receptors in general. Snyder and his colleagues (see Madras, 2013; Snyder, 1978) subsequently confirmed that the degree to which typical antipsychotics (the first generation of antipsychotic drugs) Schizophrenia: Beyond the Dopamine Theory LO 2.4 Describe two current lines of research on schizophrenia. Haloperidol Spiroperidol Although the dopamine theory of schizophrenia is still influ-ential, current lines of research into atypical antipsychotics and psychedelic drug effects are leading to interesting new perspectives. These two areas of research will be described in the following two subsections. Chlorpromazine Potency of D2 Binding Based on Snyder, S. H. (1978). Neuroleptic drugs and neurotransmitter receptors. Journal of Clinical and Experimental Psychiatry, 133, 21–31. ATYPICAL ANTIPSYCHOTICS. Currently, atypical antipsychotics (also known as second- generation antipsy-chotics) are often the drugs of choice for the treatment of schizophrenia. Atypical antipsychotics are drugs that are effective against schizophrenia but yet do not bind strongly to D2 receptors. For example, clozapine, the first atypical antipsychotic to be approved for clinical use, has an affin-ity for D1 receptors, D4 receptors, and several serotonin and histamine receptors, but only a slight affinity for D2 receptors (see Humbert- Claude et al., 2012). Aripiprazole, respiridone, and quetiapine are but a few of the other com-monly prescribed atypical antipsychotics. drugs) bind to D2 receptors is highly correlated with their effectiveness in suppressing the symptoms of schizophrenia (see Figure 2.2). For example, the butyrophenone spiroperidol had the greatest affinity for D2 receptors and the most potent antipsychotic effect. Although the evidence implicating D2 receptors in schizophrenia is strong, it has become apparent that the D2 version of the dopamine theory of schizophrenia could not explain two general findings: Although typical antipsychotics block activity at D2 receptors within hours, their therapeutic effects are usually not apparent for several weeks. Almost all antipsychotics are only effective in the treat-ment of schizophrenia’s positive symptoms, but not its negative symptoms (see Aleman et al., 2018; Osoegawa et al., 2018). Appreciation of these limitations has led to the current version of the dopamine theory. This version holds that excessive activity at D2 receptors is one factor in the disor-der but that there are many other factors as well (see Poels et al., 2014; Sibley & Shi, 2018). Those of you who read about the mesocorticolimbic dopamine pathway and the nigrostriatal dopamine pathway might be wondering which of those two pathways is affected in schizophrenia. The dopamine theory of schizophrenia proposes that schizophrenia is caused by excessive activity in the mesocorticolimbic pathway. RENEWED INTEREST IN HALLUCINOGENIC DRUGS. The study of psychedelic drugs (drugs whose primary action is to alter perception, emotion, and cog-nition) began in 1943 with the discovery of lysergic acid diethylamide (LSD) (see Garcia-Romeu & Richards, 2018; Nichols, 2016). In addition to classical hallucinogens (such as LSD, psilocybin, and mescaline), psychedelic drugs include a variety of other drugs such as the dissociative hallucinogens (e.g., ketamine and phencyclidine). Researchers have pursued two lines of research on psychedelics. One line focused on those psychedelic drugs that produce effects similar to the symptoms of psychiatric disorders (e.g., illusions, hallucinations, paranoia, panic), and they used the drugs to model the disorders. The other line focused on the feelings of boundlessness, unity, and bliss reported by some users and attempted to use psychedelics in the treatment of psychiatric disorders. Unfortunately, these promising lines of research ground to a halt in the 1970s when many governments, troubled by the association of LSD and related drugs with various societal subcultures, made it extremely difficult for researchers to study their effects, particularly in humans (see Belouin & Henningfield, 2018; Rucker, Iliff, & Nutt, 2018; but see Oram, 2016). In the 1990s, there was a gradual renewal of interest in utilizing psychedelic drugs to study the mechanisms of schizophrenia and other psychiatric disorders (see Belouin & Henningfield, 2018; Rucker, Iliff, & Nutt, 2018). This renewal was stimulated by the development of tech-niques for imaging the effects of drugs in the human brain and by an increased understanding of the mechanisms of psychedelic drug action (e.g., Tylš, Páleníček, & Horáček, 2014). This research led to three important conclusions: The psychedelic effects of classical hallucinogens, such as LSD, mimic the positive symptoms of schizophrenia (e.g., hallucinations and disorganized thought) by act-ing as an agonist of the serotonin type-2a receptor. That antagonists of the serotonin type-2a receptor are effective antipsychotics (e.g., the atypical antipsychotic risperidone) (see Girgis et al., 2018). Dissociative hallucinogens (e.g., ketamine) mimic the negative symptoms of schizophrenia by acting as antagonists of glutamate receptors (see Laruelle, 2014). Genetic and Epigenetic Mechanisms of Schizophrenia LO 2.5 Explain what is currently known about the genetics and epigenetics of schizophrenia. It is clear that schizophrenia involves multiple genetic and epigenetic mechanisms. Many genes have been linked to the disorder (see Flint & Manufò, 2014; Reardon, 2014; Ripke et al., 2014), but no single gene seems capable of causing schizophrenia by itself, although certain genes have been more strongly implicated than others (see Dhindsa & Goldstein, 2016; Sikela & Quick, 2018; Sekar et al., 2016). The study of schizophrenia-related genes and their expression is still in its early stages, but it has already pointed to several physiological changes that could play important roles in development of the disorder (see Kotlar et al., 2015). For example, the expression of schizophrenia-related genes is associated with multiple aspects of brain development (see Birnbaum & Weinberger, 2017; Jaffe et al., 2018; Smigielski et al., 2020), myelination (see Voineskos et al., 2012), transmission at glu- tamatergic and GABAergic synapses (see Sacchetti et al., 2013), and changes in dopaminergic neuron physiology (see Dong et al., 2018; but see Gürel et al., 2020); and some genes that increase a person’s susceptibility to schizophrenia have also been linked to other psychiatric and neurological dis-orders (see Rizzardi et al., 2019). A variety of early experiential factors have been implicated in the development of schizophrenia—for example, birth complications, maternal stress, prenatal infections, socioeconomic factors, urban birth or residing in an urban setting, and childhood adversity (see Owen, Sawa, & Mortensen, 2016). Such early experiences are thought to alter the typical course of neurodevelopment leading to schizophrenia in individuals who have a genetic susceptibility (see Negrón-Oyarzo et al., 2016; Owen, Sawa, & Mortensen, 2016), presumably through epigenetic mechanisms—see Birnbaum & Weinberger (2017), Hannon et al. (2016), Jaffe et al. (2016), and Sharp & Akbarian (2016). Supporting this neurodevelopmental theory of schizophrenia are (1) the fact that schizophrenia and autism spectrum disorders share many of the same causal factors (e.g., genetic risk factors, environmental triggers)—see Millan et al. (2016), and (2) the study of two 20th-century famines: the Nazi-induced Dutch famine of 1944–1945 and the Chinese famine of 1959–1961. Fetuses whose pregnant mothers suffered in those famines were more likely to develop schizophrenia as adults (see Li et al., 2015; Schmitt et al., 2014). Recent research has identified many epigenetic mecha-nisms that contribute to the emergence and persistence of schizophrenia (see Rizzardi et al., 2019). For example, DNA methylation and histone modifications have both been implicated in the expression of genes for synapse- specific proteins in prefrontal cortex neurons (see Caldeira, Peça, & Carvalho, 2019; Rizzardi et al., 2019). This and other research on the role of epigenetic mechanisms has given researchers better insight into how genes interact with the environment to produce schizophrenia (see Breen et al., 2019; Gandal et al., 2018; Girdhar et al., 2018). The role of transgenerational epigenetic mechanisms in psychiatric disorders like schizophrenia is also of great interest to researchers (see Yeshurun & Hannan, 2019). Neural Bases of Schizophrenia LO 2.6 Describe the various brain changes associated with schizophrenia. There is a long history of research on the neural bases of schizophrenia. Many studies have assessed brain develop-ment in patients with, or at risk for, schizophrenia. Four important findings have emerged from various meta-anal-yses of those studies (see Fusar-Poli et al., 2011; Steen et al., 2006; Vita et al., 2006): Individuals who have not been diagnosed with schizo-phrenia but are at risk for the disorder (e.g., because they have close relatives with schizophrenia) display volume reductions in some parts of the brain—for example, in the hippocampus (see Haukvik et al., 2018). Extensive brain changes already exist when patients first seek medical treatment and receive their first brain scans. Subsequent brain scans reveal that the brain changes continue to develop after the initial diagnosis. Alterations to different areas of the brain develop at different rates (see Gogtay & Thompson, 2010). One exciting line of research on the neural bases of schizophrenia has challenged the idea that the mesocorticolimbic dopamine pathway is involved in schizophrenia; if you remember, this was a tenet of the classic dopamine theory of schizophrenia. This line of research has shown that the neuropathological changes occur in the nigrostriatal dopamine pathway rather than in the mesocorticolimbic pathway (see McCutcheon, Abi-Dargham, & Howes, 2019). Recent research on the neural bases of schizophrenia has used modern functional brain-imaging techniques to study functional connectivity in the brains of individuals with schizophrenia. Research on functional con-nectivity in schizophrenia has been of two sorts. The first is the study of functional connectivity during hallucinations in individuals with schizophrenia. This line of research has shown that when participants with schizophrenia are hal-lucinating there is a change in the pattern of functional con-nectivity as compared to when they are not hallucinating (see Weber et al., 2020). The second line of research is exam-ining whether patterns of intrinsic functional connectivity might be used to predict treatment response to antipsychotic medications (see Chan et al., 2019). CONCLUSION. Although there has been significant prog-ress in our understanding of the mechanisms and treatment of schizophrenia, a careful reading of the research results suggests that ultimate answers will not be forthcoming until its diagnosis is “sharpened up.” There is a general consensus that those patients diagnosed with schizophrenia under the current DSM-5 criteria do not suffer from a single unitary disorder resulting from the same neural pathology (see Kim et al., 2017; Krynicki et al., 2018): The current diag-nosis seems to lump together a group of related disorders under one label. This is suggested by the variety and vari-ability of psychological symptoms, neural pathology, and by the marked variability in patient response to particular antipsychotic drugs. 31 Biopsychology of Psychiatric Disorders 491 their daily lives: to keep a job, to eat, or to maintain social contacts and personal hygiene. Sleep disturbances and thoughts of suicide are common. When this condition lasts for 2 weeks or longer, these people are said to be suffering from a clinical depression, also known as major depressive disorder. The case of S.B. introduces you to some of the main features of clinical depression. The Case of S.B., the Depressed Biopsychology Student S.B. excelled during his first year at university—earning top marks in his program of study: biosychology. However, begin-ning in the second year of his studies, S.B. began to suffer from depression: He began to sleep excessively, he had trouble concentrating on his studies, and he thought about death and suicide frequently. He also suffered from delusions: He thought he was stupid and disliked, and he felt persecuted by his instructors and peers. Having seen these symptoms previously in certain members of his family, S.B. made the astute decision of seeking out help from a psychiatrist. His psychiatrist offered him medications, but S.B. refused, as he was reminded of the many drug-related side effects he had seen in his family members. Rather, he attended psycho-therapy for the remaining years of his degree. Although it helped to talk about his problems, S.B. saw little improvement in his condition during this period. Still, he was able to complete his degree with relatively high grades and subsequently applied and was admitted to graduate studies in biopsychology. A few months after beginning graduate school, S.B.’s Depressive Disorders We commonly use the word “depression” to refer to a reac-tion to grievous loss, such as the loss of a loved one, the loss of self-esteem, or the loss of health. However, “depression” is also used to refer to a psychiatric disorder; that disorder is the focus of this module. What Are Depressive Disorders? LO 2.7 Explain what a clinical depression is. Some people experience deep depression and/or anhedonia (loss of the capacity to experience pleasure; see Husain & Roiser, 2018; Post & Warden, 2018), often for no apparent reason (see Treadway & Zald, 2011). Their depression can be so extreme that it can impair cognition (see Cambridge et al., 2018; Dillon & Pizzagalli, 2018) and makes it almost impossible for them to meet the essential requirements of depression became so severe that he could no longer function. For example, S.B. had impairments in his memory and attention that affected his ability to read; delusional ideas and suicidal thoughts constantly plagued his mind. After seeing S.B. in this state, his psychiatrist immediately hospitalized him. While he was hospitalized, he was started on an antidepressant medica-tion to calm his depression and an antipsychotic medication to help him deal with his delusional thoughts. Upon being released from the hospital, his psychiatrist advised him to take a leave of absence from his studies, which he did. S.B. returned to graduate school several months later. However, since his symp-toms still persisted despite all the medications, albeit to a lesser degree, he was barely capable of keeping things together. Don’t forget S.B.; you will learn more about him later in this chapter. Depression is often divided into two categories. Depression triggered by an obvious negative experience (e.g., the death of a friend, the loss of a job) is called reactive depression; depression with no apparent cause (as in the case of S.B.) is called endogenous depression (see Malki et al., 2014). Depression affects 2–5 percent of the global popula-tion (see Han, Russo, & Nestler, 2019). Females are about twice as likely to a receive a diagnosis of depression during their lifetime (see Kuehner, 2017), with this sex difference being most pronounced during adolescence (see Salk, Hyde, & Abramson, 2017)—although the reasons for this sex difference are still unclear, gonadal- hormone-related explanations are currently popular (see Altemus, Sarvaiya, & Epperson, 2014; Bangasser & Valentino, 2014; Kokras & Dalla, 2014; Kuehner, 2017). For reasons that are still unclear, non-caucasian individuals are more likely to suffer from chronic and more debilitating depression than caucasians (see Bailey, Mokonogho, & Kumar, 2019). The lifetime risk of completed suicide in an individual diagnosed with clinical depression has been found to range between 4 and 15 percent in various studies (see Wang et al., 2015). Clinical depressions attack children, adolescents, and adults. In adults, clinical depression is often comorbid (the tendency for two health conditions to occur together in the same individual) with one or more other health conditions—for example, anxiety disorders, coronary heart disease, and diabetes (see Scott, 2014). There are two subtypes of major depressive disorder whose cause is more apparent because of the timing of the episodes. One is seasonal affective disorder (SAD), in which episodes of depression and lethargy typically recur during particular seasons—usually during the win-ter months (see Tyrer et al., 2016). Two lines of evidence suggest that the episodes are triggered by the reduction in sunlight. One is that the incidence of the disorder is higher in Alaska (9 percent) than in Florida (1 percent), where the winter days are longer and brighter (see Melrose, 2015). The other is that light therapy (e.g., exposure to 15–30 minutes of very bright light each morning) is often effective in reducing the symptoms of SAD (see Oren, Koziorowski, & Desan, 2013; Song et al., 2015). The second subtype of major depressive disorder with an obvious cause is peripartum depression, the intense, sustained depression experienced by some women during pregnancy, after they give birth, or both (see Serati et al., 2016; Pawluski, Lonstein, & Fleming, 2017). Although estimates vary, the disorder seems to be associated with about 13 percent of pregnancies (see Silver et al., 2018). Antidepressant Drugs LO 2.8 Describe the early research that led to the discovery of antidepressant medications. Also, list each of the five major classes of antidepressant drugs, and provide one specific example of each. Five major classes of drugs have been used for the treat-ment of depressive disorders (see Willner, Scheel-Krüger, & Belzung, 2013): monoamine oxidase inhibitors, tricyclic antidepressants, selective monoamine-reuptake inhibitors, atypical antidepressants, and NMDA-receptor antagonists. MONOAMINE OXIDASE INHIBITORS. Iproniazid, the first antidepressant drug, was originally developed for the treatment of tuberculosis, for which it proved to be a dismal flop. However, interest in the antidepressant potential of the drug was kindled by the observation that it left patients with tuberculosis less concerned about their disorder. As a result, iproniazid was tested on a mixed group of psychiat-ric patients and seemed to act against clinical depression. It was first marketed as an antidepressant drug in 1957. Iproniazid is a monoamine agonist; it increases the levels of monoamines (e.g., norepinephrine and serotonin) by inhibiting the activity of monoamine oxidase (MAO), the enzyme that breaks down monoamine neurotransmitters in the cytoplasm (cellular fluid) of the neuron. MAO inhibitors have several side effects; the most dangerous is known as the cheese effect (see Finberg & Gillman, 2011). Foods such as cheese, wine, and pickles contain an amine called tyra-mine, which is a potent elevator of blood pressure. Normally, these foods have little effect on blood pressure because tyra-mine is rapidly metabolized in the liver by MAO. However, people who take MAO inhibitors and consume tyramine-rich foods run the risk of stroke caused by surges in blood pressure. TRICYCLIC ANTIDEPRESSANTS. The tricyclic antide-pressants are so named because of their antidepressant action and because their chemical structures include three rings of atoms. Imipramine, the first tricyclic antidepres-sant, was initially thought to be an antipsychotic drug. However, when its effects on a mixed sample of psychiatric patients were assessed, it had no effect against schizophre-nia but seemed to help some depressed patients. Tricyclic antidepressants block the reuptake of both serotonin and norepinephrine, thus increasing their levels in the brain. They are a safer alternative to MAO inhibitors. SELECTIVE MONOAMINE-REUPTAKE INHIBITORS. In the late 1980s, a new class of drugs—the selective serotonin-reuptake inhibitors—was introduced for treating clinical depression. Selective serotonin-reuptake inhibitors (SSRIs) are serotonin agonists that exert their agonistic effects by blocking the reuptake of serotonin from synapses—see Figure 2.3. Fluoxetine (marketed as Prozac) was the first SSRI to be developed. Now there are many more (e.g., paroxetine, sertraline, fluvoxamine). Fluoxetine’s structure is a slight variation of that of imipramine and other tricyclic anti- depressants; in fact, fluoxetine is no more effective than imipramine in treating depression. Nevertheless, it was immediately embraced by the psychiatric community and has been prescribed in many millions of cases. The remark-able popularity of fluoxetine and other SSRIs is attributable to two things: First, they have fewer side effects than tricy-clics and MAO inhibitors; second, they act against a wide range of psychological disorders in addition to depression. The success of the SSRIs spawned the introduction of a similar class of drugs, the selective norepinephrine-reuptake inhibitors (SNRIs). These (e.g., reboxetine) have proven to be just as effective as the SSRIs in the treatment of depression. Also effective are drugs that block the reuptake of more than one monoamine neurotransmitter (e.g., venla-faxine) (see Harmer, Duman, & Cowen, 2017). ATYPICAL ANTIDEPRESSANTS. Beginning in the 1980s, several new antidepressants began to appear on the market that did not neatly fit into the three aforementioned classes (i.e., MAO inhibitors, tricyclic antidepressants, and selective monoamine-reuptake inhibitors). Accordingly, a new class of antidepressant medications emerged that is really just a catch-all class comprising drugs that have many different modes of action: the atypical antidepressants (see Willner, Scheel-Krüger, & Belzung, 2013). For example, one of the drugs in this class, bupropion, has several effects on neurotransmission: It is a blocker of dopamine and norepinephrine reuptake, and it is also a blocker of nicotinic acetylcholine receptors (see Carroll et al., 2014). Another example of a drug in this class is agomelatine—a melatonin receptor agonist (see Taylor et al., 2014). There are many other drugs in this class, each with its own unique mechanism of action (see Willner, Scheel-Krüger, & Belzung, 2013). NMDA-RECEPTOR ANTAGONISTS. Beginning in the early 1990s, several studies reported a positive effect of antagonizing the glutamate NMDA receptor on depressive disorders. In the early 2000s, one agent in particular was shown to be remarkably effective: the dissociative hallu-cinogen ketamine. Remarkably, even a single low dose of ketamine rapidly reduces depression, even in patients who had been experiencing a severe episode (see Amit et al., 2015; Cui, Hu, & Hu, 2019; McGirr et al., 2015; Yang et al., 2018). However, because ketamine has undesirable side effects, researchers are now in the process of trying to identify more selective NMDA-receptor antagonists, and antago-nists of other glutamate receptors, with fewer side effects (see Duman, Sanacora, & Krystal, 2019; Malinow, 2016). EFFECTIVENESS OF DRUGS IN THE TREATMENT OF DEPRESSIVE DISORDERS. About $15 billion is spent in the United States each year on antidepressants. But how effective are antidepressants? Numerous studies have evaluated the effectiveness of antidepressant drugs against major depressive disorder. Many studies have reported that about 50 percent of clinically depressed patients improve with antidepressants (see Cipriani et al., 2018b). This rate seems quite good; however, control groups typically show a rate of improvement of about 35 percent, so only about 15 percent of depressed individuals are actually helped by the antidepressants (see Cipriani et al., 2018a). Still, one can argue that a 15 percent improvement over control conditions is certainly meaningful when one considers how debilitating and dangerous depression can be (see Cipriani et al., 2018b; Maslej et al., 2020). Recent meta-analyses have made it clear that some antidepressant drugs are more effec-tive than others, and that their relative efficacy is a function of the sex and age of the depressed individual (e.g., Cipriani et al., 2018a). Brain Stimulation to Treat Depression LO 2.9 Describe two forms of treatment for depression that utilize brain stimulation. Two treatments involving brain stimulation have been developed for depression: repetitive transcra-nial magnetic stimulation and deep brain stimulation. REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION. Repetitive transcranial magnetic stimulation (rTMS) is a form of transcranial magnetic stimulation (TMS) that involves the noninvasive delivery of repetitive magnetic pulses at either high frequencies (e.g., five pulses per second; high-frequency rTMS) or low frequencies (e.g., less than one pulse per second; low-frequency rTMS) to specific cortical areas—usually the prefrontal cortex (see Gaynes et al., 2014). High-frequency rTMS and low-frequency rTMS are believed to stimulate and inhibit, respectively, activity within those brain regions to which they are applied (see Berlim et al., 2013, 2014). Meta-analyses have shown reliable improvement of depressive symptoms after either low-frequency (see Berlim et al., 2013) or high-frequency (see Berlim et al., 2014) rTMS when compared with sham rTMS. DEEP BRAIN STIMULATION. Chronic brain stimulation through an implanted electrode (see Figure 2.4) has been shown to have a therapeutic effect in some depressed patients who have failed to respond to other treatments. Lozano and colleagues (2008) implanted the tip of a stimulation electrode into an area of the white matter of the anterior cingulate gyrus in the medial prefrontal cortex (see Figure 2.5). The stimulator, which was implanted under the skin, delivered continual pulses of electrical stimulation that could not be detected by the patients. The 20 patients in this study were selected because they had repeatedly failed to respond to conventional treatments. Journal Prompt 2.1 There are many other treatments for depression that aren’t discussed in this module. Name a few that you know of. What is the evidence for their efficacy? Considering that patients had failed to respond to other treatments, the results were strikingly positive: 60 percent showed substantial improve-ments, 35 percent were largely symptom free, and most of the patients were improved for at least 1 year (the duration of the study). These positive results have been replicated at other treatment centers (see Holtzheimer et al., 2011; Lozano et al., 2012; Lozano & Mayberg, 2015). Theories of Depression LO 2.10 Describe two theories of the etiology of major depressive disorder. There are several theories of the etiology of major depres-sive disorder. As you will soon find out, most theories are based almost entirely on those therapies that have been found to be effective against depression. MONOAMINE THEORY OF DEPRESSION. One promi-nent theory of clinical depression is the monoamine theory. The monoamine theory of depression holds that depres-sion is associated with underactivity at serotonergic and noradrenergic synapses. The theory is largely based on the fact that monoamine oxidase inhibitors, tricyclic anti-depressants, and selective monoamine-reuptake inhibi-tors are all agonists of serotonin, norepinephrine, or both. Other support for the monoamine theory of depression has been provided by autopsy studies. Norepinephrine and serotonin receptors have been found to be more numerous in the brains of deceased depressed individuals who had not received pharmacological treatment. This implicates a deficit in monoamine release: When an insufficient amount of a neurotransmitter is released at a synapse, there is usu-ally a compensatory increase in the number of receptors for that neurotransmitter—a process called up-regulation. Three lines of evidence have challenged the mono-amine theory of depression. First was the discovery that monoamine agonists, although widely prescribed, are not effective in the treatment of most depressed patients (see Malhi, Lingford-Hughes, & Young, 2016), and even when they are effective, they are only slightly better than pla-cebo (see Linde et al., 2015). Second was the observation that, although monoamine activity is potentiated almost immediately after monoamine-agonist administration, it can take days to weeks for the antidepressant effects of the drug to emerge (see Harmer, Duman, & Cowen, 2017). Third was the discovery that other neurotransmitters (e.g., GABA, glutamate, acetylcholine) play a role in the develop-ment of depression (Murrough, Abdallah, & Mathew, 2017; Northoff, 2013; Pytka et al., 2016). NEUROPLASTICITY THEORY OF DEPRESSION. Nearly all antidepressant drugs rapidly increase transmission at monoaminergic synapses, yet any therapeutic effects of those increases typically are not manifested until weeks after the beginning of drug therapy. Therefore, it is clear that the agonistic effects at monoaminergic synapses can-not be the critical therapeutic mechanism: There must be some change that occurs downstream from the synaptic 35 Biopsychology of Psychiatric Disorders 495 changes. One theory is that the critical downstream change is an increase in neuroplasticity. In a nutshell, the neuroplasticity theory of depression is that depression results from a decrease of neuroplastic pro-cesses in various brain structures (e.g., the hippocampus), which leads to neuron loss and other neural pathology (see Castrén & Hen, 2013; Miller & Hen, 2015). General support for the neuroplasticity theory of depression comes from two kinds of research: (1) research showing that stress and depression are associated with the disruption of various neuroplastic processes (e.g., a reduction in the synthesis of neurotrophins, a decrease in adult hippocam-pal neurogenesis) and (2) research showing that antidepressant treatments are associated with an enhancement of neuroplastic processes (e.g., an increase in the synthesis of neurotrophins, an increase in synaptogenesis, and an increase in adult hippocampal neurogenesis)—see Brandon and McKay (2015), Christian et al. (2014), Mahar et al. (2014), and Samuels et al. (2015). One neurotrophin has been of great interest to researchers: Brain-derived neurotropic factor (BDNF)—because treatments that improve depression (both pharmacological and nonpharmacological) have been found to increase BDNF levels only in those patients who show improvement (see Homberg et al., 2014). Indeed, it has been proposed that decreased blood levels of BDNF might be a biomarker (a biological state that is predictive of a particular disorder) for depression, and that increased blood levels of BDNF might be a biomarker for the successful treatment of depression (see Polyakova et al., 2015). Moreover, it has been hypothesized that the antidepressant-induced increase in BDNF levels boost certain neuroplastic processes (e.g., increase adult hippocampal neurogenesis) that lead to the alleviation of depression (see Björkholm & Monteggia, 2016). Genetic and Epigenetic Mechanisms of Depression LO 2.11 Describe our current state of knowledge of the genetic and epigenetic mechanisms of depression. Until very recently, most studies of the genetic contribu-tion to clinical depression were not replicable. However, since 2015, a series of studies have reliably identified many genes as contributors to depression (see Ormel, Hartman, & Snieder, 2019). Because so many different genes have been found to contribute to depression, it is considered to be a complex trait that involves many potential interactions with environ-mental factors through epigenetic mechanisms (see Heller et al., 2014; Nestler, 2014; Whalley, 2014). The general find-ing has been that several different epigenetic mechanisms contribute to depression (see Penner-Goeke & Binder, 2019) and that changes to the epigenome of an indi-vidual might one day be used to predict a future clinical depression in an individual (see Barbu et al., 2020). Neural Bases of Depression LO 2.12 Describe the various brain differences associated with major depressive disorder. Numerous structural and functional neuroimaging studies of the brains of depressed patients have been published. Structural neuroimaging studies have found consistent reductions in gray matter volumes in the prefrontal cortex, hippocampus, amygdala, and cingulate cortex (see Lener & Iosifescu, 2015). White matter reductions have also been noted in several brain regions—most reliably in the fron-tal cortex (see Russo & Nestler, 2013; Wang et al., 2014). Functional neuroimaging studies have found atypical activ-ity in frontal, cingulate, and insular cortices as well as in the amygdala, thalamus, and striatum. There are a growing number of studies that have exam-ined alterations in functional connectivity in depressed individuals (e.g., Goldstein-Piekarski et al., 2018). These studies have identified a large number of dif-ferences in the brains of individuals with depression (see Goldstein-Piekarski & Williams, 2019; Korgaonkar et al., 2019) indicating that the neural networks of depressed patients are markedly different from healthy participants. In most cases, these changes have not been clearly related to changes in behavior or cognition, but such linkages are beginning to emerge (e.g., Albert et al., 2019). CONCLUSION. Although a number of promising lines of research currently focus on the mechanisms and treat-ment of clinical depression, treatments are not much better than they were 50 years ago. Many researchers contend that current diagnostic tools, such as those that generate large heterogeneous groups of patients—like the DSM-5—are misguiding research and that more precise approaches to diagnosis are necessary (see Insel & Cuthbert, 2015). What Is Bipolar Disorder? LO 2.13 Describe the symptoms associated with each of the two types of bipolar disorder. Hypomania and mania are in some respects the opposite of depression. Hypomania is characterized by a reduced need for sleep, high energy, and positive affect. During periods of hypomania, people are talkative, energetic, impulsive, positive, and very confident. In this state, they can be very effective at certain jobs and can be great fun to be with. Mania has the same features as hypomania but taken to an extreme; it also has additional symptoms, such as delusions of grandeur, overconfidence, impulsivity, and distractibility. Mania usually involves psychosis. When mania is full-blown, the person often exhibits unbridled enthusiasm with an outflow of incessant chatter that hurtles from topic to topic. No task is too difficult. No goal is unattainable. This confidence and grandiosity, coupled with high energy, distractibility, and a leap-before-you-look impulsiveness, can result in a series of disasters. Mania often leaves behind a trail of unfinished projects, unpaid bills, and broken relationships. Those persons who only experience bouts of depression and hypomania are said to have bipolar disorder type II; those who also experience bouts of mania, or only expe-rience mania (see Makin, 2019), are said to have bipolar disorder type I. The case of S.B., previously introduced to you in the module on depressive disorders, will introduce you to the main features of both forms of bipolar disorder. The Case of S.B. Revisited: The Biopsychology Student with Bipolar Disorder S.B. continued his graduate studies in biopsychology while still suffering from a residual depression. Although he struggled through the remaining years of his program, he was successful in attaining a master’s degree in biopsychology. S.B. subsequently began a Ph.D. program in biopsychol-Bipolar Disorder Some people experience periods of clinical depression and also periods of hypomania or mania. Those who do are said to suffer from bipolar disorder. Bipolar disorder affects about 3 percent of the global population (see Ashok et al., 2017; Vieta et al., 2018), with much intercultural variability in its presentation and course (see Subramanian, Sarkar, & Kattimani, 2017). It is a serious psychiatric disorder with one of the highest rates of attempted and completed suicide (see Lima, Peckham, & Johnson, 2018; Plans et al., 2019). ogy. During the first summer after beginning this new program, S.B. started to feel exceptionally good: His mood was elevated; he was sleeping less than 3 hours per night; he became highly sociable and very charismatic; and he found he could read faster and understand materials that he had previously found difficult. Moreover, he became very productive. Indeed, many of the ideas that would later form the basis of his Ph.D. thesis came to him during this period of elation. S.B. was experiencing all the symptoms of a hypomania. Because S.B. had experienced both depression and hypomania, he now met criteria for a diagnosis of bipolar disorder type II. His hypomania persisted for several months, but things were about to take a turn for the worse. S.B. began to sleep less than 2 hours per night, and some-times he would simply not sleep at all for several days. He read incessantly—his living room was transformed into a labyrinthian pile of books and academic papers. S.B. also began to believe that he had some unique talents and insights. For example, he believed that he had developed a comprehensive theory that explained every aspect of how society functioned and he began to see linkages between everything that he thought about and experienced. He filled many notebooks with diagrams and writ-ings that he thought summarized his theory quite well; however, nobody seemed to understand his theory except for him. But this didn’t deter him. In short, he was displaying delusions of grandeur: He believed he had intellectual capacities that sur-passed all those around him. Moreover, whenever he spoke with anyone, they always told him to slow down, or they simply gave him funny looks. At this point, S.B. was in a state of mania and now met criteria for a diagnosis of bipolar disorder type I. However, his enthusiasm and positive affect began to slowly dwindle. Because nobody seemed to understand him and his theories, he felt increasingly alone and rejected. Soon, suicidal thoughts began to dominate his mind. After several weeks of experiencing intense suicidal ideation, barely sleeping, and often forgetting to eat, S.B. contacted his psychiatrist. He told his psychiatrist over the phone about his “brilliant” theory. Feeling suspicious, she asked S.B. to come see her at the hos-pital to talk about his theory further. When she saw S.B. and talked with him, she immediately realized he was in a mixed state: He was displaying symptoms of both severe depression (e.g., suicidal ideation) and mania (e.g., delusions of grandeur). She promptly committed S.B., and he was subsequently placed on a psychiatric ward where he stayed for 6 weeks. Mood Stabilizers LO 2.14 Describe the discovery of the first mood stabilizer. Ideally, mood stabilizers are drugs that effectively treat depression or mania without increasing the risk of mania or depression, respectively (see Karanti et al., 2016). Protection against the recurrence of mood episodes is important because mood episodes in bipolar disorder typically become both more severe and more frequent if left untreated (see Post, 2016; Post, Fleming, & Kapczinski, 2012). The mechanism by which mood stabilizers work is still a matter of debate (see Oruch et al., 2014; Rapoport, 2014), but for some reason many mood stabilizers are also effective in the treatment of epilepsy (see Prabhavalkar, Poovanpallil, & Bhatt, 2015; Yildiz et al., 2011) and schizophrenia (see Post, 2016). Lithium, a simple metallic ion, was the first drug found So far, the case of S.B. has introduced you to the fea-tures of both depression and bipolar disorder. Here, his case makes an important point about bipolar disorder: Contrary to popular belief, bipolar disorder does not involve rapid alternations in mood (i.e., alternations occurring within hours to days); rather, the mood episodes often last weeks to months. To put things in context, there is a subtype of bipolar disorder known as rapid cycling bipolar disorder—defined as involving 4 or more mood episodes per year (see Cao et al., 2017; Carvalho et al., 2014). S.B.’s case also makes an important point about psychi-atric diagnoses in general: Psychiatric patients often careen from one diagnosis to another (see Phillips & Kupfer, 2013). For example, S.B.’s diagnosis changed from clinical depres-sion to bipolar type II and then to bipolar type I. But stay tuned: There is more to the case of S.B. to act as a mood stabilizer. The discovery of lithium’s mood stabilizing action is yet another important pharmacological breakthrough that occurred largely by accident. John Cade, an Australian psychiatrist, injected guinea pigs with the urine of various psychiatric inpatients and found that the urine of manic patients was the most toxic (i.e., it killed the most guinea pigs). Next, he set about investigating which chemical constituent of the manic patients’ urine caused the increased toxicity: He began by injecting guinea pigs with urea (one constituent of urine) and found that it was toxic, but not nearly so toxic as the urine of the patients with mania. Something else was contributing to the toxicity of the manic patients’ urine. What was it? Cade thought it might be uric acid (another constituent of urine), so he injected both urea and lithium urate (a soluble form of uric acid that takes the form of a lithium salt) into a group of guinea pigs. Contrary to his hypothesis, he found that lithium urate protected the guinea pigs from the toxicity of the urea. Next, Cade injected some guinea pigs with both urea and lithium carbonate (another lithium salt) to check whether it was the lithium or the uric acid that was protective. He found that lithium carbonate also protected the guinea pigs from the toxicity of urea. Accordingly, Cade hypothesized that manic patients have lower levels of lithium than non-manic patients. Cade wanted to test lithium carbonate on a group of Journal Prompt 2.2 Do you think that such careening between diagnoses represents an actual change in one’s illness or a general problem with psychiatric diagnoses? manic patients, but he decided to first test it on a group of guinea pigs. The lithium carbonate seemed to calm the guinea pigs. However, we now know that at the doses he used, lithium carbonate produces extreme nausea; so, his subjects weren’t calm—they were just sick. In any case, excited by what he thought was the success of his guinea pig experiments, in 1954 Cade gave lithium to a group of 10 manic patients, 6 patients with schizophrenia, and 3 depressed patients. The lithium had a dramatic effect, but only in the manic patients. The effect was so dramatic that some of the manic patients were even discharged from hospital (see Mitchell & Hadzi-Pavlovic, 2000), something unheard of in the pre-drug era of psychiatry. Unfortunately, there was little immediate reaction to Cade’s report—few scientists were impressed by his conference presentations, and few drug companies were interested in spending money to evaluate the therapeutic potential of a metallic ion that could not be protected by a patent. Consequently, it was not until the late 1960s that lithium was conclusively shown to be an effective mood stabilizer. Over the 50 years since its introduction, lithium is still considered by many to be the best mood stabilizer (see Oruch et al., 2014; Machado-Vieira, 2018), and it is now known to have neuroprotective effects (see Kerr, Bjedov, & Sofola-Adesakin, 2018; Sun et al., 2018) and anti-suicidal effects (see Baldessarini, Tondo, & Vásquez, 2019). All mood stabilizers (i.e., lithium, certain anticon- vulsants, and certain atypical antipsychotics) act against bouts of mania, some act against depression, and some act against both (see Prabhavalkar, Poovanpallil, & Bhatt, 2015; Yildiz et al., 2011), but they do not eliminate all symptoms. Moreover, many of them produce an array of adverse side effects (e.g., weight gain, tremor, blurred vision, dizziness; see Murru et al., 2015), which often leads patients to stop taking these medications (see Jann, 2014; Schloesser, Martinowich, & Manji, 2012). Theories of Bipolar Disorder LO 2.15 Describe some factors that may contribute to the onset and maintenance of bipolar disorder. An understanding of the mechanisms underlying the development and maintenance of bipolar disorder has been hampered by the lack of a clear understanding of the mechanisms underlying the efficacy of various mood stabi-lizers (e.g., Can, Schulze, & Gould, 2014) and by the lack of an adequate animal model of bipolar disorder (see Logan & McClung, 2016). However, several physiological distur-bances have been identified that might be contributing to the onset and maintenance of bipolar disorder. For example, there is evidence of hypothalamic–pituitary–adrenal (HPA) axis dysregulation in bipolar disorder; there are marked disruptions in the circadian rhythms in both patients with bipolar disorder and their nonbipolar relatives; and there are also alterations to GABA, glutamate, and dopamine neurotransmission in patients with bipolar disorder (see Ashok et al., 2017; Beyer & Freund, 2017; Maletic & Raison, 2014). Finally, there is evidence that BDNF levels are lower in patients with bipolar disorder when they are either depressed or manic (see Maletic & Raison, 2014). One theory of bipolar disorder, the reward hypersensitivity theory of bipolar disorder (see Alloy, Nusslock, & Boland, 2015), proposes that bipolar disorder results from a dysfunctional brain reward system that overreacts to rewards or the lack thereof. For example, individuals with bipolar disorder who are euthymic (they have no symptoms of depression, hypomania, or mania) make much riskier choices than individuals without bipolar disorder (see Johnson et al., 2019). The reward hypersensitivity theory of bipolar disorder explains both the manic and depressive phases of bipolar disorder by proposing that: (1) repeatedly rewarding individuals with bipolar disorder for their activities leads to excessive goal seeking and ultimately to hypomania or mania, and (2) when people with bipolar disorder fail to achieve their goals this leads to an excessive decrease in reward seeking and to depression. Consistent with this theory is the finding that individuals with bipolar disorder display increased activity in prefrontal and striatal reward circuits in both depressive and manic states (see Alloy, Nusslock, & Boland, 2015). Many other theories of bipolar disorder exist. For example, there are emerging theories that propose a role for inflammation (see So et al., 2017), or a role for alterations in synaptic function (see Harrison, Geddes, & Tunbridge, 2017). Genetic and Epigenetic Mechanisms of Bipolar Disorder LO 2.16 Describe our current state of knowledge of the genetic and epigenetic mechanisms of bipolar disorder. Many studies have been conducted on the genetics of bipolar disorder, based on the early observation that family members of individuals with bipolar disorder have a very high likelihood of developing bipolar disorder. The take-home message from all of the genetic studies of bipolar disorder is that there are hundreds to thousands of genes associated with bipolar disorder (see Gandal et al., 2018). Studies of these genes have yielded little in the way of understanding the mechanisms of bipolar disorder. Accordingly, current research efforts are focused on identifying epigenetic mechanisms that might affect transcription of the identified genes (see Duffy et al., 2019; Gandal et al., 2018). Neural Bases of Bipolar Disorder LO 2.17 Describe the brain differences associated with bipolar disorder. Numerous MRI studies of the brains of patients with bipo-lar disorder have been published. In general, cognitive deficits are common in bipolar disorder and such deficits are associated with a variety of changes in brain function (see Lima, Peckham, & Johnson, 2019). Consistent overall reductions in gray matter volume have been reported (see Maletic & Raison, 2014). Moreover, the extent of gray matter volume reductions in frontal and limbic areas is correlated with clinical outcome (see Dusi et al., 2018). In addition, there have been reports of several specific brain structures being smaller in patients with bipolar disorder, including the medial prefrontal cortex, the left anterior cingulate, the left superior temporal gyrus, certain prefrontal regions, and the hippocampus (see Hanford et al., 2016; Knöchel et al., 2014; Otten & Meeter, 2015; Savitz, Price, & Drevets, 2014). Meta-analyses of fMRI studies of patients with bipolar disorder have found atypical activation in the frontal cortex, medial temporal lobe structures, and basal ganglia, as well as atypical functional connectivity between some of these structures while in a variety of cognitive states (see Favre et al., 2014; Maletic & Raison, 2014). The functional connec-tivity disturbances seem to be centered around networks in the brain that are involved in emotional processing (see Hafeman et al., 2019; Perry et al., 2019). 39 Biopsychology of Psychiatric Disorders 499 anxiety attack. Shortly after leaving home by herself, she would feel dizzy and sweaty, and her heart would start to pound; at that point, she would flee home to avoid a full-blown panic attack. Although M.R. could manage to go out if she was escorted by her husband or one of her children, she felt anxious the entire time. Four Anxiety Disorders LO 2.18 Describe four anxiety disorders. The following are four anxiety disorders: Generalized anxiety disorder is characterized by extreme feelings of anxiety and worry about a large number of different activities or events (see Mochcovitch et al., 2017). Anxiety Disorders Anxiety—chronic fear that persists in the absence of any direct threat—is a common psychological correlate of stress (see Mahan & Ressler, 2012). Anxiety is adaptive if it motivates effective coping behaviors; however, when it becomes so severe that it disrupts functioning, it is referred to as an anxiety disorder. All anxiety disorders are associated with feelings of anxiety (e.g., fear, worry) and with a variety of physiological stress reactions—for example, tachycardia (rapid heartbeat), hypertension (high blood pressure), nausea, breathing difficulties, sleep disturbances, and high glucocorticoid levels. Anxiety disorders are the most prevalent of all psychiatric disorders. Estimates suggest that between 14 and 34 percent of people suffer from an anxiety disorder at some point in their lives, and the incidence seems to be almost twice as great in females as in males (see Bandelow & Michaelis, 2015; Gallo et al., 2018). M.R., a woman who was afraid to leave her home, suffered from one type of anxiety disorder. The Case of M.R., the Woman Who Was Afraid to Go Out M.R. was a 35-year-old woman who developed a pathological fear of leaving her house. The onset of her problem was sudden. Following an argument with her husband, she went out to mail a letter and cool off, but before she could accomplish her task, she was overwhelmed by dizziness and fear. She immediately struggled back to her house and rarely left it again, for about 2 years. Then, she gradually started to improve. Her recovery was abruptly curtailed, however, by the death of her sister and another argument with her husband. Following the argument, she tried to go shopping, panicked, and had to be escorted home by a stranger. Following that episode, she was not able to leave her house by herself without experiencing an Specific phobias involve a strong fear or anxiety about particular objects (e.g., birds, spiders) or situations (e.g., enclosed spaces, darkness). A person with a phobia will usually try to avoid those specific objects or situations that are anxiety producing. Agoraphobia is the pathological fear of public places and open spaces. Although it might be considered as a specific phobia (see above), it is generally considered to be more incapacitating than most specific phobias and is, thus, treated as a separate diagnostic category in the DSM-5. M.R., the woman who was afraid to go out, suffered from agoraphobia. Panic disorder is characterized by recurrent rapid-onset attacks of extreme fear and severe symptoms of stress (e.g., choking, heart palpitations, shortness of breath). Such panic attacks also occur in certain cases of generalized anxiety disorder, specific phobia, and agoraphobia (see Cosci & Mansueto, 2019a; Johnson, Federici, & Shekhar, 2014). M.R., the woman who was afraid to go out, experienced panic attacks. Pharmacological Treatment of Anxiety Disorders LO 2.19 Describe three sorts of drugs used in the treatment of anxiety disorders. Three sorts of drugs are commonly prescribed for the treatment of anxiety disorders: benzodiazepines, certain antidepressants, and pregabalin (see Quagliato, Freire, & Nardi, 2018). BENZODIAZEPINES. Benzodiazepines such as chlordiazepoxide (marketed as Librium) and diazepam (marketed as Valium) are widely prescribed for the treatment of anxiety disorders. They are also prescribed as hypnotics (sleep-inducing drugs), anticonvulsants, and muscle relaxants. Indeed, benzodiazepines are the most widely prescribed psychoactive drugs; approximately 5 percent of adult North Americans are currently taking them (see Balon & Starcevic, 2020). The behavioral effects of benzodiazepines are thought to be mediated by their agonistic action on GABAA receptors. The benzodiazepines have several adverse side effects: sedation, ataxia (disruption of motor activity), tremor, nausea, and a withdrawal reaction that includes rebound anxiety. Another serious problem with benzodiazepines is that they are addictive (see Quagliato, Freire, & Nardi, 2018). Consequently, they are typically prescribed for only short-term use. ANTIDEPRESSANT DRUGS. One of the complications in studying anxiety disorders is their high comorbidity with other psychiatric disorders (e.g., Preti et al., 2018). For example, about 47 percent of individuals with a bipolar disorder and about 53 percent of individuals with major depressive disorder have a comorbid anxiety disorder (see Moscati, Flint, & Kendler, 2015; Vázquez, Baldessarini, & Tondo, 2014). Consistent with the comorbidity of anxiety disorders and clinical depression is the observation that antidepressants, such as monoamine agonists and tricyclics, are often effective against anxiety disorders (see Bandelow, 2020), and anxiolytic drugs (antianxiety drugs) are often effective against clinical depression. PREGABALIN. Pregabalin is one of the newest drugs being prescribed for anxiety disorders— it is particularly effective for generalized anxiety disorder (see Generoso et al., 2017). The effects of pregabalin are believed to be due to its ability to modulate voltage-gated calcium channels, thus affecting calcium levels inside nervous system cells. CONCLUSION. Although many drugs have been shown to produce slight, but statistically significant, improvements in groups of patients suffering from anxiety disorders, the treat-ment of anxiety disorders leaves a lot to be desired. Many patients are not helped at all by existing drug therapies, and many curtail therapy because of adverse side effects. Animal Models of Anxiety Disorders LO 2.20 Describe three animal models of anxiety disorders. Animal models have played an important role in the study of anxiety disorders and in the assessment of the anxiolytic potential of new drugs. A weakness of these models is that they typically involve animal defensive behaviors, the implicit assumption being that defensive behaviors are motivated by fear and that fear and anxiety are similar states (see Dias et al., 2013; LeDoux, 2014). Three animal behaviors that model anxiety are elevated-plus-maze performance, defensive burying, and risk assessment. Journal Prompt 2.3 What do you think is wrong with assuming that the defensive behaviors of nonhuman animals are represen-tative of anxiety? What clinical implications might this assumption have for the development of new therapies for anxiety disorders? In the elevated-plus-maze test, rats are placed on a four-armed plus-sign-shaped maze that rests about 50 centimeters above the floor. Two arms have sides and two arms have no sides, and the measure of anxiety is the proportion of time the rats spend in the enclosed arms, rather than venturing onto the exposed arms. In the defensive-burying test (see Figure 5.25), rats are shocked by a wire-wrapped wooden dowel mounted on the wall of a familiar test chamber. The measure of anxiety is the amount of time the rats spend spraying bedding material from the floor of the chamber at the source of the shock with forward thrusting movements of their head and forepaws. In the risk-assessment test, after a single brief exposure to a cat on the surface of a laboratory burrow system, rats flee to their burrows and freeze. Then, they engage in a variety of risk-assessment behaviors (e.g., scanning the surface from the mouth of the burrow or exploring the surface in a cautious stretched posture) before their behavior eventually returns to normal. The measures of anxiety in this test are the amounts of time that the rats spend in freezing and in risk assessment. The elevated-plus- maze, defensive-burying, and risk-assessment tests of anxiety have all been validated by demonstrations that benzodiazepines reduce the various indices of anxiety used in the tests, whereas nonanxiolytic drugs usually do not. However, a potential problem with this line of evidence stems from the fact that many cases of anxiety do not respond well to benzodiazepine therapy. Therefore, existing animal models of anxiety may be models of benzodiazepine-sensitive anxiety rather than of anxiety in general, and, thus, the models may not be sensitive to anxiolytic drugs that act by a different (i.e., a nonGABAergic) mechanism. Genetic and Epigenetic Mechanisms of Anxiety Disorders LO 2.21 Describe our current state of knowledge of the genetic and epigenetic mechanisms of anxiety disorders. Researchers have been unable to definitively locate genes related to anxiety disorders (see Meier & Deckert, 2019). Accordingly, research has shifted to trying to understand the environmental factors and epigenetic mechanisms that might be contributing to anxiety disorders. Many epigenetic mechanisms have been implicated in anxiety disorders, and researchers have a long way to go before they identify the critical ones (see Cosci & Mansueto, 2020b; Lin & Tsai, 2020). Part of the problem is the heterogeneity of anxiety disor-ders. There are so many different types of anxiety disorders and so many different presentations, that it will be more fruitful to study specific symptoms as opposed to focusing on diagnostic categories. Neural Bases of Anxiety Disorders LO 2.22 Describe the various brain differences associated with anxiety disorders. Like current theories of the neural bases of schizophrenia, depression, and bipolar disorder, current theories of the neural bases of anxiety disorders rest heavily on the analysis of therapeutic drug effects. The fact that many anxiolytic drugs affect GABAergic neurotransmission (e.g., the benzodiazepines) or serotoninergic neurotransmission (e.g., fluoxetine) has focused attention on those two neurotransmitters. There is substantial overlap between the brain struc-tures involved in major depressive disorder and anxiety disorders. Indeed, the prefrontal cortex, hippocampus, and amygdala, which you have just learned are implicated in major depressive disorder, have also been implicated in anxiety disorders (see Calhoon & Tye, 2015). This is hardly surprising given the comorbidity of depression and anxiety disorders and the effectiveness of many drugs against both. Although the prefrontal cortex, hippocampus, and amygdala have been implicated in both depression and anxiety disorders, the patterns of evidence differ. With major depressive disorder, you have already seen that there seems to be atrophy (shrinkage) of these structures; however, with anxiety disorders, there appears to be no significant atrophy. Most of the evidence linking these structures to anxiety disorders has come from functional brain-imaging studies in which atypical activity in these areas has been recorded during the performance of various emotional tasks (see Fonzo & Etkin, 2017; Maron & Nutt, 2017). Currently, much attention is focused on differences in intrinsic functional connectivity: Each anxiety disorder has a distinct pattern of intrinsic functional connectivity (see Northoff, 2020). Tourette’s Disorder Tourette’s disorder is the last of the psychiatric disorders discussed in this chapter. It differs from the others that have already been discussed (i.e., schizophrenia, depressive disorders, bipolar disorder, and anxiety disorders) in the 41 Biopsychology of Psychiatric Disorders 501 specificity of its symptoms. And, as you are about to learn, they are as interesting as they are specific. The case of R.G. introduces you to Tourette’s disorder. The Case of R.G.—Barking Like a Dog When R.G. was 15, he developed tics (involuntary, repetitive, stereotyped movements or vocalizations). For the first week, his tics took the form of involuntary blinking, but after that they started to involve other parts of the body, particularly his arms and legs (Spitzer et al., 1983). R.G. and his family were religious, so it was particularly distressing when his tics became verbal. He began to curse repeatedly and involuntarily. (Involuntary cursing is a common symptom of Tourette’s disorder and of several other psychiatric and neurological disorders.) R.G. also started to bark like a dog. Finally, he developed echolalia: When his mother said, “Dinner is ready,” he responded, “Is ready, is ready.” Prior to the onset of R.G.’s symptoms, he was a top student, he was happy, and he had an outgoing, engaging personality. Once his symptoms developed, he was jeered at, imitated, and ridiculed by his schoolmates. He responded by becoming anxious, depressed, and withdrawn. His grades plummeted. Once R.G. was taken to a psychiatrist by his parents, his condition was readily diagnosed—the symptoms of Tourette’s disorder are unmistakable. Medication eliminated 99 percent of his symptoms, and then his anxiety and depression lifted and he returned to his former outgoing self. Imagine how difficult it would be to get on with your life if you suffered from an extreme form of Tourette’s disorder—for example, if you frequently made obscene gestures and barked like a dog. No matter how polite, intelligent, and kind you were inside, not many people would be willing to socialize with you or employ you (see Smith, Fox, & Trayner, 2015). However, if their friends, family members, and colleagues are understanding and supportive, people with Tourette’s disorder can live happy, productive lives—for example, Tim Howard (shown in the photo on the next page—wearing the blue shirt) has Tourette’s disorder and is the goalkeeper for a USL Championship team: the Memphis 901 FC. What Is Tourette’s Disorder? LO 2.23 Describe the symptoms of Tourette’s disorder. Tourette’s disorder is a disorder of tics (involuntary, repetitive, stereotyped movements or vocalizations). It typically begins early in life—usually in childhood or early Pharmacological Treatment of Tourette’s Disorder LO 2.24 Describe how Tourette’s disorder is treated. Although tics are the defining feature of Tourette’s disorder, treatment typically begins by focusing on other aspects of the disorder. First, the patient, family mem-bers, friends, and teachers are educated about the nature of the syndrome. Second, the treatment focuses on the ancillary emo-tional problems (e.g., anxiety and depres-sion). Once these first two steps have been taken, attention turns to treating the tics. Shaun Clark/Getty Images adolescence—with simple motor tics, such as eye blinking or head movements, but the symptoms tend to become more complex and severe as the patient grows older. Common complex motor tics include hitting, touching objects, squatting, hopping, twirling, and sometimes even making lewd gestures. Common verbal tics include inarticulate sounds (e.g., barking, coughing, grunting), coprolalia (uttering obscenities), echolalia (repetition of another’s words), and palilalia (repetition of one’s own words). The symptoms usually reach a peak after a few years and gradually subside as the patient matures (see Cox, Seri, & Cavanna, 2018). Tourette’s disorder develops in 0.3–1 percent of the global population (see Serajee & Huq, 2015). It is four times more frequent in male children than in female children (see Hallett, 2015), but this sex difference is not as profound in adult patients (see Jackson et al., 2015). Some patients with Tourette’s disorder also display signs of attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or both (see Serajee & Huq, 2015). For example, R.G. was obsessed by odd numbers and refused to sit in even-numbered seats. Although the tics of Tourette’s disorder are involuntary, they can be temporarily suppressed with concentration and effort by the patient. The effect of suppression has been widely misunderstood. Many medical professionals believe that tic suppression is inevitably followed by a rebound (that the tics become even worse following a period of suppression; e.g., Novotny, Valis, & Klimova, 2018). However, this is not the case—see Figure 2.6. Journal Prompt 2.4 Tourette’s disorder is a disorder of onlookers. Explain. The tics of Tourette’s disorder are usually treated with antipsychotics (see Kim et al., 2018; Pandey & Dash, 2019; Quezada & Coffman, 2018), although behavioral interven-tions can also be effective (see Pringsheim et al., 2019). Antipsychotics can reduce tics by about 70 percent, but patients or their caregivers often refuse them because of the adverse side effects (e.g., weight gain, fatigue, dry mouth). The success of antipsychotics in blocking Tourette’s tics is consistent with the hypothesis that the disorder is related to changes in the cortical-striatal-thalamic-cortical circuit because that circuit relies heavily on dopaminergic signal-ing (see Jackson et al., 2015). Genetic and Epigenetic Mechanisms of Tourette’s Disorder LO 2.25 Describe our current state of knowledge of the genetic and epigenetic mechanisms of Tourette’s disorder. The chance of monozygotic twins both having Tourette’s dis-order is about 80 percent, whereas it is 20 percent for dizogotic twins (see Burton et al., 2020). Thus, it would appear that Tourette’s disorder is highly heritable. However, to date there have been no genes definitively linked to the disorder. Studies of the epigenetic mechanisms of Tourette’s dis- order have been more fruitful. Several studies have found specific genes that are methylated (DNA methylation is one epigenetic mechanism) in individuals with Tourette’s disorder, such as the methylation of genes for potas-sium channels. Interestingly, one gene has been identified whose degree of methylation is correlated with tic severity in individuals with Tourette’s disorder (see Burton et al., 2020). Neural Bases of Tourette’s Disorder LO 2.26 Describe the research findings related to the neural bases of Tourette’s disorder. Because Tourette’s disorder is a well-defined disorder with clearly observable symptoms, its neural bases are more amenable to study than those of the other disorders that you have already encountered in this chapter. However, there are impediments to its study (e.g., the lack of a strong link to any particular gene is problematic). The greatest difficulty in studying Tourette’s disorder is the fact that the symptoms usually subside as people age; because Tourette’s patients are rarely under care for the disorder when they die, few postmortem studies of Tourette’s disorder have been conducted. Consequently, the study of the disorder’s neural bases is based almost exclusively on brain- imaging studies, which are difficult to conduct because of the requirement that the patients remain motionless. Most research on the cerebral pathology associated with Tourette’s disorder has focused on the striatum (caudate plus putamen). Patients with this disorder tend to have smaller striatal volumes (see Jackson et al., 2015), and when they suppress their tics, fMRI activity is recorded in both the prefrontal cortex and caudate nuclei (see Thomas & Cavanna, 2013). Presumably, the decision to suppress the tics comes from the prefrontal cortex, which initiates the suppression by acting on the caudate nuclei. Accordingly, Tourette’s is sometimes viewed as the result of a dysfunc-tional caudate that is unable to suppress unwanted move-ments, like tics (see Gagné, 2019). 43 Biopsychology of Psychiatric Disorders 503 There is also evidence of dysfunctional dopaminergic and GABAergic signaling within the cortical-striatal-thalamic-cortical brain circuits in Tourette’s disorder. This finding has been of particular interest because those brain circuits are implicated in motor learning—including habit formation (see Jackson et al., 2015). Although most studies of the neural bases of Tourette’s disorder have focused on the striatum, the brain differences appear to be more widespread. For example, an MRI study of children with Tourette’s disorder (see Jackson et al., 2015) documented thinning in sensorimotor cortex gray matter that was particularly prominent in the areas that controlled the face, mouth, and larynx (voice box). P.H. is a scientist who counsels Tourette’s patients and their families. He also has Tourette’s disorder, which provides him with a useful perspective (Hollenbeck, 2001). The Case of P.H., the Neuro- scientist with Tourette’s Disorder Tourette’s disorder has been P.H.’s problem for more than three decades. Taking advantage of his position as a medical school faculty member, he regularly offers a series of lectures on the topic. Along with students, many other Tourette’s patients and their families are attracted to his lectures. Encounters with Tourette’s patients of his own generation taught P.H. a real lesson. He was astounded to learn that most of them did not have his thick skin. About half of them were still receiv-ing treatment for psychological wounds inflicted during childhood. For the most part, these patients’ deep-rooted pain and anxiety did not result from the tics themselves. They derived from being ridiculed and tormented by others and from the self-righteous advice repeatedly offered by well-meaning “clods.” The malfunction may be in a patient’s striatum, but in reality this is more a disorder of the onlooker than of the patient. We received an e-mail from a professor of biological sci-ences at Purdue University. He came across this text because it was used in his department’s behavioral neurobiology course. He thanked us for our coverage of Tourette’s disor-der but said that he found the case study “a bit eerie.” The message began with “From one case study to another,” and it ended “All the best, P.H.” Clinical Trials: Development of New Psychotherapeutic Drugs Almost daily, there are news reports of exciting discoveries that appear to be pointing to effective new therapeutic drugs or treatments for psychiatric disorders. But most often, the promise does not materialize. For example, almost 50 years after the revolution in molecular biology began, not a single form of gene therapy is yet in widespread use for psychiatric disorders. The reason is that the journey of a drug or other medical treatment from promising basic research to useful reality is excruciatingly complex, time-consuming, and expensive. Research designed to translate basic scientific discoveries into effective clinical treatments is called translational research. So far, the chapter has focused on early drug discoveries and their role in the development of theories of psy-chiatric disorders. In the early years, the development of psychotherapeutic drugs was largely a hit-or-miss process. New drugs were tested on patient pop-ulations with little justification and then quickly marketed to an unsuspecting public, often before it was discovered that they were dangerous or ineffective for their original purpose. Things have changed. The testing Table 2.1 Phases of Drug Development BASIC RESEARCH Discovery of the drug, development of efficient methods of synthesis, and testing with animal models Application to begin clinical trials and the review of basic research by government agency HUMAN CLINICAL TRIALS Phase 1 Screening for safety and finding the maximum safe dose Phase 2 Establishing most effective doses and schedules of treatment Phase 3 Clear demonstrations that the drug is therapeutic Application to begin marketing and reviews of results of clinical trials by government agency SELLING TO THE PUBLIC Recovering development costs and continuing to monitor the safety of the drug of experimental drugs on human vol-unteers and their subsequent release for sale are now strictly regulated by government agencies. The process of gaining permission from the government to market a new psychotherapeutic drug begins with the synthesis of the drug, the develop-ment of economically efficient procedures for synthesizing the drug, and the collection of evidence from nonhuman subjects showing that the drug is likely safe for human consumption and has potential therapeutic benefits. These initial steps usually take a long time—at least 5 years—and only if the evidence is sufficiently promising is permission granted to proceed to clinical trials. Clinical trials are stud-ies conducted on volunteers with the disorder to assess the therapeutic efficacy of an untested drug or other treatment. This final module of the chapter focuses on the process of conducting clinical trials—summarized in Table 2.1. Clinical Trials: The Three Phases LO 2.27 Describe the three phases of clinical trials. Once approval has been obtained from the appropriate government agencies, clinical trials of a new drug with therapeutic potential can commence. Clinical trials are conducted in three separate phases: (1) screening for safety, (2) establishing the testing protocol, and (3) final testing (see Zivin, 2000). If any one of the three phases is unsuccessful, then study of the drug is usually curtailed. Based on Zivin, J. A. (2000, April). Understanding clinical trials. Scientific American, 282, 69– 75. PHASE 1: SCREENING FOR SAFETY. The purpose of the first phase of a clinical trial is to determine whether the drug is safe for human use and, if it is, to determine how much of the drug can be tolerated. Administering the drug to humans for the first time is always a risky process because there is no way of knowing for certain how they will respond. The subjects in phase 1 are typically healthy paid volunteers. Phase 1 clinical trials always begin with tiny injections, which are gradually increased as the tests proceed. The reactions of the volunteers are meticulously monitored, and if strong adverse reactions are observed, testing is curtailed. PHASE 2: ESTABLISHING THE TESTING PROTOCOL. The purpose of the second phase of a clinical trial is to establish the protocol (the conditions) under which the final tests are likely to provide a clear result. For example, in phase 2, researchers hope to discover which doses are likely to be therapeutically effective, how frequently they should be administered, how long they need to be administered to have a therapeutic effect, what benefits are likely to occur, and which patients are likely to be helped. Phase 2 tests are conducted on volunteer patients suffering from the target disorder; the tests usually include placebo-control groups (groups of patients who receive a control substance rather than the drug), and their designs that neither the patients nor the physicians interacting with them know which treatment (drug or placebo) each patient has received. PHASE 3: FINAL TESTING. Phase 3 of a clinical trial is typically a double-blind, placebo-control study on large numbers—often, many thousands—of patients suffering from the target disorder. The design of the phase 3 tests is based on the results of phase 2 so that the final tests are likely to demonstrate positive therapeutic effects if they exist. The first test of the final phase is often not conclusive, but if it is promising, a second test based on a redesigned protocol may be conducted. In most cases, two independent successful tests are required to convince government regulatory agencies. A test is typically deemed successful if the beneficial effects outweigh any adverse side effects. Controversial Aspects of Clinical Trials LO 2.28 Identify six controversial aspects of clinical trials. The clinical trial process is not without controversy. The following are six points that have been focuses of criticism and debate (see Goldacre, 2013; London, Kimmelman, & Carlisle, 2012). REQUIREMENT FOR DOUBLE-BLIND DESIGN AND PLACEBO CONTROLS. In most clinical trials, patients are assigned to drug or placebo groups randomly and do not know for sure which treatment they are receiving. Thus, some patients whose only hope for recovery may be the latest experimental treatment will, without knowing it, receive the placebo. Drug companies and government agencies concede that this is true, but they argue that there can be no convincing evidence that the experimental treatment is effective until a double-blind, placebo-control trial has been completed. Because psychiatric disorders often improve after a placebo, a double-blind, placebo-control procedure is essential in the evaluation of any psychotherapeutic drug. THE NEED FOR ACTIVE PLACEBOS. Conventional wisdom has been that the double-blind, placebo-control procedure is the perfect control procedure to establish the effectiveness of new drugs, but it isn’t (see Benedetti, 2014). Here is a new way to think about the double- blind placebo-control procedure. At therapeutic doses, many drugs have side effects that are obvious to people taking them, and, thus, the participants in double-blind, placebo-control studies who receive the drug can often accurately guess that they are not in the placebo group (see Geuter, Koban, & Wager, 2017). This knowledge 45 Biopsychology of Psychiatric Disorders 505 may greatly contribute to the positive effects of the drug, independent of any real therapeutic effect. Accordingly, it is now widely recognized that an active placebo is better than an inert placebo as the control drug. Active placebos are control drugs that have no therapeutic effect but produce side effects similar to those produced by the drug under evaluation (see Kirsch, 2019; Shader, 2017). LENGTH OF TIME REQUIRED. Patients desperately seeking new treatments are frustrated by the amount of time needed for clinical trials. Therefore, researchers, drug companies, and government agencies are striving to speed up the evaluation process without sacrificing the quality of the procedures designed to protect patients from ineffective or dangerous treatments. It is imperative to strike the right compromise. FINANCIAL ISSUES. The drug companies pay the scientists, physicians, technicians, assistants, and patients involved in drug trials. Considering the billions these companies spend per candidate drug (see Fleming, 2018) and the fact that only about 22 percent of the candidate drugs entering phase 1 testing ever gain final approval (see Figure 2.7), it should come as no surprise that the companies are anxious to recoup their costs and that fewer are investing in novel drugs (see Grabb & Gobburu, 2017). In view of this pressure, many have questioned the impartiality of those conducting and reporting the trials (see Normile, 2014; Roest et al., 2015). The scientists themselves have often complained that the sponsoring drug company makes them sign an agreement that prohibits them from publishing or discussing negative findings without the company’s consent. This is a serious ongoing problem: Any new drug will look promising if all negative evidence is suppressed (see Goldacre, 2013). Another financial issue is profitability—drug compa-nies seldom develop drugs to treat rare disorders because such treatments will not be profitable. Drugs for which the market is too small for them to be profitable are called orphan drugs. Some governments have passed laws intended to promote the development of orphan drugs. Also, the massive costs of clinical trials have contributed to a translational bottleneck—only a small proportion of potentially valuable ideas or treatments receive funding for translational research. TARGETS OF PSYCHOPHARMACOLOGY. Hyman and Fenton (2003) have argued that a major impediment to the development of effective psychotherapeutic drugs is that the effort is often aimed at curing disease entities as cur-rently conceived—for example, as defined by the DSM-5. The current characterizations of various psychiatric disor-ders are the best they can be given the existing evidence; however, it is clear that most psychiatric disorders, as cur- rently conceived, are likely clusters of disorders, each with a different pattern of associated brain dysfunction. Thus, effective new drugs are likely to benefit only a proportion of those patients with a particular diagnosis, and thus their effectiveness might go unrecognized. LACK OF DIVERSITY. Two related issues have come to light over the past decade. First is that there is a relative lack of diversity in the volunteers used in clinical trials (see Clark et al., 2019; Polo et al., 2019). If diverse groups (e.g., different ethnicities, sexes) aren’t included in a clinical trial, then we cannot be sure that the drug will also work for indi-viduals of different sexes or ethnicities. Second is that, even when there is diversity in a clinical trial, data are typically grouped and analyzed together—obscuring group differ-ences and leading to potentially risky generalizations about the effectiveness of a drug across groups of individuals (see Eid, Gobinath, & Galea, 2019). Effectiveness of Clinical Trials LO 2.29 Discuss the relative effectiveness of clinical trials. Despite the controversy that surrounds the clinical trial process, there is no question that it works. A long, dismal history tells of charlatans who make unfounded promises and take advantage of people at the time when they are least able to care for themselves. The clinical trial process is the most objective method ever devised to assess the efficacy of a treatment. It is expensive and slow, and in need of constant refinements, and over-sight, but the process is trustworthy. (Zivin, 2000, p. 75) Certainly, the clinical trial process is far from perfect. For example, concerns about the ethics of randomized dou-ble-blind, placebo-control studies are warranted. Still, the vast majority of those in the medical and research profes-sions accept that these studies are the essential critical test of any new therapy. This is particularly true of psychothera-peutic drugs because psychiatric disorders often respond to placebo treatments (see Rutherford & Roose, 2013; Wager & Atlas, 2015) and because assessment of their severity can be greatly influenced by the expectations of the therapist. Everybody agrees that clinical trials are too expensive and take too long. But Zivin (2000) responds to this concern in the following way: Clinical trials can be trustworthy, fast, or cheap; but in any one trial, only two of the three are pos- sible. Think about it. Journal Prompt 2.5 What do you think Zivin means when he suggests that clinical trials can be trustworthy, fast, or cheap; but that in any one trial, only two of the three are possible? It is important to realize that every clinical trial is care-fully monitored as it is being conducted. Any time the results warrant it, changes to the research protocol are made to reduce costs, improve safety, and reduce the time to get the drug to patients. We think this system would be greatly improved if there was a legal requirement for all partial or completed clinical trials to be published so that patients, doctors, and scientists would have access to all of the evi-dence. What do you think? CONCLUSION. Ideally, patients in the same diagnostic category should display the same symptoms associated with the same underlying pathology caused by the same genetic and environmental factors. But more importantly, they should all respond to the same treatments. When it comes to disorders of the brain, our most complex organ, this ideal is rarely met. However, when it comes to the diag-nosis of psychiatric disorders, we have not even been close. As you progressed through this chapter, we hope you recognized the signs that the diagnosis of psychiatric dis-orders needs to be improved

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