Biopsychology of Psychiatric Disorders Chapter 18 PDF

Chapter 18 Biopsychology of Psychiatric Disorders The Brain Unhinged Matthieu Spohn/ès/Corbis Chapter Overview and Learning Objectives Schizophrenia LO 18.1 Describe the positive and negative symptoms of schizophrenia,...

Chapter 18 Biopsychology of Psychiatric Disorders The Brain Unhinged Matthieu Spohn/ès/Corbis Chapter Overview and Learning Objectives Schizophrenia LO 18.1 Describe the positive and negative symptoms of schizophrenia, and provide specific examples of each. LO 18.2 Describe the discovery of the first two widely prescribed ­antipsychotic drugs. LO 18.3 Describe the evolution of the dopamine theory of schizophrenia. LO 18.4 Describe two current lines of research on schizophrenia. LO 18.5 Explain what is currently known about the genetics and epigenetics of schizophrenia. LO 18.6 Describe the various brain changes associated with schizophrenia. 484 M18_PINE1933_11_GE_C18.indd 484 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 485 Depressive Disorders LO 18.7 Explain what a clinical depression is. LO 18.8 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. LO 18.9 Describe two forms of treatment for depression that utilize brain stimulation. LO 18.10 Describe two theories of the etiology of major depressive disorder. LO 18.11 Describe our current state of knowledge of the genetic and epigenetic mechanisms of depression. LO 18.12 Describe the various brain differences associated with major depressive disorder. Bipolar Disorder LO 18.13 Describe the symptoms associated with each of the two types of bipolar disorder. LO 18.14 Describe the discovery of the first mood stabilizer. LO 18.15 Describe some factors that may contribute to the onset and maintenance of bipolar disorder. LO 18.16 Describe our current state of knowledge of the genetic and epigenetic mechanisms of bipolar disorder. LO 18.17 Describe the brain differences associated with bipolar disorder. Anxiety Disorders LO 18.18 Describe four anxiety disorders. LO 18.19 Describe three sorts of drugs used in the treatment of anxiety disorders. LO 18.20 Describe three animal models of anxiety disorders. LO 18.21 Describe our current state of knowledge of the genetic and epigenetic mechanisms of anxiety disorders. LO 18.22 Describe the various brain differences associated with anxiety disorders. Tourette’s Disorder LO 18.23 Describe the symptoms of Tourette’s disorder. LO 18.24 Describe how Tourette’s disorder is treated. LO 18.25 Describe our current state of knowledge of the genetic and epigenetic mechanisms of Tourette’s disorder. LO 18.26 Describe the research findings related to the neural bases of Tourette’s disorder. Clinical Trials: LO 18.27 Describe the three phases of clinical trials. Development of New LO 18.28 Identify six controversial aspects of clinical trials. Psychotherapeutic Drugs LO 18.29 Discuss the relative effectiveness of clinical trials. M18_PINE1933_11_GE_C18.indd 485 22/01/2021 11:52  486 Chapter 18 This chapter is about the biopsychology of psychiatric disorders (disorders of psychological function sufficiently Schizophrenia: The Case of Lena severe to require treatment). One of the main difficulties in Lena’s mother was hospitalized with schizophrenia when Lena studying or treating psychiatric disorders is that they are was 2. As a child, Lena displayed periods of hyperactivity; as an difficult to diagnose. The psychiatrist or clinical psychologist adolescent, she was viewed as odd. She enjoyed her classes must first decide whether a patient’s psychological function and got good grades, but she had few friends. is pathological or merely an extreme of normal human Shortly after their marriage, Lena’s husband noticed that variation: For example, does a patient with a poor memory Lena was becoming more withdrawn. She would sit for hours suffer from a pathological condition, or is he merely a barely moving a muscle, often having lengthy discussions with healthy person with a poor memory? nonexistent people. If a patient is judged to be suffering from a psychiatric One day, Lena’s husband found her sitting on the floor in disorder, then the particular disorder must be diagnosed. an odd posture staring into space. She was totally unresponsive. Because we cannot yet identify the specific brain pathology When he tried to move her, Lena displayed waxy flexibility—that associated with various disorders, their diagnosis usually is, she reacted like a mannequin, not resisting movement and holding her new position until she was moved again. She was rests entirely on the patient’s symptom profile. Currently, diagnosed with schizophrenia with catatonia (schizophrenia the diagnosis is guided by the DSM-5 (the current edition characterized by long periods of immobility and waxy flexibility). of the Diagnostic and Statistical Manual of the American In the hospital, Lena displayed a speech pattern exhibited Psychiatric Association). There are two main difficulties by some individuals with schizophrenia: echolalia (vocalized rep- in diagnosing particular psychiatric disorders: (1) patients etition of some or all of what has just been heard). suffering from the same disorder often display different Doctor: How are you feeling today? symptoms, and (2) patients suffering from different Lena: I am feeling today, feeling the feelings today. disorders often display many of the same symptoms. Doctor: Are you still hearing the voices? Consequently, experts often disagree on the diagnosis of Lena: Am I still hearing the voices, voices? 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. What Is Schizophrenia? This chapter begins with discussions of five sorts of LO 18.1 Describe the positive and negative symptoms psychiatric disorders: schizophrenia, depressive disorders, of schizophrenia, and provide specific bipolar disorder, anxiety disorders, and Tourette’s disor- examples of each. der. It ends with a description of how new psychotherapeutic The major difficulty in studying and treating schizophrenia drugs are developed and tested. 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 Schizophrenia conditions (e.g., complex seizures; see Chapter 10) have symptoms that might suggest a diagnosis of schizophrenia. Schizophrenia means “the splitting of psychic functions.” Because the current definition of schizophrenia overlaps The term was coined in the early years of the 20th century with that of several different disorders, the DSM-5 prefers to describe what was assumed at the time to be the primary to use the label schizophrenia spectrum disorders to refer to symptom of the disorder: the breakdown of integration schizophrenia and related disorders (see Bhati, 2013). among emotion, thought, and action. The following are some symptoms of schizophrenia, Schizophrenia is considered to be a severe psychiatric although none of them appears in all cases. In an effort to disorder. It attacks about 1 percent of individuals of categorize cases of schizophrenia so that they can be stud- all races and cultural groups, typically beginning in ied and treated more effectively, it is common practice to adolescence or early adulthood (see Sikela & Quick, 2018). consider positive symptoms (symptoms that seem to repre- Schizophrenia occurs in many forms, but the case of Lena sent an excess of typical function) separately from negative introduces you to some of its common features (Meyer & symptoms (symptoms that seem to represent a reduction or Salmon, 1988). loss of typical function)—see Smigielski et al. (2020). M18_PINE1933_11_GE_C18.indd 486 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 487 Examples of positive symptoms include the following: interested in reports that the snakeroot plant had long been used in India for the treatment of mental illness. He gave Delusions. Delusions of being controlled (e.g., “Martians reserpine—the active ingredient of the snakeroot plant—to are making me steal”), delusions of persecution (e.g., his patients with schizophrenia and confirmed its antipsy- “My mother is poisoning me”), or delusions of grandeur chotic action. Reserpine is no longer used in the treatment (e.g., “Steph Curry admires my jump shot”). of schizophrenia because it produces a dangerous decline in Hallucinations. Imaginary voices making critical com- blood pressure at the doses needed for successful treatment. ments or telling patients what to do. Although the chemical structures of chlorpromazine Inappropriate affect. Reacting with an inappropriate and reserpine are dissimilar, their antipsychotic effects emotional response to positive or negative events. are similar in two major respects. First, the antipsychotic Disorganized speech or thought. Illogical thinking, pecu- effect of both drugs is manifested only after a patient has liar associations among ideas, belief in supernatural been medicated for 2 or 3 weeks. Second, the onset of forces. this antipsychotic effect is usually associated with motor effects similar to the symptoms of Parkinson’s disease Odd behavior. Talking in rhymes, difficulty performing (e.g., muscular rigidity, a general decrease in voluntary everyday tasks. movement). These similarities suggested to researchers Examples of negative symptoms include the following: that chlorpromazine and reserpine were acting through Affective flattening. Diminished emotional expression. the same mechanism—one that was related to Parkinson’s disease. Avolition. Reduction or absence of motivation. Catatonia. Remaining motionless, often in awkward positions for long periods. The Dopamine Theory The frequent recurrence of any two of these symp- of Schizophrenia toms for 1 month is currently sufficient for the diagnosis LO 18.3 Describe the evolution of the dopamine theory of schizophrenia—provided that one of the symptoms is of schizophrenia. delusions, hallucinations, or disorganized speech. The next major breakthrough in the study of schizophrenia came from research on Parkinson’s disease. In 1960, it Discovery of the First Antipsychotic was reported that the striatums (caudates plus putamens; Drugs see Figure 3.28) of persons with Parkinson’s disease had been depleted of dopamine (see Goetz, 2011). This LO 18.2 Describe the discovery of the first two widely finding suggested that a disruption of dopaminergic prescribed antipsychotic drugs. transmission might produce both Parkinson’s disease and The first major breakthrough in the study of the biochemistry the antipsychotic effects of chlorpromazine and reserpine. of schizophrenia was the accidental discovery in the early Thus was born the dopamine theory of schizophrenia—the 1950s of the first antipsychotic drug (a drug that is meant theory that schizophrenia is caused by too much dopamine to treat certain symptoms of schizophrenia and bipolar and, conversely, that antipsychotic drugs exert their effects disorder), chlorpromazine. Chlorpromazine was developed by decreasing dopamine levels (see McCutcheon, Abi- by a French drug company as an antihistamine. Then, in Dargham, & Howes, 2019). 1950, a French surgeon noticed that chlorpromazine given Lending instant support to the dopamine theory of prior to surgery to counteract swelling had a calming effect schizophrenia were two already well-established facts. First, on some of his patients, and he suggested that it might have a the antipsychotic drug reserpine was known to deplete the calming effect on difficult-to-handle patients with psychosis brain of dopamine and other monoamines by breaking (a loss of touch with reality). His suggestion triggered down the synaptic vesicles in which these neurotransmitters research that led to the discovery that chlorpromazine are stored. Second, drugs such as amphetamine and cocaine, alleviates the symptoms of schizophrenia: Agitated patients which can trigger episodes that resemble schizophrenia in with schizophrenia were calmed by chlorpromazine, and healthy users, were known to increase the extracellular emotionally blunted patients with schizophrenia were levels of dopamine and other monoamines in the brain. activated by it. Don’t get the idea that chlorpromazine cures An important step in the evolution of the dopamine schizophrenia. It doesn’t. But it often reduces the severity of theory of schizophrenia came in 1963, when Carlsson and symptoms enough to allow institutionalized patients to be Lindqvist assessed the effects of chlorpromazine on extra- discharged. cellular levels of dopamine and its metabolites (substances Shortly after the antipsychotic action of chlorpromazine that are created by the breakdown of another substance in was first documented, an American psychiatrist became cells). Although they expected to find that chlorpromazine, M18_PINE1933_11_GE_C18.indd 487 22/01/2021 11:52  488 Chapter 18 like reserpine, depletes the brain of Figure 18.1 Chlorpromazine is a receptor blocker at dopamine synapses. dopamine, they didn’t. The extra- Chlorpromazine was the first receptor blocker to be identified, and its discovery cellular levels of dopamine were changed psychopharmacology. unchanged by chlorpromazine, and the extracellular levels of its metabolites were increased. The researchers concluded that both 1 Chlorpromazine binds to postsynaptic dopamine receptors; it does not activate chlorpromazine and reserpine them, and it blocks the ability of dopamine to activate them. antagonize transmission at dopa- mine synapses but that they do it in different ways: reserpine by Chlorpromazine depleting the brain of dopamine Dopamine and chlorpromazine by binding to receptor dopamine receptors. Carlsson and Lindqvist argued that chlorpromazine is a receptor blocker at dopamine synapses—that is, it binds to dopamine receptors 2 The blockage of dopamine receptors by chlorpromazine sends without activating them and, in so a feedback signal to the doing, keeps dopamine from acti- presynaptic neuron, which vating them (see Figure 18.1). We increases the release of dopamine. now know that many psychoactive drugs are receptor blockers, but chlorpromazine was the first to be identified as such. 3 The feedback signal increases the release of dopamine, which is broken down in the synapse, resulting Dopamine metabolites Carlsson and Lindqvist fur- in elevated levels of dopamine Dopamine metabolites. ther postulated that the lack of activity at postsynaptic dopamine receptors sent a feedback signal to the presynaptic cells that increased their release of and the other effective antipsychotic drugs had a high dopamine, which was broken down in the synapses. This affinity for dopamine receptors, whereas ineffective explained why dopaminergic activity was reduced while antipsychotic drugs had a low affinity. There were, how- extracellular levels of dopamine stayed about the same ever, several major exceptions, including haloperidol. and ­extracellular levels of its metabolites were increased. Although haloperidol was one of the most potent anti- Carlsson and Lindqvist’s findings led to an important revi- psychotic drugs of its day, it had a relatively low a­ ffinity sion of the dopamine theory of schizophrenia: Rather than for ­dopamine receptors. high dopamine levels, the main factor in schizophrenia A solution to the haloperidol puzzle came with the was presumed to be high levels of activity at dopamine discovery that dopamine binds to more than one dopa- receptors. mine receptor subtype—five have been identified (see In the mid-1970s, Snyder and his colleagues (see Beaulieu, Espinoza, & Gainetdinov, 2015). It turns out that Creese, Burt, & Snyder, 1976; Madras, 2013) assessed the chlorpromazine and other antipsychotic drugs in the same degree to which the various antipsychotic drugs that had chemical class (the phenothiazines) all bind effectively to been developed by that time bind to dopamine recep- both D1 and D2 receptors, whereas haloperidol and the tors. First, they added radioactively labeled dopamine other antipsychotic drugs in its chemical class (the butyro- to samples of dopamine-receptor-rich neural membrane phenones) all bind effectively to D2 receptors but not to obtained from calf striatums. Then, they rinsed away the D1 receptors. unbound dopamine molecules from the samples and mea- This discovery of the selective binding of butyro­ sured the amount of radioactivity left in them to obtain a phenones to D2 receptors led to an important revision in measure of the number of dopamine receptors. Next, in the dopamine theory of schizophrenia. It suggested that other samples, they measured each drug’s ability to block schizophrenia is caused by hyperactivity specifically at D2 the binding of radioactive dopamine to the sample; the receptors, rather than at dopamine receptors in general. assumption was that the drugs with a high affinity for Snyder and his colleagues (see Madras, 2013; Snyder, dopamine receptors would leave fewer sites available for 1978) ­subsequently confirmed that the degree to which the dopamine. In general, they found that chlorpromazine typical antipsychotics (the first generation of antipsychotic M18_PINE1933_11_GE_C18.indd 488 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 489 Figure 18.2 The positive correlation between the ability Schizophrenia: Beyond the of various antipsychotics to bind to D2 receptors and their Dopamine Theory clinical potency. LO 18.4 Describe two current lines of research on schizophrenia. Although the dopamine theory of schizophrenia is still influ- ential, current lines of research into atypical ­antipsychotics Haloperidol and psychedelic drug effects are leading to interesting new Antipsychotic Potency perspectives. These two areas of research will be described Spiroperidol in the following two subsections. 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 Chlorpromazine 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 Potency of D2 Binding and histamine receptors, but only a slight affinity for D2 ­receptors (see Humbert-Claude et al., 2012). Aripiprazole, Based on Snyder, S. H. (1978). Neuroleptic drugs and neurotransmitter respiridone, and quetiapine are but a few of the other com- receptors. Journal of Clinical and Experimental Psychiatry, 133, 21–31. monly prescribed atypical antipsychotics. RENEWED INTEREST IN HALLUCINOGENIC drugs) bind to D2 receptors is highly correlated with their DRUGS. The study of psychedelic drugs (drugs whose effectiveness in suppressing the symptoms of schizophrenia primary action is to alter perception, emotion, and cog- (see Figure 18.2). For example, the butyrophenone ­spiroperidol nition) began in 1943 with the discovery of lysergic acid had the greatest affinity for D2 receptors and the most potent diethylamide (LSD) (see Garcia-Romeu & Richards, 2018; antipsychotic effect. Nichols, 2016). In addition to classical hallucinogens (such as Although the evidence implicating D2 receptors in LSD, psilocybin, and mescaline), psychedelic drugs include schizophrenia is strong, it has become apparent that the D2 a variety of other drugs such as the dissociative hallucinogens version of the dopamine theory of schizophrenia could not (e.g., ketamine and phencyclidine). explain two general findings: Researchers have pursued two lines of research on Although typical antipsychotics block activity at D2 psychedelics. One line focused on those psychedelic drugs receptors within hours, their therapeutic effects are that produce effects similar to the symptoms of psychiatric usually not apparent for several weeks. disorders (e.g., illusions, hallucinations, paranoia, panic), and they used the drugs to model the disorders. The other Almost all antipsychotics are only effective in the treat- line focused on the feelings of boundlessness, unity, and bliss ment of schizophrenia’s positive symptoms, but not its reported by some users and attempted to use psychedelics negative symptoms (see Aleman et al., 2018; Osoegawa in the treatment of psychiatric disorders. Unfortunately, et al., 2018). these promising lines of research ground to a halt in the Appreciation of these limitations has led to the current 1970s when many governments, troubled by the association version of the dopamine theory. This version holds that of LSD and related drugs with various societal subcultures, excessive activity at D2 receptors is one factor in the disor- made it extremely difficult for researchers to study their der but that there are many other factors as well (see Poels effects, particularly in humans (see Belouin & Henningfield, et al., 2014; Sibley & Shi, 2018). 2018; Rucker, Iliff, & Nutt, 2018; but see Oram, 2016). Those of you who read about the mesocorticolimbic In the 1990s, there was a gradual renewal of interest dopamine pathway and the nigrostriatal dopamine pathway in in utilizing psychedelic drugs to study the mechanisms Chapter 15 (see Figure 15.7) might be wondering which of of schizophrenia and other psychiatric disorders (see those two pathways is affected in schizophrenia. The dopa- ­Belouin & Henningfield, 2018; Rucker, Iliff, & Nutt, 2018). mine theory of schizophrenia proposes that schizophrenia This renewal was stimulated by the development of tech- is caused by excessive activity in the mesocorticolimbic niques for imaging the effects of drugs in the human brain pathway. and by an increased understanding of the mechanisms of M18_PINE1933_11_GE_C18.indd 489 22/01/2021 11:52  490 Chapter 18 psychedelic drug action (e.g., Tylš, Páleníček, & Horáček, & Akbarian (2016). Supporting this neurodevelopmental 2014). This research led to three important conclusions: theory of schizophrenia are (1) the fact that schizophrenia and autism spectrum disorders share many of the same The psychedelic effects of classical hallucinogens, such causal factors (e.g., genetic risk factors, environmental as LSD, mimic the positive symptoms of schizophrenia triggers)—see Millan et al. (2016), and (2) the study of two (e.g., hallucinations and disorganized thought) by act- 20th-century famines: the Nazi-induced Dutch famine of ing as an agonist of the serotonin type-2a receptor. 1944–1945 and the Chinese famine of 1959–1961. Fetuses That antagonists of the serotonin type-2a receptor are whose pregnant mothers suffered in those famines were effective antipsychotics (e.g., the atypical antipsychotic more likely to develop schizophrenia as adults (see Li et risperidone) (see Girgis et al., 2018). al., 2015; Schmitt et al., 2014). Dissociative hallucinogens (e.g., ketamine) mimic Recent research has identified many epigenetic mecha- the negative symptoms of schizophrenia by acting as nisms that contribute to the emergence and persistence of antagonists of glutamate receptors (see Laruelle, 2014). schizophrenia (see Rizzardi et al., 2019). For example, DNA methylation and histone modifications (see Chapter 2) have both been implicated in the expression of genes for synapse- Genetic and Epigenetic Mechanisms specific proteins in prefrontal cortex neurons (see Caldeira, of Schizophrenia Peça, & Carvalho, 2019; Rizzardi et al., 2019). This and other research on the role of epigenetic mechanisms has given LO 18.5 Explain what is currently known about the researchers better insight into how genes interact with the genetics and epigenetics of schizophrenia. environment to produce schizophrenia (see Breen et al., It is clear that schizophrenia involves multiple genetic and 2019; Gandal et al., 2018; Girdhar et al., 2018). The role of epigenetic mechanisms. Many genes have been linked to the transgenerational epigenetic mechanisms (see Chapter 2) disorder (see Flint & Manufò, 2014; Reardon, 2014; Ripke in psychiatric disorders like schizophrenia is also of great et al., 2014), but no single gene seems capable of causing interest to researchers (see Yeshurun & Hannan, 2019). schizophrenia by itself, although certain genes have been more strongly implicated than others (see Dhindsa & ­Goldstein, 2016; Sikela & Quick, 2018; Sekar et al., 2016). Neural Bases of Schizophrenia The study of schizophrenia-related genes and their LO 18.6 Describe the various brain changes associated expression (see Chapter 2; Figure 2.18) is still in its early with schizophrenia. stages, but it has already pointed to several physiological There is a long history of research on the neural bases of changes that could play important roles in development schizophrenia. Many studies have assessed brain develop- of the disorder (see Kotlar et al., 2015). For example, the ment in patients with, or at risk for, schizophrenia. Four expression of schizophrenia-related genes is associated important findings have emerged from various meta-anal- with multiple aspects of brain development (see Birnbaum yses of those studies (see Fusar-Poli et al., 2011; Steen et al., & Weinberger, 2017; Jaffe et al., 2018; Smigielski et al., 2020), 2006; Vita et al., 2006): myelination (see Voineskos et al., 2012), transmission at glu- tamatergic and GABAergic synapses (see Sacchetti et al., Individuals who have not been diagnosed with schizo- 2013), and changes in dopaminergic neuron physiology (see phrenia but are at risk for the disorder (e.g., because Dong et al., 2018; but see Gürel et al., 2020); and some genes they have close relatives with schizophrenia) display that increase a person’s susceptibility to schizophrenia have volume reductions in some parts of the brain—for also been linked to other psychiatric and neurological dis- example, in the hippocampus (see Haukvik et al., 2018). orders (see Rizzardi et al., 2019). Extensive brain changes already exist when patients A variety of early experiential factors have been first seek medical treatment and receive their first brain implicated in the development of schizophrenia—for scans. example, birth complications, maternal stress, prenatal Subsequent brain scans reveal that the brain changes infections, socioeconomic factors, urban birth or residing continue to develop after the initial diagnosis. in an urban setting, and childhood adversity (see Owen, Alterations to different areas of the brain develop at Sawa, & Mortensen, 2016). Such early experiences are different rates (see Gogtay & Thompson, 2010). thought to alter the typical course of neurodevelopment leading to schizophrenia in individuals who have a genetic One exciting line of research on the neural bases susceptibility (see Negrón-Oyarzo et al., 2016; Owen, of schizophrenia has challenged the idea that the Sawa, & Mortensen, 2016), presumably through epigenetic mesocorticolimbic dopamine pathway is involved in mechanisms (see Chapter 2)—see Birnbaum & Weinberger ­schizophrenia; if you remember, this was a tenet of the (2017), Hannon et al. (2016), Jaffe et al. (2016), and Sharp classic dopamine theory of schizophrenia. This line of M18_PINE1933_11_GE_C18.indd 490 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 491 research has shown that the neuropathological changes their daily lives: to keep a job, to eat, or to maintain social occur in the nigrostriatal dopamine pathway rather than contacts and personal hygiene. Sleep disturbances and in the mesocorticolimbic pathway (see McCutcheon, thoughts of suicide are common. When this condition lasts Abi-Dargham, & Howes, 2019). for 2 weeks or longer, these people are said to be suffering Recent research on the neural bases of schizophrenia from a clinical depression, also known as major depressive has used modern functional brain-imaging techniques to disorder. The case of S.B. introduces you to some of the study functional connectivity (see Chapter 5) in the brains of main features of clinical depression. 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 The Case of S.B., the Depressed in individuals with schizophrenia. This line of research has Biopsychology Student shown that when participants with schizophrenia are hal- lucinating there is a change in the pattern of functional con- S.B. excelled during his first year at university—earning top nectivity as compared to when they are not hallucinating marks in his program of study: biosychology. However, begin- (see Weber et al., 2020). The second line of research is exam- ning in the second year of his studies, S.B. began to suffer ining whether patterns of intrinsic functional connectivity (see from depression: He began to sleep excessively, he had trouble Chapter 5) might be used to predict treatment response to concentrating on his studies, and he thought about death and antipsychotic medications (see Chan et al., 2019). suicide frequently. He also suffered from delusions: He thought he was stupid and disliked, and he felt persecuted by his CONCLUSION. Although there has been significant prog- instructors and peers. Having seen these symptoms previously ress in our understanding of the mechanisms and treatment in certain members of his family, S.B. made the astute decision of schizophrenia, a careful reading of the research results of seeking out help from a psychiatrist. suggests that ultimate answers will not be forthcoming His psychiatrist offered him medications, but S.B. refused, until its diagnosis is “sharpened up.” There is a general as he was reminded of the many drug-related side effects he consensus that those patients diagnosed with schizophrenia had seen in his family members. Rather, he attended psycho- therapy for the remaining years of his degree. Although it helped under the current DSM-5 criteria do not suffer from a single to talk about his problems, S.B. saw little improvement in his ­unitary disorder resulting from the same neural pathology condition during this period. Still, he was able to complete his (see Kim et al., 2017; Krynicki et al., 2018): The current diag- degree with relatively high grades and subsequently applied and nosis seems to lump together a group of related disorders was admitted to graduate studies in biopsychology. under one label. This is suggested by the variety and vari- A few months after beginning graduate school, S.B.’s ability of psychological symptoms, neural pathology, and depression became so severe that he could no longer function. by the marked variability in patient response to particular For example, S.B. had impairments in his memory and attention antipsychotic drugs. 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 Depressive Disorders help him deal with his delusional thoughts. Upon being released from the hospital, his psychiatrist advised him to take a leave We commonly use the word “depression” to refer to a reac- of absence from his studies, which he did. S.B. returned to tion to grievous loss, such as the loss of a loved one, the loss graduate school several months later. However, since his symp- of self-esteem, or the loss of health. However, “depression” toms still persisted despite all the medications, albeit to a lesser is also used to refer to a psychiatric disorder; that disorder degree, he was barely capable of keeping things together. is the focus of this module. What Are Depressive Disorders? Don’t forget S.B.; you will learn more about him later in this chapter. LO 18.7 Explain what a clinical depression is. Depression is often divided into two categories. Some people experience deep depression and/or anhedonia Depression triggered by an obvious negative experience (loss of the capacity to experience pleasure; see Husain & (e.g., the death of a friend, the loss of a job) is called reactive Roiser, 2018; Post & Warden, 2018), often for no apparent depression; depression with no apparent cause (as in the reason (see Treadway & Zald, 2011). Their depression can case of S.B.) is called endogenous depression (see Malki be so extreme that it can impair cognition (see Cambridge et al., 2014). et al., 2018; Dillon & Pizzagalli, 2018) and makes it almost Depression affects 2–5 percent of the global popula- impossible for them to meet the essential requirements of tion (see Han, Russo, & Nestler, 2019). Females are about M18_PINE1933_11_GE_C18.indd 491 22/01/2021 11:52  492 Chapter 18 twice as likely to a receive a diagnosis of depression ­during MONOAMINE OXIDASE INHIBITORS. Iproniazid, the their lifetime (see Kuehner, 2017), with this sex difference first antidepressant drug, was originally developed for the being most pronounced during adolescence (see Salk, treatment of tuberculosis, for which it proved to be a dismal Hyde, & Abramson, 2017)—although the reasons for this flop. However, interest in the antidepressant potential of sex difference are still unclear, gonadal-hormone-related the drug was kindled by the observation that it left patients explanations are currently popular (see Altemus, Sarvaiya, with tuberculosis less concerned about their disorder. As a & Epperson, 2014; Bangasser & Valentino, 2014; Kokras & result, iproniazid was tested on a mixed group of psychiat- Dalla, 2014; Kuehner, 2017). For reasons that are still unclear, ric patients and seemed to act against clinical depression. It non-­caucasian individuals are more likely to suffer from was first marketed as an antidepressant drug in 1957. chronic and more debilitating depression than ­caucasians Iproniazid is a monoamine agonist; it increases the (see Bailey, Mokonogho, & Kumar, 2019). The lifetime levels of monoamines (e.g., norepinephrine and serotonin) risk of completed suicide in an individual diagnosed with by inhibiting the activity of monoamine oxidase (MAO), the ­clinical depression has been found to range between 4 and enzyme that breaks down monoamine neurotransmitters in 15 percent in various studies (see Wang et al., 2015). the cytoplasm (cellular fluid) of the neuron. MAO inhibitors Clinical depressions attack children, adolescents, and have several side effects; the most dangerous is known as adults. In adults, clinical depression is often comorbid the cheese effect (see Finberg & Gillman, 2011). Foods such (the tendency for two health conditions to occur together as cheese, wine, and pickles contain an amine called tyra- in the same individual) with one or more other health mine, which is a potent elevator of blood ­pressure. Normally, ­conditions—for example, anxiety disorders, coronary heart these foods have little effect on blood pressure because tyra- disease, and diabetes (see Scott, 2014). mine is rapidly metabolized in the liver by MAO. However, There are two subtypes of major depressive disorder people who take MAO inhibitors and consume tyramine- whose cause is more apparent because of the timing of rich foods run the risk of stroke caused by surges in blood the episodes. One is seasonal affective disorder (SAD), pressure. in which episodes of depression and lethargy typically TRICYCLIC ANTIDEPRESSANTS. The tricyclic antide- recur during particular seasons—usually during the win- pressants are so named because of their antidepressant ter months (see Tyrer et al., 2016). Two lines of evidence action and because their chemical structures include three suggest that the episodes are triggered by the reduction in rings of atoms. Imipramine, the first tricyclic antidepres- sunlight. One is that the incidence of the disorder is higher sant, was initially thought to be an antipsychotic drug. in Alaska (9 percent) than in Florida (1 percent), where the However, when its effects on a mixed sample of psychiatric winter days are longer and brighter (see Melrose, 2015). The patients were assessed, it had no effect against schizophre- other is that light therapy (e.g., exposure to 15–30 ­minutes nia but seemed to help some depressed patients. Tricyclic of very bright light each morning) is often effective in antidepressants block the reuptake of both serotonin and reducing the symptoms of SAD (see Oren, Koziorowski, & norepinephrine, thus increasing their levels in the brain. Desan, 2013; Song et al., 2015). The second subtype of major They are a safer alternative to MAO inhibitors. depressive disorder with an obvious cause is peripartum depression, the intense, sustained depression experienced SELECTIVE MONOAMINE-REUPTAKE INHIBITORS. In by some women during pregnancy, after they give birth, or the late 1980s, a new class of drugs—the selective serotonin- both (see Serati et al., 2016; Pawluski, Lonstein, & Fleming, reuptake inhibitors—was introduced for treating ­clinical 2017). Although estimates vary, the disorder seems to be depression. Selective serotonin-reuptake inhibitors associated with about 13 percent of pregnancies (see Silver (SSRIs) are serotonin agonists that exert their agonistic et al., 2018). effects by blocking the reuptake of serotonin from ­synapses—see Figure 18.3. Antidepressant Drugs Fluoxetine (marketed as Prozac) was the first SSRI to be developed. Now there are many more (e.g., paroxetine, LO 18.8 Describe the early research that led to the sertraline, fluvoxamine). Fluoxetine’s structure is a slight discovery of antidepressant medications. variation of that of imipramine and other tricyclic anti- Also, list each of the five major classes of depressants; in fact, fluoxetine is no more effective than antidepressant drugs, and provide one specific imipramine in treating depression. Nevertheless, it was example of each. immediately embraced by the psychiatric community and Five major classes of drugs have been used for the treat- has been prescribed in many millions of cases. The remark- ment of depressive disorders (see Willner, Scheel-Krüger, able popularity of fluoxetine and other SSRIs is attributable & Belzung, 2013): monoamine oxidase inhibitors, tricyclic to two things: First, they have fewer side effects than tricy- antidepressants, selective monoamine-reuptake inhibitors, clics and MAO inhibitors; second, they act against a wide atypical antidepressants, and NMDA-receptor antagonists. range of psychological disorders in addition to depression. M18_PINE1933_11_GE_C18.indd 492 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 493 Figure 18.3 Blocking of serotonin reuptake by fluoxetine (Prozac). Serotonin Serotonin receptor Fluoxetine Serotonin is Fluoxetine blocks deactivated in the the reuptake of serotonin, synapse by reuptake thus increasing the activation into the presynaptic neuron. of serotonin receptors. The success of the SSRIs spawned the introduction shown to be remarkably effective: the dissociative hallu- of a similar class of drugs, the selective norepinephrine- cinogen ketamine. Remarkably, even a single low dose of reuptake inhibitors (SNRIs). These (e.g., reboxetine) have ­ketamine rapidly reduces depression, even in patients who proven to be just as effective as the SSRIs in the treatment of had been experiencing a severe episode (see Amit et al., 2015; depression. Also effective are drugs that block the reuptake Cui, Hu, & Hu, 2019; McGirr et al., 2015; Yang et al., 2018). of more than one monoamine neurotransmitter (e.g., venla- However, because ketamine has undesirable side effects, faxine) (see Harmer, Duman, & Cowen, 2017). researchers are now in the process of trying to ­identify more selective NMDA-receptor antagonists, and antago- ATYPICAL ANTIDEPRESSANTS. Beginning in the nists of other glutamate receptors, with fewer side effects 1980s, several new antidepressants began to appear on the (see Duman, Sanacora, & Krystal, 2019; Malinow, 2016). market that did not neatly fit into the three aforementioned classes (i.e., MAO inhibitors, tricyclic antidepressants, and EFFECTIVENESS OF DRUGS IN THE TREATMENT OF selective monoamine-reuptake inhibitors). Accordingly, a DEPRESSIVE DISORDERS. About $15 billion is spent in new class of antidepressant medications emerged that is the United States each year on antidepressants. But how really just a catch-all class comprising drugs that have many effective are antidepressants? Numerous studies have different modes of action: the atypical antidepressants (see evaluated the effectiveness of antidepressant drugs against Willner, Scheel-Krüger, & Belzung, 2013). For example, major depressive disorder. Many studies have reported that one of the drugs in this class, bupropion, has several about 50 percent of clinically depressed patients improve effects on neurotransmission: It is a blocker of dopamine with antidepressants (see Cipriani et al., 2018b). This rate and norepinephrine reuptake, and it is also a blocker of seems quite good; however, control groups typically show nicotinic acetylcholine receptors (see Carroll et al., 2014). a rate of improvement of about 35 percent, so only about Another example of a drug in this class is agomelatine—a 15 percent of depressed individuals are actually helped melatonin receptor agonist (see Taylor et al., 2014). There by the antidepressants (see Cipriani et al., 2018a). Still, are many other drugs in this class, each with its own one can argue that a 15 percent improvement over control unique mechanism of action (see Willner, Scheel-Krüger, & ­conditions is certainly meaningful when one considers how Belzung, 2013). debilitating and dangerous depression can be (see Cipriani et al., 2018b; Maslej et al., 2020). Recent meta-analyses have NMDA-RECEPTOR ANTAGONISTS. Beginning in the made it clear that some antidepressant drugs are more effec- early 1990s, several studies reported a positive effect of tive than others, and that their relative efficacy is a function antagonizing the glutamate NMDA receptor on depressive of the sex and age of the depressed individual (e.g., Cipriani disorders. In the early 2000s, one agent in particular was et al., 2018a). M18_PINE1933_11_GE_C18.indd 493 22/01/2021 11:52  494 Chapter 18 Brain Stimulation to Treat Figure 18.4 Implantation of bilateral anterior cingulate electrodes Depression and a stimulator for chronic deep brain stimulation for the treatment of depression. LO 18.9 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. Bilateral electrodes REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION. Repetitive transcranial magnetic stimulation (rTMS) is a form of transcranial magnetic stimulation (TMS; see Chapter 5) 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, Stimulator leads respectively, activity within those brain regions to which they are applied (see Berlim et al., 2013, 2014). Meta-analyses have shown reliable improvement Stimulator 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 18.4) 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 Figure 18.5 The site in the anterior cingulate gyrus at which electrode into an area of the white matter of the chronic brain stimulation to subcortical white matter alleviated anterior cingulate gyrus in the medial prefrontal symptoms in treatment-resistant depressed patients. cortex (see Figure 18.5). 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 18.1 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 Anterior to other treatments, the results were strikingly cingulate ­positive: 60 percent showed substantial improve- gyrus ments, 35 percent were largely symptom free, and Corpus callosum Site of most of the patients were improved for at least 1 year brain (the duration of the study). These positive results stimulation M18_PINE1933_11_GE_C18.indd 494 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 495 have been replicated at other treatment centers (see changes. One theory is that the critical downstream change Holtzheimer et al., 2011; Lozano et al., 2012; Lozano & is an increase in neuroplasticity. ­Mayberg, 2015). In a nutshell, the neuroplasticity theory of depression is that depression results from a decrease of neuroplastic pro- Theories of Depression cesses in various brain structures (e.g., the hippocampus), which leads to neuron loss and other neural pathology LO 18.10 Describe two theories of the etiology of major (see Castrén & Hen, 2013; Miller & Hen, 2015). General depressive disorder. support for the neuroplasticity theory of depression comes There are several theories of the etiology of major depres- from two kinds of research: (1) research showing that sive disorder. As you will soon find out, most theories are stress and depression are associated with the disruption based almost entirely on those therapies that have been of various neuroplastic processes (e.g., a reduction in the found to be effective against depression. synthesis of neurotrophins, a decrease in adult hippocam- pal neurogenesis; see Chapter 9) and (2) research show- MONOAMINE THEORY OF DEPRESSION. One promi- ing that antidepressant treatments are associated with an nent theory of clinical depression is the monoamine theory. enhancement of neuroplastic processes (e.g., an increase in The monoamine theory of depression holds that depres- the synthesis of neurotrophins (see Chapter 9), an increase sion is associated with underactivity at serotonergic and in synaptogenesis, and an increase in adult hippocampal noradrenergic synapses. The theory is largely based on neurogenesis)—see Brandon and McKay (2015), Christian the fact that monoamine oxidase inhibitors, tricyclic anti- et al. (2014), Mahar et al. (2014), and Samuels et al. (2015). depressants, and selective monoamine-reuptake inhibi- One neurotrophin has been of great interest to tors are all agonists of serotonin, norepinephrine, or both. researchers: Brain-derived neurotropic factor (BDNF)—because Other support for the monoamine theory of depression treatments that improve depression (both pharmacological has been provided by autopsy studies. Norepinephrine and and nonpharmacological) have been found to increase serotonin receptors have been found to be more numerous BDNF levels only in those patients who show improvement in the brains of deceased depressed individuals who had (see Homberg et al., 2014). Indeed, it has been proposed not received pharmacological treatment. This implicates a that decreased blood levels of BDNF might be a biomarker deficit in monoamine release: When an insufficient amount (a biological state that is predictive of a particular disorder) of a neurotransmitter is released at a synapse, there is usu- for depression, and that increased blood levels of BDNF might ally a compensatory increase in the number of receptors be a biomarker for the successful treatment of depression (see for that neurotransmitter—a process called up-regulation. Polyakova et al., 2015). Moreover, it has been hypothesized Three lines of evidence have challenged the mono- that the antidepressant-induced increase in BDNF levels amine theory of depression. First was the discovery that boost certain neuroplastic processes (e.g., increase adult monoamine agonists, although widely prescribed, are not hippocampal neurogenesis) that lead to the alleviation of effective in the treatment of most depressed patients (see depression (see Björkholm & Monteggia, 2016). 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 Genetic and Epigenetic Mechanisms that, although monoamine activity is potentiated almost of Depression immediately after monoamine-agonist administration, it LO 18.11 Describe our current state of knowledge of can take days to weeks for the antidepressant effects of the genetic and epigenetic mechanisms of the drug to emerge (see Harmer, Duman, & Cowen, 2017). depression. Third was the discovery that other neurotransmitters (e.g., GABA, glutamate, acetylcholine) play a role in the develop- Until very recently, most studies of the genetic contribu- ment of depression (Murrough, Abdallah, & Mathew, 2017; tion to clinical depression were not replicable. However, ­Northoff, 2013; Pytka et al., 2016). since 2015, a series of studies have reliably identified many genes as contributors to depression (see Ormel, Hartman, NEUROPLASTICITY THEORY OF DEPRESSION. Nearly & Snieder, 2019). all antidepressant drugs rapidly increase transmission at Because so many different genes have been found to monoaminergic synapses, yet any therapeutic effects of contribute to depression, it is considered to be a complex those increases typically are not manifested until weeks trait that involves many potential interactions with environ- after the beginning of drug therapy. Therefore, it is clear mental factors through epigenetic mechanisms (see Heller that the agonistic effects at monoaminergic synapses can- et al., 2014; Nestler, 2014; Whalley, 2014). The general find- not be the critical therapeutic mechanism: There must be ing has been that several different epigenetic mechanisms some change that occurs downstream from the synaptic contribute to depression (see Penner-Goeke & Binder, 2019) M18_PINE1933_11_GE_C18.indd 495 22/01/2021 11:52  496 Chapter 18 and that changes to the epigenome (see Chapter 2) of an indi- What Is Bipolar Disorder? vidual might one day be used to predict a future clinical depression in an individual (see Barbu et al., 2020). LO 18.13 Describe the symptoms associated with each of the two types of bipolar disorder. Neural Bases of Depression Hypomania and mania are in some respects the opposite of depression. Hypomania is characterized by a reduced need LO 18.12 Describe the various brain differences for sleep, high energy, and positive affect. During periods associated with major depressive disorder. of hypomania, people are talkative, energetic, impulsive, Numerous structural and functional neuroimaging studies ­positive, and very confident. In this state, they can be very of the brains of depressed patients have been published. effective at certain jobs and can be great fun to be with. Structural neuroimaging studies have found consistent Mania has the same features as hypomania but taken to an reductions in gray matter volumes in the prefrontal cortex, extreme; it also has additional symptoms, such as ­delusions hippocampus, amygdala, and cingulate cortex (see Lener of grandeur, overconfidence, impulsivity, and distractibility. & Iosifescu, 2015). White matter reductions have also been Mania usually involves psychosis. When mania is full- noted in several brain regions—most reliably in the fron- blown, the person often exhibits unbridled enthusiasm tal cortex (see Russo & Nestler, 2013; Wang et al., 2014). with an outflow of incessant chatter that hurtles from topic ­Functional neuroimaging studies have found atypical activ- to topic. No task is too difficult. No goal is unattainable. ity in frontal, cingulate, and insular cortices as well as in the This confidence and grandiosity, coupled with high energy, amygdala, thalamus, and striatum. distractibility, and a leap-before-you-look impulsiveness, can There are a growing number of studies that have exam- result in a series of disasters. Mania often leaves behind a trail ined alterations in functional connectivity (see ­Chapter 5) of unfinished projects, unpaid bills, and broken relationships. in depressed individuals (e.g., Goldstein-Piekarski et al., Those persons who only experience bouts of depression 2018). These studies have identified a large number of dif- and hypomania are said to have bipolar disorder type II; ferences in the brains of individuals with depression (see those who also experience bouts of mania, or only expe- Goldstein-Piekarski & Williams, 2019; Korgaonkar et al., rience mania (see Makin, 2019), are said to have bipolar 2019) i­ndicating that the neural networks of depressed disorder type I. The case of S.B., previously introduced to patients are markedly different from healthy participants. you in the module on depressive disorders, will introduce In most cases, these changes have not been clearly related you to the main features of both forms of bipolar disorder. 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 The Case of S.B. Revisited: The of research currently focus on the mechanisms and treat- ment of clinical depression, treatments are not much better Biopsychology Student with than they were 50 years ago. Many researchers contend that Bipolar Disorder current diagnostic tools, such as those that generate large S.B. continued his graduate studies in biopsychology while still heterogeneous groups of patients—like the DSM-5—are suffering from a residual depression. Although he struggled misguiding research and that more precise approaches to through the remaining years of his program, he was successful diagnosis are necessary (see Insel & Cuthbert, 2015). in attaining a master’s degree in biopsychology. S.B. subsequently began a Ph.D. program in biopsychol- ogy. During the first summer after beginning this new program, S.B. started to feel exceptionally good: His mood was elevated; Bipolar Disorder he was sleeping less than 3 hours per night; he became highly sociable and very charismatic; and he found he could read faster Some people experience periods of clinical depression and and understand materials that he had previously found difficult. also periods of hypomania or mania. Those who do are said Moreover, he became very productive. Indeed, many of the to suffer from bipolar disorder. Bipolar disorder affects ideas that would later form the basis of his Ph.D. thesis came to about 3 percent of the global population (see Ashok et al., him during this period of elation. S.B. was experiencing all the 2017; Vieta et al., 2018), with much intercultural variability symptoms of a hypomania. Because S.B. had experienced both in its presentation and course (see Subramanian, Sarkar, depression and hypomania, he now met criteria for a diagnosis & Kattimani, 2017). It is a serious psychiatric disorder of bipolar disorder type II. His hypomania persisted for several with one of the highest rates of attempted and completed months, but things were about to take a turn for the worse. suicide (see Lima, Peckham, & Johnson, 2018; Plans 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 et al., 2019). M18_PINE1933_11_GE_C18.indd 496 22/01/2021 11:52  Biopsychology of Psychiatric Disorders 497 incessantly—his living room was transformed into a labyrinthian Mood Stabilizers pile of books and academic papers. S.B. also began to believe LO 18.14 Describe the discovery of the first mood that he had some unique talents and insights. For example, he believed that he had developed a comprehensive theory that stabilizer. explained every aspect of how society functioned and he began Ideally, mood stabilizers are drugs that effectively treat to see linkages between everything that he thought about and depression or mania without increasing the risk of mania or experienced. He filled many notebooks with diagrams and writ- depression, respectively (see Karanti et al., 2016). Protection ings that he thought summarized his theory quite well; however, against the recurrence of mood episodes is important because nobody seemed to understand his theory except for him. But mood episodes in bipolar disorder typically become both this didn’t deter him. In short, he was displaying delusions of more severe and more frequent if left untreated (see Post, grandeur: He believed he had intellectual capacities that sur- passed all those around him. Moreover, whenever he spoke 2016; Post, Fleming, & Kapczinski, 2012). The mechanism with anyone, they always told him to slow down, or they simply by which mood stabilizers work is still a matter of debate gave him funny looks. At this point, S.B. was in a state of mania (see Oruch et al., 2014; Rapoport, 2014), but for some reason and now met criteria for a diagnosis of bipolar disorder type I. many mood stabilizers are also effective in the treatment However, his enthusiasm and positive affect began to of epilepsy (see Prabhavalkar, Poovanpallil, & Bhatt, 2015; slowly dwindle. Because nobody seemed to understand him Yildiz et al., 2011) and schizophrenia (see Post, 2016). and his theories, he felt increasingly alone and rejected. Soon, Lithium, a simple metallic ion, was the first drug found suicidal thoughts began to dominate his mind. After several to act as a mood stabilizer. The discovery of lithium’s mood weeks of experiencing intense suicidal ideation, barely sleeping, stabilizing action is yet another important pharmacological and often forgetting to eat, S.B. contacted his psychiatrist. He breakthrough that occurred largely by accident. John Cade, told his psychiatrist over the phone about his “brilliant” theory. an Australian psychiatrist, injected guinea pigs with the Feeling suspicious, she asked S.B. to come see her at the hos- urine of various psychiatric inpatients and found that the pital to talk about his theory further. When she saw S.B. and talked with him, she immediately realized he was in a mixed urine of manic patients was the most toxic (i.e., it killed the state: He was displaying symptoms of both severe depression most guinea pigs). Next, he set about investigating which (e.g., suicidal ideation) and mania (e.g., delusions of grandeur). chemical constituent of the manic patients’ urine caused the She promptly committed S.B., and he was subsequently placed increased toxicity: He began by injecting guinea pigs with on a psychiatric ward where he stayed for 6 weeks. 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 So far, the case of S.B. has introduced you to the fea- acid (another constituent of urine), so he injected both urea tures of both depression and bipolar disorder. Here, his case and lithium urate (a soluble form of uric acid that takes the makes an important point about bipolar disorder: Contrary form of a lithium salt) into a group of guinea pigs. Contrary to popular belief, bipolar disorder does not involve rapid to his hypothesis, he found that lithium urate protected the alternations in mood (i.e., alternations occurring within guinea pigs from the toxicity of the urea. Next, Cade injected hours to days); rather, the mood episodes often last weeks some guinea pigs with both urea and lithium carbonate to months. To put things in context, there is a subtype of (another lithium salt) to check whether it was the lithium bipolar disorder known as rapid cycling bipolar disorder— or the uric acid that was protective. He found that lithium defined as involving 4 or more mood episodes per year (see carbonate also protected the guinea pigs from the toxicity of Cao et al., 2017; Carvalho et al., 2014). urea. Accordingly, Cade hypothesized that manic patients S.B.’s case also makes an important point about psychi- have lower levels of lithium than non-manic patients. atric diagnoses in general: Psychiatric patients often careen Cade wanted to test lithium carbonate on a group of from one diagnosis to another (see Phillips & Kupfer, 2013). manic patients, but he decided to first test it on a group For example, S.B.’s diagnosis changed from clinical depres- of guinea pigs. The lithium carbonate seemed to calm the sion to bipolar type II and then to bipolar type I. But stay guinea pigs. However, we now know that at the doses he tuned: There is more to the case of S.B. 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 Journal Prompt 18.2 of 10 manic patients, 6 patients with schizophrenia, and Do you think that such careening between diagnoses 3 depressed patients. The lithium had a dramatic effect, represents an actual change in one’s illness or a general problem with psychiatric diagnoses? but only in the manic patients. The effect was so dramatic that some of the manic patients were even discharged from M18_PINE1933_11_GE_C18.indd 497 22/01/2021 11:52  498 Chapter 18 hospital (see Mitchell & Hadzi-Pavlovic, 2000), something bipolar disorder who are euthymic (they have no ­symptoms unheard of in the pre-drug era of psychiatry. of depression, hypomania, or mania) make much riskier Unfortunately, there was little immediate reaction choices than individuals without bipolar ­disorder (see to Cade’s report—few scientists were impressed by his Johnson et al., 2019). The reward hypersensitivity theory conference presentations, and few drug companies were of bipolar disorder explains both the manic and depressive interested in spending money to evaluate the therapeutic phases of bipolar disorder by proposing that: (1) repeatedly potential of a metallic ion that could not be protected by rewarding individuals with bipolar disorder for their a patent. Consequently, it was not until the late 1960s that activities leads to excessive goal seeking and ultimately lithium was conclusively shown to be an effective mood to hypomania or mania, and (2) when people with bipolar stabilizer. Over the 50 years since its introduction, lithium disorder fail to achieve their goals this leads to an excessive is still considered by many to be the best mood stabilizer decrease in reward seeking and to depression. Consistent (see Oruch et al., 2014; Machado-Vieira, 2018), and it is now with this theory is the finding that individuals with bipolar known to have neuroprotective effects (see Kerr, Bjedov, & disorder display increased activity in prefrontal and striatal Sofola-Adesakin, 2018; Sun et al., 2018) and anti-suicidal reward circuits in both depressive and manic states (see effects (see Baldessarini, Tondo, & Vásquez, 2019). Alloy, Nusslock, & Boland, 2015). All mood stabilizers (i.e., lithium, certain anticon- Many other theories of bipolar disorder exist. For vulsants, and certain atypical antipsychotics) act against example, there are emerging theories that propose a role for bouts of mania, some act against depression, and some act inflammation (see So et al., 2017), or a role for alterations in against both (see Prabhavalkar, Poovanpallil, & Bhatt, 2015; synaptic function (see Harrison, Geddes, & Tunbridge, 2017). 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, d ­ izziness; Genetic and Epigenetic Mechanisms see Murru et al., 2015), which often leads patients to stop of Bipolar Disorder taking these medications (see Jann, 2014; Schloesser, LO 18.16 Describe our current state of knowledge of the ­Martinowich, & Manji, 2012). genetic and epigenetic mechanisms of bipolar disorder. Theories of Bipolar Disorder Many studies have been conducted on the genetics of bipolar LO 18.15 Describe some factors that may contribute to disorder, based on the early observation that family members the onset and maintenance of bipolar disorder. of individuals with bipolar disorder have a very high likelihood of developing bipolar disorder. The take-home An understanding of the mechanisms underlying the message from all of the genetic studies of bipolar disorder development and maintenance of bipolar disorder has is that there are hundreds to thousands of genes associated been hampered by the lack of a clear understanding of the with bipolar disorder (see Gandal et al., 2018). Studies of mechanisms underlying the efficacy of various mood stabi- these genes have yielded little in the way of understanding lizers (e.g., Can, Schulze, & Gould, 2014) and by the lack of the mechanisms of bipolar disorder. Accordingly, current an adequate animal model of bipolar disorder (see Logan research efforts are focused on identifying epigenetic & McClung, 2016). However, several physiological distur- mechanisms that might affect transcription of the identified bances have been identified that might be contributing to genes (see Duffy et al., 2019; Gandal et al., 2018). 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 Neural Bases of Bipolar Disorder disruptions in the circadian rhythms in both patients with LO 18.17 Describe the brain differences associated with bipolar disorder and their nonbipolar relatives; and there bipolar disorder. are also alterations to GABA, glutamate, and dopamine neurotransmission in patients with bipolar disorder (see Numerous MRI studies of the brains of patients with bipo- Ashok et al., 2017; Beyer & Freund, 2017; Maletic & Raison, lar disorder have been published. In general, cognitive 2014). Finally, there is evidence that BDNF (see Chapter 9) deficits are common in bipolar disorder and such deficits levels are lower in patients with bipolar disorder when they are associated with a variety of changes in brain function are either depressed or manic (see Maletic & Raison, 2014). (see Lima, Peckham, & Johnson, 2019). Consistent overall One theory of bipolar disorder, the reward hypersensit