Chapter 12 PSYC

CHAPTER 12 Psychopathology The Biology of Behavioral Disorders Neil V. Watson Simon Fraser University S. Marc Breedlove Michigan State University “My Lobotomy” After Howard Dully’s biological mother died unexpectedly when he was 4, his father married a woman named Lucille. For whatever reasons, Howard and Lucille did not get along. Sure, Howard could be rebellious and mouthy, like many other kids, but he was never violent with anyone. Likewise, he sometimes got in trouble at school for being inattentive in class or for smoking in the bathroom, but not for fighting or damaging school property, and he was not flunking out. Still, Lucille, frustrated with a headstrong boy in her house, took Howard to six different psychiatrists to find out “what was wrong with him.” All concluded that his behavior was normal. But doctor number seven, the infamous Walter Freeman, diagnosed the boy with schizophrenia. In 1960, Freeman gave 12-year-old Howard a lobotomy. First Freeman sedated the boy by giving him electroshocks—jolts of electricity across the skull that induce a seizure and render the person unconscious. Then he lifted Howard’s upper eyelids and used a hammer on an ice pick–like device to punch holes in the skull above each eye. He then inserted a device to disconnect some of Howard’s prefrontal cortex from the rest of his brain. Freeman was an old hand at the procedure, having lobotomized thousands of people, so the surgery took only 10 minutes. The total hospital charge was $200. Family members reported that Howard acted like a zombie for several days, so lethargic and disinterested in the events around him that, Freeman noted, they called Howard “lazy, stupid, dummy, and so on.” One aunt said he acted like he was permanently tranquilized. And yet Lucille still wanted Howard out of her house. Soon Howard was institutionalized, and he would spend decades in various psychiatric wards. Not until he was 50 would Howard find out what had happened to him as a child. Debilitating mental afflictions have plagued humans throughout history, plunging many people into an abyss of disordered thought and emotional chaos. We have made great progress in understanding the causes of mental health issues like schizophrenia, depression, and anxiety disorders and have developed a wide variety of treatments that are at least partly effective, but the emotional and economic costs of these illnesses remain great. And they are widespread: psychopathology affects hundreds of millions of people throughout the world. 12.1 Psychiatric Disorders Take a Huge Toll The Road Ahead We begin by considering schizophrenia, a severe disorder occurring in about 1 percent of the population, no matter where you go in the world. Learning this material should allow you to: 12.1.1 Know the most common symptoms of schizophrenia. 12.1.2 Understand the strong influence of both genes and the environment on the chances of developing schizophrenia. 12.1.3 Describe several of the structural brain differences of people with schizophrenia versus controls. 12.1.4 Discuss the several classes of antipsychotic drugs and their mechanisms of action. Changed for Life Twelve-year-old Howard Dully before, during, and after his transorbital lobotomy. The swelling around his eyes eventually went away, but Howard would spend the next four decades in various mental institutions. View larger image The exact definition and diagnosis of the major psychiatric disorders is a matter of ongoing debate because, in contrast to other diseases, mental disorders are mostly diagnosed on the basis of behavioral symptoms rather than physiological measurements. The revised fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, the DSM-5-TR, provides a standardized system for diagnosing and classifying the major psychiatric illnesses according to current knowledge (APA, 2022). The disorders that the DSM describes are startlingly prevalent in modern society. At any given time, more than 12 percent of people around the globe are affected by a major psychiatric disorder (GBD Mental Disorders Collaboration, 2022); the estimates for North America are substantially higher, perhaps due to regional differences in diagnostic criteria and access to health care. Almost 20 percent of the adult population of the United States—1 in every 5 people— experience some degree of psychiatric symptoms in the course of a year, and more than 4 percent (almost 10 million people) are so ill that they are unable to carry out major life activities, like working or living independently (FIGURE 12.1). Some rates tend to be higher for females than for males, primarily because females are more likely to be depressed. On the other hand, drug dependency and alcoholism, which are not reflected in Figure 12.1, are much more frequent in males. Note also the high rates that are evident in 18-to25-year-olds because certain psychiatric disorders—for example, schizophrenia—tend to appear in adolescence and young adulthood. Clearly, mental disorders exact an enormous toll on our lives. FIGU R E 1 2 . 1 Prevalence of Serious Mental Illness among U.S. Adults View larger image The seeds for a new, biology-based perspective in psychiatry were sown at the start of the twentieth century. At that time, thousands of people were hospitalized with the diagnosis of paralytic dementia. Characterized by the sudden onset of delusions (false beliefs strongly held in spite of contrary evidence), grandiosity (boastful self-importance), euphoria, poor judgment, impulsive behavior, and disordered thought, the disorder was originally believed to be caused by “weak character,” but postmortem analyses of their brains revealed that their illness had a physiological cause: syphilis. The subsequent discovery of antibiotic drugs that could cure syphilis soon made paralytic dementia a thing of the past, and this powerful connection between a biological problem and a mental illness prompted researchers to begin asking whether other psychiatric disorders likewise had fundamentally physiological origins. Schizophrenia is a major neurobiological challenge in psychiatry Throughout the world and across the centuries, some people have been recognized as unusual because they hear voices that others don’t, feel intensely frightened, sense persecution from unseen enemies, and generally act strangely. For many, this disordered state —now known as schizophrenia—lasts a lifetime. For others, it appears and disappears unpredictably. Schizophrenia is also a public health problem because all too many people with schizophrenia become homeless. The term schizophrenia (from the Greek schizein, “to split,” and phren, “mind”) was introduced early in the twentieth century to convey the idea that various functions of the mind—like memory, perception, and thinking—were split from each other (Bleuler, 1950, originally published in 1911). This poetic but vague definition of schizophrenia was subsequently replaced with more objective descriptions of symptom types. Today, the major symptom categories associated with schizophrenia include (1) auditory hallucinations, (2) highly personalized delusions (false beliefs), (3) changes in affect (emotion), and (4) cognitive impairments. An additional major division of schizophrenic symptoms distinguishes positive and negative symptoms (McCutcheon et al., 2019). Positive symptoms are abnormal behavioral states that have been gained— examples include the hallucinations, delusions, and excited motor behavior that are often identified as psychosis. Negative symptoms are reductions in typical functioning resulting from emotional and motivational impairments—for example, slow and impoverished thought and speech, emotional and social withdrawal, or blunted affect. There is considerable individual variation in the extent to which a person with schizophrenia exhibits positive symptoms (psychosis), negative symptoms (emotional and motivational impairments), and cognitive impairment (TABLE 12.1). The fact that the various categories of symptoms respond differently to drug treatments suggests that multiple neural mechanisms are involved in the disorder. TA B LE 1 2 . 1 Symptoms of Schizophrenia Symptom dimension Symptom category POSITIVE SYMPTOMS Refers to symptoms that are present but should not be PSYCHOSIS Hallucinations Delusions Disorganized thought and speech Bizarre behaviors NEGATIVE SYMPTOMS EMOTIONAL DYSREGULATION Symptom dimension Symptom category Refers to characteristics of the individual that are absent but should be present Lack of emotional expression Reduced facial expression (flat affect) Inability to experience pleasure in everyday activities (anhedonia) IMPAIRED MOTIVATION Reduced conversation (alogia) Diminished ability to begin or sustain activities Social withdrawal COGNITIVE SYMPTOMS Refers to problems with processing and acting on external information NEUROCOGNITIVE IMPAIRMENT Memory problems Poor attention span Difficulty making plans Reduced decision-making capacity Poor social cognition Abnormal movement patterns Schizophrenia has a heritable component For many years, genetic studies of schizophrenia were controversial because some early researchers failed to understand that genes need not act in an all-or-none fashion. For any genotype there is often a large range of alternative outcomes determined by both developmental and environmental factors, as we’ll see. Family studies If schizophrenia can be inherited, relatives of people with schizophrenia should show a higher incidence (number of new cases during a period of time) than is found in the general population. In addition, the risk of schizophrenia among relatives should increase with the closeness of the relationship, because closer relatives share a greater number of genes. Indeed, parents and siblings of people with schizophrenia have a higher risk of developing schizophrenia than do individuals in the general population (FIGURE 12.2). However, the mode of inheritance of schizophrenia is not simple; that is, it does not involve a single recessive or dominant gene (Hyman, 2018). Rather, multiple genes play a role. FIGU R E 1 2 . 2 The Heritability of Schizophrenia View larger image Adoption studies It is easy to find fault with family studies. They confuse hereditary and environmental factors because members of a family share both. But what about children who are not raised with their biological parents? In fact, studies of adopted people confirm a strong genetic factor in schizophrenia. The biological parents of adoptees with schizophrenia are far more likely to have had this disorder than are the adopting parents (Foley et al., 2017). Twin studies In twins, nature provides researchers with the opportunity for a genetic experiment. In identical (or monozygotic) twins, who derive from a single fertilized egg and thus share the same set of genes, if one of the twins develops schizophrenia, the other twin has a roughly fifty-fifty chance of also developing the disorder. But in fraternal (or dizygotic) twin pairs, who come from two fertilized eggs and thus share about 50 percent of their genes, just like any pair of siblings, this concordance (sharing of a characteristic) drops to about 17 percent (see Figure 12.2) (Cardno and Gottesman, 2000; Kläning et al., 2016). The higher concordance in the genetically identical twins is thus strong evidence of a genetic factor. Yet even with identical twins, the concordance rate for schizophrenia is only about 50 percent, so genes alone cannot fully explain whether a person will develop schizophrenia. Presumably, other factors, especially environmental influences, account for the 50 percent of identical twin pairs that are discordant (only one twin develops the disorder). Often, the twin who goes on to develop schizophrenia has a more atypical developmental history, such as lower birth weight, more physiological distress in early life, and behavior that seems more submissive, tearful, and sensitive than that of the unaffected twin (Torrey and Yolken, 2019). Subtle neurological signs, such as impaired motor coordination and difficulty with smooth movements of the eyes to follow a moving target (FIGURE 12.3), are also common in people who have schizophrenia or are at risk for developing it, and in their relatives (Avila et al., 2006; Wolf et al., 2021). In short, the twin studies show that schizophrenia has both environmental and genetic origins. FIGU R E 1 2 . 3 Eye Tracking in People with Schizophrenia versus Controls View larger image Individual genes It has been difficult to identify any single gene that causes schizophrenia to develop or increases susceptibility (Hyman, 2018). In fact, genetic analyses suggest that over 100 genes influencing the likelihood of schizophrenia are scattered across various human chromosomes (Hall and Bray, 2022). Nonetheless, a few genes are especially implicated in schizophrenia, including genes that are known to participate in synaptic plasticity (Papaleo et al., 2016). In one large Scottish family, several members who had schizophrenia were found to carry a mutant, disabled version of a gene dubbed disrupted in schizophrenia 1 (DISC1); several polymorphisms (variations) of DISC1 have now been linked to schizophrenia susceptibility (Wang et al., 2018). We’ll discuss DISC1 further a little later in the chapter. An interesting epigenetic factor (see Chapter 13) in schizophrenia is paternal age: children fathered by older men have a greater risk of developing schizophrenia (de Kluiver et al., 2017). It is thought that, because they are the product of more cell divisions than the sperm of younger men, the sperm of older men have had more opportunity to accumulate mutations caused by errors in copying the chromosomes; these mutations may contribute to the development of schizophrenia in some cases. Taken together, the genetic studies make it clear that certain genes can indeed increase the risk of developing schizophrenia, but that the environment also matters. As we’ll see next, a big factor in whether a person will develop schizophrenia is stress. RESEARCHERS AT WORK Stress Increases the Risk of Schizophrenia We’ve established that there is genetic influence on schizophrenia but also that genes alone cannot account for the disorder. What environmental factors contribute to the probability of developing schizophrenia? Research suggests that a variety of stressful events significantly increase the risk. For example, schizophrenia usually appears during a time in life that many people find stressful—the transition from childhood to adulthood, when people deal with physical, emotional, and lifestyle changes (e.g., going away to college). Another risk factor seen in multiple studies is the stress of city living. As FIGURE 12.4 shows, people living in a mediumsized city are about 1½ times more likely to develop schizophrenia than are people living in the country. What’s more, the earlier in life a person begins living in the city, the greater the risk. People living in a big city are even more likely to develop the disorder (Pedersen and Mortensen, 2001). Conversely, children who move from the city to the country have a reduced risk of developing schizophrenia (Van Os et al., 2010). We don’t know what it is about living in a city that makes schizophrenia more likely. Pollutants, greater exposure to minor diseases, crowded conditions, tense social interactions—all of these could be considered stressful. FIGU R E 1 2 . 4 City Living Increases the Risk of Schizophrenia View larger image An integrative model of schizophrenia emphasizes the interaction of factors Prenatal stress, such as infection during pregnancy, increases the likelihood that the baby will develop schizophrenia later in life (P. H. Patterson, 2007; Conway and Brown, 2019). Likewise, if the mother and baby have incompatible blood types, or the mother becomes diabetic during pregnancy, or if there is a low birth weight for some reason, the baby is more likely to develop schizophrenia (S. King et al., 2010). Pregnancy complications that deprive the fetus of oxygen also increase the probability of later schizophrenia (Wang et al., 2021). These findings suggest that relatively minor stress during development can make the difference in whether schizophrenia develops. It is fascinating, and frightening, to think that events in the womb or early childhood can so potently affect the outcome decades later, when the symptoms of schizophrenia start to appear. Thus the evidence indicates that schizophrenia results from a complex interaction of genetic factors and stress. Each life stage has its own specific features that increase vulnerability to schizophrenia: infections before birth, complications at delivery, urban living in childhood and adulthood (Powell, 2010). From this perspective, the emergence of schizophrenia and related disorders depends on whether a genetically susceptible person is subjected to environmental stressors. When they occur during specific critical periods of brain development, these various stressors may cause lasting alterations in the structure and function of the brains of genetically susceptible people, predisposing them to develop schizophrenia (FIGURE 12.5). Alteration of brain development in people with schizophrenia is indicated by the acceleration of the normal thinning of cortical gray matter, a result of synapse rearrangement (FIGURE 12.6). Perhaps it will become possible to combine brain imaging, genetic screening, and behavioral measures, to identify at-risk children early in life and design interventions to avoid the triggering effects of stress at key developmental timepoints. FIGU R E 1 2 . 5 Developmental Periods When Stress Can Lead to Schizophrenia in Genetically Susceptible People View larger image FIGU R E 1 2 . 6 Accelerated Loss of Gray Matter in Adolescents with Schizophrenia View larger image Once the interaction of genetic susceptibility and stress results in schizophrenia, the condition affects not only the person’s behavior but also the physical state of the brain, as we’ll see next. The brains of some people with schizophrenia show structural and functional changes Because the symptoms of schizophrenia can be so marked and persistent, investigators hypothesized early on that the brains of people with this illness would show distinctive and measurable structural abnormalities. Later, CT and MRI scans confirmed this idea, revealing significant, consistent anatomical differences in the brains of many people with schizophrenia (Keshavan et al., 2020). Interestingly, these scans also confirm the idea that genes alone cannot account for whether a person will develop schizophrenia. Ventricular abnormalities Most people with schizophrenia have enlarged cerebral ventricles, especially the lateral ventricles (Svancer and Spaniel, 2021) (FIGURE 12.7). What is the significance of enlarged ventricles? Because overall brain size does not seem to be affected in people with schizophrenia, or in a mouse model of schizophrenia, the enlarged ventricles must come at the expense of brain tissue. Therefore, interest has centered on possible changes in brain structures— especially limbic system structures like the hippocampus and amygdala (Chen et al., 2020)—that run alongside the lateral ventricles. FIGU R E 1 2 . 7 Ventricular Enlargement in Schizophrenia View larger image An important distinction is that twins with schizophrenia have decidedly enlarged lateral ventricles compared with their well counterparts, whose ventricles are of normal size (FIGURE 12.8). Among people with schizophrenia, those with larger ventricles benefit less from antipsychotic drugs (Garver et al., 2000). FIGU R E 1 2 . 8 Identical Genes, Different Fates View larger image Recall that a disabled version of the gene DISC1 is associated with schizophrenia in one large family. The DISC1 protein normally regulates trafficking of molecules within neurons (Tomoda et al., 2017). When researchers inserted the schizophrenia-associated mutant version of DISC1 into mice, they found that the mice developed enlarged lateral ventricles (FIGURE 12.9) that were reminiscent of the enlarged ventricles in people with schizophrenia (Pletnikov et al., 2008; Ayhan et al., 2016). FIGU R E 1 2 . 9 Enlarged Ventricles in a Mouse Model of Schizophrenia View larger image Cortical abnormalities People with schizophrenia may differ from healthy people in the structure and functional activity of the corpus callosum (Olabi et al., 2011). In addition to the accelerated cortical thinning (and reduction in subcortical volume) that we noted before (see Figure 12.6), people with schizophrenia tend to be impaired on neuropsychological tests that are sensitive to frontal cortical lesions. These findings raised the possibility that frontal cortex activity is atypical in schizophrenia. Early observations using PET found that, compared with nonschizophrenic controls, people with schizophrenia had reduced metabolic activity in the frontal lobes relative to other regions of the brain (Buchsbaum et al., 1984). This observation led to the hypofrontality hypothesis that the frontal lobes are underactive in people with schizophrenia. Neurons in the frontal cortex of people with schizophrenia have dendrites with a reduced density of synaptic spines compared with controls (Forrest et al., 2018), which may contribute to a less active frontal cortex. Reviews of many studies over the past 35 years seem to support this idea (Minzenberg et al., 2009; Penadés et al., 2017). In discordant identical twin pairs, where one twin is healthy and one has schizophrenia, reduced activity of the frontal cortex is evident only in the affected twin. Furthermore, drug treatments that alleviate symptoms of schizophrenia are associated with increased activity of frontal cortex (Vogel et al., 2016). In fact, some of the most revolutionary discoveries about schizophrenia came not from studies of structural or functional differences, but from the discovery of antipsychotic drugs, so let’s talk about them next. How’s It Going? 1. What is the incidence of psychiatric illness? At what stage of life does schizophrenia usually appear? 2. What are the major categories of symptoms in schizophrenia? Provide some examples of each symptom category. What do we mean by positive and negative symptoms of schizophrenia? 3. Review the evidence that heredity plays a role in schizophrenia. 4. What is the evidence that stress can affect whether a person will develop schizophrenia? 5. What are some of the ways in which the brains of people with schizophrenia may differ from the brains of people who do not have schizophrenia? Antipsychotic medications revolutionized the treatment of schizophrenia In the 1930s, there were no effective treatments for schizophrenia. Because people with schizophrenia were often unable to take care of themselves, they were placed in caregiving institutions. In many cases, the health and welfare of people in these (poorly funded) institutions were horribly neglected, leading to recurrent scandals. So perhaps it was in desperation that psychiatrists turned to lobotomy, the surgical separation of a portion of the frontal lobes from the rest of the brain, as a treatment for schizophrenia. Certainly there was little scientific evidence to think the surgery would be effective. But early practitioners reported nearly miraculous recoveries that, in retrospect, must be regarded as wishful thinking on the part of the physicians. The surgery may well have made these people easier to handle after their operations, but they were rarely able to leave the mental institution. Used for almost any mental disorder, not just schizophrenia, lobotomies were performed on some 40,000 people in the United States alone (Kopell et al., 2005). Another Life Stunted by Lobotomy Although it’s unclear what psychological problems she had, if any, Rosemary Kennedy (1918–2005) was given a lobotomy at age 23, performed by Walter Freeman. A sister of President John F. Kennedy, Rosemary, shown here a few years before the surgery, was permanently incapacitated and spent the rest of her long life in an institution. View larger image By the mid-twentieth century, more and more physicians were skeptical that lobotomy was effective for any disorder, and a drug discovered in the early 1950s—chlorpromazine (trade name Thorazine)—quickly replaced lobotomy as a treatment for schizophrenia. Although chlorpromazine was originally developed as an anesthetic (Charpentier et al., 1952; Ban, 2007), a lucky observation revealed that it could powerfully reduce the positive symptoms of schizophrenia. These symptoms—auditory hallucinations, delusions, and disordered thinking—were exactly the ones that kept people in mental institutions. So, the introduction of chlorpromazine truly revolutionized psychiatry, relieving symptoms for millions of people and freeing them from long-term beds in psychiatric hospitals. Poor Howard Dully, whom we met at the start of the chapter, was very unlucky to run into a physician still performing lobotomies as late as the 1960s. Why didn’t Dr. Freeman try giving Howard chlorpromazine? For one thing, the drug helps only positive symptoms, and Howard didn’t have any of those. In fact, there’s little reason to think the boy had any symptoms of schizophrenia (six psychiatrists had declared him “normal”). Sadly for Howard, his stepmother just happened upon the wrong physician at the wrong time. Despite their beneficial effects on schizophrenia, however, antipsychotics sometimes caused particular movement problems, as we see in Signs & Symptoms. The dopamine hypothesis Chlorpromazine, and other antipsychotic drugs (also known as neuroleptics) that came shortly after, were eventually found to share a specific action: they block postsynaptic dopamine receptors, particularly dopamine D receptors. Because antipsychotic drugs all blocked dopamine D receptors to some extent, researchers proposed the dopamine hypothesis: that people with 2 2 schizophrenia have an excess of either dopamine release or dopamine receptors. Interestingly, high doses of amphetamine cause an excess of dopamine to accumulate in synapses (see Chapter 4), resulting in a transient amphetamine psychosis that is strikingly similar to schizophrenia and is reversed by treatment with antischizophrenic medication. In contrast, psychedelic drugs like LSD and psilocybin, despite sometimes being called “hallucinogens,” act principally via serotonin receptors and produce effects that bear little resemblance to psychosis (Ham et al., 2017); for one thing, the effects of psychedelics are primarily visual rather than auditory. SIGNS & SYMPTOMS Long-Term Effects of Antipsychotic Drugs Few people would deny that antipsychotics are “miracle drugs.” With drug treatment, many people who might otherwise have been in mental hospitals their whole lives can take care of themselves in nonhospital settings. Unfortunately, traditional antipsychotic drugs can have other, undesirable effects as well. Soon after beginning to take these drugs, some people develop maladaptive motor symptoms called dyskinesia (from the Greek dys, “bad,” and kinesis, “motion”). Although many of these symptoms are transient and disappear when the dosage of drug is reduced, some druginduced motor changes emerge only after prolonged drug treatment—after months, sometimes years—and are effectively permanent. This condition, called tardive dyskinesia (the Latin tardus means “slow”), is characterized by repetitive, involuntary movements, especially involving the face, mouth, lips, and tongue (FIGURE 12.10). Elaborate, uncontrollable movements of the tongue are particularly prominent, including incessant rolling movements, as well as sucking or smacking of the lips. Some people show twisting and sudden jerking movements of the arms or legs (Jain and Correll, 2018). FIGU R E 1 2 . 1 0 Tardive Dyskinesia The term describes a late onset of involuntary movements, often of the lower face. This woman with tardive dyskinesia has involuntary facial movements such as her tongue popping out (left) and intense grimacing (right). View larger image The underlying mechanism for tardive dyskinesia continues to be a puzzle. It may arise from the chronic blocking of dopamine receptors, which results in receptor supersensitivity. But tardive dyskinesia frequently takes a long time to develop and tends to be irreversible—a time course that is difficult to square with the more transient receptor supersensitivity. The main feature shared by the various drugs now classified as firstgeneration antipsychotics (or typical antipsychotics) is that they are D receptor antagonists. In fact, the clinically effective dose of a first-generation antipsychotic can be predicted from its affinity for D receptors (FIGURE 12.11), as the dopamine hypothesis would predict. For example, haloperidol, discovered a few years after chlorpromazine, has a greater affinity for D receptors and quickly became the more widely used drug. Over the years, other clinical and experimental findings have bolstered the dopamine hypothesis; for example, treating people who have Parkinson’s disease with l-dopa (the metabolic precursor of dopamine) may induce schizophrenialike symptoms, presumably by boosting the synaptic availability of dopamine. In some people who have received long-term treatment with first-generation antipsychotics, discontinuation of the drugs or a lowering of the dosage results in a sudden, marked increase in positive symptoms of schizophrenia, such as delusions or hallucinations. This supersensitivity psychosis (Yin et al., 2017), thought to be a rebound effect where chronic suppression of dopamine neurotransmission causes an upregulation of dopamine receptors (see Chapter 3), can often be reversed by the administration of increased dosages of dopamine receptor–blocking agents. 2 2 2 FIGU R E 1 2 . 11 Traditional Antipsychotic Drugs Block Dopamine D Receptors View larger image However, there are problems with the dopamine hypothesis of schizophrenia. For example, there is no correspondence between the speed with which drugs block dopamine receptors (quite rapidly— within hours) and how long it takes for the symptoms to diminish (usually on the order of weeks). Furthermore, about 30 percent of people with schizophrenia don’t respond to dopamine antagonists, or in some cases, to any other treatments (Siskind et al., 2022). Thus, the relation of dopamine to schizophrenia is more complex than just hyperactive dopamine synapses. 2 Work with new types of antischizophrenic drugs, developed to reduce the motor side effects we discussed earlier, suggested that some symptoms of schizophrenia respond to modifications of other neurotransmitter systems. Called second-generation antipsychotics (or atypical antipsychotics), these drugs generally have only moderate affinity for D dopamine receptors. Instead, second-generation antipsychotics have their highest affinity for other transmitter receptors: clozapine, for example, blocks serotonin receptors (especially 5-HT receptors), as well as other receptor types. The second-generation antipsychotics were initially thought to be more effective than first-generation antipsychotics for treating schizophrenia, especially for relieving negative symptoms in addition to the positive symptoms relieved by first-generation antipsychotics. But subsequent studies comparing outcomes for people with schizophrenia who had been given the two types of drugs found no difference in overall effectiveness (P. B. Jones et al., 2006; Crossley et al., 2010; Saha et al., 2016). And although the second-generation antipsychotics are less likely than first-generation antipsychotics to cause side effects in motor function (see Figure 12.10), they may be more likely to cause weight gain (Wu et al., 2022), which causes other health problems. So, although antipsychotics were properly regarded as miracle drugs when they first became available, some are questioning whether their long-term use is the best pathway for recovery from schizophrenia. While antipsychotic medications can effectively relieve symptoms at the onset of schizophrenia, the early studies typically ended within 2 years of onset, and some longitudinal studies of treatment with antipsychotic drugs have 2 2A raised questions about their benefit, in terms of relapse rates, over longer terms (FIGURE 12.12). Researchers are investigating the use of cognitive behavioral therapy to help people with schizophrenia reduce their feelings of stress (Morrison et al., 2014)—and therefore reduce outbreaks of symptoms. There is also a growing emphasis on the effectiveness of support networks (like the Hearing Voices Movement) in helping people accept their unusual sensory experiences as meaningful expressions of individual variation (Longden et al., 2018; Higgs, 2020), and help them feel less disturbed by the voices they hear. FIGU R E 1 2 . 1 2 Long-term Outcomes with and without Antipsychotics View larger image The glutamate hypothesis Another drug that, like chlorpromazine, was initially developed as an anesthetic has a much different relationship to schizophrenia. Phencyclidine (PCP) was soon found to be a potent psychotomimetic; that is, PCP produces phenomena strongly resembling both the positive and negative symptoms of schizophrenia. Users of PCP often experience auditory hallucinations, strange depersonalization, and disorientation, and they may become violent as a consequence of their drug-induced delusions. Prolonged psychotic states can develop with chronic use of PCP. As illustrated in FIGURE 12.13, PCP acts as an NMDA receptor antagonist. PCP blocks the NMDA receptor’s central calcium channel, thereby preventing the endogenous ligand—glutamate— from having its usual effects. Early work showed that treating monkeys with PCP for 2 weeks produces a schizophrenia-like syndrome, including poor performance on a test that is sensitive to prefrontal damage (Jentsch et al., 1997). These observations prompted researchers to propose a glutamate hypothesis of schizophrenia, which suggests that schizophrenia results from defective glutamate neurotransmission (Uno and Coyle, 2019), perhaps accounting for the reduced activity in frontal cortex we described earlier. If this hypothesis is correct, you might ask whether compounds that increase glutamatergic activity would be effective antischizophrenic drugs. However, drugs that stimulate the ionotropic NMDA receptors tend to produce seizures, so NMDA receptor agonists are not an option. Instead, researchers are focusing on manipulations of other types of glutamate receptors—the metabotropic glutamate receptors (mGluR’s; see Chapter 3)—of which there are at least eight different subtypes. It is hoped that drugs with novel modes of action that target the proper class of mGluR’s may someday lead to a third generation of antipsychotics (Stansley and Conn, 2018; Shah and González-Maeso, 2019). FIGU R E 1 2 . 1 3 The Effects of PCP on the NMDA Receptor View larger image How’s It Going? 1. Evaluate the evidence supporting the dopamine hypothesis of schizophrenia, and contrast it with the evidence casting doubt on this hypothesis. 2. What distinguishes first-generation antipsychotics from second-generation antipsychotics? 3. Which drugs can induce a psychosis resembling schizophrenia? What receptor(s) do these drugs act on? FOOD FOR THOUGHT If someone you loved developed schizophrenia, what approach to treatment would you encourage them to consider? Why? 12.2 Mood Disorders Are the Most Common Psychopathologies The Road Ahead Next we will discuss mood disorders, which include depression and bipolar disorder. Studying this material will enable you to: 12.2.1 Recognize the major symptoms of depression and the warning signs of suicide. 12.2.2 Understand the influence of genes on the risks for depression. 12.2.3 Describe the several treatments available for depression, and weigh the evidence for the effectiveness of antidepressant drugs. 12.2.4 Discuss possible reasons that depression is more commonly reported among women than men. 12.2.5 Understand the symptoms of bipolar disorder, and describe the discovery that lithium can treat the condition. Disturbances of mood are a fact of life for humans; most of us experience periods of unhappiness that we commonly describe as depression. But for some people, an unhappy mood state is more than a passing malaise. Clinically, depression is characterized by a combination of unhappy mood, loss of interests, reduced energy, changes in appetite and sleep patterns, and loss of pleasure in most things. Difficulty in concentration and restless agitation or torpor are common; pessimism seems to seep into every act. Such depression can occur with no readily apparent stress, and without treatment the depression often lasts several months (Kupfer et al., 2012). Each year, more than 7 percent of American adults experience at least one episode of clinically significant depression (SAMHSA, 2018). This condition is more common in people over 40 years of age, especially women, but depression can afflict people of any age, race, or ethnicity (CDC, 2010). Along with other mental illnesses, depression can be lethal, as it may lead to suicide. Whether or not the person is depressed, many suicides appear to be impulsive acts, or are prompted by timelimited crises that would have eventually resolved themselves (Kleiman et al., 2017). For example, one classic study found that of the more than 500 people who were prevented from jumping off the Golden Gate Bridge in San Francisco, only 6 percent later went on to die by suicide (Seiden, 1978). Similarly, suicide rates went down by a third in Great Britain when that country switched from using coal gas, which contains lots of deadly carbon monoxide, to natural gas for heating and cooking. The suicide rate has remained at that reduced level in the 40+ years since (Thomas and Gunnell, 2010). Apparently those thousands of Britons who would have found it easy to follow a suicidal impulse by simply turning on the kitchen oven did not kill themselves when more planning was required. Thus, it is important for society to erect barriers, either literally (e.g., on bridges) or metaphorically, to make it difficult for people to kill themselves. Legal barriers, such as firearm legislation that mandates waiting periods, can likewise help reduce suicide rates in some regions (Anestis et al., 2019). Despite the myth that “people who want to kill themselves will succeed eventually,” when suicide is averted the first time it is seriously considered or attempted, the person is unlikely to ever try it again. TABLE 12.2 lists the warning signs that someone may be contemplating suicide. But even with numerous public health initiatives to prevent suicide in the United States, it has steadily risen over the last century (Carey, 2018). TA B LE 1 2 . 2 Warning Signs of Suicide Threatening to hurt or kill oneself or talking about wanting to hurt or kill oneself Looking for ways to kill oneself by seeking access to firearms, pills, or other means Talking or writing about death, dying, or suicide when these actions are out of the ordinary for the person Feeling hopeless Feeling rage or uncontrolled anger or seeking revenge Acting reckless or engaging in risky activities—seemingly without thinking Feeling trapped—like there’s no way out Increasing alcohol or drug use Withdrawing from friends, family, and society Feeling anxious, agitated, or unable to sleep, or sleeping all the time Experiencing dramatic mood changes Seeing no reason for living or having no sense of purpose in life Source: https://www.nimh.nih.gov/health/topics/suicide-prevention/index.shtml Note: These warning signs offer guidance about how to recognize someone at risk for suicide. If you or someone you know exhibits even a few of these signs, help and support is available at any time of day, any day of the year, in both the USA and Canada, by dialing 9- 8-8, the National Suicide Prevention Lifeline. Wrong Impulse The vast majority of people who were prevented from jumping off the Golden Gate Bridge never again attempted suicide. One of the few people to survive the jump has said, “The very second I let go, I knew I had made a big mistake” (Hines, 2013). View larger image Inheritance is an important determinant of depression Genetic studies of depressive disorders reveal strong hereditary contributions. The concordance rate for identical twins (about 40 percent) is substantially higher than for fraternal twins (about 20 percent; Torvik et al., 2019). The concordance rates for identical twins are similar whether the twins are reared apart or together. Although several early studies implicated specific chromosomes, subsequent research has failed to identify any particular gene. So, as is the case for schizophrenia, there seems to be no single gene responsible for depression. Rather, sets of multiple genes, such as the genes implicated in reward signaling, contribute to making a person more or less susceptible, and environmental factors determine whether depression results (Grotzinger et al., 2022; Gotlib et al., 2014). The brain changes with depression Most reports of differences in the brains of people with depression focus on functional changes as detected by PET or fMRI. People with depression show changes in activity in a number of brain regions, depending on whether the tasks being processed are principally cognitive or emotional in nature (S. M. Palmer et al., 2015). When people with depression are compared with control individuals, increased activation in the amygdala is especially evident during emotional processing, and increased activity in the frontal lobes is evident during more cognitively demanding tasks. Decreased activity is evident in the parietal and posterior temporal cortex and in the anterior cingulate cortex (Davey et al., 2017)—systems that have been implicated in attention (see Chapter 14). The increased activity in the amygdala—a structure involved in mediating fear (see Chapter 11)—persists even after the depression has lifted. Researchers are also investigating the role of the habenulae—a pair of small nuclei located adjacent to the pineal gland, with widespread links through the limbic system, basal forebrain, and midbrain. The lateral habenula in particular is dysfunctional in depression and may act as a sort of “antireward center” mediating the low mood and loss of pleasure that characterizes depressive illness (Hu et al., 2020). There is also evidence that people who are depressed have difficulties regulating stress hormone release. Many studies report that hippocampal volume is reduced in people with depression (Sexton et al., 2013), and there is reduced activation of the hippocampal region in people with depression during memory tasks (K. D. Young et al., 2012). But whether these changes in the hippocampus are present before the depression, and therefore contribute to its onset, remains uncertain. In any case, there are effective treatments for depression, as we discuss next. Breaking the Cycle For many people, forcing themselves to engage in exercise, even as mild as walking, can improve their mood. View larger image A wide variety of treatments are available for depression Electroconvulsive shock therapy (ECT)—the intentional induction of a large-scale seizure (Payne and Prudic, 2009)—was originally a schizophrenia treatment, born of desperation during the 1930s. Although it proved to be of little help in schizophrenia, it soon became evident that ECT could rapidly reverse severe depression. The advent of antidepressant drugs has made ECT less common, but ECT remains an important tool for treating severe, drug-resistant depression (van Diermen et al., 2018). ECT may work by temporarily disrupting key forebrain networks long enough to allow for neuroplastic remodeling of emotional regulation circuits (Ousdal et al., 2022). A less invasive technique for altering cortical activity, called repetitive transcranial magnetic stimulation (rTMS) (see Chapter 1), is likewise an effective treatment for depression (D. R. Kim et al., 2009). Another electrophysiological treatment for depression involves a pacemaker that periodically applies mild electrical stimulation to the vagus nerve (cranial nerve X; see Chapter 1). This treatment is offered in cases where drugs or ECT have been ineffective, but it remains to be established whether vagal stimulation offers a long-term solution (Grimm and Bajbouj, 2010; Blumberger et al., 2015). For rare, extremely difficult cases of depression, researchers have again turned to psychosurgery—but nothing that resembles the ravages experienced by Howard Dully. In deep brain stimulation (DBS) mild electrical stimulation is applied to targets in the limbic system of the brain, via surgically implanted electrodes, as a lastditch effort to relieve depression that resists other treatments. The effectiveness of DBS or vagal nerve stimulation for depression is difficult to evaluate, because most studies have no placebo control, but long-term follow-up suggests that DBS for depression is effective in many cases (Crowell et al., 2019). Today, the most common treatment for depression is the use of drugs that affect the monoamine transmitters: norepinephrine, dopamine, and serotonin. The first modern antidepressants were inhibitors of monoamine oxidase (MAO), the enzyme that normally inactivates monoamines in the synaptic cleft. This action of MAO inhibitors causes monoamine transmitters to accumulate to higher levels in synapses, so researchers proposed that people with depression do not get enough stimulation at monoamine synapses (this is sometimes called the monoamine hypothesis of depression). A second generation of antidepressants, called tricyclics, inhibits the reuptake of monoamines, which similarly boosts their synaptic activity. One of the ways ECT may help depression is by inducing the release of monoamines. Among the monoamines, serotonin seems to play an especially important role in depression (Svenningsson et al., 2006). A major class of modern antidepressants, the selective serotonin reuptake inhibitors (SSRIs), such as Prozac (TABLE 12.3) (see Chapter 4), act to increase synaptic serotonin levels in the brain. In rats, SSRIs increase the birth of new neurons in the hippocampus (Samuels et al., 2015; Yohn et al., 2020), which may mediate some of the mood effects of the drugs. TA B LE 1 2 . 3 Drugs Used to Treat Depression Symptom dimension Symptom category Examples Monoamine oxidase (MAO) inhibitors Inhibit the enzyme monoamine oxidase, which breaks down serotonin, norepinephrine, and dopamine Marplan, Nardil, Parnate Tricyclics and heterocyclics Inhibit the reuptake of norepinephrine, serotonin, and/or dopamine Wellbutrin, Elavil, Aventyl, Ludiomil, Norpramin Selective serotonin reuptake inhibitors (SSRIs) Block the reuptake of serotonin, having little effect on Prozac, Paxil, Zoloft Symptom dimension Symptom category Examples norepinephrine or dopamine synapses Second-generation antidepressants and investigational drugs Norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), serotonin antagonist and reuptake inhibitors (SARIs), opioid receptor modulators, ketamine Wellbutrin/Zyban (NDRI), Effexor (SNRI), Remeron (NaSSA), Oleptro (SARI), Buprenex (opioid receptor modulator) Note: The names given are the more commonly used trade names rather than chemical names. However, there are problems with the idea that reduced serotonin stimulation causes depression. We know that SSRI drugs increase synaptic serotonin within hours of administration. Yet it typically takes several weeks of SSRI treatment before people feel better. This paradox suggests that it is the brain’s response to increased synaptic serotonin that relieves the symptoms, and that this response takes time. So even though boosting serotonin helps some people, their depression may originally have been caused by other factors in the brain. A newer class of antidepressants is the serotonin-norepinephrine reuptake inhibitors (SNRIs) like Cymbalta (duloxetine) and Effexor (venlafaxine) (Hillhouse and Porter, 2015). Several other medications for depression are currently under study. For example, compounds being investigated as potential antidepressants include the glutamate receptor antagonist ketamine (see Chapter 3; Figure 12.13) that relieves depression almost instantly in some people and can be administered as nasal spray (E. E. Lee et al., 2015), in contrast to SSRIs and SNRIs, which typically must be taken for several weeks before they elevate mood. There is also growing evidence that psychedelic drugs like psilocybin and LSD can rapidly relieve depression (Nutt et al., 2020; see Table 3.4). Researchers are working to develop drugs that capture the therapeutic benefits of the psychedelic drugs without their hallucinogenic effects (Service, 2022; Cao et al., 2022). Despite the popularity of SSRIs for treating depression, treatment with cognitive behavioral therapy (CBT), a type of psychotherapy aimed at correcting negative thinking and improving interpersonal relationships, is about as effective as SSRI treatment (Butler et al., 2006). Furthermore, the rate of relapse is lower for CBT than for SSRI treatment (DeRubeis et al., 2008). Interestingly, evidence suggests that a combination of CBT and SSRI treatmentis more effective in combating depression than either one is alone (Schramm et al., 2008). Typically, CBT helps the client to recognize self-defeating modes of thinking and encourages breaking out of a cycle of self-fulfilling depression (FIGURE 12.14) and has proven effective in avoiding suicide (Mewton and Andrews, 2016). Furthermore, while there is no doubt that current antidepressants do help many people who are depressed, evidence has accumulated that the benefits may not be as great, or as universal, as was originally believed (Turner et al., 2008), as we discuss in Signs & Symptoms, next. FIGU R E 1 2 . 1 4 Depression’s Endless Treadmill View larger image SIGNS & SYMPTOMS Mixed Feelings about Antidepressants At their introduction in the late 1980s and 1990s, selective serotonin reuptake inhibitors (SSRIs) represented a major revolution in depression treatment and soon became one of the most widely prescribed medications. And while there remain important questions about the efficacy and safety of SSRIs for children or teenagers (Zhou et al., 2020), including elevated risk of suicide with some drugs, millions of children and teens have been given prescriptions. Needless to say, the development and sales of antidepressants have provided a huge windfall for the pharmaceuticals industry. Now that SSRIs and SNRIs have been with us for decades, researchers are turning to retrospective analyses to reevaluate the efficacy of these drugs. In part, these large-scale metaanalyses (analyses that combine the results of many previously published studies) have been prompted by the concern that for various reasons—public appetite, profit motives, the tendency of journals to publish only positive findings—studies that failed to find effects of SSRIs may historically have been underreported. The results of these metaanalyses have been mixed, but they at least give us cause to take a sober second look at SSRI usage. As illustrated in FIGURE 12.15, some systematic reviews of the clinical research seem to show that while modern antidepressant drugs are indeed effective, their effects are modest in size and tend to be evident only in people with the most severe depression (Cipriani et al., 2018). Furthermore, long-term use of SSRIs can create a dependency on the drug, with unpleasant psychological and physiological withdrawal symptoms on discontinuation (Horowitz and Taylor, 2019). Conversely, other large meta-analytic studies, also based on multiple clinical trials, have reported evidence of clear beneficial effects of SSRIs relative to placebos for people of all ages and with all levels of severity of depression, particularly when more sensitive measures of depression are employed (Hieronymus et al., 2019, 2020). FIGU R E 1 2 . 1 5 When Are Antidepressants More Effective Than Placebos? View larger image This controversy seems likely to rage on for a while. In any case, the question of whether antidepressants sufficiently improve people’s quality of life, along with the individual characteristics of those who are most likely to benefit, are important focuses for future research (Hengartner and Plöderl, 2022). Why do more females than males develop depression? Studies all over the world show that more women than men experience major depression. In the United States, women are twice as likely as men to have major depression (Brody et al., 2018). Some researchers suggest that the apparent sex difference reflects different patterns of help-seeking behavior by males and females—that women are willing to use health facilities, while men see that as a sign of weakness. But sex differences in the incidence of depression also are evident in door-to-door surveys (J. S. Hyde and Mezulis, 2020), which would appear to rule out the simple explanation that women seek treatment more often than men do. Instead, women experience more depression as a result of life experiences than men (Altemus et al., 2014; Bangasser and Cuarenta, 2021), and sex differences are evident in responses to treatment with antidepressants (Sramek et al., 2016), further highlighting the need to include sex as a key element in the design of research studies (Galea et al., 2020). Researchers are studying whether some aspects of sex differences in depression involve endocrine physiology. The appearance of clinical depression often is related to events in the female reproductive cycle —for example, before menstruation, during use of contraceptive pills, following childbirth, and during menopause. Although there is little relation between circulating levels of individual hormones and measures of depression, the phenomenon of postpartum depression, a bout of depression immediately preceding and/or following childbirth, suggests that some combination of hormones can precipitate depression. About one out of every seven pregnant women will show symptoms of depression (Dietz et al., 2007). Because postpartum depression may affect the mother’s relationship with her child, resulting in long-lasting negative effects on the child’s well-being (Brummelte and Galea, 2016), there is growing concern about this problem. However, there is also evidence that SSRIs taken by pregnant women may affect the later behavior of their children (Oberlander et al., 2010; Brandlistuen et al., 2015), and it is uncertain whether exposure to SSRIs via breast milk will have a long-term effect. Thus CBT offers the safest treatment for postpartum depression, and researchers continue to weigh the costs and benefits of supplementing that therapy with antidepressant medication (Grieb and Ragan, 2019). Depression Women are more likely than men to develop depression. View larger image Scientists are still searching for animal models of depression Everyone agrees that an animal model of depression could be invaluable, as it might reveal underlying mechanisms or offer a convenient way to screen potential treatments. But it’s not clear that any animal model has lived up to this promise so far. If depression were caused by the mutation of a particular gene, it might be possible to create a model by introducing that mutated gene in mice. But as we noted above, human depression is influenced by many genes, each having a modest effect alone. Plus, some of the most powerful symptoms of depression are internal—apathy and a feeling of hopelessness—and thus are difficult to assess in species we can’t talk to. Still, many of the signs of depression—such as decreased social contact, problems with eating, and changes in activity—are observable behaviors. So researchers have used these behaviors, often linked to general anhedonia (reduced ability to feel pleasure), to evaluate animal models of depression. In one classic model— learned helplessness—an animal is exposed to a repetitive stressful stimulus, such as an electrical shock, that it cannot escape. Like depression, learned helplessness has been linked to a decrease in serotonin function (Maier and Seligman, 2016) and also to mechanisms that control the release of dopamine (B. Li et al., 2011), the main reward signal in the brain. Removing the olfactory bulb from rodents also creates a model of depression: the animals display irritability, preferences for alcohol, and elevated levels of corticosteroids—all of which are reversed by many antidepressants. A strain of rats created through selective breeding—the Flinders Sensitive Line—has been proposed as a model of depression because these animals show reduced overall activity, reduced body weight, learning difficulties, and exaggerated response to chronic stress (Overstreet and Wegener, 2013). These varied animal models may be useful in finding the essential mechanisms that cause and maintain depression in humans. Sleep characteristics change in affective disorders Difficulty falling asleep and inability to maintain sleep are common in depression. In addition, EEG sleep studies of people with depression show certain abnormalities that go beyond difficulty falling asleep (Hertenstein et al., 2019). The sleep of people with major depressive disorders is marked by a striking reduction in stage 3, or slow-wave, sleep (see Chapter 10) and a corresponding increase in stages 1 and 2 (FIGURE 12.16A). Similarly, people with depression enter rapid-eye-movement sleep (REM sleep) much sooner after sleep onset (FIGURE 12.16B); the length of time before REM sleep begins correlates with the severity of depression. Furthermore, the distribution of REM sleep across the night is altered, with an increased amount of REM sleep occurring during the first half of sleep, as though REM sleep were displaced toward an earlier period in the night (Palagini et al., 2013). FIGU R E 1 2 . 1 6 Sleep and Depression View larger image As with these links between the daily rhythm of sleep and depression, seasonal rhythms have been implicated in a particular depressive condition known as seasonal affective disorder (SAD). In bipolar disorder, mood cycles between extremes Bipolar disorder is characterized by periods of depression alternating with periods of excessively expansive mood (or mania) that includes sustained overactivity, talkativeness, strange grandiosity, and increased energy. The rate at which the alternation occurs varies between individuals: some people exhibit rapid-cycling bipolar disorder, defined as consisting of four or more distinct cycles in one year (and some individuals have many more cycles than that; some may even show several cycles per day). Men and women are equally affected by bipolar disorder, and the age of onset is usually much earlier than that of depression. Bipolar disorder is clearly heritable, with several different genes affecting the probability of the disorder (Hara et al., 2023). The neural basis of bipolar disorder is not fully understood, but people with bipolar disorder exhibit enlarged ventricles on brain scans, as is seen in schizophrenia (see Figure 12.8). Changes may be evident in several cortical and subcortical structures, such as the amygdala, hippocampus, cingulate, and frontal cortex (Dobri et al., 2022) The observed pattern of changes in the brain and behavior of people with bipolar disorder has led to a recognition that bipolar disorder has more in common with schizophrenia than with depression, so the older term manic depression has been largely abandoned. For example, the self-aggrandizing ideas and extreme talkativeness of people in the manic phase of bipolar disorder (e.g., “The president called me this morning to thank me for my efforts”) resemble the frank delusions seen in schizophrenia. In addition, families in which some individuals have been diagnosed with bipolar disorder are more likely than other families to have individuals with a diagnosis of schizophrenia (Cheng et al., 2021). In contrast to schizophrenia, however, treatment with antipsychotic medications has only modest benefits. Instead, most people with bipolar disorder benefit from taking the element lithium (Severus et al., 2018), a treatment discovered entirely by accident, as we discuss in Researchers at Work (FIGURE 12.17). RESEARCHERS AT WORK The Entirely Accidental Discovery of Lithium Therapy The effect of lithium on bipolar disorder was discovered purely by accident when it was intended as an inert control in an experiment focusing on the urea in lithium urate (FIGURE 12.17), so the mechanism of action is not understood. FIGU R E 1 2 . 1 7 Surprisingly Calm Guinea Pigs View larger image Because lithium has a narrow range of safe doses (see Figure 3.6), care must be taken to avoid toxic side effects of an overdose. Nevertheless, well-managed lithium treatment produces marked relief for many people with bipolar disorder and even has been reported to increase the volume of gray matter in their brains (G. J. Moore et al., 2009). The fact that the manic phases blocked by lithium are so exhilarating may be the reason that some people with bipolar disorder stop taking the medication. Unfortunately, doing so means that the depressive episodes return as well. As in depression, transcranial magnetic stimulation provides a nonpharmacological treatment alternative in difficult cases of bipolar disorder (Goldwaser et al., 2020). Furthermore, mounting evidence suggests that some forms of CBT for mild cases of bipolar disorder can be as effective as drug treatments (Salcedo et al., 2018) and perhaps can be beneficially combined with other forms of treatment. A Disturbance in the Force Actress Carrie Fisher (1956–2016), who played Princess Leia/Leia Organa in five Star Wars movies, wrote about her struggles with bipolar disorder. View larger image How’s It Going? 1. What are the symptoms of depression, and how does depression differ from simple sadness? 2. What treatments for depression arose in the twentieth century, and which treatment is used most often today? 3. Summarize the evidence for and against the use of SSRIs in depression. Why is the use of SSRIs controversial? 4. What is bipolar disorder, and how does it compare with depression and with schizophrenia? How is it treated? FOOD FOR THOUGHT It seems surprising that there are heritable aspects of schizophrenia, depression, and bipolar disorder—why hasn’t natural selection eliminated the genetic variation that contributes to these disorders? 12.3 Anxiety Disorders, TraumaRelated Disorders, and ObsessiveCompulsive Disorder All Involve Severe Fears and Worries That Interfere with Daily Life The Road Ahead We conclude the chapter by considering anxiety disorders, among the most common of psychiatric conditions. The material will permit you to: 12.3.1 Describe the symptoms of several anxiety disorders. 12.3.2 Name the various medications used to treat anxiety disorders and their mechanisms of action. 12.3.3 Discuss the data indicating whether some people are initially more vulnerable to posttraumatic stress disorder (PTSD). 12.3.4 Describe the several treatments for obsessivecompulsive disorder (OCD), including controversial trials of brain surgery and stimulation. All of us have at times felt apprehensive and fearful. But some people experience this state with an intensity that is overwhelming and includes irrational fears; a sense of terror; body sensations such as dizziness, difficulty breathing, trembling, and shaking; and a feeling of loss of control. Anxiety can be lethal: men with panic disorder are more likely than others to die from cardiovascular disease or suicide (De La Vega et al., 2018). The DSM-5-TR distinguishes several major types of anxiety disorders: Phobic disorders are intense, irrational fears that become centered on a specific object, activity, or situation that the person feels compelled to avoid. Another type of anxiety disorder is panic disorder, characterized by recurrent transient attacks of intense fearfulness. In generalized anxiety disorder, persistent, excessive anxiety and worry are experienced for months. There is a strong genetic contribution to each of these disorders (Shih et al., 2004; Oler et al., 2010) and distinctive underlying neurobiological predispositions to the development of anxiety disorders (Shackman et al., 2013). Some people who experience recurrent panic attacks have temporal lobe abnormalities, especially in the left hemisphere (Vythilingam et al., 2000; Van Tol et al., 2010). Given the special role of the amygdala in mediating fear (see Chapter 11), changes may be particularly evident in the amygdala and associated circuitry within the temporal lobes (Rauch et al., 2003). Drug treatments provide clues to the mechanisms of anxiety Throughout history, people have consumed all sorts of substances trying to control anxiety; some of the most familiar include alcohol, cannabis, and opiates like opium and heroin. In the 1950s the tranquilizing drug meprobamate (Miltown) was introduced, and it became an instant best seller, ushering in a modern age of anxiety pharmacotherapy. Soon researchers discovered a new class of drugs called benzodiazepines, which quickly replaced Miltown as the favored drugs for treating anxiety. One type of benzodiazepine— diazepam (trade name Valium)—is one of the most prescribed drugs in history. Other commonly prescribed benzodiazepines include alprazolam (Xanax), triazolam (Halcion), and lorazepam (Ativan). Drugs that combat anxiety are termed anxiolytics (“anxietydissolving”), although they are also useful for preventing seizures or for treating insomnia. The anxiolytic drugs are also discussed in Chapter 3. Anxiolytic benzodiazepines interact with binding sites that are part of GABA receptors, especially the GABA receptors, where they act as noncompetitive agonists. Recall from Chapter 3 that GABA is the most common inhibitory transmitter in the brain. When GABA is released from a presynaptic terminal and activates postsynaptic A receptors, the target neuron becomes hyperpolarized and thus fires fewer action potentials. On their own, benzodiazepines have little effect on GABA receptors; instead, their presence allows synaptic GABA to produce a much greater degree of hyperpolarization in the postsynaptic cell than would ordinarily be the case. In other words, benzodiazepines boost GABA-mediated postsynaptic inhibition, reducing the excitability of postsynaptic neurons. Interestingly, the brain probably makes its own anxiety-relieving substances that interact with the benzodiazepine-binding site on the GABA receptor; the neurosteroid allopregnanolone is one candidate for this function. Drugs designed to have similar actions are effective anxiolytics in both rats and humans, and reportedly also help prevent seizures and depression (Cerne et al., 2022). As you can see in FIGURE 12.18, benzodiazepine/GABA receptors are widely distributed throughout the brain, especially in the cerebral cortex and some subcortical areas, such as the hippocampus and the amygdala. A A FIGU R E 1 2 . 1 8 The Distribution of Benzodiazepine Receptors in the Human Brain View larger image Although the benzodiazepines remain an important category of anxiolytics, especially for acute attacks, other anxiety-relieving drugs have been developed with less abuse potential than benzodiazepines. A notable example is the drug buspirone (BuSpar), an agonist at serotonin 5-HT receptors that can provide relief from anxiety. SSRI/SNRI drugs like escitalopram (Lexapro), venlafaxine (Effexor), and fluoxetine (Prozac), which increase the stimulation of serotonin receptors (and norepinephrine receptors, in the case of SNRIs), are 1A nominally antidepressants but can also be effective for treating anxiety disorders. In posttraumatic stress disorder, horrible memories won’t go away Some people experience especially awful moments in life that seem indelible, resulting in vivid impressions that persist for years. The kind of event that seems particularly likely to produce subsequent stress disorders is intense and is usually associated with witnessing abusive violence and/or death. Examples include the sudden loss of a close friend, rape, torture, kidnapping, traumatic injury or death of others, or profound social dislocation, such as in forced migration. In these cases, memories of horrible events intrude into consciousness and produce the same intense visceral arousal—the fear and trembling and general autonomic activation—that the original event caused. These traumatic memories are easily reawakened by stressful circumstances and even by harmless stimuli that somehow prompt recollection of the original event. An ever-watchful and fearful stance is typical of individuals with posttraumatic stress disorder (PTSD), formerly called combat fatigue, war neurosis, or shell shock. As you might expect, PTSD is particularly common in combat veterans and emergency first responders (Inoue et al., 2023; Prioux et al., 2023), but it can affect anyone who has experienced a sudden, deeply distressing event. Although related in some ways to anxiety disorders, posttraumatic stress disorder is now recognized in the DSM-5-TR as a separate entity. Genetic factors affect vulnerability to PTSD, as indicated in twin studies of Vietnam War veterans who had seen combat, which showed that monozygotic twins were more similar than dizygotic twins. People who display combat-related PTSD show (1) memory changes such as amnesia for some war experiences, (2) flashbacks, and (3) deficits in short-term memory. These memory disturbances suggest involvement of the hippocampus (see Chapter 13), and indeed the volume of the right hippocampus is smaller in combat veterans with PTSD than in those without it, with no differences in other brain regions (Logue et al., 2018). It was once widely assumed that stressful episodes caused the hippocampus to shrink, but some veterans with PTSD had left their monozygotic twins at home, and it turns out that the nonstressed twins without PTSD also tended to have a smaller hippocampus (Gilbertson et al., 2002). So some inherited characteristic that’s associated with having a small hippocampus, and perhaps a reduced rate of adult neurogenesis (J. S. Snyder et al., 2011; Kheirbek et al., 2012), may increase susceptibility to developing PTSD if the person is exposed to stress. In Gulf War veterans with more severe PTSD, marked hippocampal size difference is associated with markers of inflammatory processes (O’Donovan et al., 2015), which can strongly contribute to neural degeneration and decreased neurogenesis. Delayed Reaction Many combat veterans experience the symptoms of PTSD for years afterward. View larger image A comprehensive psychobiological model of the development of PTSD draws connections from PTSD’s memory disturbances to the neural mechanisms of fear conditioning, behavioral sensitization, and extinction. Work in animals has revealed that fear conditioning—memory for a stimulus that the animal has learned to associate with a negative event—is very persistent and involves the amygdala and brainstem pathways that are part of a circuit of startle response behavior (see Chapter 11). The persistence of memory and fear in PTSD may depend on the failure of mechanisms to forget. There is also a hormonal link, because people with PTSD exhibit a paradoxical long-term reduction in cortisol (stress hormone) levels (Wichmann et al., 2017), perhaps due to persistent increases in sensitivity to cortisol. If, as a result, they feel the effect of stress hormones more strongly than other people do, that greater effect might repeatedly retrigger the fear response, making it harder for them to forget stressful events (FIGURE 12.19). Cognitive behavioral therapy for PTSD typically involves very gradually increasing the client’s (imagined or real) exposure to those stimuli and conditions that trigger flashbacks, until they no longer trigger responses (Foa and McLean, 2016). This approach can be combined with drugs that block the effects of stress hormones (see Chapter 13), and emerging evidence suggests that under closely controlled conditions, the recreational drug MDMA (known as Ecstasy; Chapter 4) can relieve the symptoms of PTSD in some people, without the need to painfully relive traumatic experiences (Mitchell et al., 2021). FIGU R E 1 2 . 1 9 A Neural Model of Posttraumatic Stress Disorder View larger image In obsessive-compulsive disorder, thoughts and acts keep repeating Most of us aspire to be neat and clean, especially when we discover a thick layer of dust under the furniture or perhaps realize we’ve created yet another tottering pile of papers and bills. And of course, having certain small rituals in our lives—making coffee a certain way in the morning, wishing everyone good night before going to bed— can be a comfort amid the chaos of daily life. But when do orderliness and routine cross the line into pathology? People with obsessive-compulsive disorder (OCD) lead lives riddled with repetitive rituals and persistent thoughts that they feel powerless to control or stop, despite recognizing that the behaviors are abnormal. In people with OCD, routine acts that we all engage in, such as checking whether the door is locked when we leave our home, become compulsions, acts that are repeated over and over. Recurrent thoughts, or obsessions, such as fears of germs or other potential harms in the world, invade the consciousness. These symptoms progressively isolate a person from ordinary social engagement with the world. For many people with OCD, hours each day are consumed by compulsive acts such as repetitive hand washing. TABLE 12.4 summarizes some of the symptoms of OCD. TA B LE 1 2 . 4 Symptoms of Obsessive-Compulsive Disorder Symptoms (most to least common by type) OBSESSIONS (THOUGHTS) Dirt, germs, or environmental toxins Something terrible happening (e.g., fire, death or illness of self or loved one) Symmetry, order, or exactness Religious obsessions Body wastes or secretions (urine, stool, saliva, etc.) Lucky or unlucky numbers Forbidden, aggressive, or perverse sexual thoughts, images, or impulses Fear of harming self or others Household items Intrusive nonsense sounds, words, or music COMPULSIONS (ACTS) Performing excessive or ritualized hand washing, showering, bathing, tooth brushing, or grooming Repeating rituals (e.g., going in or out of a door, getting up from or sitting down on a chair) Checking (doors, locks, stove, appliances, emergency brake on car, paper route, homework, etc.) Engaging in miscellaneous rituals (such as writing, moving, speaking) Decontaminating Touching Counting Ordering or arranging Symptoms (most to least common by type) Preventing harm to self or others Hoarding or collecting Cleaning household or inanimate objects Source: After S. E. Swedo et al., 1989. Arch. Gen. Psychiatry 46: 335. Determining the number of people with OCD is difficult, especially because people with this disorder tend to hide their symptoms (Newth and Rachman, 2001). Between 1 percent and 2 percent of adults are affected by chronic OCD worldwide (Hollander et al., 2016), and early evidence suggests that both the severity and prevalence of OCD was worsened by the COVID-19 pandemic and social response (Van Ameringen et al., 2022). In many cases, the initial symptoms of OCD appear in childhood, but the peak age for onset is 25–44 years. People with OCD display changes in the structure and activity of prefrontal cortex, cingulate cortex, basal ganglia, and the insula (van den Heuvel et al., 2022). Happily, OCD responds to treatment in most cases. OCD shows excellent response to cognitive behavioral therapy (Öst et al., 2016; Abramowitz et al., 2018) and also to several drugs. What do the effective OCD drugs—like fluoxetine (Prozac), fluvoxamine (Luvox), and clomipramine (Anafranil)—tend to have in common? They share the ability to inhibit the reuptake of serotonin at serotonergic synapses, thereby increasing the synaptic availability of serotonin (Pittenger, 2021). This observation suggests that the dysfunction of serotonergic neurotransmission plays a central role in OCD. Recall that we already discussed SSRIs like Prozac that inhibit the reuptake of serotonin when we discussed treatments for depression. How can the same drug help two disorders that seem so different? For one thing, depression often accompanies OCD, so the two disorders may be related. Furthermore, functional brain imaging suggests that the same SSRI drugs alter the activity of the orbitofrontal prefrontal cortex in people with OCD (Saxena et al., 2001) while affecting primarily ventrolateral prefrontal cortex in people with depression. There is a heritable genetic component to OCD; as with schizophrenia and depression, several genes contribute to susceptibility to this disorder (Pauls et al., 2014), including genes related to serotonin signaling (Sinopoli et al., 2017). There is also evidence that OCD can be triggered by infections (Orlovska et al., 2017). Upon observing that numerous children exhibiting OCD symptoms had recently been treated for strep throat, Dale et al. (2005) found that many children with OCD are producing antibodies to brain proteins. Perhaps, in mounting an immune response to the streptococcal bacteria, these children also make antibodies that attack their own brains. The genetic link may be that some people are more likely than others to produce antibodies to the brain proteins. In recent years, deep brain stimulation (DBS) has been tried for many psychiatric disorders that do not respond to medication, and OCD is no exception (Karas et al., 2019). Although some individuals reportedly experience relief with DBS, studies so far have had relatively few participants and often necessarily lack proper control groups (for example, people who receive the implantation surgery but not the stimulation), so it is difficult to conclusively establish whether the DBS is effective (Naesström et al., 2016). In extremely rare cases, psychosurgery may be a treatment of last resort. Unlike the notorious frontal lobotomies, these surgeries target much smaller regions. For example, about one-third of severely disabled people with OCD who undergo cingulotomy (making lesions that interrupt pathways within the cingulate cortex) (FIGURE 12.20) experience significant relief from OCD symptoms (Shah et al., 2008; Pepper et al., 2015). But even here it is difficult to rule out a placebo effect of the cingulotomy, as you cannot ethically ask some people to undergo sham neurosurgery, opening up their skull to then not make a lesion, as a control group. Frontal lobotomy, which causes much more extensive damage to the brain, is virtually never performed today. So we can be pretty confident that no one else will share Howard Dully’s fate, lobotomized for being a teenager. Many researchers believe that OCD is part of a spectrum of related disorders that includes Tourette’s syndrome, the topic of our final Signs & Symptoms for this chapter. FIGU R E 1 2 . 2 0 Neurosurgery to Treat Obsessive-Compulsive Disorder View larger image SIGNS & SYMPTOMS Tics, Twitches, and Snorts: The Unusual Character of Tourette’s Syndrome The faces of people with Tourette’s syndrome may twitch in an insistent way, and every now and then, out of nowhere, they may blurt out an odd sound. Other tics may involve flinging the arms, kicking the legs, or making violent shoulder movements. People with Tourette’s are also supersensitive to tactile, auditory, and visual stimuli (J. H. Cox et al., 2018). Many people with Tourette’s report that an urge to emit verbal or phonic tics builds up and that giving in to the urge brings relief. Although popular media often portray people with Tourette’s as shouting out insults and profanities (a symptom called coprolalia), verbal tics of that sort are rare. Tourette’s syndrome begins early in life; the mean age of diagnosis is 6–7 years (Groth, 2018), and the syndrome is 3–4 times more common in males than in females. FIGURE 12.21A draws a portrait of the chronology of symptoms. Often people with Tourette’s also exhibit attention deficit hyperactivity disorder (ADHD) or OCD (Eapen et al., 2016). Children with Tourette’s display a thinning of primary somatosensory and motor cortex representing facial, oral, and laryngeal structures (Sowell et al., 2008), suggesting that the tics mediated by these regions may be underinhibited by cortex. FIGU R E 1 2 . 2 1 Portrait of Tourette’s Syndrome View larger image Family studies indicate that genetics plays an important role in this disorder. Among discordant monozygotic twin pairs, the twin with Tourette’s has a greater density of dopamine D receptors in the caudate nucleus of the basal ganglia than the unaffected twin has. This observation suggests that differences in the dopaminergic system (Mogwitz et al., 2013), especially in the basal ganglia (Maia and Conceição, 2018), may be important (D receptor binding in an affected individual is illustrated in FIGURE 12.21B). The contemporary view is that Tourette’s syndrome is polygenic: mediated in a complex manner by multiple genes that have yet to be fully identified (Qi et al., 2017; Lin et al., 2022) (see Figure 12.22). Treatment with the antipsychotic drug haloperidol, a dopamine D receptor antagonist, significantly reduces tic frequency and is a primary treatment for Tourette’s syndrome. Unfortunately, this treatment can have unpleasant side effects, as noted earlier, but some people with Tourette’s also respond well to the second-generation antipsychotics, which may bring fewer side effects. Behavior modification techniques aimed at reducing the frequency of symptoms, especially tics, help some people learn how to replace their obvious tics with behaviors that are more subtle and socially acceptable (McGuire et al., 2015). DBS, which we mentioned earlier, may also benefit people with Tourette’s. In this case, battery-powered stimulating electrodes are aimed bilaterally at targets within the thalamus, in regions associated with the control of movement. Activation of the electrodes is reported to bring dramatic and almost 2 2 2 immediate relief from symptoms (Porta et al., 2009; Baldermann et al., 2016). An important aspect of future research on psychiatric disorders and their treatment will be the growing appreciation that on genetic grounds, many disorders cluster together on continuums (Marshall, 2020). With the advent of powerful new methodologies, such as genome-wide association studies (GWAS) that allow researchers to screen the entire genomes of people with mental disorders, it is increasingly clear that many disorders are not so distinct from one another as was once believed (Grotzinger et al., 2022). FIGURE 12.22 illustrates the striking interrelatedness of genetic risk for some of the major psychiatric disorders. Schizophrenia and bipolar disorder, for example, show a strong genetic correlation, with a 50 percent genetic overlap between the two disorders (Brainstorm Consortium et al., 2018). Similar relationships are seen between a number of other psychiatric diagnoses, such as anxiety disorders and depression. FIGU R E 1 2 . 2 2 Genetic Relationships View larger image How’s It Going? 1. What are the main types of anxiety disorders? 2. What class of drugs is the most common anxiolytic, and what effect do these drugs have on transmitter systems? 3. Describe PTSD and the hypothesis that the disorder is a special case of fear conditioning. 4. What is OCD, and what treatments are available to combat it? FOOD FOR THOUGHT We’ve seen that the definition and diagnosis of mental illnesses is complicated by the fact that currently they are described mostly on the basis of behavioral symptoms. What will be needed next in order to refine the diagnostic categories of psychiatry? Will AI technology be able to help, any time soon? RECOMMENDED READING Beidel, D. C., and Frueh, B. C. (2018). Adult Psychopathology and Diagnosis (8th ed.). New York, NY: Wiley. Charney, D. S., Nestler, E. J., Sklar, P., and Buxbaum, J. D. (Eds.). (2018). Charney & Nestler’s Neurobiology of Mental Illness (5th ed.). New York, NY: Oxford University Press. Huettel, S. A., Song, A. W., and McCarthy, G. (2014). Functional Magnetic Resonance Imaging (3rd ed.). Sunderland, MA: Oxford University Press/Sinauer. Martino, D., and Leckman, J. F. (Eds.). (2013). Tourette Syndrome. Oxford, UK: Oxford University Press. McClintock, S. M., and Choi, J. (Eds.). (2022). Neuropsychology of Depression. New York, NY: Guilford. Meyer, J. S., Farrar, A. M., Biezonski, D., and Yates, J. R. (2022). Psychopharmacology: Drugs, the Brain, and Behavior (4th ed.). New York, NY: Oxford University Press. Pollan, M. (2019). How to Change Your Mind: What the New Science of Psychedelics Teaches Us about Consciousness, Dying, Addiction, Depression, and Transcendence. New York, NY: Penguin. Solomon, A. (2015). The Noonday Demon: An Atlas of Depression (2nd ed.). New York, NY: Scribner. VISUAL SUMMARY You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material. Visual Summary Chapter 12 View larger image LIST OF KEY TERMS anhedonia antipsychotic anxiety disorders anxiolytics benzodiazepines Bipolar disorder chlorpromazine clozapine cognitive behavioral therapy (CBT) concordance deep brain stimulation (DBS) delusions depression dopamine hypothesis dyskinesia Electroconvulsive shock therapy (ECT) fear conditioning first-generation antipsychotics genome-wide association studies (GWAS) glutamate hypothesis habenulae hypofrontality hypothesis ketamine learned helplessness lithium lobotomy meta-analyses monoamine oxidase (MAO) Negative symptoms obsessive-compulsive disorder (OCD) Phencyclidine (PCP) Positive symptoms postpartum depression posttraumatic stress disorder (PTSD) psychotomimetic repetitive transcranial magnetic stimulation (rTMS) schizophrenia second-generation antipsychotics selective serotonin reuptake inhibitors (SSRIs) supersensitivity psychosis tardive dyskinesia tics Tourette’s syndrome