12 Psychopathology The Biology of Behavioral Disorders
"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. Howard was rebellious in the way that virtually all kids are--sassing back, breaking curfew, skipping out on church. But Howard was never violent with his stepmother (or anyone else). He sometimes got in trouble at school, for not paying attention in class or for smoking in the bathroom, but not for fighting or damaging school property. Howard's grades were erratic--an A on a test one day, an F on a test the next--but 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 famous Walter Freeman, diagnosed the boy as schizophrenic. 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 the boy's upper eyelids and used a hammer on an ice pick- like device to punch holes in Howard's 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 report 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 mental wards. Not until he was 50 did Howard find out what had happened to him as a child, a journey he movingly recounts in his memoir, My Lobotomy (Dully and Fleming, 2007).
Debilitating mental afflictions have plagued humans throughout history, plunging their victims 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.
12.1The Toll of Psychiatric Disorders Is Huge
From H. Dully and C. Fleming, 2007. My Lobotomy. New York, NY: Crown. Courtesy of Howard Dully 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 Animation 12.2: Brain Explorer
We begin by considering schizophrenia, a severe disorder occurring in about 1% 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. The fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the DSM-5, provides a standardized system for diagnosing and classifying the major psychiatric illnesses according to current knowledge (American Psychiatric Association, 2013). Worldwide, between 15% and 50% of the population report psychiatric symptoms at some point in life, with North Americans positioned at the top end of this range (Kessler et al., 2007). About 19% of the adult population of the United States experiences psychiatric symptoms in the course of a year (SAMHSA, 2013), and of this number more than 4% (equating to almost 10 million people) are so ill that they are unable to carry out major life activities, like working or living independently. As shown in FIGURE 12.1, these rates are 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- to 25-year-olds because certain psychiatric disorders--for example, schizophrenia--tend
FIGURE 12.1 Prevalence of Serious Mental
Overall Female Male 18-25 26-49 50+ White Black Hispanic Asian NH/OPI* AI/AN ** 2+ races
Illness among U.S. Adults in 2017 (After National
Institute of Mental Health, 2018. Past year preva-
lence of serious mental illness among U.S. adults
(2017). Bethesda, MD. Data courtesy of SAMHSA. Last updated February 2019. www.nimh.nih. Sex Age Race
gov/health/statistics/prevalence/serious-mental-
*NH/OPI = Native Hawaiian/Other Paci c Islander
to appear in adolescence and young adulthood. Clearly, mental disorders exact an enormous toll on our lives. The seeds for a biological perspective in psychiatry were sown at the start of the twentieth century. At that time, almost a quarter of the patients in mental hospitals suffered from so-called paralytic dementia, featuring sudden onset of delusions (false beliefs strongly held in spite of contrary evidence), grandiosity (boastful self-importance), euphoria, poor judgment, impulsive behavior, disordered thought, and physiological signs like abnormal pupillary constriction (Argyll-Robertson, 1869). 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. With the advent of antibiotics to cure syphilis, paralytic dementia has virtually disappeared. This finding opened the door to biological explanations for other mental illnesses. 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 (Bark, 2002; Heinrichs, 2003). 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 description of schizophrenia was subsequently replaced with a more objective definition (K. Schneider, 1959) focusing on "first-rank symptoms," which include (1) auditory hallucinations, (2) highly personalized delusions, and (3) changes in affect (emotion). By the 1980s it became clear that many schizophrenia symptoms could be viewed as belonging to two general groups: positive and negative (McCutcheon et al., 2019). Positive symptoms are abnormal behavioral states that have been gained; examples include hallucinations, delusions, and excited motor behavior. Negative symptoms are abnormalities resulting from the loss of normal functions--for example, slow and impoverished thought and speech, emotional and social withdrawal, or blunted affect. Researchers now recognize that schizophrenia is a complex syndrome in which individuals exhibit varying degrees of distinct but correlated categories of symptoms. The contemporary view of the symptoms of schizophrenia retains the distinction between positive symptoms (psychosis) and negative symptoms (emotional and motivational impairments) but recognizes an additional dimension: 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. 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
delusion A false belief that is strongly held in spite of contrary evidence. schizophrenia A severe psychopathological disorder characterized by negative symptoms such as emotional withdrawal and flat affect, by positive symptoms such as hallucinations and delusions, and by cognitive symptoms such as poor attention span. positive symptom In psychiatry, an abnormal behavioral state. Examples include hallucinations, delusions, and excited motor behavior. negative symptom In psychiatry, an abnormality that reflects insufficient functioning. Examples include emotional and social withdrawal, and blunted affect.
TABLE 12.1 Symptoms of Schizophrenia
POSITIVE SYMPTOMS Refers to symptoms that are present but should not be
PSYCHOSIS Hallucinations Delusions Disorganized thought and speech Bizarre behaviors
NEGATIVE SYMPTOMS Refers to characteristics of the individual that are absent but should be present
EMOTIONAL DYSREGULATION 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
concordance Sharing of a characteristic by both individuals of a pair of twins.
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.
Lifetime risk of developing schizophrenia (%)
The more closely related a person is to someone
with schizophrenia, the greater are that person's
chances of also developing schizophrenia.
FIGURE 12.2 The Heritability of Schizophrenia (After I. I. Gottesman, 1991. Schizophrenia genesis: The origins of madness. Freeman. New York, NY.)
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 an excellent 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% of their genes, just like any pair of siblings, this concordance (sharing of a characteristic) drops to about 17% (see Figure 12.2) (Cardno and Gottesman, 2000). 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%
General pop ulation (t Fhird d ousin i S r p st o c uses e U g n ree s) Nep cles/aun hews ts /n G ie r c a e n s dchildren H alf sibling s schizop Siblings wChildren hrenic iptha one Sibrent Di l z in ygoti gs c twins Monoz Parents ygotic tw ins
Camera monitors the eye's re ection in the glass.
FIGURE 12.3 Eye Tracking in People with Schizophrenia versus Controls (After P. J. Benson et al., 2012. Biol. Psychiatry 72: 716. Courtesy of Philip Benson.)
(some estimates are higher [Hilker et al., 2018], some lower [Joseph, 2013b]), so genes alone cannot fully explain whether a person will develop schizophrenia. Presumably, other factors, especially environmental influences, account for the 50% of identical twin pairs that are discordant (only one twin develops the disorderW).aOtsofnte/nBr,etehdelovtewin who goes on to develop schizophrenia has an abnormal develTohpemMeinndt'aslMhaicshtionrey, such as lower birth weight, more physiological distress in Foundations of Brain and Behavior 4e early life, and behavior that seems more submissive, tearful, and sensitive than that oMf Mth4e_u12n.0a3ffe0c6t/e0d4/t2w0in (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 (Avila et al., 2006). In short, the twin studies show that schizophrenia has both environmental and genetic origins. 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 many different human chromosomes (Birnbaum and Weinberger, 2017; Foley et al., 2017). Nonetheless, a few genes have been identified that appear to be abnormal in a small proportion of schizophrenia cases, including genes that are known to participate in synaptic plasticity (J. L. Kennedy et al., 2003; Mei and Xiong, 2008). In one large Scottish family, several members who had schizophrenia also carried a mutant, disabled version of a gene, which was therefore named disrupted in schizophrenia 1 (DISC1). 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 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.
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 medium-sized
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.
2 People living in a large city are twice as likely to develop schizophrenia as people living in the countryside.
2.50 2.25 Big city 2.00 1.75 Small city 1.50
3 The risk of schizophrenia for people living in smaller cities is somewhere in between.
4 Children who move to the city later in life have a lower risk than children who move to the city earlier in life.
1 The risk of people living in rural areas is taken as a baseline.
FIGURE 12.4 City Living Increases the Risk of Schizophrenia (After C. B. Pedersen and P. B. Mortensen, 2001. Arch. Gen. Psychiatry 58: 1039.)
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_12.04 09/04/20
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; A. S. Brown, 2011). 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). Birth complications that deprive the baby of oxygen also increase the probability of schizophrenia (M. C. Clarke et al., 2011). These findings suggest that relatively minor stress during development can make the difference in whether schizophrenia develops. It is fascinating, and frightening, to
From L. D. Selemon and N. Zecevic, 2015. Transl. Psychiary 5: e623 . CC BY 4.0
Prenatal stress (maternal infection, malnutrition, hypoxia at delivery)
Stress (cannabis use, minority status, forced immigration, social challenges)
FIGURE 12.5 Developmental Periods When Stress Can Lead to Schizophrenia in Genetically Susceptible People
think that events in the womb or early childhood can affect the outcome 16 or 20 years later, when the schizophrenia appears. 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. These various stressors occur during critical phases of brain development (FIGURE 12.5), which may be affected by stress to lead to schizophrenia in genetically susceptible people. 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).
Although neuron loss is a normal part of development... Control adolescents
...adolescents with schizophrenia lose gray matter over wide regions at a faster rate. Adolescents with schizophrenia
From P. M. Thompson et al., 2001. Proc. Natl. Acad. Sci., U.S.A. 98: 11650. © 2001 National Academy of Sciences, U.S.A. Courtesy of Paul Thompson
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e Dragon y Media Group MM4e_12.05 08/24/20
FIGURE 12.6 Accelerated Loss of Gray Matter in Adolescents with Schizophrenia Additional brain imagery is available at the USC Laboratory of NeuroImaging: www.loni.usc.edu.
Perhaps it will become possible to combine brain imaging, genetic screening, and behavioral measures, to identify at-risk children early in life, when interventions to reduce stress might prevent schizophrenia later in life. 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 (Olabi et al., 2011) (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 that run alongside the lateral ventricles, as discussed in A STEP FURTHER 12.1, on the website. 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). 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).
FIGURE 12.7 Ventricular Enlargement in Schizophrenia (After N. C. Andreasen et al., 1990. Arch. Gen. Psychiatry 47: 1008.)
MRIs courtesy of E. Fuller Torrey and Daniel Weinberger
Although the two members of each set of identical twins shown here have the same genes...
FIGURE 12.8 Identical Genes, Different Fates
Well ...only the twins with larger ventricles have schizophrenia.
CORTICAL ABNORMALITIES People with schizophrenia differ from controls 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 abnormal in schizophrenia. Early observations Wuastisnong/PBEreTedfloouvne d that, compared with nonschizophrenic controls, people with schizo- The Mind's Machine FpouhnrdeantiioanshoafdBrraeidnuancdedBemhaevtioarb4oelic activity in the frontal lobes relative to other regions of the brain (Buchsbaum et al., 1984). This observation led to the hypofrontality hypothesis MthMa4tet_h12e.0f8ron0t6a/l0l4o/b2e0s are underactive in people with schizophrenia. 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. Behavioral evidence indicates that hypofrontality is especially problematic during difficult cognitive tasks that depend on the frontal lobes for accurate
hypofrontality hypothesis The idea that schizophrenia may reflect underactivation of the frontal lobes.
Transgenic mice expressing the DISC1 mutation associated with schizophrenia in humans develop enlarged lateral ventricles (green) reminiscent of those in people with schizophrenia. Mutant
From M. V. Pletnikov et al., 2008. Mol. Psychiatry 13: 13. Printed by permission from Springer Nature
FIGURE 12.9 Enlarged Ventricles in a Mouse Model of Schizophrenia
lobotomy The surgical separation of a portion of the frontal lobes from the rest of the brain, once used as a treatment for schizophrenia and many other ailments. chlorpromazine An early antipsychotic drug that revolutionized the treatment of schizophrenia. dyskinesia Difficulty or distortion in voluntary movement. tardive dyskinesia A disorder associated with first-generation antipsychotic use and characterized by involuntary movements, especially of the face and mouth. supersensitivity psychosis An exaggerated "rebound" psychosis that may emerge when doses of antipsychotic medication are reduced. Another Victim of 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.
performance, such as the Wisconsin Card Sorting Task (see Figure 14.21). Unlike control participants, people with schizophrenia show little increase in their prefrontal activation during the task (D. R. Weinberger et al., 1994). In many cases, drugs that alleviate symptoms of schizophrenia, discussed next, also increase the activation of frontal cortex (Vogel et al., 2016). 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 differ from the brains of controls? The severity of schizophrenia led to desperate treatment attempts 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 patients 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 the patients easier to handle, 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). Antipsychotic medications revolutionized the treatment of schizophrenia 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"). Unfortunately for Howard, his stepmother just happened upon the wrong physician at the wrong time. Unfortunately, sometimes people taking antipsychotics develop undesirable side effects in movement, as we see in Signs & Symptoms, next.
Few people would deny that antipsychotics are "miracle drugs."
results in what is called receptor supersensitivity. Tardive
With drug treatment, many people who might otherwise have
dyskinesia frequently takes a long time to develop and tends
been in mental hospitals their whole lives can take care of them- to be irreversible. Long-term treatment with antipsychotic drugs
can also have another undesirable effect. In some people, dis-
Unfortunately, antipsychotic drugs can have other, undesir-
continuation of the drugs or a lowering of the dosage results in a
able effects as well. Soon after beginning to take these drugs,
sudden, marked increase in positive symptoms of schizophrenia,
some people develop maladaptive motor symptoms called
such as delusions or hallucinations. This supersensitivity
dyskinesia (from the Greek dys, "bad," and kinesis, "motion").
psychosis (Yin et al., 2017) can often be reversed by the
Although many of these symptoms are transient and disappear
administration of increased dosages of dopamine receptor-
when the dosage of drug is reduced, some drug-induced motor
drug treatment--after months, sometimes years--and are effectively permanent. This condition, called tardive
Tardive dyskinesia may result in involuntary rolling of the tongue and smacking of the lips.
tardive dyskinesia continues to be a puzzle. It may arise from the chronic
FIGURE 12.10 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).
THE DOPAMINE HYPOTHESIS Chlorpromazine and other antipsychotic drugs (also known as neuroleptics) that came aloWnagtsoanl/iBttreleedllaotveer were eventually found The Mind's Machine to share a specific action: they block postFsoyunndaaptitoincs odfoBpraainmanind eBerheavcieorp4teors, particularly dopamine D2 receptors. Because antipsychotic drugs all blocked dopamine D2 receptors to some extent, researchers prMoMpo4se_e1d2.t1h0e d06o/p0a4/m2i0ne hypothesis: that people with 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. You might think that hallucinogenic drugs, like LSD, would similarly produce a schizophrenia-like state, but in fact there is little resemblance; for one thing, the effects of hallucinogens are primarily visual rather than auditory. All of the various drugs that are now classified as first-generation antipsychotics (or typical antipsychotics) are D2 receptor antagonists. In fact, the clinically effective dose of a first-generation antipsychotic can be predicted from its affinity for D2
See Video 12.3: Tardive Dyskinesia antipsychotic Also called neuroleptic. Any of a class of drugs that alleviate symptoms of schizophrenia, typically by blocking dopamine receptors. dopamine hypothesis The idea that schizophrenia results from either excessive levels of synaptic dopamine or excessive postsynaptic sensitivity to dopamine. first-generation antipsychotic Also called typical antipsychotic. An antischizophrenic drug that shows antagonist activity at dopamine D2 receptors.
FIGURE 12.11 Traditional Antipsychotic Drugs
Block Dopamine D2 Receptors (After P. Seeman and T. Tallerico, 1998. Mol. Psychiatry 3: 123.)
Drugs with a higher af nity for D2 receptors can effectively treat schizophrenia at lower doses.
Af nity of drug for dopamine D2 receptors
second-generation antipsychotic Also called atypical antipsychotic. An antipsychotic drug that has primary actions other than or in addition to the dopamine D2 receptor antagonism that characterizes the first-generation antipsychotics. clozapine A second-generation antipsychotic that blocks 5HT2A receptors.
receptors (FIGURE 12.11), as the dopamine hypothesis would predict. For example, haloperidol, discovered a few years after chlorpromazine, has a greater affinity for D2 receptors and quickly became the more widely used drug. Over the years, other clinical andWeatxspone/riBmreeendltoavlefindings have bolstered the dopamine hypothesis; for example, treatinTghpe eMoipndle'swMhaochhinaeve Parkinson's disease with l-dopa (the metabolic precursor of dopaFmounindaet)iomnsaoyf BinradinuacnedsBcehhaivzioorp4herenia-like symptoms, presumably by boosting the synaptMicMav4ae_il1a2b.1i1lity0o6f/d04o/p2a0mine. However, there are also several problems with the hypothesis. 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). Thus, the relation of dopamine to schizophrenia is more complex than just hyperactive dopamine synapses. Furthermore, work with new types of antischizophrenic drugs, developed to reduce motor side effects we mentioned 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 the D2 dopamine receptors that are the principal site of action of the first-generation antipsychotics. Instead, second-generation antipsychotics have their highest affinity for other transmitter receptors: clozapine, for example, blocks serotonin receptors (especially 5-HT2A receptors), as well as other receptor types. Second-generation antipsychotics are just as effective as the older generation of drugs for relieving the symptoms of schizophrenia. So, if the problem is as simple as an overstimulation of dopamine receptors, why are the second-generation antipsychotics effective? For example, clozapine can increase dopamine release in frontal cortex (Bortolozzi et al., 2010)--hardly what we would expect if excess dopaminergic activity lies at the root of schizophrenia. In fact, it seems that supplementing antipsychotic treatments with l-dopa (thereby increasing dopaminergic activity) actually helps reduce symptoms of schizophrenia (Jaskiw and Popli, 2004).
Until recently, almost all clinicians believed that second-genera-
tion antipsychotics were more effective than first-generation antipsy-
chotics for treating schizophrenia, especially for relieving negative symptoms in addition to the positive symptoms relieved by first-generation antipsychotics. But several studies comparing the outcome
for schizophrenic participants who had been given the two types of
drugs found no difference (P. B. Jones et al., 2006; Crossley et al., 2010;
Saha et al., 2016). Although the second-generation antipsychotics are less likely than first-generation antipsychotics to cause side effects in
motor function (see Figure 12.10), they are more likely to cause weight
gain (Sikich et al., 2008). So the overall outcome for quality of life ap-
pears equivalent for the two types of drugs (Heres et al., 2006).
Although antipsychotics were regarded as miracle drugs when they first became available, some are questioning whether their continued use is all that beneficial. Early studies typically ended 2 years after psychosis began, but later studies suggest a longer-last-
0 01234 56 Time from start of study (yrs)
ing recovery without the drugs (FIGURE 12.12).
THE GLUTAMATE HYPOTHESIS Another drug that, like chlorpromazine, was initially developed as an anesthetic has a much different relationship to schizophrenia. Phencyclidine (PCP) was
the proportion of people who avoid relapse in the rst two years...
soon found to be a potent psychotomimetic; that is, PCP produc- FIGURE 12.12 Long-term Outcomes with and
es phenomena strongly resembling both the positive and negative without Antipsychotics (After L. Wunderink, 2019.
symptoms of schizophrenia. Users of PCP often experience aWudatis-on/BrTehedelroAvedv Psychopharmacol 9: 1. CC BY-NC 4.0.)
tory hallucinations, strange depersonalization, and disorientaTtihoenM, ind's Machine Foundations of Brain and Behavior 4e and they may become violent as a consequence of their drug-in-
duced delusions. Prolonged psychotic states can develop wMiMth4e_12.12 08/25/20
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
PCP is a noncompetitive NMDA antagonist. While PCP is bound, no other ligand can activate the NMDA receptor.
The resemblance of PCP-induced psychosis to schizophrenia has prompted a glutamate hypothesis of schizophrenia.
FIGURE 12.13 The Effects of PCP on the NMDA Receptor
phencyclidine (PCP) Also called angel dust. An anesthetic agent that is also a psychedelic drug. PCP makes many people feel dissociated from themselves and their environment. psychotomimetic A drug that induces a state resembling schizophrenia.
endogenous ligand--glutamate--from having its usual effects. 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). Other antagonists of NMDA receptors, such as ketamine, have similar effects. These and other observations prompted researchers to propose a glutamate hypothesis of schizophrenia (Uno and Coyle, 2019), which suggests that schizophrenia results from an underactivation of glutamate receptors, which might account for the reduced activity in frontal cortex (Marek et al., 2010)--the hypofrontality 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 the metabotropic glutamate receptors--mGluRs--of which there are at least eight different subtypes (Mueller et al., 2004). Although results from clinical trials with early candidate drugs have been disappointing (Stauffer et al., 2013), researchers hope that targeting the proper class of mGluRs with drugs that have novel modes of action may someday lead to a new generation of antipsychotics (Stansley and Conn, 2018). 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?
12.2Mood Disorders Are the Most Common Psychopathologies
ketamine A dissociative anesthetic drug, similar to PCP, that acts as an NMDA receptor antagonist. glutamate hypothesis The idea that schizophrenia may be caused, in part, by understimulation of glutamate receptors. depression A psychiatric condition characterized by such symptoms as an unhappy mood; loss of interests, energy, and appetite; and difficulty concentrating.
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 the 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; the person may dwell on thoughts of death or even contemplate suicide. Pessimism seems to seep into every act (Solomon, 2001). 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% 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 time-limited 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% later went on to commit suicide (Seiden, 1978). Similarly, suicide rates went down by a third in Britain when that country switched from using coal gas, which contains lots of deadly carbon monoxide, to natural gas for heating. 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 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. Despite public health initiatives to combat suicide in the United States, it has steadily risen this century (Carey, 2018). Inheritance is an important determinant of depression Genetic studies of depressive disorders reveal strong hereditary contributions. The concordance rate for identical twins (about 40%) is substantially higher than for fraternal twins (about 20%) (K. E. Whitfield et al., 2008). 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 (Risch et al., 2009). So, as is the case for schizophrenia, there is no single gene for depression. Rather, many genes contribute to making a person more or less susceptible, and environmental factors determine whether depression results.
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).
TABLE 12.2 Warning Signs of Suicidea
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 aDeveloped by the U.S. Department of Health and Human Services, 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, you can call the National Suicide Prevention Lifeline at 1-800-273-TALK (1-800-273-8255) at any time of day, any day of the year.
Breaking the Cycle For many people, forcing themselves to engage in exercise, even as mild as walking, can improve their mood. electroconvulsive shock therapy (ECT) A last-resort treatment for unmanageable depression, in which a strong electrical current is passed through the brain, causing a seizure. repetitive transcranial magnetic stimulation (rTMS) A noninvasive treatment in which repeated pulses of focused magnetic energy are used to stimulate the cortex through the scalp. monoamine oxidase (MAO) An enzyme that breaks down monoamine neurotransmitters, thereby inactivating them. selective serotonin reuptake inhibitor (SSRI) An antidepressant drug that blocks the reuptake of transmitter at serotonergic synapses.
The brain changes with depression Most reports of differences in the brains of depressed people focus on functional changes as detected by PET or fMRI. Depressed people 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 depressed people 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--systems that have been implicated in attention (see Chapter 14) (Davey et al., 2017). The increased activity in the amygdala--a structure involved in mediating fear (see Chapter 11)--persists even after the depression has lifted. Descendants of people with severe depression also have a thinner cortex across large swaths of the right hemisphere than do control participants (B. S. Peterson et al., 2009), which might make them vulnerable to depression. There is also evidence that people who are depressed have difficulties regulating stress hormone release, as discussed in A STEP FURTHER 12.2, on the website. Many studies report hippocampal volume is reduced in people with depression (Sexton et al., 2013), and there is reduced activation of the hippocampal region in depressed people during memory tasks (K. D. Young et al., 2012). But whether these changes in the hippocampus are present before the depression, and therefore may be a contributing cause of the disorder, or are a result of the depression remains unknown. In any case, there are effective treatments for depression, as we discuss next. 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 (M. Fink and Taylor, 2007). A more modern technique for altering cortical electrical activity, called repetitive transcranial magnetic stimulation (rTMS) (see Chapter 1), is likewise being developed as a treatment for depression (D. R. Kim et al., 2009). Today, the most common treatment for depression is the use of drugs that affect the monoamine transmitters: norepinephrine, dopamine, and serotonin. The first 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 depressed people 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. ECT may help depression 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 (Sahay and Hen, 2007), which may mediate some of the mood effects of the drugs. 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
TABLE 12.3 Drugs Used to Treat Depression
Inhibit the enzyme monoamine oxidase, which breaks down serotonin, norepinephrine, and dopamine
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 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)
aThe names given are the more commonly used trade names rather than chemical names.
feel better. This paradox suggests that it is the brain's response to increased synaptic se- cognitive behavioral therapy
rotonin 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 in-
(CBT) Psychotherapy aimed at correcting negative thinking and consciously changing behaviors as a way of changing feelings.
hibitors (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), a PCP-like
drug that relieves depression almost instantly (E. E. Lee et al., 2015), in contrast to
SSRIs and SNRIs, which typically must be taken for several weeks before they ele-
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). In-
terestingly, CBT and SSRI treatment together are 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
CBT aims to break the cycle at one or more of these points, via directed
depression (FIGURE 12.14) and has proven effective in avoiding suicide (Mewton and Andrews, 2016). Fur-
changes in behavior, thought exercises, and changes in physical activity.
thermore, while there is no doubt that current anti-
depressants do help many people who are depressed, evidence has accumulated that for a significant number of people, part of the benefit may actually be a place-
Behavior (reduced) Become less active and avoid people and situations
Mood (low) Feel guilty, discouraged, inadequate, and worthless
bo effect (Turner et al., 2008), as we discuss in Signs &
FIGURE 12.14 Depression's Endless Treadmill
At their introduction, selective serotonin reuptake inhibitors
evidence of clear beneficial effects of SSRIs relative to placebos
(SSRIs) represented a major revolution in depression treatment. for people of all ages and with all levels of severity of depression
Heavily marketed to the public and to health professionals,
(Gibbons et al., 2012). One possibility is that the relationship be-
SSRIs soon became one of the most widely prescribed medica- tween symptom severity and SSRI efficacy is a statistical artifact
tions, propelling an incredible 400% increase in antidepressant
of the methodology employed in order to combine studies in a
prescriptions by 2008. In fact, for 18- to 44-year-olds, antidepres- meta-analysis. And while there are reservations about the effica-
sants are prescribed more than any other drug; more than one in cy of SSRIs for children or teenagers (Bower, 2006), millions of
ten adult Americans is currently using antidepressant medication American children and teens have been given prescriptions for
(Pratt et al., 2011). Needless to say, the development and sales
SSRIs despite a reported increased risk of suicide in these age
of antidepressants have provided a huge windfall for the pharma- groups (Olfson et al., 2006).
This controversy seems likely to rage on for a while. In the
Now that SSRIs have been with us for more than 20 years,
meantime, a prudent course of action is to deploy CBT as a first-
researchers have turned to retrospective analyses to reevaluate rank treatment in moderate cases, supplemented with antide-
the efficacy of SSRIs. In part, these large-scale meta-analyses
pressant medication in more severe or nonresponsive cases.
(analyses that combine the results of many pre-
viously 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
For patients with mild to moderate depression, drug and placebo were equally effective.
Only for those who were most severely depressed at the outset, about 13% of all patients, was the drug more effective than the placebo.
failed to find effects of SSRIs may historically
have been underreported. The results of these 20 meta-analyses 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, systematic 12
reviews of the clinical research seem to show
that while modern antidepressant drugs are indeed effective, their effects are modest in size 4
and evident in only the most severely depressed people (Fournier et al., 2010; Cipriani et al, 2018). Other large meta-analytic studies, also
based on multiple clinical trials, find stronger
FIGURE 12.15 When Are Antidepressants More Effective Than Placebos? (After J. C. Fournier et al., 2010. JAMA 303: 47.)
meta-analysis A type of quantitative review of a field of research, in which the results of multiple previous studies are combined in order to identify overall patterns that are consistent across studies. deep brain stimulation (DBS) Mild electrical stimulation through an electrode that is surgically implanted deep in the brain.
An unusual treatment for depression involves a pacemaker that periodically ap- plies mild electrical stimulation to the vagus nerve (cranial nerve X; see Chapter 1). This treWatamtsoenn/tBirseeodflfoevreed in cases where drugs or ECT have been ineffective, but it The Mind's Machine remainsFotuonbdaetioensstaofbBlirsahineadndwBheheatvhioerr4veagal stimulation is a long-term solution (Grimm and Bajbouj, 2010; Blumberger et al., 2015). For extremely difficult cases of depression, reMseMar4ceh_1e2r.s15hav0e8/t2u4r/n20ed again to psychosurgery--but nothing that resembles the ravages suffered by Howard Dully. In deep brain stimulation (DBS) surgery, del- icate electrodes are surgically implanted in the cingulate cortex or other brain sites (Kringelbach et al., 2007). The effectiveness of DBS or vagal nerve stimulation for depression is difficult to evaluate, because most studies have no placebo control (R. Robinson, 2009). In the few placebo-controlled studies, where the participant was un- aware of whether electrical stimulation was provided, the treatment appeared to be less effective than it seemed in initial, uncontrolled reports (Kisely et al., 2018; Widge et al., 2018), suggesting that the promising early results of DBS and vagal stimulation may have been due to placebo effects.
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. Some researchers have emphasized gender differences in 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 behavior (Tronick and Reck, 2009), 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). 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 (Nestler and Hyman, 2010). 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 to evaluate animal models of depression. In one type of stress 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. 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
Psychopathology395 Depression For reasons that are not understood, women are more likely than men to develop depression. postpartum depression A bout of depression that afflicts a woman either immediately before or after giving birth. learned helplessness A learning paradigm in which individuals are subjected to inescapable, unpleasant conditions.
(A) Sleep pattern of someone with depression
People with depression spend little or no time in stage 3 sleep. (Compare with Figure 10.12.)
People with depression also enter their rst REM period earlier in the night. Thus, REM sleep seems to be distributed differently in people with depression.
FIGURE 12.16 Sleep and Depression (B after J. C. Gillin et al., 1981. Psychiatry Research 4: 73, and D. J. Kupfer et al., 1982. Neurobiol. Aging 3: 351.)
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). 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), which is described in A STEP FURTHER 12.3, on the website.
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_12.16 08/30/20 bipolar disorder A psychiatric disorder characterized by periods of depression that alternate with excessive, expansive moods.
In bipolar disorder, mood cycles between extremes Affecting about 2.6% of the U.S. population each year (Kessler et al., 2005), 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 (Smoller and Finn, 2003; Faraone et al., 2004). The neural basis of bipolar disorder is not fully understood, but people with bipolar disorder exhibit enlarged ventricles on brain scans (Arnone et al., 2009), as is seen in schizophrenia (see Figure 12.8). The more manic episodes the person has experienced, the greater the ventricular enlargement, suggesting a worsening of brain loss over time (Moorhead et al., 2007). 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") may 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
(Lichtenstein et al., 2009; Van Os and Kapur, 2009). And although first-generation antipsychotics do not seem to help, the newer, second-generation antipsychotics seem to help dampen the manic phase in people with bipolar disorder. However, most people who have bipolar disorder benefit from taking the element lithium (Severus et al., 2018), a treatment discovered entirely by accident, as we discuss next.
lithium A chemical element that often relieves the symptoms of bipolar disorder.
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.
FIGURE 12.17 Surprisingly Calm Guinea Pigs (After J. F. Cade, 1949. Med. J. Aust. 2: 349.) Question Do people with bipolar disorder have too much urea in circulation?
Hypothesis Injecting urea into guinea pigs will make them manic. Test Cade (1949) found that he could dissolve higher concentrations of urea into solution if he used a urea-lithium combination, lithium urate, rather than urea alone. Other guinea pigs, the control group, got injections of lithium alone. "Both groups act sedated."
Instead of the lithium urate making the guinea pigs manic, it calmed them. But in another
surprise, the control injections of lithium alone were just as effective for calming the animals
(Howland, 2007). Intrigued, Cade took some lithium himself and, upon finding it harmless, tried
giving it to people with bipolar disorder. Almost all of the treated people showed a remarkable
recovery, and many who had been institutionalized for years could finally return home.
Conclusion Lithium alone calms guinea pigs and relieves symptoms of bipolar disorder in humans. Note that this conclusion has nothing to do with the original question. This experiment demonstrates the importance of having a good control group. If Cade had not injected some guinea pigs with lithium alone, he might have wrongly concluded that urea has a calming effect. WatsonB/eBcraeuedselovlitehium has a narrow range of safe doses (see Figure 3.6), care must be taken to TheaMvoiinddt'os xMicacshidineeeffects of an overdose. Nevertheless, well-managed lithium treatment produces Foundations of Brain and Behavior 4e marked relief for many people with bipolar disorder and even has been reported to increase the MMvo4elu_m12e.1o7f g0ra6y/0m4/a2tt0er in their brains (G. J. Moore et al., 2009).
398CHAPTER12 anxiety disorder Any of a class of psychological disorders that includes recurrent panic states and generalized persistent anxiety disorder.
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 may provide a nonpharmacological treatment alternative in difficult cases of bipolar disorder (Michael and Erfurth, 2004). 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. 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?
12.3There Are Several Types of Anxiety Disorders
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.
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 post-traumatic stress disorder (PTSD). 12.3.4 Describe the several treatments for obsessive-compulsive 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 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
This PET scan of benzodiazepine receptors shows their wide
Throughout history, people have consumed all sorts of substances in the hopes of controlling anxiety. The list includes alcohol, bromides, cannabis, opiates, and barbiturates. In the 1950s the tranquilizing drug
distribution in the brain, especially the cortex. Highest concentrations are in red; lowest concentrations are in blue.
meprobamate (Miltown) was introduced, and it became an instant best
seller, ushering in the 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 anx-
iety. One type of benzodiazepine--diazepam (trade name Valium)--
is one of the most prescribed drugs in history. Other commonly pre-
scribed benzodiazepines include Xanax, Halcion, and Ativan. Such
drugs that combat anxiety are termed anxiolytics ("anxiety-dissolv-
ing"), although they also may have anticonvulsant and sleep-inducing
properties. The anxiolytic drugs are also discussed in Chapter 3.
Anxiolytic benzodiazepines interact with binding sites that are part
of GABA receptors, especially the GABAA 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 receptors, it hy-
perpolarizes the target neuron and therefore inhibits it from firing. Ben-
zodiazepines alone have little effect on the GABAA receptor, but when benzodiazepines are present, GABA produces a markedly enhanced hy-
perpolarization. In other words, benzodiazepines boost GABA-mediated
postsynaptic inhibition, reducing the excitability of postsynaptic neurons. Interestingly, the brain probably makes its own anxiety-relieving
FIGURE 12.18 The Distribution of Benzodiazepine Receptors in the Human Brain
substances that interact with the benzodiazepine-binding site on the
GABA receptor; the neurosteroid allopregnanolone is a prime candidate
for this function. Drugs developed to act at this site are effective anxiolytics in both rats
FIGURE
GABAA receptors are widely distributed throughout the brain, especially in thFeoucnedraetbiornaslof Brain and Behavior 4e
cortex and some subcortical areas, such as the hippocampus and the amygdala.
pecially for acute attacks, other anxiety-relieving drugs have been developed that lack
the abuse potential of the benzodiazepines. A notable example is the drug buspirone
(Buspar), an agonist at serotonin 5-HT1A receptors that can provide relief from anxiety. This effect is consistent with functional-imaging research that reveals an abnormal
density of 5-HT1A receptors in the brains of people with anxiety disorders (Neumeister et al., 2004). SSRI antidepressants, such as paroxetine (Paxil) and fluoxetine (Prozac),
which increase the stimulation of serotonin receptors, are also sometimes effective
In post-traumatic 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 the rest of their lives. 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, 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 becomes the portrait of individuals afflicted with what is called post-traumatic stress disorder (PTSD), formerly called
benzodiazepine Any of a class of antianxiety drugs that are noncompetitive agonists of GABAA receptors in the central nervous system. One example is diazepam (Valium). anxiolytic A substance that is used to reduce anxiety. Examples include alcohol, opiates, barbiturates, and the benzodiazepines. post-traumatic stress disorder (PTSD) A disorder in which memories of an unpleasant episode repeatedly plague the person.
Delayed Reaction Many combat veterans experience the symptoms of PTSD for years afterward. fear conditioning A form of classical conditioning in which fear comes to be associated with previously neutral stimuli.
combat fatigue, war neurosis, or shell shock. Although related in some ways to anxiety disorders, post-traumatic stress disorder is now recognized in the DSM-5 as a separate entity. Analysis of a random sample of Vietnam War veterans has indicated that 19% had PTSD at some point after service. This was the rate for all Vietnam veterans; when the researchers focused more specifically on veterans exposed to intense war zone stressors, more than 35% developed PTSD at some point, and most of them still had the symptoms of this disorder decades later (Dohrenwend et al., 2006). Gulf War veterans likewise have high rates of PTSD (Institute of Medicine, 2010). 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. 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). In
1 The original trauma activates two systems.
2 The brainstem system sensitizes the person to related stimuli in the future.
Acute neurochemical responses: · Locus coeruleus (norepinephrine) · Ventral tegmental area (dopamine) · Endogenous opioids · Corticotropin-releasing hormone
Reciprocal interactions may facilitate encoding and retrieval of traumatic memories.
FIGURE 12.19 A Neural Model of Post-traumatic Stress Disorder (After D. S. Charney et al., 1993. Arch. Gen. Psychiatry 50: 295.)
Sensory and cognitive associations to original trauma
3 The amygdala system conditions Traumatic remembrance a long-lasting fearful reaction.
Chapter 13 we will discuss research-based methods that have been proposed to help people forget traumatic life events by having them recall the event while under the influence of a drug that dampens the stress response. 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. Determining the number of people afflicted with OCD is difficult, especially because people with this disorder tend to hide their symptoms (Newth and Rachman, 2001). It is estimated that nearly 1% of adults in the United States will have "severe" OCD symptoms in any given year (Kessler et al., 2005). In many cases, the initial symptoms of this disorder appear in childhood; the peak age group for onset of OCD, however, is 25-44 years. People with OCD display increased metabolic rates in the orbitofrontal cortex, cingulate cortex, and caudate nuclei (Chamberlain et al., 2008). 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
TABLE 12.4 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 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.
obsessive-compulsive disorder (OCD) An anxiety disorder in which the affected individual experiences recurrent unwanted thoughts and engages in repetitive behaviors without reason or the ability to stop.
Tourette's syndrome A disorder involving heightened sensitivity to sensory stimuli that may be accompanied by verbal or physical tics.
several drugs. What do 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. 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). But again there are few participants and many of the studies have no control condition (when no stimulation is provided to the electrode), so it is difficult to assess whether the DBS is effective (Naesström et al., 2016). Psychosurgery may be a treatment of last resort. Unlike lobotomies, these surgeries target much smaller regions. In one study, about one-third of severely disabled people with OCD who underwent cingulotomy (making lesions that interrupt pathways in the cingulate cortex) (FIGURE 12.20) benefited (Shah et al., 2008; Pepper et al., 2015). 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, to provide 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 suffer the fate of Howard Dully, lobotomized for being a teenager. Many researchers believe that OCD is part of a spectrum of related disorders (Olson, 2004), such as Tourette's, the topic of our final Signs & Symptoms for this chapter.
These MRIs show the brain of a person who underwent a cingulotomy--the disruption of cingulate cortex connections--in an attempt to treat OCD. (B) Sagittal view
From R. L. Martuza et al., 1990. J. Neuropsychiatry Clin. Neurosci. 2: 331, courtesy of Robert L. Martuza
FIGURE 12.20 Neurosurgery to Treat Obsessive-Compulsive Disorder
Tics, Twitches, and Snorts: The Unusual Character of Tourette's Syndrome
The faces of people with Tourette's twitch in an insistent way, and every now and then, out of nowhere, they blurt out an odd sound. At times they fling their arms, kick their legs, or make violent shoulder movements. People with Tourette's syndrome 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.
FIGURE 12.21 Portrait of Tourette's Syndrome (Part A after J. Jagger et al., 1982. Schizophr. Bull. 8: 267.)
(A) The chronology of Tourette's symptoms
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 D2 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 (D2 receptor binding in an affected individual is illustrated in FIGURE 12.21B). The contemporary view is that Tourette's syndrome is mediated in a complex manner by many genes rather than just one (Hallett, 2015; Qi et al., 2017). Treatment with haloperidol, a dopamine D2 receptor antagonist that is better known as a first-generation antipsychotic drug (see Figure 12.11), 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 immediate relief from symptoms (Porta et al., 2009; Baldermann et al., 2016). (B) D2 receptor binding in Tourette's syndrome 12 13
S. S. Wolf et al., 1996. Science 273: 1225. Courtesy of Steven Wolf
View Activity 12.1: Concept Matching: Psychopathology
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? 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. Meyer, J. S., and Quenzer, L. F. (2018). Psychopharmacology: Drugs, the Brain, and Behavior (3rd ed.). Sunderland, MA: Oxford University Press/Sinauer. Solomon, A. (2001). The Noonday Demon: An Atlas of Depression. New York, NY: Scribner. Steketee, G. (Ed.). (2011). The Oxford Handbook of Obsessive Compulsive and Spectrum Disorders. New York, NY: Oxford University Press.
12 · 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.
Lifetime risk of developing schizophrenia (%)
1 Population studies find that psychiatric disorders are prevalent in modern society. Studies of families, twins, and adoptees demonstrate a strong role of genetic factors in schizophrenia. Rather than a single gene determining whether a person will develop schizophrenia, several genes contribute to the risk. Review Figures 12.1 and 12.2, Table 12.1, Animation 12.2
General pop ulation (t Fhird d ousin i S r p st o c uses e U g n ree s) Nep cles/aun hews ts /n G ie r c a e n s dchildren H alf sibling s schizop Siblings wChildren hrenic iptha one Sibrent Di l z in ygoti gs c twins Monoz Parents ygotic tw ins
2 Structural changes in the brains of people with schizophrenia--including enlarged ventricles--may arise from early developmental problems. The emergence of schizophrenia depends on the interaction of genes that make a person vulnerable to environmental stressors. Review Figures 12.3-12.9
Af nity of drug for dopamine D2 receptors
3 The frontal lobes are less active in people with schizophrenia than in people without it. Biochemical theories of schizophrenia emphasize the importance of the dopamine, glutamate, and serotonin receptors. First-generation antipsychotics block dopamine D2 receptors, while second-generation antipsychotics block serotonin 5-HT2A receptors in addition to acting on dopamine receptors. Review Figures 12.11-12.13, Video 12.3
4 Depression also has a strong genetic factor. Serotonin has been implicated in this disorder. In general, females are more likely than males to experience depression. People with depression show increased activity in the frontal cortex and the amygdala, as well as disrupted sleep patterns. Review Figures 12.14-12.16
5 There is considerable evidence that suicide is often an impulsive act, so intervening in cases of people showing the warning signs of suicide can save lives. Review Table 12.2 7 Bipolar disorder is characterized by extreme mood swings and subtle changes in the brain, and it has a complex genetic component. The disorder is commonly treated with lithium. Review Figure 12.17
TABLE 12.3 Drugs Used to Treat Depression Symptom dimension Symptom category
Monoamine oxidase (MAO) inhibitors Tricyclics and heterocyclics Selective serotonin reuptake inhibitors (SSRIs)
Inhibit the enzyme monoamine oxidase, which breaks down serotonin, norepinephrine, and dopamine Inhibit the reuptake of norepinephrine, serotonin, and/or dopamine Block the reuptake of serotonin, having little effect on norepinephrine or dopamine synapses
Marplan, Nardil, Parnate Wellbutrin, Elavil, Aventyl, Ludiomil, Norpramin Prozac, Paxil, Zoloft
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)
aThe names given are the more commonly used trade names rather than chemical names.
6 The most effective treatment for most cases of depression is a combination of cognitive behavioral therapy (CBT) and a selective serotonin reuptake inhibitor (SSRI). Review Table 12.3
8 Anxiety states are characterized by functional changes in the temporal lobes, particularly the amygdala. Benzodiazepines, a type of anxiolytic (antianxiety drug), enhance the inhibitory effects of receptors for the transmitter GABA. Drugs affecting serotonergic synapses may also reduce anxiety. Review Figure 12.18
9 Post-traumatic stress disorder (PTSD) is characterized by an inability to forget horrible experiences. Temporal lobe atrophy in this disorder may be caused by chronic exposure to stress hormones. Review Figure 12.19
Acute neurochemical responses: · Locus coeruleus (norepinephrine) · Ventral tegmental area (dopamine) · Endogenous opioids · Corticotropin-releasing hormone
Reciprocal interactions may facilitate encoding and retrieval of traumatic memories.
Sensory and cognitive associations to original trauma
10 Obsessive-compulsive disorder (OCD) is characterized by changes in basal ganglia and frontal cortex and linked to serotonin. A restricted type of neurosurgery is sometimes used to treat the most severe cases of anxiety disorders. In Tourette's syndrome, overstimulation of dopamine receptors induces motor and verbal tics and compulsions. Review Figure 12.21, Table 12.4, Activity 12.1
The Mind's Machine digital resources include additional videos, flashcards, and other study tools.