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PowerPoint Presentation for Physiology of Behavior 11th Edition by Neil R. Carlson Prepared by Grant McLaren, Edinboro University of Pennsylvania This multimedia product and its contents are protected under copyright law. The following are prohibited by law: • any public performance or display, including transmission of any image over a network; • preparation of any derivative work, including extraction, in whole or in part, of any images; •any rental lease, or lending of the program. COPYRIGHT © ALLYN & BACON 2012 Schizophrenia and the Affective Disorders Chapter 16 Schizophrenia and the Affective Disorders • Schizophrenia • Description • Heritability • Pharmacology of Schizophrenia: The Dopamine Hypothesis • Schizophrenia as a Neurological Disorder • Section Summary 3 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia and the Affective Disorders • Major Affective Disorders • Description • Heritability • Biological Treatments • The Monoamine Hypothesis • The Amygdala and the Prefrontal Cortex: Role of the 5-HT Transporter • Role of Neurogenesis • Role of Circadian Rhythms • Section Summary 4 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia and the Affective Disorders • Most of the discussion in this book has concentrated on the physiology of normal, adaptive behavior. • The last three chapters summarize research on the nature and physiology of syndromes characterized by maladaptive behavior: mental disorders and drug abuse. • The symptoms of mental disorders include deficient or inappropriate social behaviors; illogical, incoherent, or obsessional thoughts; inappropriate emotional responses, including depression, mania, or anxiety; and delusions and hallucinations. 5 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia and the Affective Disorders • Research in recent years indicates that many of these symptoms are caused by abnormalities in the brain, both structural and biochemical. • This chapter discusses two serious mental disorders: schizophrenia and the major affective disorders. • Chapter 17 discusses anxiety disorders, autism, attention deficit disorder, and disorders caused by stress. • Chapter 18 discusses drug abuse. 6 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Schizophrenia is a serious mental disorder that afflicts approximately 1 percent of the world’s population. • Its monetary cost to society is enormous; in the United States, this figure exceeds that of the cost of all cancers (Thaker and Carpenter, 2001). • Descriptions of symptoms in ancient writings indicate that the disorder has been around for thousands of years (Jeste et al., 1985). 7 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • The major symptoms of schizophrenia are universal, and clinicians have developed criteria for reliably diagnosing the disorder in people of a wide variety of cultures (Flaum and Andreasen, 1990). • Schizophrenia is probably the most misused psychological term in existence. • The word literally means “split mind,” but it does not imply a split or multiple personality. 8 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • The man who invented the term, Eugen Bleuler (1911–1950), intended it to refer to a break with reality caused by disorganization of the various functions of the mind, such that thoughts and feelings no longer worked together normally. 9 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Schizophrenia is characterized by three categories of symptoms: positive, negative, and cognitive (Mueser and McGurk, 2004). • Schizophrenia • a serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors 10 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Positive symptoms make themselves known by their presence. • Positive Symptom • a symptom of schizophrenia evident by its presence: delusions, hallucinations, or thought disorders 11 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Positive symptoms include thought disorders, hallucinations, and delusions. • A thought disorder—disorganized, irrational thinking—is probably the most important symptom of schizophrenia. • Thought Disorder • disorganized, irrational thinking 12 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Schizophrenics have great difficulty arranging their thoughts logically and sorting out plausible conclusions from absurd ones. • In conversation, they jump from one topic to another as new associations come up. • Sometimes, they utter meaningless words or choose words for rhyme rather than for meaning. 13 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Delusions are beliefs that are obviously contrary to fact. • Delusion • a belief that is clearly in contradiction to reality 14 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Delusions of persecution are false beliefs that others are plotting and conspiring against oneself. • Delusions of grandeur are false beliefs in one’s power and importance, such as a conviction that one has godlike powers or has special knowledge that no one else possesses. • Delusions of control are related to delusions of persecution; the person believes (for example) that he or she is being controlled by others through such means as radar or a tiny radio receiver implanted in his or her brain. 15 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • The third positive symptom of schizophrenia is hallucinations, perceptions of stimuli that are not actually present. • The most common schizophrenic hallucinations are auditory, but they can also involve any of the other senses. • The typical schizophrenic hallucination consists of voices talking to the person. 16 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Sometimes, the voices order the person to do something; sometimes, they scold the person for his or her unworthiness; sometimes, they just utter meaningless phrases. • Olfactory hallucinations are also fairly common; often they contribute to the delusion that others are trying to kill the person with poison gas. (See Table 16.1.) 17 COPYRIGHT © ALLYN & BACON 2012 Table 16.1, page 555 18 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • In contrast to the positive symptoms, the negative symptoms of schizophrenia are known by the absence or diminution of normal behaviors: flattened emotional response, poverty of speech, lack of initiative and persistence, anhedonia (inability to experience pleasure), and social withdrawal. • Negative Symptom • a symptom of schizophrenia characterized by the absence of behaviors that are normally present: social withdrawal, lack of affect, and reduced motivation 19 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • The cognitive symptoms of schizophrenia are closely related to the negative symptoms and may be produced by abnormalities in overlapping brain regions. • Cognitive Symptom • a symptom of schizophrenia that involves cognitive deficits; difficulty in sustaining attention, deficits in learning and memory, poor abstract thinking, and poor problem solving 20 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • Cognitive symptoms include difficulty in sustaining attention, low psychomotor speed (the ability to rapidly and fluently perform movements of the fingers, hands, and legs), deficits in learning and memory, poor abstract thinking, and poor problem solving. • Negative symptoms and cognitive symptoms are not specific to schizophrenia; they are seen in many neurological disorders that involve brain damage, especially to the frontal lobes. 21 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Description • The symptoms of schizophrenia typically appear gradually and insidiously, over a period of three to five years. • Negative symptoms are the first to emerge, followed by cognitive symptoms. • The positive symptoms follow several years later. • As we will see later, this progression of symptoms provides some hints about the nature of the brain abnormalities that are responsible for them. 22 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • One of the strongest pieces of evidence that schizophrenia is a biological disorder is that it appears to be heritable. • Both adoption studies (Kety et al., 1968, 1994) and twin studies (Gottesman and Shields, 1982; Tsuang, Gilbertson, and Faraone, 1991) indicate that schizophrenia is a heritable trait. 23 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • If schizophrenia were a simple trait produced by a single gene, we would expect to see this disorder in at least 75 percent of the children of 2 schizophrenic parents if the gene were dominant. • If it were recessive, all children of two schizophrenic parents should become schizophrenic. • However, the actual incidence is less than 50 percent, which means either that several genes are involved or that having a “schizophrenia gene” imparts a susceptibility to develop schizophrenia, the disease itself being triggered by other factors. 24 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • If the susceptibility hypothesis is true, then we would expect that some people carry a “schizophrenia gene” but do not express it; that is, their environment is such that schizophrenia is never triggered. • One such person would be the nonschizophrenic member of a pair of monozygotic twins who are discordant for schizophrenia. • The logical way to test this hypothesis is to examine the children of both members of discordant pairs. 25 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • Gottesman and Bertelsen (1989) found that the percentage of schizophrenic children was identical for both members of such pairs: 16.8 percent for the schizophrenic parents and 17.4 percent for the nonschizophrenic parents. • For the dizygotic twins, the percentages were 17.4 percent and 2.1 percent, respectively. • These results provide strong evidence for the heritability of schizophrenia and also support the conclusion that carrying a “schizophrenia gene” does not mean that a person will necessarily become schizophrenic. (See Figure 16.1.) 26 COPYRIGHT © ALLYN & BACON 2012 Figure 16.1, page 556 27 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • So far, researchers have not located a single “schizophrenia gene,” although researchers have found many genes that appear to increase the likelihood of this disease. • So far, no single gene has been shown to cause schizophrenia in the way that mutations in the genes for -secretase or amyloid precursor protein apparently produce Alzheimer’s disease. • For example, Walsh et al. (2008) suggest that a large number of rare mutations play a role in the development of schizophrenia. 28 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • The effect of paternal age provides further evidence that genetic mutations may affect the incidence of schizophrenia (Brown et al., 2002; Sipos et al., 2004). • Several studies have found that the children of older fathers are more likely to develop schizophrenia. • Most investigators believe that the increased incidence of schizophrenia is caused by mutations in the spermatocytes, the cells that produce sperms. • These cells divide every 16 days after puberty, which means that they have divided approximately 540 times by age 35. 29 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Heritability • In contrast, women’s oocytes divide twenty-three times before the time of birth and only once after that. • The likelihood of a copying error in DNA replication when a cell divides increases with the number of cell divisions, and an increase in copying errors may cause an accumulation of mutations that are responsible for an increased incidence of schizophrenia. 30 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Pharmacology of Schizophrenia: The Dopamine Hypothesis • Pharmacological evidence suggests that the positive symptoms of schizophrenia are caused by abnormalities in DA neurons. • The dopamine hypothesis suggests that the positive symptoms of schizophrenia are caused by overactivity of DA synapses. 31 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • Around the middle of the twentieth century, a French surgeon named Henri Laborit discovered that a drug used to prevent surgical shock seemed also to reduce anxiety. • A French drug company developed a related compound called chlorpromazine, which seemed to be even more effective (Snyder, 1974). 32 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • Chlorpromazine was tried on patients with a variety of mental disorders: mania, depression, anxiety, neuroses, and schizophrenia (Delay and Deniker, 1952a, 1952b). • Chlorpromazine • a dopamine receptor blocker; a “first generation” antipsychotic drug • The drug was not very effective in treating neuroses or affective psychoses, but it had dramatic effects on schizophrenia. 33 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • The discovery of the antipsychotic effects of chlorpromazine profoundly altered the way in which physicians treated schizophrenic patients and made prolonged hospital stays unnecessary for many of them (the patients, that is). • The efficacy of antipsychotic drugs has been established in many double-blind studies (Baldessarini, 1977). • The drugs actually eliminate, or at least diminish, the patients' positive symptoms. 34 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • The beneficial effects are not just a change in the patient's attitudes; the hallucinations and delusions go away or at least become less severe. • Since the discovery of chlorpromazine, many other drugs have been developed that relieve the positive symptoms of schizophrenia. • These drugs were found to have one property in common: They block D 2 and D3 dopamine receptors (Creese, Burt, and Snyder, 1976; Strange, 2008). 35 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • Another category of drugs has the opposite effect: namely, production of the positive symptoms of schizophrenia. • The drugs that can produce these symptoms have one known pharmacological effect in common: They act as dopamine agonists. 36 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Effects of Dopamine Agonists and Antagonists • These drugs include amphetamine, cocaine, and methylphenidate (which block the reuptake of dopamine) and L-DOPA (which stimulates the synthesis of dopamine). • The symptoms that these drugs produce can be alleviated with antipsychotic drugs, a result that further strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking dopamine receptors. 37 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia The Search for Abnormalities in Dopamine Transmission in the Brains of Schizophrenic Patients • Is there any evidence that dopaminergic activity in the brains of schizophrenic patients is indeed abnormal? • Let’s look at some of the evidence. • Studies have found evidence that dopaminergic neurons may indeed release more dopamine (Laruelle et al., 1996; Breier et al., 1997). • A functional-imaging study by Laruelle and his colleagues measured the release of dopamine caused by an intravenous injection of amphetamine. 38 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia The Search for Abnormalities in Dopamine Transmission in the Brains of Schizophrenic Patients • As we saw in Chapter 4, amphetamine stimulates the release of dopamine, apparently by causing the dopamine transporters that are present in the terminal buttons to run backward, pumping dopamine out rather than retrieving it after it has been released. • Of course, this effect inhibits the reuptake of dopamine as well. • Laruelle and his colleagues found that amphetamine caused the release of more dopamine in the striatum of schizophrenic patients than in normal subjects. • They also found that patients with greater amounts of dopamine release showed greater increases in positive symptoms. (See Figure 16.2.) 39 COPYRIGHT © ALLYN & BACON 2012 Figure 16.2, page 558 40 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia The Search for Abnormalities in Dopamine Transmission in the Brains of Schizophrenic Patients • Another possibility—that the brains of schizophrenic patients contain a greater number of dopamine receptors—received much attention for several years. • Because the earliest antipsychotic drugs appeared to work by blocking D 2 receptors, the earliest studies looked for increases in the numbers of these receptors in the brains of schizophrenics. 41 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia The Search for Abnormalities in Dopamine Transmission in the Brains of Schizophrenic Patients • Researchers have performed two types of analyses: postmortem measurements in the brains of deceased schizophrenic patients and PET scans after treatment with radioactive ligands for dopamine receptors. • Reviews of these studies (Kestler, Walker, and Vega, 2001; Stone, Morrison, and Pilowsky, 2007) concluded that there might be modest increases in the numbers of D 2 receptors in the brains of schizophrenics, but that it seems unlikely that these increases are the primary cause of the disorder. 42 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • The discovery of drugs that reduce or eliminate the symptoms of schizophrenia has had a revolutionary effect on the treatment of this disorder. • But for many years, all the drugs commonly used to treat schizophrenia caused at least some symptoms resembling those of Parkinson’s disease: slowness in movement, lack of facial expression, and general weakness. • For most patients, these symptoms were temporary. • Unfortunately, a more serious side effect occurred in approximately one-third of all patients who took the “classic” antipsychotic drugs for an extended period. 43 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • Individuals with schizophrenia may develop symptoms of a neurological disorder called tardive dyskinesia. • Tardus means “slow,” and dyskinesia means “faulty movement”; thus, tardive dyskinesia is a late-developing movement disorder. • Tardive Dyskinesia • a movement disorder that can occur after prolonged treatment with antipsychotic medication; characterized by involuntary movements of the face and neck 44 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • Tardive dyskinesia appears to be the opposite of Parkinson's disease. • Whereas patients with Parkinson's disease have difficulty moving, patients with tardive dyskinesia are unable to stop moving. • Indeed, dyskinesia commonly occurs when patients with Parkinson's disease receive too much L-DOPA. 45 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • The accepted explanation for tardive dyskinesia has been a phenomenon known as supersensitivity—a compensatory mechanism in which some types of receptors become more sensitive if they are inhibited for a period of time by a drug that blocks them. • Presumably, when D 2 receptors in the caudate nucleus and putamen are chronically blocked by an antipsychotic drug, they become supersensitive, which in some cases overcompensates for the effects of the drug, causing the neurological symptoms to occur. 46 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • Fortunately, the wish expressed by Larry’s physician has come true. Researchers have discovered medications that treat the symptoms of schizophrenia without producing neurological side effects, and it appears that tardive dyskinesia has become a thing of the past. • Better yet, these drugs, the atypical antipsychotic medications, reduce both the positive symptoms and negative symptoms—even those of many patients who were not significantly helped by the older antipsychotic drugs. Clozapine, the first of the atypical antipsychotic medications, has been joined by several others, including risperidone, olanzapine, ziprasidone, and aripiprazole. 47 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Consequences of Long-Term Drug Treatment of Schizophrenia • Clozapine • an atypical antipsychotic drug; blocks D 4 receptors in the nucleus accumbens 48 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Schizophrenia as a Neurological Disorder • So far, I have been discussing the physiology of the positive symptoms of schizophrenia—principally, hallucinations, delusions, and thought disorders. • These symptoms could very well be related to one of the known functions of dopaminergic neurons: reinforcement. 49 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Schizophrenia as a Neurological Disorder • But the negative and cognitive symptoms of schizophrenia are very different. • Whereas the positive symptoms are unique to schizophrenia (and to amphetamine or cocaine psychosis), the negative and cognitive symptoms are similar to those produced by brain damage caused by several different means. 50 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Schizophrenia as a Neurological Disorder • There appear to be three possibilities: • Predisposing factors (genetic, environmental, or both) give rise to: • 1) abnormalities in both DA transmission and in the prefrontal cortex • 2) abnormalities in DA transmission that cause abnormalities in the prefrontal cortex • 3) abnormalities in the prefrontal cortex that cause abnormalities in DA transmission 51 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Brain Abnormalities in Schizophrenia • Although schizophrenia has traditionally been labeled a psychiatric disorder, most patients with schizophrenia exhibit neurological symptoms that suggest the presence of brain damage—in particular, the symptoms categorized as negative symptoms and cognitive symptoms. • Although these symptoms can be caused by a variety of neuropathological conditions and hence are not unique to schizophrenia, their presence suggests that schizophrenia may be associated with brain damage (or perhaps abnormal brain development) of some kind. 52 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Brain Abnormalities in Schizophrenia • Many studies have found evidence of loss of brain tissue in CT and MRI scans of schizophrenic patients. In one of the earliest studies, Weinberger and Wyatt (1982) obtained CT scans of eighty chronic schizophrenics and sixty-six normal controls of the same mean age (twenty-nine years). • Without knowledge of the patients’ diagnoses, researchers measured the area of the lateral ventricles in the scan that cut through them at their largest extent, and they expressed this area relative to the area of brain tissue in the same scan. 53 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Brain Abnormalities in Schizophrenia • The relative ventricle size of the schizophrenic patients was more than twice as great as that of normal control subjects. (See Figure 16.3.) • The most likely cause of the enlarged ventricles is loss of brain tissue; thus, the scans provide evidence that chronic schizophrenia is associated with brain abnormalities. 54 COPYRIGHT © ALLYN & BACON 2012 Figure 16.3, page 559 55 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Brain Abnormalities in Schizophrenia • In fact, Hulshoff-Pol et al. (2002) found that although everyone loses some cerebral gray matter as they age, the rate of tissue loss is greater in schizophrenic patients. (See Figure 16.4.) 56 COPYRIGHT © ALLYN & BACON 2012 Figure 16.4, page 559 57 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Brain Abnormalities in Schizophrenia • Gutierrez-Galvo et al. (2010) found that both patients with schizophrenia and their nonschizophrenic relatives showed loss of gray matter in the frontal and temporal cortex, suggesting that genetic factors affected cortical development and increased susceptibility to factors that cause schizophrenia. • Presumably, the nonschizophrenic relatives did not encounter these factors. 58 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Possible Causes of Brain Abnormalities • As we saw earlier, schizophrenia is a heritable disease, but its heritability is less than perfect. • Why do fewer than half the children of parents with chronic schizophrenia become schizophrenic? • Perhaps what is inherited is a defect that renders people susceptible to some environmental factors that adversely affect brain development or cause brain damage later in life. 59 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Possible Causes of Brain Abnormalities • According to this hypothesis, having some “schizophrenia genes” makes a person more likely to develop schizophrenia if he or she is exposed to these factors. • In other words, schizophrenia is caused by an interaction between genetic and environmental factors. • But as we shall see, the absence of “schizophrenia genes” does not guarantee that a person will not develop schizophrenia; some cases of schizophrenia occur even in families with no history of schizophrenia or related mental illnesses. 60 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Epidemiology is the study of the distribution and causes of diseases in populations. • Epidemiology • the study of the distribution and causes of diseases in populations • Epidemiological studies examine the relative frequency of diseases in groups of people in different environments and try to correlate the disease frequencies with factors that are present in these environments. 61 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Evidence from these studies indicates that the incidence of schizophrenia is related to several environmental factors: season of birth, viral epidemics, population density, prenatal malnutrition, maternal stress, and substance abuse (Brown and Derkits, 2010; King, St-Hilaire, and Heidkamp, 2010). 62 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Many studies have shown that people born during the late winter and early spring are more likely to develop schizophrenia—a phenomenon known as the seasonality effect. • Seasonality Effect • the increased incidence of schizophrenia in people born during late winter and early spring 63 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • For example, Kendell and Adams (1991) studied the month of birth of over 13,000 schizophrenic patients born in Scotland between 1914 and 1960. • They found that disproportionately more patients were born in February, March, April, and May. (See Figure 16.5.) 64 COPYRIGHT © ALLYN & BACON 2012 Figure 16.5, page 560 65 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • These results have been confirmed by studies in several parts of the Northern Hemisphere (Davies et al., 2003). • In the Southern Hemisphere, some studies have reported that a disproportionate number of schizophrenic births take place during late winter and early spring—during the months of August through December—while others have found no effect (McGrath and Welham, 1999). 66 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Several studies have found that the seasonality effect occurs primarily in cities, but is rarely found in the countryside. • In fact, the likelihood of developing schizophrenia is approximately three times higher in people who live in the middle of large cities than in those who live in rural areas (Eaton, Mortensen, and Frydenberg, 2000). 67 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Because vitamin D plays an important role in brain development, this deficiency may be a risk factor for schizophrenia. • These considerations suggest that at least some of the increased incidence of schizophrenia in city dwellers and those who live in cold climates may be attributable to a vitamin D deficiency. 68 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Some investigators have suggested that with the increased use of sunscreens, which can reduce the production of vitamin D by the skin by up to 98 percent, people should take daily vitamin D supplements to compensate for the decreased absorption of ultraviolet radiation by the skin (Tavera-Mendoza and White, 2007). 69 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • Another prenatal effect was discovered by Susser and his colleagues (Susser and Lin, 1992; Susser et al, 1996), who found a twofold increase in the incidence of the offspring of women who were pregnant during the Hunger Winter, a severe food shortage that occurred in the Netherlands when Germany blockaded the country during World War II. • Davis and Bracha (1996) suggest that the specific cause of the famine-related schizophrenia may have been a thiamine deficiency—or, more precisely, an abrupt buildup of toxins in the brains of the developing fetuses when their mothers suddenly began eating a normal diet when the blockade ended in May 1945. 70 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • As we saw in Chapter 14, sudden refeeding after a thiamine deficiency can cause brain damage. Other studies have shown that underweight women are more likely to give birth to babies who later develop schizophrenia and that low birth-weight babies have a higher incidence of schizophrenia (Kunugi, Nanko, and Murray, 2001; Wahlbeck et al., 2001). 71 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Epidemiological Studies • A final environmental risk factor for development of schizophrenia is maternal substance abuse—particularly smoking. • Zammit et al. (2009) studied the effects of maternal use of tobacco, cannabis, or alcohol during pregnancy and found that tobacco use was associated with increased risk. 72 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Complications of Pregnancy and Childbirth • Good evidence indicates that obstetric complications can also cause schizophrenia. • In fact, several studies have found that if a schizophrenic person does not have relatives with a schizophrenic disorder, that person is more likely to have had a history of complications at or around the time of childbirth, and the person is more likely to develop the schizophrenic symptoms at an earlier age. 73 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Complications of Pregnancy and Childbirth • A meta-analysis of eight studies by Cannon, Jones, and Murray (2002) found that the most important factors are complications of pregnancy, including diabetes of the mother, Rh incompatibility between mother and fetus, bleeding, and preeclampsia (also known as toxemia, a condition characterized by high blood pressure, edema, and protein in the urine); abnormal fetal development, including low birth weight, congenital malformations, and reduced head circumference; and complications of labor and delivery, including emergency Caesarean section, atonic (flabby) uterus, and fetal oxygen deprivation. • According to Boksa (2004), the most important characteristic of complications of labor and delivery is interruption of the blood flow or oxygen supply to the brain. 74 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Both behavioral and anatomical evidence indicates that abnormal prenatal development is associated with schizophrenia. • Let’s first considerable behavioral evidence. Walker and her colleagues (Walker, Savoie, and Davis, 1994; Walker, Lewine, and Neumann, 1996) obtained home movies from families with a schizophrenic child. 75 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • They had independent observers examine the behavior of the children. • In comparison with their normal siblings, the children who subsequently became schizophrenic displayed more negative affect in their facial expressions and were more likely to show abnormal movements. 76 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Minor physical anomalies, such as a high-steepled palate or especially wide-set or narrow-set eyes, have also been shown to be associated with the incidence of schizophrenia (Schiffman et al., 2002). (See Table 16.2.) • These differences were first reported in the late nineteenth century by Kraepelin, one of the pioneers in schizophrenia research. 77 COPYRIGHT © ALLYN & BACON 2012 Figure 16.2, page 562 78 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • As Schiffman and his colleagues note, these anomalies provide evidence of factors that have adverse effects on development. • They found that people with schizophrenic relatives normally have an 11.9 percent likelihood of developing schizophrenia. • This likelihood increases to 30.8 percent in people who also have minor physical anomalies; thus, the factors that produce minor physical anomalies are at least partly independent of the genetic factors associated with schizophrenia. 79 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Suddath et al. (1990) obtained evidence that differences in the structure of the brain may reflect this discordance. • The investigators examined MRI scans of monozygotic twins who were discordant for schizophrenia and found that in almost every case, the twin with schizophrenia had larger lateral and third ventricles. • In addition, the anterior hippocampus was smaller in the schizophrenic twin, and the total volume of the gray matter in the left temporal lobe was reduced. 80 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Figure 16.6 shows a set of MRI scans from a pair of twins; as you can see, the lateral ventricles are larger in the brain of the twin with schizophrenia. (See Figure 16.6.) • As we will see later, research has found that comparison of twins discordant for schizophrenia also provides evidence of degeneration in specific regions of the cerebral cortex. 81 COPYRIGHT © ALLYN & BACON 2012 Figure 16.6, page 563 82 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Thus, because all prenatal factors should be identical, any differences must be a result of factors in the postnatal environment. • However, some investigators have pointed out that the prenatal environment of monozygotic twins is not identical. • In fact, there are two types of monozygotic twins: monochorionic and dichorionic. 83 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • The formation of monozygotic twins occurs when the blastocyst (the developing organism) splits in two—when it clones itself. • If twinning occurs before day 4, the two organisms develop independently, each forming its own placenta. That is, the twins are dichorionic. • The chorion is the outer layer of the blastocyst, which gives rise to the placenta. • If twinning occurs after day 4, the two organisms become monochorionic, sharing a single placenta. (See Figure 16.7.) 84 COPYRIGHT © ALLYN & BACON 2012 Figure 16.7, page 563 85 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • Although studies have found that people who develop schizophrenia show some abnormalities even during childhood, the symptoms of schizophrenia itself rarely begin before late adolescence or early adulthood. • If schizophrenia does begin during childhood, the symptoms are likely to be more severe. • Figure 16.8 shows a graph of the ages of first signs of mental disorder in males and females diagnosed with schizophrenia. (See Figure 16.8.) 86 COPYRIGHT © ALLYN & BACON 2012 Figure 16.8, page 564 87 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • A study by Thompson et al. (2001) found dramatic evidence for loss of cortical gray matter during adolescence in patients with early-onset schizophrenia. • The investigators used structural MRI procedures to measure the volume of the gray matter of the cerebral cortex at two-year intervals in schizophrenic patients and control subjects. 88 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Evidence for Abnormal Brain Development • The investigators found that several regions of the cerebral cortex—especially the dlPFC—were reduced in the schizophrenic twins. (I’ll say more about this part of the brain in the next subsection.) • The colors “warmer” than blue in the scans shown in Figure 16.9 indicate regions where the mean difference between the schizophrenic and nonschizophrenic twins was statistically significant. (See Figure 16.9.) 89 COPYRIGHT © ALLYN & BACON 2012 Figure 16.9, page 565 90 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • As we saw, schizophrenia has positive, negative, and cognitive symptoms. • The positive symptoms may be caused by hyperactivity of dopaminergic synapses, and the negative and cognitive symptoms may be caused by developmental or degenerative changes in the brain. • Is there a relationship between these categories of schizophrenic symptoms? • An accumulating amount of evidence suggests that the answer is yes. 91 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • The evidence reviewed in the previous subsection indicates that schizophrenia is associated with abnormalities in many parts of the brain, especially the prefrontal cortex. • Weinberger (1988) first suggested that the negative symptoms of schizophrenia are caused primarily by hypofrontality, decreased activity of the frontal lobes—in particular, of the dlPFC. • Hypofrontality • decreased activity of the prefrontal cortex; believed to be responsible for the negative symptoms of schizophrenia 92 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • Many studies have shown that schizophrenic patients do poorly on neuropsychological tests that are sensitive to prefrontal damage. • Figure 16.10 shows composite functional MRI scans from a study by MacDonald et al. (2005) of subjects with schizophrenia and normal comparison subjects taken while the people were performing a task that required concentration and focused attention. • As you can see, the dlPFC was activated in the normal subjects but not in the subjects with schizophrenia. (See Figure 16.10.) 93 COPYRIGHT © ALLYN & BACON 2012 Figure 16.10, page 565 94 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • What might produce the hypofrontality that so many studies have observed? • As we saw in the discussion of the dopamine hypothesis of schizophrenia, dopamine agonists such as cocaine and amphetamine can cause positive symptoms of schizophrenia. 95 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • Two other drugs, PCP (phencyclidine, also known as “angel dust”) and ketamine (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia (Adler et al., 1999; Lahti et al., 2001; Avila et al., 2002). • Because PCP and ketamine elicit the full range of the symptoms of schizophrenia, many researchers believe that studying the physiological and behavioral effects of these drugs will help to solve the puzzle of schizophrenia. 96 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • The negative and cognitive symptoms produced by ketamine and PCP are apparently caused by a decrease in the metabolic activity of the frontal lobes. • Jentsch et al. (1997) administered PCP to monkeys twice a day for two weeks. • Then, one week later, they tested the animals on a task that involves reaching around a barrier for a piece of food, which is performed poorly by monkeys with lesions of the prefrontal cortex. • Normal monkeys performed well, but those that had been treated with PCP showed a severe deficit. (See Figure 16.11.) 97 COPYRIGHT © ALLYN & BACON 2012 Figure 16.11, page 566 98 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • Abnormalities also began appearing in the mesocortical dopaminergic system that projects to the prefrontal cortex, which resulted in a lower level of dopamine in this region. • While these changes were occurring, behavioral abnormalities resembling those of schizophrenia began to emerge. • These findings suggest that abnormalities in the pyramidal neurons of the prefrontal cortex constitute the primary cause of the process that leads to schizophrenia. (See Figure 16.12.) 99 COPYRIGHT © ALLYN & BACON 2012 Figure 16.12, page 566 100 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • The findings of another study supports a different hypothesis—that abnormalities in the striatal dopaminergic system may constitute the primary cause of the process that leads to schizophrenia. • Lewis, Hashimoto, and Volk (2005) reviewed evidence that the hypofrontality seen in people with schizophrenia appear to be a result of deficits in inhibitory GABAergic transmission in the dlPFC that disrupts normal electrical rhythms generated in this region. 101 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • Li et al. (2011) used a genetically modified viral vector to insert genes in the striatum of mice (including both the dorsal striatum and the nucleus accumbens) that increased the production of D2 dopamine receptors there. • Like the study by Niwa and her colleagues, this procedure caused the development of behavioral deficits characteristic of schizophrenia, including abnormal activity of the dlPFC, caused by a deficit in inhibitory GABAergic transmission in this region. (See Figure 16.13.) 102 COPYRIGHT © ALLYN & BACON 2012 Figure 16.13, page 567 103 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • The atypical antipsychotic drugs seem to do the impossible: They increase dopaminergic activity in the prefrontal cortex and reduce it in the mesolimbic system. • Let’s examine the action of a so-called “third generation” antipsychotic drug, aripiprazole (Winans, 2003; Lieberman, 2004). Aripiprazole acts as a partial agonist at dopamine receptors. 104 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • A partial agonist is a drug that has a very high affinity for a particular receptor but activates that receptor less than the normal ligand does. • Partial Agonist • a drug that has a very high affinity for a particular receptor but activates that receptor less than the normal ligand does; serves as an agonist in regions of low concentration of the normal ligand and as an antagonist in regions of high concentrations 105 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • This means that in a patient with schizophrenia, aripiprazole serves as an antagonist in the mesolimbic system, where too much dopamine is present, but serves as an agonist in regions such as the prefrontal cortex, where too little dopamine is present. • Hence, this action appears to account for the ability of aripiprazole to reduce all three categories of schizophrenic symptoms. (See Figure 16.14.) 106 COPYRIGHT © ALLYN & BACON 2012 Figure 16.14, page 567 107 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex • Schizophrenia is a puzzling and serious disorder, which has stimulated many ingenious hypotheses and much research. • Some hypotheses have been proved wrong; others have not yet been adequately tested. Possibly, future research will find that all of these hypotheses (including the ones I have discussed) are incorrect or that one that I have not mentioned is correct. • However, I am impressed with recent research, and I believe that we have real hope of finding the causes of schizophrenia in the near future. • With the discovery of the causes, we can hope for the discovery of methods of prevention and not just treatment. 108 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • Researchers have made considerable progress in the past few years in their study of the physiology of mental disorders, but many puzzles still remain. • Schizophrenia consists of positive, negative, and cognitive symptoms, the first involving the presence of unusual behavior and the latter two involving the absence or deficiency of normal behavior. • Because schizophrenia is strongly heritable, it must have a biological basis. • Evidence indicates that not all cases are caused by heredity, and many people who appear to carry “schizophrenia genes” do not become schizophrenic. 109 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • Recent evidence suggests that paternal age is a factor in schizophrenia, presumably because of the increased likelihood of mutations in the chromosomes of cells that produce sperms. • A large variety of rare mutations or epigenetic factors may predispose people to schizophrenia, and some investigators suspect that some of the genes that affect susceptibility to schizophrenia are involved in the production of non-coding RNA, which plays important regulatory roles. 110 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • The dopamine hypothesis, which was inspired by the findings that dopamine antagonists alleviate the positive symptoms of schizophrenia and that dopamine agonists increase or even produce them, states that the positive symptoms of schizophrenia are caused by hyperactivity of dopaminergic synapses in the mesolimbic system, which targets the nucleus accumbens and amygdala. • The involvement of dopamine in reinforcement could plausibly explain the positive effects of schizophrenia; inappropriately reinforced thoughts could persist and become delusions. 111 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • There is no evidence that an abnormally large amount of dopamine is released under resting conditions, but PET studies indicate that the administration of amphetamine causes a larger release of dopamine in the brains of schizophrenics. • Evidence indicates that the brains of schizophrenic patients may contain slightly increased numbers of D 2 dopamine receptors, but this increase does not appear to play a primary role in the incidence of schizophrenia. 112 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • The fact that the negative and cognitive symptoms of schizophrenia are not alleviated by “classical” antipsychotic drugs poses an unsolved problem for the dopamine hypothesis. • In addition, these drugs cause parkinsonian side effects (usually temporary) and often, in patients who receive long-term treatment, tardive dyskinesia. 113 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • Atypical antipsychotic drugs, including clozapine, risperidone, olanzapine, ziprasidone, and aripiprazole, are much less likely to produce parkinsonian side effects and apparently do not produce tardive dyskinesia. • In addition, these drugs reduce positive symptoms as well as negative ones, and they reduce the symptoms of some patients who are not helped by traditional antipsychotic medication. 114 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • MRI scans and the presence of signs of neurological impairments indicate the presence of brain abnormalities in schizophrenic patients. • Studies of the epidemiology of schizophrenia indicate that season of birth, viral epidemics during pregnancy, a cold climate, increased population density, and prenatal malnutrition all contribute to the occurrence of schizophrenia. • The most sensitive period appears to occur during the second trimester of pregnancy. A vitamin D deficiency, caused by insufficient exposure to sunlight or insufficient intake of the vitamin itself, may at least partly account for the effects of season of birth, population density, a cold climate, and maternal nutrition. 115 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • Obstetric complications also increase the risk of schizophrenia, even in people who have no family history of the disorder. • In addition, movies of young children who became schizophrenic indicate the early presence of abnormalities in movements and facial expressions. 116 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • More evidence is provided by the presence of an increased size of the third and lateral ventricles and a decreased size of the hippocampus in the schizophrenic member of monozygotic twins who are discordant for schizophrenia. • The increased concordance rate of monochorionic monozygotic twins provides further evidence that hereditary and prenatal environmental factors may interact. 117 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • The symptoms of schizophrenia often emerge soon after puberty, when the brain is undergoing important maturational changes. • Some investigators believe that the disease process of schizophrenia begins prenatally, lies dormant until puberty, and then causes a period of neural degeneration that causes the symptoms to appear. 118 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • The negative symptoms of schizophrenia appear to be a result of hypofrontality (decreased activity of the dorsolateral prefrontal cortex), which may be caused by a decreased release of dopamine in this region. • Schizophrenic patients do poorly on tasks that require activity of the prefrontal cortex, and functional-imaging studies indicate that the prefrontal cortex is hypoactive when the patients attempt to perform these tasks. 119 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • The drugs PCP and ketamine mimic both the positive and negative symptoms of schizophrenia. • Long-term administration of PCP to monkeys disrupts their performance of a reaching task that requires the prefrontal cortex. • Furthermore, the disruption is related to the decrease in prefrontal dopaminergic activity caused by the drug. • Evidence suggests that hypofrontality causes an increase in the activity of dopaminergic neurons in the mesolimbic system, thus producing the positive symptoms of schizophrenia. 120 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • Connections between the prefrontal cortex and the ventral tegmental area appear to be responsible for this phenomenon. • Clozapine reduces hypofrontality, increases monkeys’ performance on the reaching task, decreases the release of dopamine in the ventral tegmental area—and decreases both the positive and negative symptoms of schizophrenia. • An even newer “third generation” antipsychotic drug, aripiprazole, serves as a partial agonist for dopamine receptors, increasing activation of DA receptors in regions that contain little dopamine (such as the prefrontal cortex) and decreasing activation of DA receptors in regions that contain excessive amounts of dopamine (such as the nucleus accumbens). 121 COPYRIGHT © ALLYN & BACON 2012 Schizophrenia Section Summary • PCP and ketamine act as indirect antagonists for NMDA receptors. Glycine, D-serine, and sarcosine, which serve as NMDA receptor agonists, reduce the negative symptoms of schizophrenia, providing further support for the PCP model of this disorder. • Ketamine causes psychotic reactions in adults, but not children. • Similarly, PCP causes brain abnormalities in adult (but not juvenile) rats. • These disparities may be related to the apparent changes in the brain that are responsible for the emergence of the symptoms of schizophrenia after puberty. 122 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders • Affect, as a noun, refers to feelings or emotions. • Just as the primary symptom of schizophrenia is disordered thoughts, the major affective disorders (also called mood disorders) are characterized by disordered feelings. 123 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • Feelings and emotions are essential parts of human existence; they represent our evaluation of the events in our lives. • In a very real sense, feelings and emotions are what human life is all about. • The emotional state of most of us reflects what is happening to us: Our feelings are tied to events in the real world and are usually the result of reasonable assessments of the importance these events have for our lives. • But for some people, affect becomes divorced from reality. 124 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • These people have feelings of extreme elation (mania) or despair (depression) that are not justified by events in their lives. • For example, depression that accompanies the loss of a loved one is normal, but depression that becomes a way of life—and will not respond to the sympathetic effort of friends and relatives or even to psychotherapy—is pathological. • Depression has a prevalence of approximately 3 percent in men and 7 percent in women, which makes it the fourth leading cause of disability (Kessler et al., 2003). 125 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • There are two principal types of major affective disorders. • The first type is characterized by alternating periods of mania and depression—a condition called bipolar disorder. • Bipolar Disorder • a serious mood disorder characterized by cyclical periods of mania and depression 126 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • This disorder afflicts men and women in approximately equal numbers. • Episodes of mania can last a few days or several months, but they usually take a few weeks to run their course. • Bipolar disorder is often severe, disabling, and treatment-resistant (Chen, Henter, and Manji, 2010). • The episodes of depression that follow generally last three times as long as the mania. 127 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • The episodes of depression that follow generally last three times as long as the mania. The second type is major depressive disorder (MDD), characterized by depression without mania. • Major Depressive Disorder (MDD) • a serious mood disorder that consists of unremitting depression or periods of depression that do not alternate with periods of mania • This depression may be continuous and unremitting or, more typically, may come in episodes. 128 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • Severely depressed people usually feel extremely unworthy and have strong feelings of guilt. The affective disorders are dangerous; a person who suffers from a major affective disorder runs a considerable risk of death by suicide. • According to Chen and Dilsaver (1996), 15.9 percent of people with MDD and 29.2 percent of people with bipolar disorder attempt to commit suicide • Schneider, Muller, and Philipp (2001) found that the rate of death by unnatural causes (not all suicides are diagnosed as such) for people with affective disorders was 28.8 times higher than expected for people of the same age in the general population. 129 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • Depressed people have very little energy, and they move and talk slowly, sometimes becoming almost torpid. • At other times, they may pace around restlessly and aimlessly. • They may cry a lot. • They are unable to experience pleasure and lose their appetite for food and sex. Their sleep is disturbed; they usually have difficulty falling asleep and awaken early and find it difficult to get to sleep again. Even their body functions become depressed; they often become constipated, and secretion of saliva decreases. 130 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • Episodes of mania are characterized by a sense of euphoria that does not seem to be justified by circumstances. • The diagnosis of mania is partly a matter of degree; one would not call exuberance and a zest for life pathological. • People with mania usually exhibit nonstop speech and motor activity. 131 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Description • Manic people flit from topic to topic and often have delusions, but they lack the severe disorganization that is seen in schizophrenia. • They are usually full of their own importance and often become angry or defensive if they are contradicted. • Frequently, they go for long periods without sleep, working furiously on projects that are often unrealistic. 132 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Heritability • Evidence indicates that a tendency to develop an affective disorder is a heritable characteristic. (See Hamet and Tremblay, 2005, for a review.) • For example, Rosenthal (1971) found that close relatives of people who suffer from affective psychoses are ten times more likely to develop these disorders than are people without afflicted relatives. • Gershon et al. (1976) found that if one member of a set of monozygotic twins was afflicted with an affective disorder, the likelihood that the other twin was similarly afflicted was 69 percent. In contrast, the concordance rate for dizygotic twins was only 13 percent. • The heritability of the affective disorders implies that they have a physiological basis. 133 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Heritability • A review of genome-wide association studies (Terracciano et al., 2010) found that the RORA gene, involved in control of circadian rhythms, had the strongest association with the occurrence of major depressive disorder. • Evidence suggested that another gene, GRM8, which codes for the production of a metabolic glutamate receptor, may also be involved. McGrath et al. (2009) found that RORB, another clock gene, was associated with rapid cycling bipolar disorder seen in children. • As we sill see later in this chapter, disturbances in sleep and circadian rhythms may play a role in the development of affective disorders. 134 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Season of Birth • As we saw in the discussion of schizophrenia earlier in this chapter, season of birth plays a significant role in the incidence of schizophrenia. • In particular, people born in late winter and early spring are more likely to develop schizophrenia than people born at other times. • One suggested explanation for this phenomenon is the fact that the second trimester of pregnancy—a critical time of fetal development—coincides with winter flu season. 135 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Season of Birth • A seasonality effect—but a different one—is seen in the incidence of major depression. • Döme et al. (2010) examined the season of birth of 80,000 people who committed suicide in Hungary in the 1930s, early-to-mid 1940s, and 1969. (Hungary has one of the highest rates of suicide in the world.) • The incidence of suicide was significantly higher in summer, with a peak in July. (See Figure 16.15.) • So far, there is no explanation for this phenomenon. 136 COPYRIGHT © ALLYN & BACON 2012 Figure 16.15, page 571 137 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • There are several established and experimental biological treatments for major depressive disorder: monoamine oxidase (MAO) inhibitors, drugs that inhibit the reuptake of norepinephrine or serotonin or interfere with NMDA receptors, electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, bright-light therapy (phototherapy), and sleep deprivation. (Phototherapy and sleep deprivation are discussed in a later section of this chapter.) 138 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Bipolar disorder can be treated by lithium and some anticonvulsant drugs. • The fact that these disorders often respond to biological treatment provides additional evidence that they have a physiological basis. • Furthermore, the fact that lithium is effective in treating bipolar affective disorder but not major depressive disorder suggests that there is a fundamental difference between these two illnesses (Soares and Gershon, 1998). 139 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Before the 1950s, there was no effective drug treatment for depression. In the late 1940s, clinicians noticed that some drugs used for treating tuberculosis seemed to elevate the patient’s mood. • Researchers subsequently found that a derivative of these drugs, iproniazid, reduced symptoms of psychotic depression (Crane, 1957). 140 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Iproniazid inhibits the activity of MAO, which destroys excess monoamine transmitter substances within terminal buttons. • Thus, the drug increases the release of dopamine, norepinephrine, and serotonin. Other MAO inhibitors were soon discovered. • Unfortunately, MAO inhibitors can have harmful side effects, so they must be used with caution. 141 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Fortunately, another class of antidepressant drugs was soon discovered that did not have these side effects: the tricyclic antidepressants. • Tricyclic Antidepressant • a class of drugs used to treat depression; inhibits the reuptake of norepinephrine and serotonin but also affects other neurotransmitters; named for the molecular structure • These drugs were found to inhibit the reuptake of 5-HT and norepinephrine by terminal buttons. 142 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • By retarding reuptake, the drugs keep the neurotransmitter in contact with the postsynaptic receptors, thus prolonging the postsynaptic potentials. • Thus, both the MAO inhibitors and the tricyclic antidepressant drugs are monoaminergic agonists. 143 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Since the discovery of the tricyclic antidepressants, other drugs have been discovered that have similar effects. • The most important of these are the specific serotonin reuptake inhibitors (SSRI), whose action is described by their name. • Specific Serotonin Reuptake Inhibitor (SSRI) • an antidepressant drug that specifically inhibits the reuptake of serotonin without affecting the reuptake of other neurotransmitters 144 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • These drugs (for example, fluoxetine [Prozac], citalopram [Celexa], and paroxetine [Paxil]) are widely prescribed for their antidepressant properties and for their ability to reduce the symptoms of obsessive-compulsive disorder and social phobia (described in Chapter 17). 145 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Another class of antidepressant drugs has been developed, the serotonin and norepinephrine reuptake inhibitors (SNRI), which also do what their name indicates. • Norepinephrine and Serotonin Reuptake Inhibitor (SNRI) • an antidepressant drug that specifically inhibits the reuptake of norepinephrine and serotonin without affecting the reuptake of other neurotransmitters • These include milnacipran, duloxetine, and venlafaxine, with relative effects on 5-HT and noradrenergic transporters of 1:1, 1:10, and 1:30, respectively (Stahl et al., 2005). • SSRIs and SNRIs have fewer nonspecific actions, and therefore fewer side effects, than the tricyclic antidepressants. 146 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Cerletti tried the procedure on dogs. • He then used the procedure on humans and found it to be safer than the chemical treatment that was previously used. • As a result of Cerletti’s experiments, electroconvulsive therapy (ECT) became a common treatment for mental illness. • Electroconvulsive Therapy (ECT) • a brief electrical shock, applied to the head, that results in an electrical seizure; used therapeutically to alleviate severe depression 147 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Before a person receives ECT, he or she is anesthetized and is given a drug similar to curare, which paralyzes the muscles, preventing injuries that might be produced by a convulsion. (Of course, the patient is attached to a respirator until the effects of this drug wear off.) • Electrodes are placed on the patient’s scalp (most often to the non-speech-dominant hemisphere, to avoid damaging verbal memories), and a jolt of electricity triggers a seizure. 148 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Usually, a patient receives three treatments per week until maximum improvement is seen, which usually involves six to twelve treatments. • The effectiveness of ECT has been established by placebo studies, in which some patients are anesthetized but not given shocks (Weiner and Krystal, 1994). • Although ECT was originally used for a variety of disorders, including schizophrenia, we now know that its usefulness is limited to treatment of mania and depression. (See Figure 16.16.) 149 COPYRIGHT © ALLYN & BACON 2012 Figure 16.16, page 572 150 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Between 20 and 40 percent of patients with major depressive disorder do not show a significant response to initial treatment with an antidepressant drug. • When patients do not respond, physicians will try different drugs. Some of these patients do eventually respond, but others do not and exhibit treatment-resistant depression. • Treatment-Resistant Depression • a major depressive disorder whose symptoms are not relieved after trials of several different treatments 151 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • The reason that the list of biological treatments presented in the first paragraph of this section is so long is because no single treatment works for all patients—and for some patients, no treatment works at all. • The existence of so many patients with treatment-resistant depression has motivated researchers to try to develop ways to alleviate the symptoms of patients who continue to suffer. 152 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Researchers have investigated another procedure designed to provide some of the benefits of ECT without introducing the risk of cognitive impairments or memory loss. • As we saw in Chapter 5, transcranial magnetic stimulation (TMS) is accomplished by applying a strong localized magnetic field into the brain by passing an electrical current through a coil of wire placed on the scalp. 153 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • The magnetic field induces an electrical current in the brain. • Several studies suggested that TMS applied to the prefrontal cortex reduces the symptoms of depression without producing any apparent negative side effects ( Padberg and Moller, 2003; Fitzgerald, 2004; Kito, Hasegawa, and Koga, 2011). • Most studies show a response rate of less than 30 percent, and long-term relapse rates appear to be similar to those seen with ECT (Holtzheimer and Mayberg, 2011). 154 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • As we saw in Chapter 15, direct electrical stimulation of the brain of the subthalamic nucleus provides significant relief of the symptoms of Parkinson’s disease. • Preliminary research also suggests that deep brain stimulation (DBS) may also be a useful therapy for treatment-resistant depression (Mayberg et al., 2005; Lozano et al., 2008). 155 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Mayberg and her colleagues implanted electrodes just below the subgenual anterior cingulate cortex (subgenual ACC), a region of the medial prefrontal cortex. • Subgenual Anterior Cingulate Cortex (subgenual ACC) • a region of the medial prefrontal cortex located below the “knee” at the front of the corpus callosum; plays a role in the symptoms of depression 156 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • If you look at a sagittal view of the corpus callosum, you will see that the front of this structure looks like a bent knee—genu, in Latin. • The subgenual ACC is located below the “knee” at the front of the corpus callosum. Response to the stimulation began soon, and it increased with time. • One month after surgery, 35 percent of the patients showed an improvement in symptoms, and 10 percent showed a complete remission. • Six months after surgery, sixty percent showed improvement, and thirty-five percent showed remission. 157 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • As I mentioned earlier, most antidepressant drugs currently in use act as noradrenergic or serotonergic agonists by inhibiting the reuptake of these neurotransmitters. • Evidence shows that an NMDA antagonist, ketamine, may alleviate the symptoms of treatment-resistant depression. • Research with laboratory animals found that injections of ketamine reduced behaviors similar to those seen in depressed humans, and imaging studies with humans suggested that depressed patients showed increased brain levels of glutamate, which suggests that interference with glutamatergic transmission might have therapeutic effects (Yilmaz et al., 2002; Sanacora et al., 2004). 158 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Zarate et al., (2006) administered injections of ketamine or placebo to patients with treatment-resistant depression. • In less than 2 hours after the ketamine injections, 71 percent of the patients showed an improvement in their symptoms, and 29 percent showed a remission of their symptoms. This positive response persisted for at least one week. (See Figure 16.17.) 159 COPYRIGHT © ALLYN & BACON 2012 Figure 16.17, page 574 160 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • The therapeutic effect of lithium, the drug used to treat bipolar affective disorders, is very rapid. • Lithium • A chemical element: lithium carbonate is used to treat bipolar disorder. • This drug, which is administered in the form of lithium carbonate, is most effective in treating the manic phase of a bipolar affective disorder; once the mania is eliminated, depression usually does not follow (Gerbino, Oleshansky, and Gershon, 1978; Soares and Gershon, 1998). 161 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Some clinicians and investigators have referred to lithium as psychiatry’s wonder drug: It does not suppress normal feelings of emotions, but it leaves patients able to feel and express joy and sadness in response to events in their lives. • Similarly, it does not impair intellectual processes; many patients have received the drug continuously for years without any apparent ill effects (Fieve, 1979). • Between 70 and 80 percent of patients with bipolar disorder show a positive response to lithium within 1–2 weeks (Price and Heninger, 1994). 162 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Researchers have found that lithium has many physiological effects, but they have not yet discovered the pharmacological effects of lithium that are responsible for its ability to eliminate mania (Phiel and Klein, 2001). • Some researchers suggest that the drug stabilizes the population of certain classes of neurotransmitter receptors in the brain (especially serotonin receptors), thus preventing wide shifts in neural sensitivity (Jope et .al., 1996) 163 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Biological Treatments • Others have shown that lithium may increase the production of neuroprotective proteins that help to prevent cell death (Manji, Moore, and Chen, 2001). • In fact, Moore et al. (2000) found that four weeks of lithium treatment for bipolar disorder increased the volume of cerebral gray matter in the patients’ brains, a finding that suggests that lithium facilitates neural or glial growth. 164 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders The Monoamine Hypothesis • The fact that depression can be treated with MAO inhibitors and drugs that inhibit the reuptake of monoamines suggested the monoamine hypothesis: Depression is caused by insufficient activity of monoaminergic neurons. • Monoamine Hypothesis • a hypothesis that states that depression is caused by a low level of activity of one or more monoaminergic synapses • Because the symptoms of depression are not relieved by potent dopamine agonists such as amphetamine or cocaine, most investigators have focused their research efforts on the other two monoamines: norepinephrine and serotonin. 165 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders The Monoamine Hypothesis • Delgado et al. (1990) developed an ingenious approach to study of the role of serotonin in depression: the tryptophan depletion procedure. • Tryptophan Depletion Procedure • a procedure involving a low-tryptophan diet and a tryptophan-free amino acid “cocktail” that lowers brain tryptophan and consequently decreases the synthesis of 5-HT • They studied depressed patients who were receiving antidepressant medication and were currently feeling well. • For one day, they had the patients follow a low-tryptophan diet (for example, salad, corn, cream cheese, and a gelatin dessert). 166 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders The Monoamine Hypothesis • Then the next day, the patients drank an amino acid “cocktail” that contained no tryptophan. • The uptake of amino acids through the blood–brain barrier is accomplished by amino acid transporters. • Because the patients’ blood level of tryptophan was very low and that of the other amino acids was high, very little tryptophan found its way into the brain, and the level of tryptophan in the brain fell drastically. • Thus, the treatment lowered the level of serotonin in the brain. 167 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the 5-HT Transporter • Several studies have accumulated evidence that implicates the serotonin transporter in depression. • A portion of the gene—the promoter region—for the 5-HT transporter (5-HTT) comes in two forms, short and long. • A longitudinal study by Caspi et al. (2003) followed 847 people over a period of more than 20 years, starting at 3 years of age, and recorded the occurrence of stressful events in their lives, including abuse during childhood, romantic disasters, bereavements, illnesses, and job crises. 168 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the 5-HT Transporter • The investigators found that the probability of major depression and suicidality increased with the number of stressful life events the people had experienced. • Moreover, the increase was much greater for people with one or two copies of the short alleles for the 5-HTT promoter. • This study showed evidence of an interaction between environment and genetics. (See Figure 16.18.) 169 COPYRIGHT © ALLYN & BACON 2012 Figure 16.18, page 576 170 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the 5-HT Transporter • The results of many other studies suggested that the 5-HTT promoter played an important role in the development of depression. • For example, Rausch et al. (2002) found that depressed people with two long alleles for this gene were more likely to respond to treatment with an antidepressant drug than were those with one or two short alleles. 171 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the 5-HT Transporter • In fact, people with two long alleles were even more likely to respond to the placebo. • A study by Lee et al. (2004) found that depressed people with two long alleles who were treated with antidepressant drugs had a much better long-term outcome (up to three years) than did people with one or two short alleles. • Neumeister et al. (2002) found that tryptophan depletion was more likely to produce symptoms of depression in people with one or two short alleles. 172 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the 5-HT Transporter • Unfortunately, several meta-analyses of the studies investigating a possible role of the 5HTT promoter in depression have concluded that although some studies have found positive effects, when the results of all published studies are combined, no significant effects emerged (Risch et al., 2009; Taylor, Sen, and Bhagwagar, 2010; Vovoamo et al., 2010). • Until further research shows otherwise, it appears that a role of the 5-HTT promoter in depression is unproven. 173 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the Frontal Cortex • Mayberg and her colleagues (Mayberg et al., 2005; Mayberg, 2009; Holtzheimer and Mayberg, 2011) suggest that the frontal cortex plays a critical role in development of depression. • In particular, they hypothesize that the subgenual ACC serves as an important focal point in a network of brain regions that are involved in the regulation of mood, and that a decrease in the activity of this region is consistently seen after successful antidepressant treatment. 174 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the Frontal Cortex • Figure 16.19 shows functional imaging scans of patients with treatment-resistant depression taken before deep brain stimulation of the subgenual ACC (a), after three months of DBS (b), and after six months of DBS (c). Increases are shown in red, and decreases are shown in blue. • As you can see, the subgenual ACC initially was hyperactive, but after DBS successfully reduced symptoms of depression, this region decreased its activity. 175 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the Frontal Cortex • The responses are redrawn from the scans published in Mayberg et al. (2005) on a drawing of a midsagittal view of the brain. • Changes in activity that were seen in more lateral regions of the prefrontal cortex are not shown. (See Figure 16.19.) 176 COPYRIGHT © ALLYN & BACON 2012 Figure 16.19, page 577 177 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of the Frontal Cortex • Figure 16.20 shows the results of functional imaging scans of the medial frontal region of depressed patients who were successfully treated with a variety of treatments, including DBS; transcranial magnetic stimulation (TMS) of the prefrontal cortex; ECT; vagus nerve stimulation (VNS); and administration of an SSRI, an SNRI, and a placebo. • Successful treatment led to decreased activity in the subgenual ACC. • As in Figure 16.19, increases in activity after successful treatment are shown in red; decreases are shown in blue. (See Figure 16.20.) 178 COPYRIGHT © ALLYN & BACON 2012 Figure 16.20, page 578 179 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Neurogenesis • As we saw in Chapters 3 and 13, neurogenesis can take place in the dentate gyrus—a region of the hippocampal formation—in the adult brain. • Several studies with laboratory animals have shown that stressful experiences that produce the symptoms of depression suppress hippocampal neurogenesis, and the administration of antidepressant treatments—including MAO inhibitors, tricyclic antidepressants, SSRIs, ECT, and lithium—increases neurogenesis. 180 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Neurogenesis • In addition, the delay in the action of antidepressant treatments is about the same length as the time it takes for newborn neurons to mature. • Moreover, if neurogenesis is suppressed by a low-level dose of X-radiation, antidepressant drugs lose their effectiveness. (See Samuels and Hen, 20011, for a review.) • There is currently no way to measure the rate of neurogenesis in the human brain. • So far, all the evidence about human neurogenesis has been by extrapolation from studies with laboratory animals. 181 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Neurogenesis • However, a study by Pereira et al. (2007) used an MRI procedure that permitted them to estimate the blood volume of particular regions of the hippocampal formation in both mice and humans. • They found that exercise (running wheels for the mice, an aerobic exercise regimen for humans) increased the blood volume of the dentate gyrus—the region where neurogenesis takes place—in both species. (As we will see in the next section of this chapter, exercise is an effective treatment for depression.) 182 COPYRIGHT © ALLYN & BACON 2012 Figure 16.21, page 579 183 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Circadian Rhythms • One of the most prominent symptoms of depression is disordered sleep. • The sleep of people with depression tends to be shallow; slow-wave delta sleep (stages 3 and 4) is reduced, and stage 1 is increased. • Sleep is fragmented; people tend to awaken frequently, especially toward the morning. • In addition, REM sleep occurs earlier, the first half of the night contains a higher proportion of REM periods, and REM sleep contains an increased number of rapid eye movements (Kupfer, 1976; Vogel et al., 1980). (See Figure 16.22.) 184 COPYRIGHT © ALLYN & BACON 2012 Figure 16.22, page 579 185 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Circadian Rhythms • Evidence also suggests that up to 90 percent of people who experience an episode of depression report changes in their patterns of sleep and usually have difficulty initiating and maintaining a good night’s sleep (Wulff et al., 2010). • In addition, persistent insomnia in a person with a history of depressive episodes increases the risk of relapsing into another one—too, sleep disruption experienced by new mothers increases the risk of post-partum depression (Posmontier, 2008). 186 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders REM Sleep Deprivation • One of the most effective antidepressant treatments is sleep deprivation, either total or selective. • Selective deprivation of REM sleep, accomplished by monitoring people’s EEG and awakening them whenever they show signs of REM sleep, alleviates depression (Vogel et al., 1975; Vogel et al., 1990). • The therapeutic effect, like that of the antidepressant medications, occurs slowly, over the course of several weeks. 187 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders REM Sleep Deprivation • Some patients show long-term improvement even after the deprivation is discontinued; thus, it is a practical as well as an effective treatment. • In addition, regardless of their specific pharmacological effects, other treatments for depression suppress REM sleep, delaying its onset and decreasing its duration (Scherschlicht et al., 1982; Vogel et al., 1990; Grunhaus et al., 1997; Thase, 2000). 188 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders REM Sleep Deprivation • These facts suggest that REM sleep and mood might somehow be causally related. • These results suggest that an important effect of successful antidepressant treatment may be to suppress REM sleep, and the changes in mood may be a result of this suppression. • However, at least one antidepressant drug has been shown in a double-blind, placebocontrolled study not to suppress REM sleep (Mayers and Baldwin, 2005). • Thus, suppression of REM sleep cannot be the only way in which antidepressant drugs work. 189 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Slow-Wave Sleep Deprivation • Another form of selective sleep deprivation, slow-wave sleep deprivation (SWS deprivation), effectively reduces depressive symptoms in some patients. • A trial study by Landsness et al. (2011) had people with major depressive disorder sleep in a laboratory equipped with EEG monitoring equipment. • Whenever slow waves appeared in a person’s EEG, the investigators presented sounds that suppressed the slow waves without waking the person up. 190 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Slow-Wave Sleep Deprivation • The results were promising: self-rated symptoms of depression decreased in most of the patients. (See Figure 16.23.) • Although the investigators did not directly manipulate REM sleep, SWS deprivation also affected the percentage of total sleep time spent in REM sleep. • In fact, decreases in REM sleep were positively correlated with decreases in ratings of depressive symptoms. 191 COPYRIGHT © ALLYN & BACON 2012 Figure 16.23, page 579 192 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Slow-Wave Sleep Deprivation • Thus, it is possible that the beneficial results of SWS deprivation were actually produced by suppression of REM sleep. • However, REM sleep deprivation usually produces a therapeutic effect over the course of several weeks, and the benefits in this study occurred after just one night of SWS deprivation. • This promising approach appears to deserve further study. 193 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Total Sleep Deprivation • Total sleep deprivation also has an antidepressant effect. • Unlike specific deprivation of REM sleep, which takes several weeks to reduce depression, total sleep deprivation produces immediate effects (Wu and Bunney, 1990). • Typically, the depression is lifted by the sleep deprivation but returns the next day, after a normal night’s sleep. • In fact, ketamine treatment and total sleep deprivation are the only treatments that produce an immediate (but transient) effect. 194 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Total Sleep Deprivation • Wu and Bunney suggest that during sleep, the brain produces a chemical that has a depressogenic effect in susceptible people. • During waking, this substance is gradually metabolized and hence inactivated. Some of the evidence for this hypothesis is presented in Figure 16.24. • The data are taken from eight different studies (cited by Wu and Bunney, 1990) and show self-ratings of depression of people who did and did not respond to sleep deprivation. • Total sleep deprivation improves the mood of patients with major depression approximately two-thirds of the time. (See Figure 16.24.) 195 COPYRIGHT © ALLYN & BACON 2012 Figure 16.24, page 580 196 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Total Sleep Deprivation • Although total sleep deprivation is not a practical method for treating depression (it is obviously impossible to keep people awake indefinitely), several studies suggest that partial sleep deprivation can hasten the beneficial effects of antidepressant drugs. • For example, Leibenluft et al. (1993) found that depriving treatment-resistant patients of sleep either early or late in the night facilitated treatment with antidepressant medication. • Some investigators have found that intermittent total sleep deprivation (say, twice a week for four weeks) can have beneficial results (Papadimitriou et al., 1993). 197 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • Yet another phenomenon relates depression to sleep and waking—or, more specifically, to the mechanisms that are responsible for circadian rhythms. • Some people become depressed during the winter season, when days are short and nights are long (Rosenthal et al., 1984). 198 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • The symptoms of this form of depression, called seasonal affective disorder (SAD), are somewhat different from those of major depression; both forms include lethargy and sleep disturbances, but seasonal depression includes a craving for carbohydrates and an accompanying weight gain. • Seasonal Affective Disorder (SAD) • a mood disorder characterized by depression, lethargy, sleep disturbances, and craving for carbohydrates during the winter season when days are short 199 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • SAD, like MDD and bipolar disorder, appears to have a genetic basis. In a study of 6439 adult twins, Madden et al. (1996) found that SAD ran in families, and they estimated that at least 29 percent of the variance in seasonal mood disorders could be attributed to genetic factors. • One of the genetic factors that contribute to susceptibility to SAD is a particular allele of the gene responsible for the production of melanopsin, the retinal photopigment that detects the presence of light and synchronizes circadian rhythms (Wulff et al., 2010). 200 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • Gonzalez and Aston-Jones (2006; 2008) found that rats that spent six weeks in total darkness exhibited behavioral symptoms of depression in an animal model of this disorder. • In addition, the investigators found increased apoptosis (programmed cell death) in noradrenergic neurons of the locus coeruleus, dopaminergic neurons of the ventral tegmental area, and serotonergic neurons of the raphe nuclei. 201 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • In addition, they observed fewer NE, DA, and 5-HT terminals in the prefrontal cortex. (You will recall from Chapter 9 that these monoaminergic regions play an important role in sleep and waking.) • Administration of desipramine, an antidepressant drug, decreased the both the behavioral and anatomical signs of depression. • Perhaps, the authors note, the anatomical changes they observed are responsible for the depressant effects of prolonged exposure to limited amounts of light. (See Figure 16.25.) 202 COPYRIGHT © ALLYN & BACON 2012 Figure 16.25, page 581 203 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • SAD can be treated by phototherapy: exposing people to bright light for several hours a day (Rosenthal et al., 1985; Stinson and Thompson, 1990). • Phototherapy • treatment of seasonal affective disorder by daily exposure to bright light • As you will recall, circadian rhythms of sleep and wakefulness are controlled by the activity of the suprachiasmatic nucleus of the hypothalamus. • Light serves as a zeitgeber; that is, it synchronizes the activity of the biological clock to the day–night cycle. 204 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • One possibility is that people with SAD require a stronger-than-normal zeitgeber to reset their biological clock. • According to Lewy et al. (2006), SAD is caused by a mismatch between cycles of sleep and cycles of melatonin secretion. 205 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • Normally, secretion of melatonin begins in the evening, before people go to sleep. • In fact, the time between the onset of melatonin secretion and the midpoint of sleep (halfway between falling asleep and waking up in the morning) is approximately six hours. • People with SAD most often show a phase delay between cycles of melatonin and sleep; that is, the time interval between the onset of melatonin secretion and the midpoint of sleep is more than six hours. 206 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Role of Zeitgebers • Exposure to bright light in the morning or administration of melatonin late in the afternoon (or, preferably, both treatments) advances the circadian cycle controlled by the biological clock in the suprachiasmatic nucleus. (These cycles were discussed in Chapter 9.) • Those people with SAD who show a phase advance in their cycles can best be treated with exposure to bright light in the evening and administration of melatonin in the morning. (See Figure 16.26.) • By the way, phototherapy has been found to help patients with major depressive disorder, especially in conjunction with administration of antidepressant drugs (Terman, 2007). 207 COPYRIGHT © ALLYN & BACON 2012 Figure 16.26, page 581 208 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • The major affective disorders include bipolar disorder, with its cyclical episodes of mania and depression, and major depressive disorder. • Heritability studies suggest that genetic anomalies are at least partly responsible for these disorders. 209 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • MDD has been treated by several established or experimental biological treatments: MAO inhibitors, drugs that block the reuptake of norepinephrine and serotonin (tricyclic antidepressants, SSRIs, and SNRIs), ECT, TMS, deep brain stimulation, vagus nerve stimulation, and sleep deprivation. 210 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • Bipolar disorder can be successfully treated by lithium salts and anticonvulsant drugs. • Lithium appears to stabilize neural transmission, especially in serotonin-secreting neurons. • It also appears to protect neurons from damage and perhaps facilitate their repair. 211 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • The therapeutic effect of noradrenergic and serotonergic agonists and the depressant effect of reserpine, a monoaminergic antagonist, suggested the monoamine hypothesis of depression: that depression is caused by insufficient activity of monoaminergic neurons. • Depletion of tryptophan (the precursor of 5-HT) in the brain causes a recurrence of depressive symptoms in depressed patients who are in remission, which lends further support to the conclusion that 5-HT plays a role in mood. • However, although SSRIs have an immediate effect on serotonergic transmission in the brain, they do not relieve the symptoms of depression for several weeks, so the simple monoamine hypothesis appears not to be correct. 212 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • Functional-imaging studies found a increased activity in the amygdala and decreased activity in the subgenual ACC. • Stressful life experiences increase the likelihood of depression in people with one or two short alleles of the 5-HT transporter promoter gene, and a better response to antidepressant treatment is seen in depressed people with two long alleles. • Structural and functional-imaging studies have found a decrease in the volume of the amygdala and subgenual ACC and evidence for a weakened negative feedback loop from the amygdala to the subgenual ACC to the dorsal ACC back to the amygdala. 213 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • Presumably, these changes occur because increased serotonergic activity associated with the presence of short alleles for the 5-HTT promoter affects prenatal brain development. • Stressful experiences suppress hippocampal neurogenesis, and antidepressant treatments increase it. • In addition, the effects of antidepressant treatments are abolished by suppression of neurogenesis. 214 COPYRIGHT © ALLYN & BACON 2012 Major Affective Disorders Section Summary • Sleep disturbances are characteristic of affective disorders. • In fact, total sleep deprivation rapidly (but temporarily) reduces depression in many people, and selective deprivation of REM sleep does so slowly (but more lastingly) . • In addition, almost all effective antidepressant treatments suppress REM sleep. • A specific form of depression, seasonal affective disorder, can be treated by exposure to bright light. • Clearly, the mood disorders are somehow linked to biological rhythms. 215 COPYRIGHT © ALLYN & BACON 2012