Larry had become a permanent resident of the state hospital. His parents had originally hoped that treatment would help him enough that he could live in a halfway house with a small group of other young men, but his condition was so serious that he required constant supervision. Larry had severe schizophrenia. The medication he was taking helped, but he still exhibited severe psychotic symptoms. In addition, he had begun showing signs of a neurological disorder that seemed to be getting worse.

Larry had always been a difficult child, shy and socially awkward. He had no real friends. During adolescence he became even more withdrawn and insisted that his parents and older sister keep out of his room. He stopped taking meals with the family, and he even bought a small refrigerator of his own for his room so that he could keep his own food, which he said he preferred to that “pesticide-contaminated” food his parents ate. His grades in school, which were never outstanding, got progressively worse, and when he was seventeen years old, he dropped out of high school.

Larry’s parents recognized that something was seriously wrong with him. Their family physician suggested that Larry see a psychiatrist and gave them the name of a colleague that he respected, but Larry flatly refused to go. Within a year after he had quit high school, he became frankly psychotic. He heard voices talking to him, and sometimes his parents could hear him shouting for the voices to go away. He was convinced that his parents were trying to poison him, and he would eat only factory-sealed food that he had opened himself. Although he kept his body clean—sometimes he would stand in the shower for an hour “purifying” himself—his room became frightfully messy. He insisted on keeping old cans and food packages because, he said, he needed to compare them with items his parents brought from the store to be sure they were not counterfeit.

One day, while Larry was in the shower purifying himself, his mother cleaned his room. She filled several large plastic garbage bags with the cans and packages and put them out for the trash collector. As she reentered the house, she heard a howling noise from upstairs. Larry had emerged from the shower and discovered that his room had been cleaned. When he saw his mother coming up the stairs, he screamed at her, cursed her savagely, and rushed down the stairs toward her. He hit her so hard that she fell down the stairs, landing heavily on the floor below. He wheeled around, ran up the stairs, and went into his room, slamming the door behind him.

An hour later, Larry’s father discovered his wife unconscious at the foot of the stairs. She soon recovered from the mild concussion she had sustained, but Larry’s parents realized that it was time for him to be put in custody. Because he had attacked his mother, a judge ordered that he be temporarily detained and, as a result of a psychiatric evaluation, had him committed to the state hospital. The diagnosis was “schizophrenia, paranoid type.”

In the state hospital, Larry was given Thorazine (chlorpromazine), which helped considerably. For the first few weeks, he showed some symptoms that are commonly seen in Parkinson’s disease—tremors, rigidity, a shuffling gait, and lack of facial expression—but these symptoms cleared up spontaneously, as his physician had predicted. The voices still talked to him occasionally, but less often than before, and even then he could ignore them most of the time. His suspiciousness decreased, and he was willing to eat with the residents in the dining room. But he still obviously had paranoid delusions, and the psychiatric staff was unwilling to let him leave the hospital. For one thing, he refused to take his medication voluntarily. Once, after he had suffered a serious relapse, the staff discovered that he had only been pretending to swallow his pills and was later throwing them away. After that, they made sure that he swallowed them.

After several years, Larry began developing more serious neurological symptoms. He began pursing his lips and making puffing sounds; later, he started grimacing, sticking his tongue out, and turning his head sharply to the left. The symptoms became so severe that they interfered with his ability to eat. His physician prescribed an additional drug, which reduced the symptoms considerably but did not eliminate them. As he explained to Larry’s parents, “His neurological problems are caused by the medication that we are using to help with his psychiatric symptoms. These problems usually do not develop until a patient has taken the medication for many years, but Larry appears to be one of the unfortunate exceptions. If we take him off the medication, the neurological symptoms will get even worse. We could reduce the symptoms by giving him a higher dose of the medication, but then the problem would come back later, and it would be even worse. All we can do is try to treat the symptoms with another drug, as we have been doing. We really need a medication that helps treat schizophrenia without producing these tragic side effects.”

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. 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.

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 ). 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. People often say that they “feel schizophrenic” about an issue when they really mean that they have mixed feelings about it. A person who sometimes wants to build a cabin in the wilderness and live off the land and at other times wants to take over the family insurance agency might be undecided, but he or she is not schizophrenic. 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.

Schizophrenia is characterized by three categories of symptoms: positive, negative, and cognitive (Mueser and McGurk, 2004). Positive symptoms make themselves known by their presence. They include thought disorders, hallucinations, and delusions. A thought disorder —disorganized, irrational thinking—is probably the most important symptom of schizophrenia. 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. Delusions are beliefs that are obviously contrary to fact. 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.

schizophrenia A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors.

positive symptom A symptom of schizophrenia evident by its presence: delusions, hallucinations, or thought disorders.

thought disorder Disorganized, irrational thinking.

delusion A belief that is clearly in contradiction to reality.

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. 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 . )

hallucination Perception of a nonexistent object or event.

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. The cognitive symptoms of schizophrenia are closely related to the negative symptoms and may be produced by abnormalities in overlapping brain regions. These 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. As we will see later in this chapter, positive symptoms appear to involve excessive activity in some neural circuits that include dopamine as a neurotransmitter, and negative symptoms and cognitive symptoms appear to be caused by developmental or degenerative processes that impair the normal functions of some regions of the brain. (Look again at Table 16.1 . )

negative symptom A symptom of schizophrenia characterized by the absence of behaviors that are normally present: social withdrawal, lack of affect, and reduced motivation.

cognitive symptom A symptom of schizophrenia that involves cognitive deficits, such as difficulty in sustaining attention, deficits in learning and memory, poor abstract thinking, and poor problem solving.

TABLE 16.1 Positive and Negative Symptoms of Schizophrenia

Schizophrenic Symptom

Positive

Hallucinations

Thought disorders

Delusions

Persecution

Grandeur

Control

Negative

Flattened emotional response

Poverty of speech

Lack of initiative and persistence

Anhedonia

Social withdrawal

Cognitive

Difficulty in sustaining attention

Low psychomotor speed

Deficits in learning and memory

Poor abstract thinking

Poor problem solving

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.

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.

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 two 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.

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. Gottesman and Bertelsen ( 1989 ) found that the percentage of schizophrenic children was nearly 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 . )

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. A review by Crow ( 2007 ) notes that evidence for linkage to susceptibility for schizophrenia has been reported for twenty-one of the twenty-three pairs of chromosomes, but many of the findings have not been replicated. So far, no single gene has been shown to cause schizophrenia, in the way that mutations in the genes for γ-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.

One rare mutation involves a gene known as DISC1 (disrupted in schizophrenia 1). This gene is involved in regulation of embryonic and adult neurogenesis, neuronal migration during embryonic development, function of the postsynaptic density in excitatory neurons, and function of mitochondria (Brandon et al., 2009 ; Kim et al., 2009 ; Park et al., 2010 ; Wang et al., 2010 ). Mutations of this gene have been found in some families with a high incidence of schizophrenia (Chubb et al., 2008 ; Schumacher et al., 2009 ). Although the incidence of DISC1 mutation is very low, its presence appears to increase the likelihood of schizophrenia by a factor of 50 (Blackwood et al., 2001 ). This mutation also appears to increase the incidence of other mental disorders, including bipolar disorder, major depressive disorder, and autism (Kim et al., 2009 ). I will describe research on the role of DISC1 malfunction in an animal model later in this chapter.

FIGURE 16.1 Heredity and Schizophrenia

The diagram outlines evidence that people can have an unexpressed “schizophrenia gene.”

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 sixteen days after puberty, which means that they have divided approximately 540 times by age thirty-five. 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.

Several researchers (for example, Tsankova et al., 2007 ; Swerdlow, 2011 ) suggest that epigenetic mechanisms, as well as mutations, may contribute to the development of schizophrenia. Epigenetic (“on top of the genes”) mechanisms control the expression of genes. The long strands of DNA that constitute the chromosomes are wound around a series of proteins known as histones. Groups of atoms can attach to the amino acids in the histone proteins and change their characteristics. For example, when methyl groups (–CH3) attach to histone proteins, the regions of DNA wound around them draws in more tightly, which prevents these regions from being translated into messenger RNA. Thus, methylation of histone proteins prevents the expression of particular genes. (Other groups of atoms can also bind with histone proteins and either inhibit or promote gene expression.) Many epigenetic changes are initiated by environmental events such as exposure to toxins, and some epigenetic changes can be transmitted to offspring.

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.

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 ). Chlorpromazine was tried on patients with a variety of mental disorders: mania, depression, anxiety, neuroses, and schizophrenia (Delay and Deniker, 1952a , 1952b ). The drug was not very effective in treating neuroses or affective psychoses, but it had dramatic effects on schizophrenia.

chlorpromazine A dopamine receptor blocker; a “first-generation” antipsychotic drug.

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. 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 D2 and D3 dopamine receptors (Creese, Burt, and Snyder, 1976 ; Strange, 2008 ).

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. 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.

How might we explain the apparent link between overactivity of dopaminergic synapses and the positive symptoms of schizophrenia? As we saw in Chapter 4 and Chapter 13 , the most important systems of dopaminergic neurons begin in two midbrain nuclei: the substantia nigra and the ventral tegmental area. Most researchers believe that the mesolimbic pathway, which begins in the ventral tegmental area and ends in the nucleus accumbens and amygdala, is more likely to be involved in the positive symptoms of schizophrenia. As we saw in Chapter 13 , the activity of dopaminergic synapses in the mesolimbic system appear to be a vital link in the process of reinforcement. Drugs that act as agonists at these synapses (such as cocaine and amphetamine) strongly reinforce behavior; if taken in large doses, they also produce the positive symptoms of schizophrenia. Perhaps the two effects of the drugs are related. If reinforcement mechanisms were activated at inappropriate times, then inappropriate behaviors—including delusional thoughts—might be reinforced. At one time or another, all of us have had some irrational thoughts, which we normally brush aside and forget. But if neural mechanisms of reinforcement became active while these thoughts were occurring, we would tend to take them more seriously. In time, full-fledged delusions might develop. Fibiger ( 1991 ) suggests that paranoid delusions may be caused by increased activity of the dopaminergic input to the amygdala. As we saw in Chapter 11 , the amygdala is involved with conditioned emotional responses elicited by aversive stimuli. The amygdala receives a strong projection from the mesolimbic dopaminergic system, so Fibiger’s suggestion is certainly plausible. In fact, Pinkham et al. ( 2011 ) found that schizophrenic people with active paranoia were more likely to misidentify a neutral facial expression as one showing anger. Schizophrenic people who were not currently exhibiting paranoid symptoms identified neutral facial expressions as did control subjects.

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. 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 the 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 . )

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 D2 receptors, the earliest studies looked for increases in the numbers of these receptors in the brains of schizophrenics. 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 D2 receptors in the brains of schizophrenics but that it seems unlikely that these increases are the primary cause of the disorder.

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.

FIGURE 16.2 Results of the study by Laruelle et al. (1996)

(a) Relative amount of dopamine released in response to amphetamine. (b) Relationship between dopamine release and changes in positive symptoms of schizophrenic patients.

(Based on data from Laruelle et al., 1996 .)

As a result of taking an antipsychotic medication, Larry, the schizophrenic man described at the opening of this chapter, developed a neurological disorder called tardive dyskinesia . Tardus means “slow,” and dyskinesia means “faulty movement”; thus, tardive dyskinesia is a late-developing movement disorder. (In Larry’s case it actually came rather early.)

tardive dyskinesia A movement disorder that can occur after prolonged treatment with antipsychotic medication, characterized by involuntary movements of the face and neck.

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. 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 D2 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.

supersensitivity The increased sensitivity of neurotransmitter receptors; caused by damage to the afferent axons or long-term blockage of neurotransmitter release.

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. To understand how these drugs work, we first need to know more about the results of research on the neuropathology of schizophrenia, which brings us to the next section.

clozapine An atypical antipsychotic drug; blocks D4 receptors in the nucleus accumbens.

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. 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. (In fact, some investigators do not distinguish between negative symptoms and cognitive symptoms.) Many pieces of evidence suggest that these symptoms of schizophrenia are indeed a result of brain abnormalities, especially in the prefrontal cortex. 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, or (3) abnormalities in the prefrontal cortex that cause abnormalities in DA transmission.

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.

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 they 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. The relative ventricle size of the schizophrenic patients was more than twice as great as that of normal control subjects. (See Figure 16.3 . )

FIGURE 16.3 Relative Ventricular Size in Chronic Schizophrenics and Controls

(Based on data from Weinberger and Wyatt, 1982 .)

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. 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 . )

Gutiérrez-Galve 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.

FIGURE 16.4 Cerebral Gray Matter and Schizophrenia

The graph shows changes in volume of cerebral gray matter with age in normal subjects and people with schizophrenia.

(Based on data from Hulshoff-Pol et al., 2002 .)

Many studies have investigated the specific locations of abnormalities in the brain of schizophrenics; these studies are described in a later section of this chapter.

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. 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. Let’s look at the evidence concerning environmental factors that increase the risk of schizophrenia.

Epidemiological Studies.

Epidemiology is the study of the distribution and causes of diseases in populations. Thus, 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. 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 ). Let’s examine each of these factors in turn.

epidemiology The study of the distribution and causes of diseases in populations.

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 . 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 . ) 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).

seasonality effect The increased incidence of schizophrenia in people born during late winter and early spring.

FIGURE 16.5 The Seasonality Effect

The graph shows the number of schizophrenic births per 10,000 live births.

(Based on data from Kendell and Adams, 1991 .)

What factors might be responsible for the seasonality effect? One possibility is that pregnant women may be more likely to contract a viral illness during a critical phase of their infants’ development. The brain development of the fetus may be adversely affected either by a toxin produced by the virus or—more likely—by the mother’s antibodies against the virus, which cross the placenta barrier and attack cells of the developing fetus. As Pallast et al. ( 1994 ) note, the winter flu season coincides with the second trimester of pregnancy of babies born in late winter and early spring. (As we shall see later, evidence suggests that critical aspects of brain development occur during the second trimester.) In fact, Kendell and Adams ( 1991 ) found that the relative number of schizophrenic births in late winter and early spring was especially high if the temperature was lower than normal during the previous autumn—a condition that keeps people indoors and favors the transmission of viral illnesses.

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 ). Because viruses are more readily transmitted in regions with high population densities, this finding is consistent with the hypothesis that at least one of the causes of the seasonality effect is exposure of pregnant women to viral illnesses during the second trimester. However, Pedersen and Mortensen ( 2001 ) found that, up to the age of fifteen years, the longer a person lives in a city, the more likely it becomes that the person develops schizophrenia. Thus, an urban environment may also affect people’s susceptibility to schizophrenia post-natally as well as prenatally.

If the viral hypothesis is true, then an increased incidence of schizophrenia should be seen in babies born a few months after an influenza epidemic, whatever the season. Several studies have observed just that (Mednick, Machon, and Huttunen, 1990 ; Sham et al., 1992 ). A study by Brown et al. ( 2004 ) examined stored samples of blood serum that had been taken during pregnancy from mothers of children who later developed schizophrenia. They found elevated levels of interleukin-8, a protein secreted by cells of the immune system. The presence of this chemical indicates the presence of an infection or other inflammatory process, and supports the suggestion that maternal infections during the second trimester can increase the incidence of schizophrenia in the women’s children. Brown ( 2006 ) notes that research has found that maternal infection with at least two other infections diseases—rubella (German measles) and toxoplasmosis—are associated with an increased incidence of schizophrenia.

Although cold weather and crowding may contribute to the seasonality effect by increasing the likelihood of infectious illness, another variable may also play a role: a vitamin D deficiency. Dealberto ( 2007 ) notes that Northern European researchers have observed a threefold increase in the incidence of schizophrenia in immigrants and the children of immigrants—especially in dark-skinned people. Vitamin D is a fat-soluble chemical that is produced in the skin by the action of ultraviolet rays on a chemical derived from cholesterol. People whose ancestors lived near the equator, where the sunlight is intense all year long, have dark skin, while those whose ancestors lived in more extreme latitudes (such as Northern Europeans) have light skin. The evolutionary change of the skin color of Northern Europeans from the original dark skin to light skin is an adaptation that permitted them to make more vitamin D in conditions of less intense sunlight. When people with dark skin move to more northern regions, they and their offspring are likely to sustain a vitamin D deficiency because the pigment in their skin blocks much of the ultraviolet radiation. In addition, many people of African origin are lactose intolerant and hence drink less milk, which is now fortified with vitamin D. 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. 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 ).

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 schizophrenia in 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. 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 ).

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. Even paternal tobacco use increased this risk, which suggest that secondhand smoke was sufficient to adversely affect fetal development. Excessive alcohol intake increased the risk of schizophrenia only if the mother drank more than 210 ml of pure alcohol per week. Of course, as we saw in Chapter 15 , alcohol intake during pregnancy puts the fetus at risk for development of fetal alcohol syndrome.

Many studies have found an interaction between hereditary factors and the environmental factors that I have just reviewed (Mittal, Ellman, and Cannon, 2008 ; Brown and Derkits, 2010 ; Freedman, 2010 ). For example, a person born to a woman who had pyelonephritis during pregnancy is twice as likely to develop schizophrenia and four times more likely to do so if he or she has a family history of schizophrenia. (Pyelonephritis is an infectious disease introduced through the urinary tract that is often associated with pregnancy.) By itself, maternal depression does not increase the risk of developing schizophrenia in a woman’s offspring, but the likelihood of schizophrenia increases by a factor of four in the case of familial genetic risk.

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. 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.

A study by Rehn et al. ( 2004 ) provided direct evidence that deprivation of an adequate blood supply to the uterus and placenta can have harmful effects on brain development. The investigators produced chronic placental insufficiency in pregnant guinea pigs by tying off one uterine artery at midgestation. When the offspring of these animals reached adolescence, they showed reduced brain weight and enlarged cerebral ventricles but no sign of gliosis in the brain. As we will see in the next subsection, these changes are also seen in the brains of people with schizophrenia.

Evidence for Abnormal Brain Development.

Both behavioral and anatomical evidence indicates that abnormal prenatal development is associated with schizophrenia. Let’s first consider 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. 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. (The ratings were done blind; the observers did not know which children subsequently became schizophrenic.)

A study by Schiffman et al. ( 2004 ) confirmed these results. In 1972, 265 Danish children, aged 11–13 years, were videotaped briefly while eating lunch. In 1991, the investigators examined the medical records of these children and determined which of them had developed schizophrenia. Raters, who did not know the identities of the children, found that the children who later developed schizophrenia displayed less sociability and deficient psychomotor functioning. The results of these studies are consistent with the hypothesis that although the symptoms of schizophrenia are not seen in childhood, the early brain development of children who later become schizophrenic is not entirely normal.

TABLE 16.2 Examples of Minor Physical Abnormalities Associated with Schizophrenia

Location	Description
Head	Two or more hair whorls
	Head circumference outside normal range
Eyes	Skin fold at inner corner of eye
	Wide-set eyes
Ears	Low-seated ears
	Asymmetrical ears
Mouth	High-steepled palate
	Furrowed tongue
Hands	Curved fifth finger
	Single transverse crease in palm
Feet	Third toe longer than second toe
	Partial webbing of two middle toes

Source: Adapted from Schiffman et al., 2002 .

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. 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.

As I mentioned earlier, some monozygotic twins are discordant for schizophrenia; that is, one of them develops schizophrenia, and the other does not. 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. 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.

FIGURE 16.6 MRI Scans of the Brains of Twins Discordant for Schizophrenia

The arrows point to the lateral ventricles. (a) Normal twin. (b) Twin with schizophrenia.

(Courtesy of D. R. Weinberger, National Institute of Mental Health, Saint Elizabeth’s Hospital, Washington, DC.)

In the past, most researchers assumed that discordance for schizophrenia in monozygotic twins must be caused by differential exposure to some environmental factors after birth. Not only are monozygotic twins genetically identical, but they also share the same intrauterine environment. 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. 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 . )

FIGURE 16.7 Monozygotic Twins

(a) Monochorionic twins, sharing a single placenta. (b) Dichorionic twins, each with its own placenta.

The placenta plays an extremely important role in prenatal development. It transports nutrients to the developing organism from the mother’s circulation and transports waste products to her, which she metabolizes in her liver or excretes in her urine. It also constitutes the barrier through which toxins or infectious agents must pass if they are to affect fetal development. The prenatal environments of monochorionic twins, who share a single placenta, are obviously more similar than those of dichorionic twins. Thus, we might expect that the concordance rates for schizophrenia of monochorionic monozygotic twins should be higher than those of dichorionic monozygotic twins, and as Davis, Phelps, and Bracha ( 1995 ) reported, they are. Davis and his colleagues examined sets of monozygotic twins who were concordant and discordant for schizophrenia. They used several indices to estimate whether a given pair was monochorionic or dichorionic. (For example, twins with mirror images of physical features such as fingerprints, handedness, birthmarks, or hair swirls are more likely to be monochorionic.) The investigators estimated that the concordance rate for schizophrenia was 10.7 percent in the dichorionic twins and 60 percent in the monochorionic twins. These results provide strong evidence for an interaction between heredity and environment during prenatal 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 . )

FIGURE 16.8 Age at First Sign of Psychotic Symptoms in Schizophrenic Patients

(Based on data from Häfner et al., 1993 .)

In a review of the literature, Woods ( 1998 ) notes that MRI studies suggest that schizophrenia is not caused by a degenerative process, as are Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease, in which neurons continue to die over a period of years. Instead, a sudden, rapid loss of brain volume typically occurs during young adulthood, with little evidence for continuing degeneration. Woods suggests that the disease process of schizophrenia begins prenatally and then lies dormant until puberty, when some unknown mechanism triggers degeneration of some population of neurons. The brain abnormalities that develop prenatally account for the deficits in social behavior and poor academic performance seen in people who later become schizophrenic. Then, sometime after puberty, when many developmental changes occur in the brain, more serious degeneration occurs, and the symptoms of schizophrenia begin to appear.

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. Adolescence is a time when “pruning” takes place in the brain, and the MRI scans showed an expected loss of cortical gray matter in nonschizophrenic subjects of about 0.5–1.0 percent. However, the loss of tissue was approximately twice as large in schizophrenic subjects. The degeneration started in the parietal lobes, and the wave of destruction continued rostrally, including the temporal lobes, somatosensory and motor cortex, and dorsolateral prefrontal cortex (dlPFC). A subsequent study from the same laboratory (T. D. Cannon et al., 2002 ) compared the cortical gray matter of brains of members of identical twin pairs who were discordant for schizophrenia. Identical twins are genetically identical, so differences in their cortical gray matter are presumably related to the presence or absence of schizophrenia. The investigators found that several regions of the cerebral cortex—especially the dlPFC—was 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 . )

The evidence I have cited so far suggests that the most important cause of schizophrenia is disturbance of normal prenatal brain development that, in most cases, ultimately manifests itself after puberty. Presumably, genetic factors make some fetuses more sensitive to events that can disturb development. In addition, damage caused by obstetric complications can lead to development of schizophrenia even in the absence of hereditary factors. The effect of these factors is reflected in cortical development and, perhaps, in altered activity at dopaminergic synapses.

FIGURE 16.9 Cortical Gray Matter in Monozygotic Twins Discordant for Schizophrenia

The scans show regions of the cerebral cortex that were smaller in the brains of the schizophrenic people compared with their normal twins, which indicates regions affected by the disorder. Colors “warmer” than blue indicate regions where mean difference between the two groups of twins was statistically significant.

(From Cannon, T. D., Thompson, P. M., van Erp, T. G., et al. Proceedings of the National Academy of Sciences, USA, 2002, 99, 3228–3233.)

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.

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. Many studies have shown that schizophrenic patients do poorly on neuro-psychological 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 . )

hypofrontality Decreased activity of the prefrontal cortex; believed to be responsible for the negative symptoms of schizophrenia.

FIGURE 16.10 Hypofrontality in Schizophrenia

The images show composite functional MRI scans of subjects with schizophrenia and normal comparison subjects taken while the people were performing a task that required concentration and focused attention. The schizophrenic subjects show deficient activation of the dorsolateral prefrontal cortex (hypofrontality).

(From MacDonald, A. W., Carter, C. S., Kerns, J. G., Ursu, S., Barch, D. M., Holmes, A. J., Stenger, V. A., and Cohen, J. D. American Journal of Psychiatry, 2005, 162, 475–484. Reprinted with permission from the American Journal of Psychiatry. Copyright © 2005 American Psychiatric Association.)

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. 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.

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 . )

As you might recall from Chapter 4 , PCP is an indirect antagonist of NMDA-receptors. (So is ketamine.) By inhibiting the activity of NMDA receptors, PCP suppresses the activity of several regions of the brain—most notably, the dlPFC. These drugs also decrease the level of dopamine utilization in this region (Elsworth et al., 2008 ), possibly as a result of the inhibitory effect on NMDA receptors. The hypoactivity of NMDA and dopamine receptors appears to play an important role in the production of negative and cognitive symptoms: Suppression of these receptors causes hypofrontality, which appears to be the primary cause of these two categories of symptoms.

FIGURE 16.11 Chronic PCP Treatment and Perseveration

The graphs show the effects of two weeks of PCP treatment on the performance by monkeys on a task that requires reaching around a barrier. An increased number of reaches toward the barrier is an indication of perseveration of an incorrect response.

(Based on data from Jentsch et al., 1997 .)

We also saw that the atypical antipsychotic drug clozapine alleviates the positive, negative, and cognitive symptoms of schizophrenia. It also reduces the psychotic symptoms that are triggered in humans by ketamine (Malhotra et al., 1997 ). (Because PCP has toxic effects, it is not normally used in studies with human subjects.) In a study with monkeys, Youngren et al. ( 1999 ) found that injection of clozapine, which causes a decrease in the release of dopamine by the mesolimbic system, which apparently reduces the positive symptoms, also causes an increase in the release of dopamine in the prefrontal cortex, which apparently reduces the negative and cognitive symptoms.

I mentioned earlier that a mutation of the DISC1 gene is a known genetic cause of schizophrenia. Niwa et al. ( 2010 ) infused a small interfering RNA (siRNA) that targeted the DISC1 gene into progenitor cells of the ventricular zone of fetal mice. (You will recall from Chapter 3 that these progenitor cells give rise to the brain’s neurons.) The procedure suppressed DISC1 expression in pyramidal neurons of the prefrontal cortex during the last week of fetal development. At first, these neurons appeared normal, but at around the time of puberty, abnormalities were seen in the physiological characteristics of pyramidal neurons in the prefrontal cortex and in the structure of their dendritic spines. 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 . )

FIGURE 16.12 Role of DISC1 in the Development of Schizophrenia

Niwa et al. ( 2010 ) infused a siRNA that prevented the expression of DISC1 in progenitor cells in the ventricular zone of fetal mice. Although neurons in the prefrontal cortex appeared normal after birth, they developed abnormalities in dendritic spines of these neurons after puberty that led to behavioral abnormalities resembling those of schizophrenia. In humans, the symptoms of schizophrenia usually emerge after puberty.

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. 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. As in 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 . )

FIGURE 16.13 Role of Dopamine D2 Receptors in the Development of Schizophrenia

Li et al. ( 2011 ) used a viral vector to increase expression of dopamine D2 receptors in the striatum of mice. As a result, GABAergic transmission decreased in the dorsolateral prefrontal cortex, and the abnormal neural activity there led to behavioral deficits characteristic of schizophrenia.

The research findings presented in this subsection explain why the “classic” antipsychotic drugs fail to reduce negative and cognitive symptoms: One of the causes of these symptoms is decreased activation of dopamine receptors in the prefrontal cortex, and drugs that block dopamine receptors would, if anything, make these symptoms worse. What is different about the newer atypical antipsychotic drugs that enables them to reduce all three categories of schizophrenic symptoms?

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. 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. 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 . )

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.

FIGURE 16.14 Effects of a Partial Agonist

The diagram explains the differential effects of a partial agonist in regions of high and low concentrations of the normal ligand. Numbers beneath each receptor indicate the degree of opening of the ion channel: 1.0 = fully open, 0.5 = partially open, 0.0 = fully closed. Partial agonists decrease the mean opening when the extracellular concentration of the neurotransmitter is high and increase it when the extracellular concentration of the neurotransmitter is low.

Before I conclude this section, I want to mention an interesting sidelight that might have some relevance to the causes of schizophrenia. As we saw, ketamine and PCP have similar effects. Ketamine is used as an anesthetic for children and animals. It is not often used as an anesthetic in adult humans because it produces episodes of psychosis when the person awakens after the surgery. Ketamine does not have this effect in prepubertal children, and administration of PCP does not damage the brains of rats until the animals reach puberty (Marshall and Longnecker, 1990 ; Stone, Morrison, and Pilowsky, 2007 ). No one knows why ketamine (and probably PCP) produces psychotic behavior only in adults; perhaps the explanation is related to the fact that the symptoms of schizophrenia also emerge after puberty. (Whatever developmental changes occur after puberty that make the brain susceptible to the psychotic effects of NMDA antagonists may also be related to the emergence of symptoms of schizophrenia at this time.)

Farber et al. ( 1995 ) found that large doses of another indirect NMDA antagonist, MK-801, produced brain abnormalities in adult rats but not in prepubertal rats. Between the age of puberty and full adulthood, the animals’ brains became more and more sensitive to the effects of the drug. These findings provide further support for the hypothesis that developmental changes that begin around the time of puberty may play a role in the development of schizophrenia.

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.

SECTION SUMMARY: Schizophrenia

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. 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.

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. 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 D2 dopamine receptors, but this increase does not appear to play a primary role in the incidence of schizophrenia. 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. 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.

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. 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. 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.

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.

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.

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. 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, and 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).

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.

■ THOUGHT QUESTION

Suppose that a young schizophrenic woman insists on living in the streets and refuses to take antipsychotic medication. She is severely disturbed; she is under-nourished and often takes intravenous drugs, which expose her to the risk of AIDS. Her parents have tried to get her to seek help, but she believes that they are plotting against her. Suppose further that we can predict with 90 percent accuracy that she will die within a few years. She is not violent, and she has never talked about committing suicide, so we cannot prove that her behavior constitutes an immediate threat to herself or to others. Should her parents be able to force her to receive treatment, or does she have an absolute right to be left alone, even if she is mentally ill?

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.

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. 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 ).

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 . 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. The second type is major depressive disorder (MDD) , characterized by depression without mania. This depression may be continuous and unremitting or, more typically, may come in episodes. Mania without periods of depression sometimes occurs, but it is rare.

bipolar disorder A serious mood disorder characterized by cyclical periods of mania and depression.

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.

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. 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.

· [A psychiatrist] asked me if I was suicidal, and I reluctantly told him yes. I did not particularize—since there seemed no need to—did not tell him that in truth many of the artifacts of my house had become potential devices for my own destruction: the attic rafters (and an outside maple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to receive the flow from my opened arteries. The kitchen knives in their drawers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of active responsibility, and I had toyed with the idea of self-induced pneumonia—a long frigid, shirt-sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident … by walking in front of a truck on the highway nearby. … Such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivious daydreams are to persons of robust sexuality. (Styron, 1990 , pp. 52–53)

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. They 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. (Sometimes, their work is fruitful; George Frideric Handel wrote Messiah, one of the masterpieces of choral music, during one of his periods of mania.)

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.

Genetic studies have found evidence that genes on several chromosomes may be implicated in the development of the affective disorders, but the findings of most of the earlier linkage studies have not been replicated (Hamet and Tremblay, 2005 ). A review of genomewide 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 will see later in this chapter, disturbances in sleep and circadian rhythms may play a role in the development of 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 that disease. 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. 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 for those born in summer, with a peak in July. (See Figure 16.15 . ) So far, there is no explanation for this phenomenon.

FIGURE 16.15 Suicide and Season of Birth

Incidence of suicide as a function of month of birth in 80,000 people who committed suicide in Hungary in the mid-twentieth century.

(Based on data of Döme et al., 2010 .)

Biological Treatments

There are several established and experimental biological treatments for major depressive disorder: monoamine oxidase (MAO) inhibitors, drugs that inhibit the reup-take 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.) 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 ).

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 ). 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.

Fortunately, another class of antidepressant drugs was soon discovered that did not have these side effects: the tricyclic antidepressants . These drugs were found to inhibit the reuptake of 5-HT and norepinephrine by terminal buttons. 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.

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.

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. 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 ). Another class of antidepressant drugs has been developed, the serotonin and norepinephrine reuptake inhibitors (SNRI) , which also do what their name indicates. 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.

specific serotonin reuptake inhibitor (SSRI) An antidepressant drug that specifically inhibits the reuptake of serotonin without affecting the reuptake of other neurotransmitters.

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.

Another biological treatment for depression has an interesting history. Early in the twentieth century, a physician named von Meduna noted that psychotic patients who were also subject to epileptic seizures showed improvement immediately after each attack. He reasoned that the violent storm of neural activity in the brain that constitutes an epileptic seizure somehow improved the patients’ mental condition. He developed a way to produce seizures by administering a drug, but the procedure was dangerous to the patient. In 1937, Ugo Cerletti, an Italian psychiatrist, developed a less dangerous method for producing seizures (Cerletti and Bini, 1938 ). He had previously learned that the local slaughterhouse applied a jolt of electricity to animals’ heads to stun them before killing them. The electricity appeared to produce a seizure that resembled an epileptic attack. He decided to attempt to use electricity to induce a seizure more safely.

Cerletti tried the procedure on dogs and found that an electrical shock to the skull did produce a seizure and that the animals recovered with no apparent ill effects. 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. 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 nonspeech-dominant hemisphere, to avoid damaging verbal memories), and a jolt of electricity triggers a seizure. 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 . )

electroconvulsive therapy (ECT) A brief electrical shock, applied to the head, that results in an electrical seizure; used therapeutically to alleviate severe depression.

FIGURE 16.16 A Patient Being Prepared for Electroconvulsive Therapy.

(Photo Researchers, Inc.)

Antidepressant drug treatment has some adverse side effects, including nausea, anxiety, sexual dysfunction, and weight gain. However, the major problem is that, in a substantial percentage of patients, the drug fails to relieve their depression. 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 . 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.

treatment-resistant depression A major depressive disorder whose symptoms are not relieved after trials of several different treatments.

Even when depressed patients respond to treatment with antidepressant drugs, they do not do so immediately; improvement in symptoms is not usually seen before two to three weeks of drug treatment. In contrast, the effects of ECT are more rapid. A few seizures induced by ECT can often snap a person out of a deep depression within a few days. Remission of symptoms is greater than 50 percent, but relapse is a common problem (Holtzheimer and Mayberg, 2011 ). Although prolonged and excessive use of ECT causes brain damage, resulting in long-lasting impairments in memory (Squire, 1974 ), the judicious use of ECT during the interim period before antidepressant drugs become effective has undoubtedly saved the lives of some suicidal patients.

How does ECT exert its antidepressant effect? It has been known for a long time that seizures have an anticonvulsant effect: ECT decreases brain activity and raises the seizure threshold of the brain, making it less likely for another seizure to occur (Sackeim et al., 1983 ; Nobler et al., 2001 ). The changes associated with this effect may be responsible for reducing the symptoms of depression. However, evidence concerning nature of the antidepressant effects of ECT is still inconclusive (Bolwig, 2011 ).

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. 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 ).

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 ). Mayberg and her colleagues implanted electrodes just below the subgenual anterior cingulate cortex (subgenual ACC) , a region of the medial prefrontal cortex. 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, 60 percent showed improvement, and 35 percent showed remission.

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.

Deep brain stimulation has also been directed toward the nucleus accumbens. You will recall from Chapter 13 that the release of dopamine in this region plays a critical role in reinforcement and the response to pleasurable stimuli. In fact, animals will press a lever that causes stimulation of this region. Because depression is characterized by sadness, apathy, and loss of pleasure, this region appeared to be a logical target for DBS. Bewernick et al. (2010) found that DBS of the nucleus accumbens did indeed reduce the symptoms of depression in 50 percent of treatment-resistant patients who had previously shown no response to pharmacological treatment, psychotherapy, or ECT.

Another experimental treatment for depression, electrical stimulation of the vagus nerve, shows some promise of reducing the symptoms of depression (Groves and Brown, 2005 ). Vagus nerve stimulation provides an indirect form of brain stimulation. It is painless and does not elicit seizures—in fact, the procedure was originally developed as a treatment to prevent seizures in patients with seizure disorders. The stimulation is accomplished by means of an implanted device similar to the one used for deep brain stimulation, except that the stimulating electrodes are attached to the vagus nerve. Approximately 80 percent of the axons in the vagus nerve are afferent, so electrical stimulation of the vagus nerve activates several regions of the brain stem. A review of the literature by Daban et al. ( 2008 ) concluded that the procedure showed promise in treatment of patients with treatment-resistant depression but that further double-blind clinical trials are needed to confirm its efficacy.

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 ). Zarate et al. ( 2006 ) administered injections of ketamine or placebo to patients with treatment-resistant depression. In less than two 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 . )

FIGURE 16.17 Treatment of Depression with Ketamine

The graph shows the effects of ketamine on symptoms of depression.

(Based on data from Zarate et al., 2006 .)

Along with ECS, ketamine is a very effective but short-term treatment for severe depression. Like ECS, the best use of ketamine may be to reduce the likelihood of suicide in severely depressed patients until another, slower-acting treatment can take effect. Unfortunately, by definition, people with treatment-resistant depression have not responded to other treatments, You will recall from the discussion of schizophrenia earlier in this chapter that chronic administration of ketamine or PCP, another NMDA antagonist, produces the symptoms of schizophrenia. Clearly, depression cannot be treated with long-term administration of large doses of ketamine, but in a test of safety of repeated doses of ketamine, ann het Rot et al. (2010) found that administration of six infusions of a moderate dose over a period of twelve days produced a strong antidepressant effect with only mild or transient side effects. The beneficial effects lasted an average of nineteen days, with one patient free of symptoms for over three months.

The therapeutic effect of lithium , the drug used to treat bipolar affective disorders, is very rapid. 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 ). 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 a week or two (Price and Heninger, 1994 ).

lithium A chemical element; lithium carbonate is used to treat bipolar disorder.

Lithium does have adverse side effects. The therapeutic index (the difference between an effective dose and an overdose) is low. Side effects include hand tremors, weight gain, excessive urine production, and thirst. Toxic doses produce nausea, diarrhea, motor incoordination, confusion, and coma. Because of the low therapeutic index, patients’ blood levels of lithium must be tested regularly to be certain that they do not receive an overdose. Unfortunately, some patients are not able to tolerate the side effects of lithium, and even more unfortunately, lithium is by far the most effective treatment for bipolar disorder.

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 ). 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. We saw earlier in this chapter that schizophrenia can be caused by a mutation of the DISC1 gene, which is normally involved in neurogenesis, neuronal migration, function of the postsynaptic density in excitatory neurons, and mitochondrial function. Research indicates that the lithium has an effect on the function of DISC1 in the postsynaptic density. Mutation of DISC1 increases the likelihood of bipolar disorder as well as schizophrenia, and lithium appears to compensate for the adverse effects of this mutation (Brandon et al., 2009 ; Flores et al., 2011 ).

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. 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.

monoamine hypothesis A hypothesis that states that depression is caused by a low level of activity of one or more monoaminergic synapses.

As we saw earlier in this chapter, the dopamine hypothesis of schizophrenia was suggested by the fact that dopamine agonists can produce the symptoms of schizophrenia and dopamine antagonists can reduce them. Similarly, the monoamine hypothesis of depression was suggested by the fact that monoamine antagonists can produce the symptoms of depression and monoamine agonists can reduce them. As you will recall from Chapter 4 , the drug reserpine blocks the activity of transporters that fill synaptic vesicles in monoaminergic terminals with the neurotransmitter. Reserpine was previously used to lower blood pressure by blocking the release of norepinephrine in muscles in the walls of blood vessels, which causes these muscles to relax. However, reserpine has a serious side effect: By interfering with the release of serotonin and norepinephrine in the brain, it can cause depression. In fact, in the early years of its use as a hypotensive agent, up to 15 percent of the people who received it became depressed (Sachar and Baron, 1979 ). As we can see, a monoamine antagonist produces the symptoms of depression, and monoamine agonists alleviate them.

Delgado et al. ( 1990 ) developed an ingenious approach to study of the role of serotonin in depression: the tryptophan depletion procedure . 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). 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. As you will recall, tryptophan is the precursor of 5-HT, or serotonin. Thus, the treatment lowered the level of serotonin in the brain.

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.

Delgado and his colleagues found that the tryptophan depletion caused most of the patients to relapse back into depression. Then, when they began eating a normal diet again, they recovered. These results strongly suggest that the therapeutic effect of at least some antidepressant drugs depends on the availability of serotonin in the brain. Subsequent studies have confirmed these results. These studies also indicate that tryptophan depletion has little or no effect on the mood of healthy subjects, but it does lower the mood of people with a personal history or family history of affective disorders (Young and Leyton, 2002 ; Neumeister et al., 2004 ).

Most investigators believe that the simple monoamine hypothesis—that depression is caused by low levels of norepinephrine or serotonin—is just that: too simple. The effects of tryptophan depletion certainly suggest that serotonin plays a role in depression, but depletion causes depression only in people with a personal or family history of depression. An acute decrease in serotonergic activity in healthy people with no family history of depression has no effect on mood. Thus, there appear to be physiological differences in the brains of the vulnerable people. Also, although SSRIs and SNRIs increase the level of 5-HT or norepinephrine in the brain very rapidly, the drugs do not relieve the symptoms of depression until they have been taken for several weeks. This fact suggests that something other than a simple increase in monoaminergic activity is responsible for the normalization of mood. Many investigators believe that the increased extracellular levels of monoamines produced by administration of antidepressant drugs begin a chain of events that eventually produce changes in the brain that are ultimately responsible for antidepressant effect. The nature of this chain of events is still unknown.

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 twenty years, starting at three years of age, and recorded the occurrence of stressful events in their lives, including abuse during childhood, romantic disasters, bereavements, illnesses, and job crises. 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 . )

FIGURE 16.18 Stressful Life Events, 5-HTT, and Depression

The graph shows the probability of major depression and suicide ideation or attempts as a function of number of previous stressful life events of people with two long alleles (L/L), one short allele (S/L), or two short alleles (S/S) of the promoter region of the 5-HT transporter gene.

(Based on data from Caspi et al., 2003 .)

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. 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.

Unfortunately, several meta-analyses of the studies investigating a possible role of the 5-HTT 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.

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.

As we saw earlier, deep brain stimulation targeted at the subgenual ACC has been found to provide relief of depressive symptoms. In fact, a reliable finding in neuro-imaging studies of depressed patients is hyperactivity of this region, along with decreased activity in other regions of the frontal cortex, including the dorsolateral PFC, the ventrolateral PFC, the ventromedial PFC, and the orbitofrontal cortex (Mayberg, 2009 ). Studies have shown that a variety of successful antidepressant treatments reliably decrease the activity of the subgenual ACC and, usually, increase the activity of other regions 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. 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 . )

FIGURE 16.19 Effects of Deep Brain Stimulation of the Subgenual ACC

Mayberg et al. ( 2005 ) implanted stimulating electrodes in the subgenual ACC of patients with treatment-resistant depression. The figure shows functional imaging scans of the patients (a) before DBS, (b) after three months of DBS, and (c) after six months of DBS. Increased activity is shown in red; decreased activity is shown in blue. The subgenual ACC initially showed increased activity, which decreased during the course of stimulation, and also reduced the symptoms of depression.

(From Mayberg, H. S., Lozano, A. M., Voon, V., et al. Neuron, 2005, 45, 651–660. Reprinted with permission.)

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 . )

Why does successful treatment of the symptoms of depression appear to be linked to decreased activity in the subgenual ACC and increased activity in regions of the prefrontal cortex? As we just saw, the subgenual ACC is reciprocally connected with several regions of the prefrontal cortex. It is also connected with the amygdala, hippocampus, and nucleus accumbens. As we saw in Chapter 11 , the prefrontal cortex plays an important role in inhibition of the amygdala, which is involved in the acquisition and expression of negative emotional responses such as fear. Thus, successful treatment of the symptoms of depression, which decreases the activity of the subgenual ACC, may result in decreased activity of the amygdala through direct connections between these two structures and through indirect connections via the prefrontal cortex. The precise role of the subgenual ACC will be elucidated only through further research.

Role of Neurogenesis

As we saw in Chapter 3 and Chapter 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. 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, 2011 , 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. 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.) Histological procedures verified that increased neurogenesis in the mouse brain correlated with the increased blood volume, which strongly supports the conclusion that the exercise induces neurogenesis in the human brain, as well. (See Figure 16.21 . )

FIGURE 16.20 Decreased Activation of the Subgenual ACC After a Variety of Successful Treatments for Depression

The figure shows a standard drawing of an anterior midsagittal view of the human brain with tracings of regions of increased (red) or decreased (blue) activation seen in functional imaging studies of brain responses to successful treatment for the symptoms of depression. Treatment with (a) DBS, (b) TMS, (c) VNS, (d) SSRI, (e) SNRI, (f) placebo.

[Tracings of brain activity from (a) Mayberg et al. ( 2005 ), (b) Kito et al. ( 2011 ), (c) Pardo et al. ( 2008 ), (d) Mayberg et al. ( 2002 ), (e) Kennedy et al. ( 2007 ), (f) Mayberg et al. ( 2002 ).]

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 . )

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, and sleep disruption, experienced by new mothers, increases the risk of post-partum depression (Posmontier, 2008 ).

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. 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 ). 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, placebo-controlled 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.

FIGURE 16.21 Exercise and Neurogenesis

The scans show the effect of a program of aerobic exercise on the blood volume of regions of the human hippocampal formation. This measure serves as an indirect measure of neurogenesis. (a) Subregions of the hippocampus. EC = entorhinal cortex, DG = dentate gyrus, SUB = subiculum. (b) Regional blood volume. “Hotter” colors indicate increased blood volume.

(From Pereira, A. C., Huddleston, D. E., Brickman, A. M., et al. Proceedings of the National Academy of Sciences, USA, 2007, 104, 5638–5643. Reprinted with permission.)

FIGURE 16.22 Sleep and Depression

The diagram illustrates patterns of the stages of sleep of a normal subject and of a patient with major depression. Note the reduced sleep latency, reduced REM latency, reduction in slow-wave sleep (stages 3 and 4), and general fragmentation of sleep (arrows) in the depressed patient.

(From Gillin, J. C., and Borbély, A. A. Trends in Neurosciences, 1985, 8, 537–542. Reprinted with permission.)

SLOW-WAVE SLEEP DEPRIVATION

FIGURE 16.23 Slow-Wave Sleep Deprivation

The diagram shows self ratings of depressive symptoms of patients with major depressive disorder before and after a night’s sleep during which EEG slow-waves were suppressed with an acoustic stimulus. Each line indicates the ratings of a single subject. Arrows indicate group medians.

(Based on data from Landsness et al., 2001.)

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. 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. 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.

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. 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 . )

FIGURE 16.24 Antidepressant Effects of Sleep Deprivation

The graph shows the mean mood rating of responding and nonresponding patients deprived of one night’s sleep as a function of the time of day.

(Based on data from Wu and Bunney, 1990 .)

Why do only some people profit from sleep deprivation? This question has not yet been answered, but several studies have shown that it is possible to predict who will profit and who will not (Riemann, Wiegand, and Berger, 1991 ; Haug, 1992 ; Wirz-Justice and Van den Hoofdakker, 1999 ). In general, depressed patients whose mood remains stable will probably not benefit from sleep depression, whereas those whose mood fluctuates probably will. The patients who are most likely to respond are those who feel depressed in the morning but then gradually feel better as the day progresses. In these people, sleep deprivation appears to prevent the depressogenic effects of sleep from taking place and simply permits the trend to continue. If you examine Figure 16.24 , you can see that the responders were already feeling better by the end of the day. This improvement continued through the sleepless night and during the following day. The next night they were permitted to sleep normally, and their depression was back the following morning. As Wu and Bunney note, these data are consistent with the hypothesis that sleep produces a substance with a depressogenic effect. (Look again at Figure 16.24 . )

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 ).

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 ). 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. (As you will recall, people with major depression tend to lose their appetite.)

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.

SAD, like MDD and bipolar disorder, appears to have a genetic basis. In a study of 6,439 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 ).

González 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. 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 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 . )

FIGURE 16.25 Effects of Living in Total Darkness on Monoaminergic Systems

Rats that spent 6 weeks in total darkness showed apoptosis (cell death) in the NE neurons of the locus coeruleus, DA neurons of the ventral tegmental area, and 5-HT neurons of the raphe nuclei. The graph shows the number of terminal buttons in the prefrontal cortex from neurons in each of these areas after the 6-week period.

[Based on data from Gonzalez and Aston-Jones ( 2006 , 2008 ).]

SAD can be treated by phototherapy : exposing people to bright light for several hours a day (Rosenthal et al., 1985 ; Stinson and Thompson, 1990 ). 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. 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. 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 delaybetween 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. 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 ).

phototherapy Treatment of seasonal affective disorder by daily exposure to bright light.

FIGURE 16.26 Cycles of Sleep and Melatonin Secretion

Normally, melatonin secretion begins in the evening, approximately six hours before the midpoint of sleep. Most people with seasonal affective disorder begin secreting melatonin earlier, showing a phase delay between cycles of melatonin and sleep. A few people with this disorder show a phase advance, with melatonin secretion beginning at a later time.

(Based on data from Lewy et al., 2006 .)

Phototherapy is safe and effective treatment for SAD. According to a study by Wirz-Justice et al. ( 1996 ), a special apparatus is not even needed. The authors found that a one-hour walk outside each morning reduced the symptoms of SAD. They noted that even on an overcast winter day, the early morning sky provides considerably more illumination than normal indoor artificial lighting, so a walk outside increases a person’s exposure to light. The exercise helps, too. Many studies (for example, Dunn et al., 2005 ) have shown that a program of exercise improves the symptoms of depression.

SECTION SUMMARY: Major Affective Disorders

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. 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. 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.

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.

Functional-imaging studies found 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. 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.

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.

■ THOUGHT QUESTION

A television commentator, talking in particular about the suicide of a young pop star and in general about unhappy youth, asked with exasperation, “What would all these young people be doing if they had real problems like a Depression, World War II, or Vietnam?” People with severe depression often try to hide their pain because they fear that others will scoff at them and say that they have nothing to feel unhappy about. If depression is caused by abnormal brain functioning, are these remarks justified? How would you feel if you were severely depressed and people close to you berated you for feeling so sad and told you to snap out of it and quit feeling sorry for yourself? Do you think the expression of attitudes like this would decrease the likelihood of a depressed person committing suicide?

Review Questions

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Describe the symptoms of schizophrenia and discuss the evidence that some forms of schizophrenia are heritable.

Discuss drugs that alleviate or produce the positive symptoms of schizophrenia; discuss research into the nature of a possible dopamine abnormality in the brains of schizophrenics.

Discuss evidence based on population studies that the negative symptoms of schizophrenia may result from brain damage.

Discuss direct evidence that schizophrenia is associated with brain damage.

Discuss the relationship between the prefrontal cortex in the positive and negative symptoms of schizophrenia.

Describe the two major affective disorders, the heritability of these diseases, and their physiological treatments.

Summarize the monoamine hypothesis of depression, evidence for brain abnormalities, and evidence concerning the role of the subgenual ACC in depression.

Explain the role of circadian and seasonal rhythms in affective disorders: the effects of REM sleep deprivation, slow-wave sleep deprivation, total sleep deprivation, and seasonal affective disorder.

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■ THE NERVOUS SYSTEM

Schizophrenia is arguably the psychopathology for which the neural bases have been best characterized. Many neural systems appear to be disrupted in patients with schizophrenia. Hypoactivity in the frontal cortex appears to be a cause of many of the symptoms of schizophrenia. The Nervous System module of the virtual brain shows this brain region.