Chapter 15

1. Chapter 15 Schizophrenia, Affective Disorders, and Anxiety Disorders

2. Schizophrenia 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).

3. Schizophrenia Schizophrenia A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors. Positive symptoms: delusions, hallucinations Negative Symptoms: social withdrawal, lack of motivation

4. Schizophrenia The symptoms of schizophrenia typically appear gradually and insidiously, over a period of 3 to 5 years. Negative symptoms are the first to emerge, followed by cognitive symptoms. The positive symptoms follow several years later.

5. Schizophrenia 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.

6. Schizophrenia So far, researchers have not yet located a “schizophrenia gene,” although many candidates have been found. Walsh et al. (2008) suggest that a large number of rare mutations play a role in the development of schizophrenia.

7. The Dopamine Hypothesis The explanation that has received the most attention from researchers is the dopamine hypothesis, which suggests that the positivesymptoms of schizophrenia are caused by overactivity of synapses between dopaminergic neurons of the ventral tegmental area and neurons in the nucleus accumbens and amygdala. 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 the patients.

8. The Dopamine Hypothesis 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).

9. The Dopamine Hypothesis Clozapine, the first of the atypical antipsychotic medications, has been joined by several others, including risperidone, olanzapine, ziprasidone, and aripiprazole.

10. Schizophrenia as a Neurological Disorder Weinberger and Wyatt (1982) obtained CT scans of eighty chronic schizophrenics and sixty-six normal controls of the same mean age (29 years). They found that the relative size of the lateral ventricles of the schizophrenic patients was more than twice as great as that of the normal control subjects. The most likely cause of the enlarged ventricles is loss of brain tissue; thus, the CT 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.

11. Figure 15.1 Relative Ventricular Size in Chronic Schizophrenics and Controls

12. Figure 15.2 Cerebral Gray Matter and Schizophrenia. The graph shows changes in volume of cerebral gray matter with age in normal subjects and people with schizophrenia.

13. Schizophrenia as a Neurological Disorder Seasonality effect The increased incidence of schizophrenia in people born during late winter and early spring. 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 their fetuses may be adversely affected either by a toxin produced by the virus or by the mother’s antibodies against the virus.

14. Figure 15.3 The Seasonality Effect. The graph shows the number of schizophrenic births per 10,000 live births.

15. Figure 15.5 Age at First Sign of Psychotic Symptoms in Schizophrenic Patients

16. Schizophrenia as a Neurological Disorder Many studies have shown evidence from MRI scans and postmortem examination of brain tissue that schizophrenia is associated with abnormalities in many parts of the brain (Shenton et al., 2001). In recent years the prefrontal cortex has received a great deal of attention. Weinberger (1988) first suggested that the negative symptoms of schizophrenia are caused primarily by hypofrontality.

17. Figure 15.6 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).

18. Schizophrenia as a Neurological Disorder This hypofrontality causes negative and cognitive symptoms to emerge. As the hypofrontality becomes more severe, decreased output from the prefrontal cortex to the ventral tegmental area causes a decrease in dopaminergic transmission to the prefrontal cortex and an increase in dopaminergic transmission to the nucleus accumbens.

19. Schizophrenia as a Neurological Disorder The atypical antischizophrenic drugs seem to do the impossible: They increase dopaminergic activity in the prefrontal cortex and reduce it in the nucleus accumbens. Aripiprazole acts as a partial agonist at dopamine receptors. 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.

20. Major Affective Disorders 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.

21. Major Affective Disorders Evidence indicates that a tendency to develop an affective disorder is a heritable characteristic. 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.

22. Major Affective Disorders Biological Treatments There are several established and experimental biological treatments for major depressive disorder: monoamine oxidase (MAO) inhibitors, drugs that inhibit the reuptake of norepinephrine or serotonin, electroconvulsive therapy (ECT), transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, bright-light therapy (phototherapy), and sleep deprivation.

23. Major Affective Disorders Biological Treatments Bipolar disorder can be treated by lithium and some anticonvulsant drugs. The fact that these disorders often respond to biological treatment provides additional evidence that they have a physiological basis.

24. Major Affective Disorders 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. Specific serotonin reuptake inhibitor (SSRI) An antidepressant drug that specifically inhibits the reuptake of serotonin without affecting the reuptake of other neurotransmitters. Serotonin and norepinephrine reuptake inhibitor (SNRI) An antidepressant drug that specifically inhibits the reuptake of norepinephrine and serotonin without affecting the reuptake of other neurotransmitters.

25. Figure 15.12 A Patient Being Prepared for Electroconvulsive Therapy

26. Major Affective Disorders Biological Treatments Preliminary research suggests that direct electrical stimulation of the brain (deep brain stimulation) may also be a useful therapy for treatment-resistant depression (Mayberg et al., 2005; Lozano et al., 2008). The investigators implanted stimulating electrodes just below the subgenual anterior cingulate cortex (subgenual ACC), a region of the medial prefrontal cortex.

27. Major Affective Disorders Biological Treatments Functional imaging studies have shown that the both vagus nerve stimulation and deep brain stimulation cause a progressive decrease in the activity of several brain regions, including the subgenual ACC (Lozano et al., 2008; Pardo et al., 2008). 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.

28. Major Affective Disorders The Monoamine Hypothesis The fact that depression can be treated with MAO inhibitors and drugs that inhibit the reuptake of monoamines suggested the monoamine hypothesis: Depression is caused by insufficient activity of monoaminergic neurons. 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.

29. Major Affective Disorders Evidence for Brain Abnormalities In a review of the relevant literature, Drevets (2001) suggests that the amygdala and several regions of the prefrontal cortex play special roles in the development of depression. A study by Abercrombie et al. (1998) found that the activity of the amygdala of depressed patients was positively correlated with the severity of their depression.

30. Major Affective Disorders Evidence for Brain Abnormalities Drevets et al. (1997) found that the subgenual ACC shows a lower level of activation in depressed patients. As the bar graph in Figure 15.14 shows, the activity of this region increases during a manic episode in patients with bipolar disorder(Drevets et al., 1997). Thus the activity of this region decreases during times of negative mood and increases during times of positive mood.

31. Major Affective Disorders Role of Circadian Rhythms One of the most prominent symptoms of depression is disordered sleep. The sleep of people with depression tends to be shallow; slow-wave delta sleep (stages 3 and 4) is reduced, and stage 1 is increased. Sleep is fragmented; people tend to awaken frequently, especially toward the morning.

32. Major Affective Disorders Role of Circadian Rhythms 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, 1990).

33. Major Affective Disorders Role of Circadian Rhythms The therapeutic effect, like that of the antidepressant medications, occurs slowly, over the course of several weeks. 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.

34. Major Affective Disorders Role of Circadian Rhythms 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.

35. Major Affective Disorders Role of Circadian Rhythms 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 (Szuba, Baxter, and Fairbanks, 1991; Leibenluft and Wehr, 1992).

36. Major Affective Disorders Role of 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.

37. Major Affective Disorders Role of Circadian Rhythms Phototherapy Treatment of seasonal affective disorder by daily exposure to bright light. Light serves as a zeitgeber; that is, it synchronizes the activity of the biological clock to the day–night cycle.

38. Anxiety Disorders A psychological disorder characterized by tension, overactivity of the autonomic nervous system, expectation of an impending disaster, and continuous vigilance for danger.

39. Anxiety Disorders Panic disorder A disorder characterized by episodic periods of symptoms such as shortness of breath, irregularities in heartbeat, and other autonomic symptoms, accompanied by intense fear. Generalized anxiety disorder A disorder characterized by excessive anxiety and worry serious enough to cause disruption of people’s lives. Social anxiety disorder A disorder characterized by excessive fear of being exposed to the scrutiny of other people that leads to avoidance of social situations in which the person is called on to perform.

40. Anxiety Disorders Functional imaging studies suggest that the amygdala and the cingulate, prefrontal, and insular cortices are involved in anxiety disorders. Monk et al. (2008) found that adolescents with generalized anxiety disorder showed increased activation of the amygdala and decreased activation of the ventrolateral prefrontal cortex while looking at angry faces.

41. Anxiety Disorders Anxiety disorders are sometimes treated with benzodiazepines. As we just saw, increased activity of the amygdala is a common feature of the anxiety disorders. The amygdala contains a high concentration of GABAA receptors, which are the target of the benzodiazepines. Much evidence suggests that serotonin plays a role in anxiety disorders.

42. Figure 15.23 Fluvoxamine and Panic Disorder. The graph shows the effects of fluvoxamine (an SSRI) on the severity of panic disorder.

43. Anxiety Disorders Obsessive-compulsive disorder (OCD) A mental disorder characterized by unwanted thoughts or ideas with which a person is preoccupied (obsessions) and feeling that one is obliged to perform a behavior, even if one prefers not to do so (compulsions). Obsessions include concern or disgust with bodily secretions, dirt, germs, and such; fear that something terrible might happen; and a need for symmetry, order, or exactness. Most compulsions fall into one of four categories: counting, checking, cleaning, and avoidance.

44. Anxiety Disorders Evidence suggests that OCD has a genetic origin. Several studies have found a greater concordance for obsessions and compulsions in monozygotic twins than in dizygotic twins (Hettema, Neale, and Kendler, 2001). At least two studies suggest that chromosome 9 contains a region associated with OCD (Hanna et al., 2002; Willour et al., 2004).

45. Anxiety Disorders Not all cases of OCD have a genetic origin; the disorder sometimes occurs after brain damage caused by various means, such as birth trauma, encephalitis, and head trauma (Hollander et al., 1990; Berthier et al., 1996). In particular, the symptoms of OCD appear to be associated with damage to or dysfunction of the basal ganglia, cingulate gyrus, and prefrontal cortex (Giedd et al., 1995; Robinson et al., 1995).

46. Anxiety Disorders In fact, some patients with severe OCD have been successfully treated with cingulotomy—the surgical destruction of the cingulum bundle, which connects the prefrontal cortex with the limbic system; helps to reduce intense anxiety and the symptoms of obsessive-compulsive disorder.