chapter 15 schizophrenia, affective disorders, and anxiety disorders copyright © 2014 pearson...

Chapter 15Schizophrenia, Affective Disorders, and Anxiety Disorders

Copyright © 2014 Pearson Education, Inc. All Rights Reserved

SchizophreniaDescription

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).

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.



schizophreniaA serious mental disorder characterized by

disordered thoughts, delusions, hallucinations, and often bizarre behaviors.

positive symptomA symptom of schizophrenia evident by its

presence: delusions, hallucinations, or thought disorders.



thought disorderDisorganized, irrational thinking.

delusionA belief that is clearly in contradiction to reality.

hallucinationPerception of a nonexistent object or event.


Schizophrenia

Description

negative symptomA symptom of schizophrenia characterized by the

absence of behaviors that are normally present: social withdrawal, lack of affect, and reduced motivation.

cognitive symptomA symptom of schizophrenia characterized by

cognitive difficulties, such as deficits in learning and memory, poor abstract thinking, and poor problem solving.


Schizophrenia

Description

The symptoms of schizophrenia typically appear gradually and insidiously, over a period of three to five years.

Negative symptoms are the first to emerge, followed by cognitive symptoms.

The positive symptoms follow several years later.

As we will see later, this progression of symptoms provides some hints about the nature of the brain abnormalities that are responsible for them.


Schizophrenia

Heritability

One of the strongest pieces of evidence that schizophrenia is a biological disorder is that it appears to be heritable.

Both adoption studies (Kety et al., 1968, 1994) and twin studies (Gottesman and Shields, 1982; Tsuang, Gilbertson, and Faraone, 1991) indicate that schizophrenia is a heritable trait.


Schizophrenia

Heritability

So far, researchers have not yet located a single “schizophrenia gene,” although researchers have found many candidate 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 21 of the 23 pairs of chromosomes, but many of the findings have not been replicated.

So far, no single gene has been shown to cause schizophrenia.


Schizophrenia

Pharmacology of Schizophrenia: The Dopamine Hypothesis

Pharmacological evidence suggests that the positive symptoms of schizophrenia are caused by abnormalities in DA neurons.

The dopamine hypothesis suggests that the positive symptoms of schizophrenia are caused by overactivity of DA synapses.


Schizophrenia


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


Schizophrenia


Most researchers believe that the mesolimbic pathway, which begins in the ventral tegmental area and ends in the nucleus accumbens and amygdala, is likely to be involved in the symptoms of schizophrenia.

As we saw in Chapter 12, the activity of dopaminergic synapses in the mesolimbic system appears to be a vital link in the process of reinforcement.


Schizophrenia


The positive symptoms of schizophrenia also include disordered thinking and unpleasant, often terrifying delusions.

The disordered thinking may be caused by disorganized attentional processes; the indiscriminate activity of the dopaminergic synapses in the nucleus accumbens makes it difficult for the patients to follow an orderly, rational thought sequence.

Fibiger (1991) suggests that paranoid delusions may be caused by increased activity of the dopaminergic input to the amygdala.


Schizophrenia


Recent years have seen the development of the atypical antipsychotic medications, which reduce both the positive symptoms and negative symptoms of schizophrenia—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.


Schizophrenia

Schizophrenia as a Neurological Disorder

Compared to the positive symptoms, the negative and cognitive symptoms of schizophrenia are very different.

Whereas the positive symptoms are unique to schizophrenia, the negative and cognitive symptoms are similar to those produced by brain damage caused by several different means.

Many pieces of evidence suggest that these symptoms of schizophrenia are indeed a result of brain abnormalities in the prefrontal cortex.


Schizophrenia

Schizophrenia as a Neurological Disorder

There appear to be three possibilities: Predisposing factors (genetic, environmental, or both) give rise to:

1) abnormalities in both DA transmission and in the prefrontal cortex

2) abnormalities in DA transmission that cause abnormalities in the prefrontal cortex

3) abnormalities in the prefrontal cortex that cause abnormalities in DA transmission.


Schizophrenia

Schizophrenia as a Neurological DisorderEvidence 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, poor control of eye movements and unusual facial expressions (Stevens, 1982).

In addition, many studies have found evidence of loss of brain tissue in CT and MRI scans of schizophrenic patients.


Schizophrenia


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).

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. (See Figure 15.1.)


Schizophrenia


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.


Schizophrenia

Schizophrenia as a Neurological DisorderPossible Causes of Brain Abnormalities

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.


Schizophrenia

Schizophrenia as a Neurological DisorderEpidemiological Studies

epidemiologyThe study of the distribution and causes of diseases

in populations.

Evidence from these studies indicates that the incidence of schizophrenia is related to several environmental factors:, season of birth, viral epidemics, population density, and substance abuse (Brown and Derkits, 2010; King, St-Hilaire, and Heidkamp, 2010).


Schizophrenia


seasonality effectThe increased incidence of schizophrenia in people

born during late winter and early spring.

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 15.2.)


Schizophrenia


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.


Schizophrenia


Similarly, Eaton, Mortensen, and Frydenberg (2000) reported that schizophrenia is approximately three times higher in people who live in the middle of large cities than in those who live in rural areas, presumably because the transmission of infectious illnesses is facilitated by increased population density.


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.


Schizophrenia


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.


Schizophrenia


Even paternal tobacco use increased this risk, which suggest that second-hand 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.


Schizophrenia

Schizophrenia as a Neurological DisorderEvidence for Abnormal Brain Development

Both behavioral and anatomical evidence indicates that abnormal prenatal development is associated with schizophrenia.

The results of these studies are consistent with the hypothesis that although the symptoms of schizophrenia are not normally seen in childhood, the early brain development of children who later become schizophrenic is not entirely normal.


Schizophrenia


The concordance rate of monozygotic twins for schizophrenia is less than 100 percent.

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.


Schizophrenia


The prenatal environments of monochorionic twins, who share a single placenta, are 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.


Schizophrenia


In fact, they are.

Davis, Phelps, and Bracha (1995) found 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.


Schizophrenia


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 15.4 shows a graph of the ages of first signs of mental disorder in males and females diagnosed with schizophrenia. (See Figure 15.4.)


Schizophrenia

Relationship between Positive and Negative Symptoms: Role of the Prefrontal Cortex

As we saw, schizophrenia has positive, negative, and cognitive symptoms.

The positive symptoms may be caused by hyperactivity of dopaminergic synapses, and the negative and cognitive symptoms may be caused by developmental or degenerative changes in the brain.


Schizophrenia


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 dorsolateral prefrontal cortex (dlPFC).

In fact, schizophrenic patients do poorly on neuropsychological tests that are sensitive to prefrontal damage.


Schizophrenia


hypofrontalityDecreased activity of the prefrontal cortex; believed

to be responsible for the negative symptoms of schizophrenia.


Schizophrenia


The atypical antipsychotic drug clozapine alleviates the positive, negative, and cognitive symptoms of schizophrenia.

In a study with monkeys, Youngren et al. (1999) found that injections of clozapine, which cause an increase in the release of dopamine in the prefrontal cortex, also causes a decrease in the release of dopamine by the mesolimbic system, which apparently reduces the negative and cognitive symptoms.


Schizophrenia


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.

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.


Major Affective Disorders

major affective disorderA serious mood disorder; includes unipolar

depression and bipolar disorder.

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

Depression has a prevalence of approximately 3 percent in men and 7 percent in women, which makes it the 4th leading cause of disability (Kessler et al., 2003).

There are two principal types of major affective disorders:

1. Bipolar Disorder

2. Major Depressive Disorder



Description

bipolar disorderA 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.



Description

Severely depressed people usually feel 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.



Description

Depressed people have very little energy, and they move and talk slowly, sometimes becoming almost torpid.

At other times, they may pace around restlessly and aimlessly. They may cry a lot.

They are unable to experience pleasure and lose their appetite for food and sex.

Their sleep is disturbed; they usually have difficulty falling asleep and awaken early and find it difficult to get to sleep again.



Description

Episodes of mania are characterized by a sense of euphoria that does not seem to be justified by circumstances.

The diagnosis of mania is partly a matter of degree; one would not call exuberance and a zest for life pathological.

People with mania usually exhibit nonstop speech and motor activity.



Description

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.



Heritability

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.



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.




tricyclic antidepressantA 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.

electroconvulsive therapy (ECT)A brief electrical shock, applied to the head, that

results in an electrical seizure; used therapeutically to alleviate severe depression.




Remission of symptoms is greater than 50%, 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.




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.

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.




Deep brain stimulation has also been directed toward the nucleus accumbens.

The release of dopamine in this region plays a critical role in reinforcement and the response to pleasurable stimuli.

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.




The therapeutic effect of lithium, the drug used to treat bipolar affective disorders, is very rapid.

lithiumA chemical element; lithium carbonate is used to

treat bipolar disorder.

This drug, which is administered in the form of lithium carbonate, is most effective in treating the manic phase of a bipolar affective disorder; once the mania is eliminated, depression usually does not follow.



The Monoamine Hypothesis

The monoamine hypothesis of depression was suggest by the fact that monoamine antagonists can produce the symptoms of depression and monoamine agonists can reduce them.

tryptophan depletion procedureA 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.




Although SSRIs and SNRIs change the 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 in 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 Frontal Cortex

Figure 15.10 shows the results of functional imaging scans of the medial frontal region of depressed patients who were successfully treated with a variety of treatments.

Increases in activity after successful treatment are shown in red; decreases are shown in blue.

Successful treatment led to decreased activity in the subgenual ACC. (See Figure 15.10.)



Role of the Frontal Cortex

The 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.


Anxiety Disorders

anticipatory anxietyA fear of having a panic attack; may lead to the development of agoraphobia.

agoraphobiaA fear of being away from home or other protected places.


Anxiety Disorders

generalized anxiety disorderA disorder characterized by excessive anxiety and

worry serious enough to cause disruption of their lives.

social anxiety disorderA 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.


Anxiety DisordersPossible Causes

Family studies and twin studies indicate that panic disorder, generalized anxiety disorder, and social anxiety disorder all have a hereditary component (Hettema, Neale, and Kendler, 2001; Merikangas and Low, 2005).

Genetic investigations indicate that variations in the gene that encodes production the BDNF protein may play a role in anxiety disorders.

BDNF (brain-derived neurotrophic factor) regulates neuronal survival and differentiation during development, plays a role in long-term potentiation and memory, and is associated with anxiety and depression (Yu et al., 2009).


Anxiety DisordersPossible Causes

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.

Stein et al. (2007) found that college students with a high level of anxiety showed increased activation of the amygdala and the insular cortex, both of which correlated positively with students’ anxiety measures.


Anxiety DisordersTreatment

Anxiety disorders are sometimes treated with benzodiazepines.

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.



Benzodiazepines are often used for emergency medical treatment for anxiety disorders because the therapeutic effects of these drugs have a rapid onset.

However, they are less satisfactory for long-term treatment.

They cause sedation, they induce tolerance and withdrawal symptoms, and they have a potential for abuse.

For these reasons, researchers have been seeking other drugs to treat anxiety disorders.



Much evidence suggests that serotonin plays a role in anxiety disorders too.

Even though the symptoms of the anxiety disorders discussed in this subsection are very different from those of obsessive-compulsive.

Specific serotonin reuptake inhibitors, which serve as potent serotonin agonists (such as fluoxetine), have become the first-line medications for treating all of these disorders—preferably in combination with cognitive behavior therapy.


Anxiety DisordersObsessive-Compulsive Disorder

The incidence of obsessive-compulsive disorder is 1–2 percent.

Females are slightly more likely than males to have this diagnosis. OCD most commonly begins in young adulthood (Robbins et al., 1984).

People with severe symptoms of this disorder are unlikely to marry, perhaps because of the common obsessional fear of dirt and contamination or because of the shame associated with the rituals they are compelled to perform, which causes them to avoid social contacts.


Anxiety DisordersObsessive-Compulsive Disorder

obsessive-compulsive disorder (OCD)A mental disorder characterized by obsessions and compulsions.

obsessionAn unwanted thought or idea with which a person is preoccupied.

compulsionThe feeling that one is obliged to perform a

behavior, even if one prefers not to do so.


Anxiety DisordersObsessive-Compulsive DisorderPossible Causes

Evidence suggests that obsessive-compulsive disorder 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).



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).



Several functional imaging studies have found evidence of increased activity in the frontal lobes and caudate nucleus in patients with OCD.

A review by Whiteside, Port, and Abramowitz (2004) found that functional imaging studies consistently found increased activity of the caudate nucleus and the prefrontal cortex.


Anxiety DisordersObsessive-Compulsive DisorderTreatment

The prefrontal cortex and the cingulate cortex are involved in emotional reactions, so it is not surprising to learn that they might be implicated in OCD.

In fact, some patients with severe OCD have been successfully treated with cingulotomy.

cingulotomyThe 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.


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symptoms of schizophrenia

single schizophrenia

cognitive symptoms

positive symptoms

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