Transcript Schizophrenia

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