Schizophrenia

Schizophrenia is a disabling disorder characterized by perceptual, emotional, and intellectual deficits, loss of contact with reality, and inability to function in life.

An estimated 3 million Americans will develop schizophrenia during their lifetime.

100,000 patients take up 20% of psychiatric beds in the U.S.

Many more receive outpatient care.

Schizophrenia is a psychosis, which means the individual has severe disturbances of reality, orientation, and thinking.

The term schizophrenia was coined in 1911 by the Swiss psychiatrist Eugen Bleuler from the combination of two Greek words meaning “split mind.” The term refers to the distortion of thought and emotion, which are “split off” from reality.

The schizophrenic has some combination of several symptoms:

Hallucinations – internally generated perceptual experiences, such as voices telling the person what to do.

Delusion – false, unfounded beliefs, such as that one is a messenger from God.

Paranoia – characterized by delusions of persecution.

Disordered thought

Inappropriate emotions or lack of emotion

Social withdrawal

Schizophrenics are usually subdivided into diagnostic categories based on which of these symptoms is predominant, such as paranoid or catatonic.

Researchers have disagreed about whether to consider related spectrum disorders, such as schizotypal personality or schizoid personality, as a form of schizophrenia.

Schizophrenia afflicts men and women about equally often.

Men usually show the first symptoms during the teens or twenties, while the onset for women ordinarily comes about a decade later.

Acute symptoms develop suddenly and are typically more responsive to treatment.

The prognosis is reasonably good in spite of brief relapses.

Symptoms that develop gradually and persist for a long time with poor prognosis are called chronic.

Schizophrenia is a familial disorder, which means that the incidence of schizophrenia is higher among the relatives of schizophrenics than it is in the general population.

Identical twins of schizophrenics are three times as likely to be schizophrenic as the fraternal twins of schizophrenics.

The heritability for schizophrenia has been estimated at between .60 and .90.

This means that 10-40% of the variability is due to environmental factors.

Information from adoption studies gives a more impressive indication of genetic influence.

These studies show that adopting out of a schizophrenic home provides little or no protection from schizophrenia.

Schizophrenia

In spite of the difficulties, researchers have made significant progress recently and have identified a handful of genes responsible for schizophrenia with reasonably good assurance.

The genes are concerned primarily with neuronal migration, neuroreceptor development or sensitivity, and neurotransmitter activity.

Researchers are also teasing out the genes’ relationships to behavioral symptoms.

Most researchers agree that genes determine only the person’s vulnerability for the illness.

Both heredity and environment are needed to explain the etiology (causes) of schizophrenia.

According to the vulnerability model, some threshold of causal forces must be exceeded in order for the illness to occur.

Environmental challenges combine with a person’s genetic vulnerability to exceed that threshold.

Schizophrenia

Positive symptoms involve the presence or exaggeration of behaviors, such as delusions, hallucinations, thought disorder, and bizarre behavior.

Negative symptoms are characterized by the absence or insufficiency of normal behaviors, and include lack of affect (emotion), inability to experience pleasure, lack of motivation, poverty of speech, and impaired attention.

Schizophrenia

Little could be done to treat psychotic patients until the mid-1950s, when a variety of antipsychotic medications arrived on the scene.

As often is the case in medicine, and more particularly in mental health, these new drugs had not been designed for this purpose – researchers had too little understanding of the disease to do so.

Doctors tried chlorpromazine with a wide variety of mental illnesses because it calmed surgical patients, and it helped with schizophrenics.

However, it was not clear why chlorpromazine worked, because tranquilizers have little or no usefulness in treating schizophrenia.

Amphetamine overdose causes psychotic behavior indistinguishable from schizophrenia, complete with hallucinations and paranoid delusions.

In time, researchers were able to determine that amphetamine produces these symptoms by increasing dopaminergic activity.

This discovery eventually led to the dopamine hypothesis, that schizophrenia involves excessive dopamine activity in the brain.

According to the theory, blockade of type D₂ dopamine receptors is essential for a drug to have an antipsychotic effect, and effectiveness is directly related to the drug’s blocking potency.

Prolonged use of antidopamine drugs often produces tardive dyskinesia, tremors and involuntary movements caused by blocking of dopamine receptors in the basal ganglia.

The effect appears to be due to a compensatory increase in the sensitivity of D₂ receptors in the basal ganglia.

Since the early 1990s we have seen the introduction of several new antipsychotic drugs that are referred to as atypical.

One way atypical antipsychotics are different is that they target D₂ receptors much less, so they produce motor problems only at much higher doses.

Atypical antipsychotics are 15-25% more effective than conventional antipsychotics.

Although atypical antipsychotics mostly target receptors other than the D_2, those that lack at least a modest effect at D₂ receptors are therapeutically ineffective.

The drug phencyclidine (PCP) causes some of the symptoms of schizophrenia, and mimics schizophrenia better than amphetamine does.

PCP inhibits the NMDA glutamate receptor, which suggests that reduced glutamate might be a factor in schizophrenia.

The glutamate theory, that reduced glutamate activity is involved in schizophrenia, holds considerable theoretical and therapeutic promise.

The glutamate system influences the number of dopamine receptors.

Atypical antipsychotics also affect the serotonin system, which helps regulate the dopamine system.

Several studies have found reduced cortical gray matter, reduced limbic area volume, enlarged fissures and sulci and enlarged ventricles in the brains of schizophrenics. These deficits are often accompanied by enlarged ventricles.

Ventricular enlargement serves as a marker or indicator of the tissue deficiency, because the ventricles expand to take up space normally occupied by brain cells.

Recent attention has emphasized disordered connections between parts of the brain rather than local malfunction.

This approach is consistent with findings of reduced white matter in the brains of schizophrenics.

Many schizophrenics perform poorly on the Wisconsin Card Sorting Task, which requires the individual to switch from one card sorting strategy to another.

Many schizophrenics perform poorly on the test, persisting with the previous sorting strategy.

Normal individuals show increased activation in the prefrontal area during the test, and schizophrenics do not.

This hypofrontality apparently involves dopamine deficiency, because administering amphetamine to schizophrenics increases blood flow in the prefrontal cortex and improves performance on the Wisconsin Card Sorting Task.

Some of the brain defects in schizophrenia apparently stem from problems during pregnancy or at the time of birth.

Prenatal problems include physical complications and emotional stresses on the mother.

One indication that birth and pregnancy complications contribute to brain deficits is that they are associated with enlarged ventricles later in life.

The winter effect refers to the fact that more schizophrenics are born during the winter and spring than during any other time of the year.

Infants born between January and May would have been in the second trimester of prenatal development in the fall or early winter, when there is a high incidence of infectious diseases.

There is good evidence that the mother’s exposure to viral infections during the fourth to sixth months of pregnancy increases the risk of schizophrenia.

Prenatal starvation is another pathway to schizophrenia.

Affective Disorders

Almost all of us occasionally experience depression, an intense feeling of sadness.

In major depression a person often feels sad to the point of hopelessness for weeks at a time, loses the ability to enjoy life, relationships, and sex, and experiences loss of energy and appetite, slowness of thought, and sleep disturbance.

In some cases the person is also agitated or restless.

Stress is often a contributing factor, but major depression can occur for no apparent reason.

Mania involves excess energy and confidence that often lead to grandiose schemes.

Decreased need to sleep, increased sexual drive, and abuse of drugs are common.

Depression may appear alone as unipolar depression, or depression and mania may occur together in bipolar disorder.

In bipolar disorder, the individual alternates between periods of depression and mania.

Mania can occur without periods of depression, but this is rare.

Bipolar patients often show psychotic symptoms such as delusions, hallucinations, paranoia, or bizarre behavior.

The most recent data indicate that one in five people will suffer a mood disorder in their lifetime, most likely depression.

Women are two to three times more likely than men to suffer from unipolar depression during their lifetime.

Bipolar illness occurs equally often in both sexes at a rate of about 4%.

The risk for major depression increases with age in men, whereas women experience their peak risk between the ages of 35 and 45.

The period of greatest risk for bipolar disorder is in the early 20s to around the age of 30.

When one identical twin has an affective disorder, the probability the other twin will have the illness as well is about 69%, compared to 13% in fraternal twins.

In depression, heritability is somewhere around .37, with the number somewhat higher for women than for men.

Bipolar disorder is more heritable, with recent estimates of .85 and .93.

Iproniazid was introduced as a treatment for tuberculosis, but it was soon discovered that the drug produced elevation of mood and was an effective antidepressant.

Iproniazid’s ability to increase activity at the monoamine receptors led researchers to the monoamine hypothesis, that depression involved reduced activity at norepinephrine and serotonin synapses.

All the effective antidepressant drugs increase the activity of norepinephrine and serotonin, or both, at the synapses.

Some block the destruction of excess monoamines in the terminals (monoamine oxidase inhibitors), while others block reuptake at the synapse (tricyclic antidepressants).

Second-generation antidepressants affect a single neurotransmitter. For example, Prozac (fluoxetine) is one of several selective serotonin reuptake inhibitors.

These synaptic effects occur within hours, but symptom improvement takes two to three weeks.

Electroconvulsive therapy (ECT) involves applying 70 to 130 volts of electricity to the head of an anesthetized patient, to produce a seizure and convulsions. Without the seizure activity in the brain that produces the convulsions, the treatment does not work.

ECT is usually reserved for patients who do not respond to the medications or who cannot take them due to extreme side effects or because of pregnancy.

Like the drugs, ECT increases the sensitivity of postsynaptic serotonin receptors. In addition, the sensitivity of autoreceptors on the terminals of norepinephrine- and dopamine-releasing neurons is reduced, so the release of those transmitters is increased.

The circadian rhythm – the one that is a day in length – tends to be phase advanced in affective disorder patients.

Patients also enter rapid eye movement sleep (REM) earlier in the night and spend more time in REM than normal.

Some patients who are unresponsive to medication can get relief from their depression by readjusting their circadian rhythm.

Some depressed patients also benefit from a reduction in REM sleep.

Some people’s depression rises and falls with the seasons and is known as seasonal affective disorder (SAD).

Most SAD patients are more depressed during the fall and winter, then improve in the spring and summer.

A smaller number experience depression in the summer and improve in the winter.

A treatment for winter depression is phototherapy – having the patient sit in front of high-intensity lights for a couple of hours or more a day.

Lithium, a metal administered in the form of lithium carbonate, is the medication of choice for bipolar illness.

It is most effective during the manic phase, but it also prevents further depressive episodes.

Lithium most likely stabilizes neurotransmitter and receptor systems to prevent the large swings seen in manic-depressive cycling.

As with schizophrenia, affective disorders are associated with structural abnormalities in several brain areas.

There are volume deficits in the hippocampus and in prefrontal areas, especially the dorsolateral cortex and subgenual prefrontal cortex. 

The amygdala is increased in volume. These structural alterations are accompanied by changes in activity level.

Anxiety Disorders

A person with generalized anxiety has a feeling of stress and unease most of the time, and overreacts to stressful conditions.

In panic disorder the person has a sudden and intense attack of anxiety, with symptoms like rapid breathing, high heart rate, and feelings of impending disaster.

A person with a phobia experiences fear or stress when confronted with a particular situation such as crowds, heights, enclosed spaces, open spaces, dogs, or snakes.

Benzodiazepines have been the most frequently used anxiolytic (antianxiety) drugs in the past.

Benzodiazepines increase receptor sensitivity to the inhibitory transmitter GABA.

A deficit in benzodiazepine receptors may be one cause of anxiety disorder.

Anxiety also appears to involve low activity at serotonin synapses.

Antianxiety drugs initially suppress serotonin activity, then produce a compensatory increase.

A number of brain structures are activated in anxiety, including the amygdala and the locus coeruleus.

Both structures participate in more specific emotions, such as fear.

Drugs which decrease action in the locus coeruleus are anxiolytic; drugs which increase its action increase anxiety.

Obsessive-compulsive disorder (OCD) consists of two behaviors, obsessions and compulsions, which occur in the same person.

An obsession is a recurring thought.

A person may be annoyed by a tune that mentally replays over and over, or by troubling thoughts such as wishing harm to another person.

A compulsion is an recurring action.

The compulsive individual is compelled to engage in ritualistic behavior, such as touching a door frame three times before passing through, endless hand washing, or checking to see if appliances are turned off.

PET studies show that OCD patients have increased activity in the orbital frontal cortex and in a part of the basal ganglia, the caudate nuclei. This excess activity decreases following successful drug treatment and even behavior therapy.

White matter abnormalities suggest a defect in connections of the cingulate gyrus with a circuit involving the basal ganglia, thalamus, and cortex, which apparently results in a loss of impulse control.

Researchers believe that OCD patients are high in serotonergic activity. But the only drugs that consistently improve OCD symptoms are antidepressants that inhibit serotonin reuptake.

Family and twin studies indicate that the anxiety disorders are genetically influenced, with heritabilities ranging between .20 and .43, depending on the disorder.

Understanding the hereditary underpinnings of anxiety is difficult because of significant genetic overlap with other disorders.

Over 90% of individuals with anxiety disorders have a history of other psychiatric problems.

The overlap with affective disorders is particularly strong.

50-60% of patients with major depression also have a history of one or more anxiety disorders and panic disorder is found in 16% of bipolar patients.