A. Substance Abuse: A maladaptive pattern of substance use leading to clinically significant impairment of distress as defined by the APA (1994) in the DSM-IV (p.182).

B. Alcoholism or alcohol dependence: A common type of substance abuse that produces significant harm to people's lives, and those people find themselves continuing to drink in excess even after deciding to quit or reduce their drinking.

C. Researchers distinguish two major types of alcoholism:

I . Type I (or Type A) Alcoholism: This type of alcoholism is less dependent on genetic factors, develops gradually over years, affects men and women equally, and is generally less severe.

2. Type II (or Type B) Alcoholism: This type of alcoholism has a strong genetic basis, a rapid and early onset, affects men primarily, is more severe, and more associated with criminality.

D. Alcohol Metabolism and Antabuse

I . Acetaldehyde: A poisonous substance created when ethyl alcohol (drinking alcohol) is metabolized in the liver. Acetaldehyde is then further metabolized into acetic acid, a chemical the body can use as a source of energy.

2. Acetaldehyde dehydrogenase is the enzyme used to convert acetaldehyde into acetic acid.

3. Some people have an abnormal gene for acetaldehyde dehydrogenase so they metabolize alcohol slowly. One half of people in China and Japan have the gene that slows acetaldehyde metabolism.

4. Anatabuse (disulfiram): A drug that blocks the effects of the enzyme acetaldehyde dehydrogenase by binding to its copper ion. Anatabuse is used to treat alcoholism as after Antabuse administration ingesting alcohol leads to sickness.

E. Risk Factors for Alcohol Abuse

1. Less than average intoxication after drinking a small to moderate amount of alcohol.

2. Experiencing more than average relief from tension after drinking alcohol.

II. Mood Disorders

A. Major Depression: According to DSM-IV people with major depression feel sad, helpless, and lacking in energy and pleasure for weeks at a time. Individuals with major depression also feel worthless, have trouble sleeping, can not concentrate, get little pleasure from sex or food, may contemplate suicide, and in many cases can hardly imagine being happy.

1. Evidence of genetic or other biological predispositions to depression exists in many cases. This is especially true if you have relatives with depression that started before age 30 or if you are a woman.

2. The most severe depression is often seen in people who have suffered a traumatic situation and are already a little depressed.

3. Depression is usually episodic, not constant; someone may feel normal for weeks, months, or years between episodes of depression.

4. Most women experience the blues for a day or two after giving birth; only about 20 percent experience postpartum depression (depression after giving birth).

5. Most people suffering from depression have decreased activity in the left hemisphere and increased activity in the right prefrontal cortex.

6. Borna disease: Viral infection of the nervous system leading to periods of frantic activity alternating with periods of inactivity. In a study conducted in the early 1990's across three continents, 30 percent of severely depressed patients tested positive for the Boma virus; these findings, as well as those of other studies, suggest a relationship between the Boma virus and depression.

7. Antidepressant drugs: Drugs used for the treatment of depression and other mood disorders. These drugs fall into three categories:

• Tricyclics: Prevent the presynaptic neuron from reabsorbing catecholamines or serotonin after releasing them (this allows the neurotransmitter to remain longer in the synaptic cleft to stimulate postsynaptic receptors).

• Monoamine oxidase inhibitors (MA01s): Block the enzyme monoamine oxidase (MAO) from metabolizing catecholamines and serotonin into inactive forms.

• Selective serotonin reuptake inhibitors (SSRIs): similar to tricyclics, but are specific to the neurotransmitter serotonin. Ex: fluoxetine (Prozac).

• Atypical Antidepressants: A miscellaneous group of drugs with antidepressants effects and mild side effects including bupropion (Wellbutrin), which inhibits reuptake of dopamine and to some extent norepinephrine; venlaxfine, which inhibit the reuptake of serotonin and norepinephrine; and nefazodone, which specifically blocks serotonin type 2A receptors and blocks reuptake of serotonin and norepinephrine.

Most of antidepressants have delayed effects that limit the excitation of the postsynaptic cell. One effect is to decrease the sensitivity of the postsynaptic cell. Another the excess neurotransmitter in the synaptic cleft stimulates autoreceptors (a negative feedback receptor on the presynatpic terminal) on the presynaptic terminal, decreasing further release of neurotransmitter.

8. Other therapies for depression

• Placebo Effect: A benefit due to the expectation of improvement or mere passage of time. Only two-thirds of patients respond to either psychotherapy or antidepressants 'and one-third to one-half of all depressed patients improve when given a placebo (inactive drug). Thus, it appears that much of the benefit of psychotherapy and drugs in depressed patients is a placebo effect

• Electroconvulsive therapy (ECT): Inducing seizures with an electric shock to the head. ECT is usually applied every other day for about two weeks. About half of those who respond well to ECT relapse into depression within six months unless they are given antidepressant drugs or other therapies to prevent it.

• Most depressed people enter REM sleep within 45 minutes after going to bed compared to about 80 minutes for non-depressed people. One way to treat depression is to have the individual go to sleep earlier than usual, in phase with his or her temperature cycle; another way is to have the depressed person stay awake all night.\

B. Bipolar disorder (Manic-depression disorder): Alternating between episodes of depression and mania (characterized by restless activity, excitement, laughter, rambling speech, and loss of inhibitions). The mean age of onset of bipolar disorder is the late 20's.

I . There is a strong hereditary basis for bipolar disorder however no specific gene for this disorder has been located.

2. Lithium salts are the most effective therapy for bipolar disorder, but how it works remains unknown. Other drug treatments include anticonvulsant drugs such as valproic acid.

C. Seasonal affective disorder (SAD): Depression that reoccurs seasonally, usually in the winter.

1. SAD is most common in regions closest to the poles, where the nights are very long in winter and very short in summer.

2. It is possible to treat SAD by exposing the person to very bright lights for about an hour either early in the morning or in the evening.

III. Schizophrenia

A. Schizophrenia: A disorder characterized both by deteriorating ability to function in

everyday life and by some combination of delusions, hallucinations, movement disorder, thought disorder, and inappropriate emotional expression.

I . Although schizophrenia was originally called dementia praecox, Eugen Bleuler came up with the term schizophrenia in 1911, which has been preferred ever since.

2. Positive symptoms: Behaviors that are present that should be absent. Positive symptoms fall into two clusters that do not correlate strongly with each other:

• The psychotic cluster of positive symptoms consists of delusions (unfounded beliefs) and hallucinations (abnormal sensory experiences).

• The disorganized cluster of positive symptoms consists of inappropriate emotions, bizarre behavior and thought disorder (inability to use and understand abstract concepts).

3. Negative symptoms: Behaviors that are absent that should be present, such as deficits of social interaction and emotional expression.

4. Schizophrenia can be either acute (a sudden onset with a good possibility of returning to normal in a short time) or chronic (a gradual onset and a long-term course).

5. Expressed emotions: Hostile expressions by the caretaker of someone with schizophrenia that can aggravate the condition

6. Schizophrenia occurs in all ethnic groups and about equally in men and women; however, it usually develops at an earlier age in men.

B. Genetics

1. For monozygotic schizophrenic twins there is about a 50 percent concordance (agreement), and a 15 percent concordance for dizygotic twins. The greater concordance in monozygotic twins does not necessary mean a genetic cause as a pure genetic effect would have a 100 percent concordance and the greater environmental similarity in monozygotic twins as compared to dizyogotic twins may also influence the concordance rates.

2. Adopted children who develop schizophrenia usually have adopting relatives that are psychologically non-nal, but a high percentage of the biological relatives have schizophrenia.

3. Paternal half-siblings: Siblings with the same father but different mothers. A Danish study found that of sixty-three adopted schizophrenics with paternal halfsiblings, eight of the half-siblings had schizophrenia also (a concordance above the 1 percent prevalence in the population).

4. Danish studies suggest that children of non-schizophrenic twins have almost the same risk of schizophrenia as do the children of twins with schizophrenia. However, due to the small sample size no conclusion is justified.

C. The Neurodevelopmental hypothesis: Schizophrenia is caused in large part by abnormalities to the nervous system during the prenatal or neonatal periods.

1 . Many people with schizophrenia had problems before or shortly after birth that could have affected their brain development, including poor nutrition and low birth weight, and complications during delivery such as extensive maternal bleeding or prolonged labor.

2. Season-of-birth effect: Tendency for those born in winter to have a slightly greater probability of developing schizophrenia than those who are not; this tendency occurs only in nontropical climates. Many scientists believe that a viral infection during a fall pregnancy accounts for the season-of-birth effect.

3. MRI studies reveal that many schizophrenics have a slightly smaller prefrontal cortex, temporal cortex, hippocampus, and amygdala than non-schizophrenic adults. They also have larger than normal ventricles.

4. People suffering from schizophrenia have slightly larger right hemispheres compared to non-schizophrenic adults which tend to have larger left hemispheres. They also have lower than normal overall activity in the left hemisphere.

5. The areas of the brain that most consistently show signs of abnormality in schizophrenics are the ones that mature the most slowly, such as the prefrontal cortex.

6. At a microscopic level people with schizophrenia have smaller than normal cell bodies and some of their neurons fail to arrange themselves in the neat orderly manner of normal brains.

7. An important issue related to the neurodevelopmental hypothesis is why do the symptoms show up after 20 years of age if the damage occurs early in brain development. It is currently thought that the early damage to the brain is done in areas that are slow to mature such as the prefrontal cortex so the damage produces only minor symptoms in childhood but increasing impairments when the brain area fully matures.

D. Dopamine hypothesis of schizophrenia: According to this hypothesis, schizophrenia results from excess activity at certain dopamine synapses. The primary evidence for this hypothesis is the type of drugs that relieve and aggravate the symptoms of schizophrenia.

I . Chlorpromazine (Thorazine): First drug used successfully for the treatment of schizophrenia.

2. Antipsychotic drugs (neuroleptic drugs): Drugs used for the treatment of schizophrenia. These drugs work primarily by blocking dopamine receptors. a. Phenothiazines: A class of neuroleptic drugs, which includes chlorpromazine. b. Butyrophenones: A class of neuroleptic drugs which includes haloperidol (trade name Haldol).

3. Substance-induced psychotic disorder: Disorder characterized by hallucinations and delusions caused by drugs such as cocaine, amphetamine, and LSD that increase the activity of doparnine synapses.

4. Stress exacerbates the symptoms of schizophrenia and causes the release of dopamine from the prefrontal cortex an area believed to be important in schizophrenia.

5. Excess production and release of doparnine cannot be the sole cause of schizophrenia. Drugs that block dopamine receptors do so almost immediately, but their effects on behavior build up gradually over 2 or 3 weeks. Also, levels of dopamine and its metabolites are generally normal in schizophrenics. Furthermore, the research on dopamine receptors has yielded complicated results that are hard to interpret.

E. Glutamate hypothesis of schizophrenia: Idea that schizophrenia results from deficient activity at certain glutamate synapses. As dopamine inhibits glutamate activity in many parts of the brain, much of the evidence supporting the dopamine hypothesis of schizophrenia also supports the glutamate theory of schizophrenia.

1 . Phencyclidine (PCP): A drug that blocks glutamate type NMDA receptors. PCP administration produces a type of psychosis more similar to schizophrenia than that of drugs like cocaine as it induces both negative and positive symptoms. Moreover, PCP does not produce psychosis in preadolescents and PCP produces a much more severe psychosis in people with a history of schizophrenia.

2. Researchers have found that the brains of schizophrenic people release lower than normal amounts of glutamate in the prefrontal cortex and hippocampus. Also, measurements of RNA molecules associated with certain genes indicate deficient expression of glutamate receptors in the temporal lobe, hippocampus, and prefrontal cortex of schizophrenic patients.

3. Because increasing glutamate activity in the brain would be extremely risky, there are no drugs used to treat schizophrenia which directly stimulate glutamate activity. However, there are some experimental compounds that may someday be used to treat schizophrenia, such as the metabotropic glutamate agonist, LY 354740, which blocks the behavioral effects of PCP in rats and prevents its disruption of activity in the prefrontal cortex. Another possibility is the amino acid glycine which enhances the effects of glutamate at NMDA synapses.

F. The Search for Improved Drugs

I . Mesolimbocortical system: A set of neurons which project from the midbrain tegmenturn to the limbic system. This area is believed to be the area in which antipsychotics have their beneficial effects.

2. Tardive dyskinesia: A serious side effect of antipsychotics; this disorder is characterized by tremors and other involuntary movements. Tardive dyskinesia is probably due to denervation supersensitivity cause by the prolonged blockade of dopamine receptors.

3. Atypical antipsychotics: New drugs that alleviate the symptoms of schizophrenia while seldom if ever producing movement problems.

4. Clozapine: An atypical antipsychotic that alleviates both positive and negative symptoms of schizophrenia. Unfortunately, clozapine has for a side effect the tendency to decrease white blood cell counts.