Chapter 16

1. Chapter 16 Schizophrenia and the Affective Disorders

2. Schizophrenia • A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors • Afflicts ~1% of population • Probably the most misused psychological term – literally means “split mind”, so often confused with multiple personality disorder • Positive symptoms – symptoms evident by their presence • Thought disorders – disorganized, irrational thinking (most important symptom) • Delusions – a belief that is clearly in contradiction to reality • Persecution – false beliefs that others are plotting against oneself • Grandeur – false beliefs in one’s own power • Control – belief that one is being controlled by others • Hallucinations – perception of a nonexistent object or event

3. Schizophrenia • Negative symptoms – characterized by the absence of behaviors that are normally present • Flattened emotional response • Poverty of speech • Lack of initiative and persistence • Inability to experience pleasure • Social withdrawal • Heritability • Both adoption and twin studies indicate that schizophrenia is a heritable trait • If there is a “schizophrenia gene”, then it must be triggered by some type of env’tal event • Study shows that higher paternal age is positively correlated with diagnosis of schizophrenia

4. Pharmacology of Schizophrenia • Dopamine hypothesis – suggest that schizophrenia is caused by overactivity of DA synapses, probably those in the mesolimbic pathway • Effects of DA agonists and antagonist • A drug used to prevent surgical shock, chlorpromazine, was dramatically effective in reducing symptoms of schizophrenia • Since this discovery, many other drugs have been developed that relieve the positive symptoms of schizophrenia; All of these drugs block DA receptors • DA agonists act to produce positive symptoms of schizophrenia (e.g amphetamine, cocaine and L-DOPA) • The mesolimbic pathway is most likely involved in schizophrenia; could be caused by reinforcing effects of this pathway for any of the behaviors found with positive symptoms

5. Pharmacology of Schizophrenia • Effects of DA agonists and antagonist • Schizophrenics often report feelings of elation and euphoria at the beginning of a schizophrenic episode, suggesting that this is caused by hyperactivity of DA neurons involved in reinforcement • Paranoid delusions may be caused by increased activity of the DA input to the amygdala • Amygdala is involved with conditioned emotional responses for aversive events • DA transmission abnormalities • DA neurons may release more DA • Amphetamine administration caused the release of more DA in the striatum of schizophrenic patients; patients with greater amounts of DA showed greater increases in positive symptoms • There may be moderate increases in the numbers of D2 receptors, but it is unlikely that that is the cause of the disorder • Clozapine – an atypical antipsychotic drug; blocks D4 receptors in the nucleus accumbens

6. Pharmacology of Schizophrenia • Long-term drug treatment • The symptoms of up to 1/3 of all schizophrenic patients are not substantially reduced by antipsychotic drugs • Many drugs produce serious side effects • Until recently, all drugs caused at least some symptoms resembling those of Parkinson’s disease: slow movement, lack of facial expression, general weakness • Tardive dyskinesia – a movement disorder that can occur after prolonged treatment with antipsychotic medication, characterized by involuntary movements of the face and neck • Caused by overstimulation of DA receptors • Why would antagonists cause overstimulation of DA receptors? • Supersensitivity – the increased sensitivity of NT receptors; caused by damage to the afferent axons or long-term blockage of NT release • However, new drugs have been developed that do not produce these long-term side effects – atypical antipsychotic drugs (Clozapine)

7. Schizophrenia as a neurological disorder • Whereas the positive symptoms are unique to schizophrenia, the negative symptoms are similar to those produced by brain damage caused by several different means • Brain abnormalities in schizophrenia • Patients with schizophrenia exhibit neurological symptoms that suggest brain damage (e.g. poor control of eye movements, unusual facial expressions) • This suggests that schizophrenia may be associated with brain damage of some kind • MRI and CT studies have found loss of brain tissue in patients with schizophrenia • Relative size of lateral ventricles was more than twice the size of control subjects

8. Schizophrenia as a neurological disorder • Possible causes of brain abnormalities • Why do less than ½ the children of schizophrenic patients become schizophrenic? • Perhaps what is inherited is a susceptibility to environmental factors that may lead to some type of brain damage • Development of disorder is most likely caused by interaction b/t genes and environment • However, people can develop schizophrenia without and family history • Epidemiology – study of distribution and causes of diseases in populations; try to correlate disease frequencies with factors that are present in the env’t • People born during late winter and early spring are more likely to develop schizophrenia – seasonality effect • Possibly caused by higher likelihood of mother contracting viral illness • Also more likely to occur in cities rather than countryside

9. Schizophrenia as a neurological disorder • Possible causes of brain abnormalities • People born far from the equator are more likely to develop schizophrenia – latitude effect • Decreased winter temp may magnify seasonality effects • Famine (especially thiamine deficiency) during pregnancy may cause schizophrenia in offspring • Underweight women are more likely to give birth to babies who later develop schizophrenia; low birth-weight babies have higher incidence of schizophrenia • Vitamin D deficiency • Rh incompatibility • Red blood cells of Rh-positive person contain Rh factor • If fetus is Rh incompatible with mother, then increased likelihood of schizophrenia in offspring

10. Schizophrenia as a neurological disorder • Evidence for abnormal brain development • Prenatal brain development of children who become schizophrenic is not normal • Reports of both behavioral and anatomical abnormalities • Children who later became schizophrenic displayed more negative affect in their facial expressions and were more likely to show abnormal movements • Some monozygotic twins are discordant (i.e. one develops it, the other does not) for schizophrenia: difference in brain structure (one has larger ventricles, degeneration in specific regions of cerebral cortex) • Monochorionic (share one placenta) vs. dichorionic (separate placentas) in monozygotic twins: concordance rate for schizophrenia was lower in dichorionic vs. monochorionic • Schizophrenia not caused by degeneration, but by a rapid loss of brain volume during young adulthood • Does not involve death of neurons, but a loss of neuropil,the network of dendrites and axons in the brain

11. Schizophrenia as a neurological disorder • Positive and negative symptoms: Prefrontal cortex • Is there a relationship b/t the 2 categories of symptoms? • Negative symptoms caused by hypofrontality (decreased activity of the frontal lobes), primarily in the dorsolateral prefrontal cortex • May be caused by decrease in release of DA in prefrontal cortex, mediated mostly by D1 receptors • Chronic abuse of PCP (indirect glutamate antagonist) causes a decrease of metabolic activity in frontal lobes • Chronic PCP treatment reduces DA activity in the prefrontal cortex, which in turn produces hypofrontality that appears to be responsible for the negative symptoms of schizophrenia • Prefrontal hypoactivity (neg. symptoms) causes mesolimbic DA hyperactivity (pos. symptoms) • Clozapine causes an increase in DA release in prefrontal cortex, and decrease of DA release in nucleus accumbens

12. Major Affective Disorders • Affect – refers to feelings or emotions • Major affective disorders – a serious mood disorder; includes unipolar and bipolar disorder • Bipolar disorder – characterized by cyclical periods of mania (extreme elation) and depression (extreme despair); episodes of mania generally shorter than episodes of depression • Unipolar depression – consists of unremitting depression or periods of depression that do not alternate with periods of mania • Depression causes very little energy, crying, inability to experience pleasure, disturbed sleep, depressed bodily functions • Mania involves sense of euphoria, nonstop speech and motor activity, easily angered, go without sleep

13. Major Affective Disorders • Heritability • The tendency to develop a major affective disorder is heritable • A single dominant gene is responsible for susceptibility to developing bipolar disorder • Physiological treatments • MAO inhibitors • Drugs (e.g. Iproniazid) that inhibit the activity of MAO, the enzyme that destroys excess monoamine transmitter substance within terminal buttons, increase the release of DA, NE and 5-HT • Have serious side effects, e.g. cheese effect with pressor amines • Tricyclic antidepressants • Inhibit the reuptake of 5-HT and NE by terminal buttons • This keeps the NT in contact with the postsynaptic receptor, thus prolonging the postsynaptic potentials • Specific serotonin reuptake inhibitors (SSRI) • Inhibit reuptake of 5-HT • Widely prescribed for depression and for symptoms of OCD and social phobia

14. Major Affective Disorders • Physiological treatments • Electroconvulsive therapy (ECT) • Electrodes placed on patients scalp deliver a jolt of electricity to trigger a seizure • Most effective with mania and depression • Effects are rapid, as compared to drugs • Lithium • Most effective in treating the manic phase of bipolar disorder • Does not suppress normal feelings of emotion • Does not impair intellectual processes • Does have some side effects, including hand tremors, weight gain, excessive urine production and thirst • Some patients with bipolar disorder have trouble continuing with medication • Those who cannot tolerate side effects can take carbamazepine, an anti-seizure medication

15. Major Affective Disorders • Role of monoamines • Monoamine hypothesis: hypothesis that states that depression is caused by a low level of activity of one or more monoaminergic synapses • Since the symptoms of depression do not respond to potent DA agonists (e.g. amphetamine or cocaine), researchers have focused on NE and 5-HT • Depression can be caused by monoamine antagonists • e.g. reserpine • Suicidal depression is related to decreased CSF levels of 5-HIAA, a metabolite of 5-HT that is produced when MAO breaks it down • Families of subjects with low levels of 5-HIAA were more likely to include people with depression • Suggests that 5-HT metabolism or release is genetically controlled and is linked to depression

16. Major Affective Disorders • Role of monoamines • Tryptophan depletion procedure • Depressed patients currently taking medication • Gave low-tryptophan diet, follwed by an amino acid “cocktail”, which would inhibit what little tryptophan was left from entering the brain • Tryptophan depletion caused most of the patients to relapse back into depression • However, recovered after resuming normal diet • This has no effect on healthy, non-depressed subjects, but does lower the mood of people with a family history of affective disorders

17. Major Affective Disorders • A role for Substance P? • A peptide secreted as a NT and neuromodulator in several regions of the brain • May be involved in emotional behavior, the response to stress, and the symptoms of depression • Long-term admin of antidepressants cause a reduction of substance P levels in several regions of the brain • MK-869, a drug that blocks the receptor for substance P (NK1) shows a reduction in depressive symptoms • Substance P antagonists appear to act independently of drugs that reduce depression by blocking the reuptake of 5-HT and NE

18. Major Affective Disorders • Evidence for brain abnormalities • Studies have found abnormalities in the prefrontal cortex, basal ganglia, and cerebellum of patients with unipolar depression, and abnormalities of the cerebellum in those with bipolar disorder • Found in young patients, which suggests the presence of a developmental abnormality or a degenerative process that occurs early in life • Repeated episodes of depression and mania caused an increase in the size of the lateral ventricles • The amygdala and several regions of the prefrontal cortex play a role in the development of depression • Activity of amygdala of depressed patients was correlated with the severity of their depression • Orbitofrontal cortex generally more active in depressed patients • Subgenual prefrontal cortex shows a lower level of activation in depressed patients; activity in this region is increased during manic episodes

19. Major Affective Disorders • Evidence for brain abnormalities • Silent cerebral infarctions • A small cerebrovascular accident (stroke) that causes minor brain damage without producing obvious neurological symptoms • Appears to be a major cause of late-onset depression (first occurs later in life) • Risk factors are similar for stroke (e.g. smoking, hypertension)

20. Major Affective Disorders • Role of circadian rhythms • One of the most prominent symptoms of depression is disordered sleep • Sleep of depressed individuals is shallow, Stages 3 & 4 are reduced, Stage 1 is increased • REM sleep occurs earlier • Selective deprivation of REM sleep alleviates depression • The effect occurs slowly like that of drugs • Other treatments for depression suppress REM sleep, suggesting that REM sleep and mood may be correlated • Successful ECT treatments suppress REM sleep in depressed patients • Total sleep deprivation produces immediate effects • Perhaps, during sleep a substance is produced that has a depressogenic effect • Depressed patients whose moods fluctuate more often will benefit from sleep deprivation more

21. Major Affective Disorders • Role of Zeitgebers • Seasonal affective disorder – a mood disorder characterized by depression, lethargy, sleep disturbances, and craving for carbohydrates during the winter season when days are short • Summer depression – a mood disorder characterized by depression, sleep disturbances, and loss of appetite • Seasonal affective disorder appears to have a genetic basis • Molecular genetic studies suggest that seasonal affective disorder may be linked to genes involved in production of the 5-HT transporter and the 5-HT2A receptor • SAD can be treated with phototherapy, treatment of exposing people to bright light for several hours a day