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Chapter 16 – Schizophrenia and the Affective Disorders


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Chapter 16 – Schizophrenia and the Affective Disorders

  1. 1. Chapter 16 Schizophrenia and the Affective Disorders
  2. 2. Schizophrenia <ul><li>A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors </li></ul><ul><li>Afflicts ~1% of population </li></ul><ul><li>Probably the most misused psychological term – literally means “split mind”, so often confused with multiple personality disorder </li></ul><ul><li>Positive symptoms – symptoms evident by their presence </li></ul><ul><ul><li>Thought disorders – disorganized, irrational thinking (most important symptom) </li></ul></ul><ul><ul><li>Delusions – a belief that is clearly in contradiction to reality </li></ul></ul><ul><ul><ul><li>Persecution – false beliefs that others are plotting against oneself </li></ul></ul></ul><ul><ul><ul><li>Grandeur – false beliefs in one’s own power </li></ul></ul></ul><ul><ul><ul><li>Control – belief that one is being controlled by others </li></ul></ul></ul><ul><ul><li>Hallucinations – perception of a nonexistent object or event </li></ul></ul>
  3. 3. Schizophrenia <ul><li>Negative symptoms – characterized by the absence of behaviors that are normally present </li></ul><ul><ul><li>Flattened emotional response </li></ul></ul><ul><ul><li>Poverty of speech </li></ul></ul><ul><ul><li>Lack of initiative and persistence </li></ul></ul><ul><ul><li>Inability to experience pleasure </li></ul></ul><ul><ul><li>Social withdrawal </li></ul></ul><ul><li>Heritability </li></ul><ul><ul><li>Both adoption and twin studies indicate that schizophrenia is a heritable trait </li></ul></ul><ul><ul><li>If there is a “schizophrenia gene”, then it must be triggered by some type of env’tal event </li></ul></ul><ul><ul><li>Study shows that higher paternal age is positively correlated with diagnosis of schizophrenia </li></ul></ul>
  4. 4. Pharmacology of Schizophrenia <ul><li>Dopamine hypothesis – suggest that schizophrenia is caused by overactivity of DA synapses, probably those in the mesolimbic pathway </li></ul><ul><li>Effects of DA agonists and antagonist </li></ul><ul><ul><li>A drug used to prevent surgical shock, chlorpromazine , was dramatically effective in reducing symptoms of schizophrenia </li></ul></ul><ul><ul><li>Since this discovery, many other drugs have been developed that relieve the positive symptoms of schizophrenia; All of these drugs block DA receptors </li></ul></ul><ul><ul><li>DA agonists act to produce positive symptoms of schizophrenia (e.g amphetamine, cocaine and L-DOPA) </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  5. 5. Pharmacology of Schizophrenia <ul><li>Effects of DA agonists and antagonist </li></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Paranoid delusions may be caused by increased activity of the DA input to the amygdala </li></ul></ul><ul><ul><ul><li>Amygdala is involved with conditioned emotional responses for aversive events </li></ul></ul></ul><ul><li>DA transmission abnormalities </li></ul><ul><ul><li>DA neurons may release more DA </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><ul><ul><li>There may be moderate increases in the numbers of D 2 receptors, but it is unlikely that that is the cause of the disorder </li></ul></ul></ul><ul><ul><ul><li>Clozapine – an atypical antipsychotic drug; blocks D 4 receptors in the nucleus accumbens </li></ul></ul></ul>
  6. 6. Pharmacology of Schizophrenia <ul><li>Long-term drug treatment </li></ul><ul><ul><li>The symptoms of up to 1/3 of all schizophrenic patients are not substantially reduced by antipsychotic drugs </li></ul></ul><ul><ul><li>Many drugs produce serious side effects </li></ul></ul><ul><ul><ul><li>Until recently, all drugs caused at least some symptoms resembling those of Parkinson’s disease: slow movement, lack of facial expression, general weakness </li></ul></ul></ul><ul><ul><li>Tardive dyskinesia – a movement disorder that can occur after prolonged treatment with antipsychotic medication, characterized by involuntary movements of the face and neck </li></ul></ul><ul><ul><ul><li>Caused by overstimulation of DA receptors </li></ul></ul></ul><ul><ul><li>Why would antagonists cause overstimulation of DA receptors? </li></ul></ul><ul><ul><ul><li>Supersensitivity – the increased sensitivity of NT receptors; caused by damage to the afferent axons or long-term blockage of NT release </li></ul></ul></ul><ul><ul><li>However, new drugs have been developed that do not produce these long-term side effects – atypical antipsychotic drugs (Clozapine) </li></ul></ul>
  7. 7. Schizophrenia as a neurological disorder <ul><li>Whereas the positive symptoms are unique to schizophrenia, the negative symptoms are similar to those produced by brain damage caused by several different means </li></ul><ul><li>Brain abnormalities in schizophrenia </li></ul><ul><ul><li>Patients with schizophrenia exhibit neurological symptoms that suggest brain damage (e.g. poor control of eye movements, unusual facial expressions) </li></ul></ul><ul><ul><li>This suggests that schizophrenia may be associated with brain damage of some kind </li></ul></ul><ul><ul><li>MRI and CT studies have found loss of brain tissue in patients with schizophrenia </li></ul></ul><ul><ul><ul><li>Relative size of lateral ventricles was more than twice the size of control subjects </li></ul></ul></ul>
  8. 8. Schizophrenia as a neurological disorder <ul><li>Possible causes of brain abnormalities </li></ul><ul><ul><li>Why do less than ½ the children of schizophrenic patients become schizophrenic? </li></ul></ul><ul><ul><ul><li>Perhaps what is inherited is a susceptibility to environmental factors that may lead to some type of brain damage </li></ul></ul></ul><ul><ul><ul><li>Development of disorder is most likely caused by interaction b/t genes and environment </li></ul></ul></ul><ul><ul><ul><li>However, people can develop schizophrenia without and family history </li></ul></ul></ul><ul><ul><li>Epidemiology – study of distribution and causes of diseases in populations; try to correlate disease frequencies with factors that are present in the env’t </li></ul></ul><ul><ul><li>People born during late winter and early spring are more likely to develop schizophrenia – seasonality effect </li></ul></ul><ul><ul><ul><li>Possibly caused by higher likelihood of mother contracting viral illness </li></ul></ul></ul><ul><ul><ul><li>Also more likely to occur in cities rather than countryside </li></ul></ul></ul>
  9. 9. Schizophrenia as a neurological disorder <ul><li>Possible causes of brain abnormalities </li></ul><ul><ul><li>People born far from the equator are more likely to develop schizophrenia – latitude effect </li></ul></ul><ul><ul><ul><li>Decreased winter temp may magnify seasonality effects </li></ul></ul></ul><ul><ul><li>Famine (especially thiamine deficiency) during pregnancy may cause schizophrenia in offspring </li></ul></ul><ul><ul><li>Underweight women are more likely to give birth to babies who later develop schizophrenia; low birth-weight babies have higher incidence of schizophrenia </li></ul></ul><ul><ul><li>Vitamin D deficiency </li></ul></ul><ul><ul><li>Rh incompatibility </li></ul></ul><ul><ul><ul><li>Red blood cells of Rh-positive person contain Rh factor </li></ul></ul></ul><ul><ul><ul><li>If fetus is Rh incompatible with mother, then increased likelihood of schizophrenia in offspring </li></ul></ul></ul>
  10. 10. Schizophrenia as a neurological disorder <ul><li>Evidence for abnormal brain development </li></ul><ul><ul><li>Prenatal brain development of children who become schizophrenic is not normal </li></ul></ul><ul><ul><ul><li>Reports of both behavioral and anatomical abnormalities </li></ul></ul></ul><ul><ul><ul><li>Children who later became schizophrenic displayed more negative affect in their facial expressions and were more likely to show abnormal movements </li></ul></ul></ul><ul><ul><ul><li>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) </li></ul></ul></ul><ul><ul><ul><li>Monochorionic (share one placenta) vs. dichorionic (separate placentas) in monozygotic twins: concordance rate for schizophrenia was lower in dichorionic vs. monochorionic </li></ul></ul></ul><ul><ul><li>Schizophrenia not caused by degeneration, but by a rapid loss of brain volume during young adulthood </li></ul></ul><ul><ul><ul><li>Does not involve death of neurons, but a loss of neuropil,the network of dendrites and axons in the brain </li></ul></ul></ul>
  11. 11. Schizophrenia as a neurological disorder <ul><li>Positive and negative symptoms: Prefrontal cortex </li></ul><ul><ul><li>Is there a relationship b/t the 2 categories of symptoms? </li></ul></ul><ul><ul><li>Negative symptoms caused by hypofrontality (decreased activity of the frontal lobes), primarily in the dorsolateral prefrontal cortex </li></ul></ul><ul><ul><ul><li>May be caused by decrease in release of DA in prefrontal cortex, mediated mostly by D 1 receptors </li></ul></ul></ul><ul><ul><li>Chronic abuse of PCP (indirect glutamate antagonist) causes a decrease of metabolic activity in frontal lobes </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><ul><li>Prefrontal hypoactivity (neg. symptoms) causes mesolimbic DA hyperactivity (pos. symptoms) </li></ul></ul><ul><ul><ul><li>Clozapine causes an increase in DA release in prefrontal cortex, and decrease of DA release in nucleus accumbens </li></ul></ul></ul>
  12. 12. Major Affective Disorders <ul><li>Affect – refers to feelings or emotions </li></ul><ul><li>Major affective disorders – a serious mood disorder; includes unipolar and bipolar disorder </li></ul><ul><li>Bipolar disorder – characterized by cyclical periods of mania (extreme elation) and depression (extreme despair); episodes of mania generally shorter than episodes of depression </li></ul><ul><li>Unipolar depression – consists of unremitting depression or periods of depression that do not alternate with periods of mania </li></ul><ul><li>Depression causes very little energy, crying, inability to experience pleasure, disturbed sleep, depressed bodily functions </li></ul><ul><li>Mania involves sense of euphoria, nonstop speech and motor activity, easily angered, go without sleep </li></ul>
  13. 13. Major Affective Disorders <ul><li>Heritability </li></ul><ul><ul><li>The tendency to develop a major affective disorder is heritable </li></ul></ul><ul><ul><li>A single dominant gene is responsible for susceptibility to developing bipolar disorder </li></ul></ul><ul><li>Physiological treatments </li></ul><ul><ul><li>MAO inhibitors </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><ul><ul><li>Have serious side effects, e.g. cheese effect with pressor amines </li></ul></ul></ul><ul><ul><li>Tricyclic antidepressants </li></ul></ul><ul><ul><ul><li>Inhibit the reuptake of 5-HT and NE by terminal buttons </li></ul></ul></ul><ul><ul><ul><li>This keeps the NT in contact with the postsynaptic receptor, thus prolonging the postsynaptic potentials </li></ul></ul></ul><ul><ul><li>Specific serotonin reuptake inhibitors (SSRI) </li></ul></ul><ul><ul><ul><li>Inhibit reuptake of 5-HT </li></ul></ul></ul><ul><ul><ul><li>Widely prescribed for depression and for symptoms of OCD and social phobia </li></ul></ul></ul>
  14. 14. Major Affective Disorders <ul><li>Physiological treatments </li></ul><ul><ul><li>Electroconvulsive therapy (ECT) </li></ul></ul><ul><ul><ul><li>Electrodes placed on patients scalp deliver a jolt of electricity to trigger a seizure </li></ul></ul></ul><ul><ul><ul><li>Most effective with mania and depression </li></ul></ul></ul><ul><ul><ul><li>Effects are rapid, as compared to drugs </li></ul></ul></ul><ul><ul><li>Lithium </li></ul></ul><ul><ul><ul><li>Most effective in treating the manic phase of bipolar disorder </li></ul></ul></ul><ul><ul><ul><li>Does not suppress normal feelings of emotion </li></ul></ul></ul><ul><ul><ul><li>Does not impair intellectual processes </li></ul></ul></ul><ul><ul><ul><li>Does have some side effects, including hand tremors, weight gain, excessive urine production and thirst </li></ul></ul></ul><ul><ul><ul><li>Some patients with bipolar disorder have trouble continuing with medication </li></ul></ul></ul><ul><ul><ul><li>Those who cannot tolerate side effects can take carbamazepine , an anti-seizure medication </li></ul></ul></ul>
  15. 15. Major Affective Disorders <ul><li>Role of monoamines </li></ul><ul><ul><li>Monoamine hypothesis : hypothesis that states that depression is caused by a low level of activity of one or more monoaminergic synapses </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Depression can be caused by monoamine antagonists </li></ul></ul><ul><ul><ul><li>e.g. reserpine </li></ul></ul></ul><ul><ul><li>Suicidal depression is related to decreased CSF levels of 5-HIAA, a metabolite of 5-HT that is produced when MAO breaks it down </li></ul></ul><ul><ul><li>Families of subjects with low levels of 5-HIAA were more likely to include people with depression </li></ul></ul><ul><ul><ul><li>Suggests that 5-HT metabolism or release is genetically controlled and is linked to depression </li></ul></ul></ul>
  16. 16. Major Affective Disorders <ul><li>Role of monoamines </li></ul><ul><ul><li>Tryptophan depletion procedure </li></ul></ul><ul><ul><ul><li>Depressed patients currently taking medication </li></ul></ul></ul><ul><ul><ul><li>Gave low-tryptophan diet, follwed by an amino acid “cocktail”, which would inhibit what little tryptophan was left from entering the brain </li></ul></ul></ul><ul><ul><ul><li>Tryptophan depletion caused most of the patients to relapse back into depression </li></ul></ul></ul><ul><ul><ul><ul><li>However, recovered after resuming normal diet </li></ul></ul></ul></ul><ul><ul><ul><li>This has no effect on healthy, non-depressed subjects, but does lower the mood of people with a family history of affective disorders </li></ul></ul></ul>
  17. 17. Major Affective Disorders <ul><li>A role for Substance P? </li></ul><ul><ul><li>A peptide secreted as a NT and neuromodulator in several regions of the brain </li></ul></ul><ul><ul><li>May be involved in emotional behavior, the response to stress, and the symptoms of depression </li></ul></ul><ul><ul><li>Long-term admin of antidepressants cause a reduction of substance P levels in several regions of the brain </li></ul></ul><ul><ul><li>MK-869, a drug that blocks the receptor for substance P (NK 1 ) shows a reduction in depressive symptoms </li></ul></ul><ul><ul><li>Substance P antagonists appear to act independently of drugs that reduce depression by blocking the reuptake of 5-HT and NE </li></ul></ul>
  18. 18. Major Affective Disorders <ul><li>Evidence for brain abnormalities </li></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Found in young patients, which suggests the presence of a developmental abnormality or a degenerative process that occurs early in life </li></ul></ul><ul><ul><li>Repeated episodes of depression and mania caused an increase in the size of the lateral ventricles </li></ul></ul><ul><ul><li>The amygdala and several regions of the prefrontal cortex play a role in the development of depression </li></ul></ul><ul><ul><ul><li>Activity of amygdala of depressed patients was correlated with the severity of their depression </li></ul></ul></ul><ul><ul><ul><li>Orbitofrontal cortex generally more active in depressed patients </li></ul></ul></ul><ul><ul><ul><li>Subgenual prefrontal cortex shows a lower level of activation in depressed patients; activity in this region is increased during manic episodes </li></ul></ul></ul>
  19. 19. Major Affective Disorders <ul><li>Evidence for brain abnormalities </li></ul><ul><ul><li>Silent cerebral infarctions </li></ul></ul><ul><ul><ul><li>A small cerebrovascular accident (stroke) that causes minor brain damage without producing obvious neurological symptoms </li></ul></ul></ul><ul><ul><ul><li>Appears to be a major cause of late-onset depression (first occurs later in life) </li></ul></ul></ul><ul><ul><ul><li>Risk factors are similar for stroke (e.g. smoking, hypertension) </li></ul></ul></ul>
  20. 20. Major Affective Disorders <ul><li>Role of circadian rhythms </li></ul><ul><ul><li>One of the most prominent symptoms of depression is disordered sleep </li></ul></ul><ul><ul><li>Sleep of depressed individuals is shallow, Stages 3 & 4 are reduced, Stage 1 is increased </li></ul></ul><ul><ul><li>REM sleep occurs earlier </li></ul></ul><ul><ul><li>Selective deprivation of REM sleep alleviates depression </li></ul></ul><ul><ul><ul><li>The effect occurs slowly like that of drugs </li></ul></ul></ul><ul><ul><ul><li>Other treatments for depression suppress REM sleep, suggesting that REM sleep and mood may be correlated </li></ul></ul></ul><ul><ul><li>Successful ECT treatments suppress REM sleep in depressed patients </li></ul></ul><ul><ul><li>Total sleep deprivation produces immediate effects </li></ul></ul><ul><ul><ul><li>Perhaps, during sleep a substance is produced that has a depressogenic effect </li></ul></ul></ul><ul><ul><li>Depressed patients whose moods fluctuate more often will benefit from sleep deprivation more </li></ul></ul>
  21. 21. Major Affective Disorders <ul><li>Role of Zeitgebers </li></ul><ul><ul><li>Seasonal affective disorder – a mood disorder characterized by depression, lethargy, sleep disturbances, and craving for carbohydrates during the winter season when days are short </li></ul></ul><ul><ul><li>Summer depression – a mood disorder characterized by depression, sleep disturbances, and loss of appetite </li></ul></ul><ul><ul><li>Seasonal affective disorder appears to have a genetic basis </li></ul></ul><ul><ul><ul><li>Molecular genetic studies suggest that seasonal affective disorder may be linked to genes involved in production of the 5-HT transporter and the 5-HT 2A receptor </li></ul></ul></ul><ul><ul><li>SAD can be treated with phototherapy , treatment of exposing people to bright light for several hours a day </li></ul></ul>