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Chapter 16 Schizophrenia and the Affective Disorders 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 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 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 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 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 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? Until recently, all drugs caused at least some symptoms resembling those of Parkinson’s disease: slow movement, lack of facial expression, general weakness 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) 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 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 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 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 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 Chronic abuse of PCP (indirect glutamate antagonist) causes a decrease of metabolic activity in frontal lobes May be caused by decrease in release of DA in prefrontal cortex, mediated mostly by D1 receptors 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 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 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 Tricyclic antidepressants 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 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 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 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 5HIAA, 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 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 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 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 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) 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 Successful ECT treatments suppress REM sleep in depressed patients Total sleep deprivation produces immediate effects The effect occurs slowly like that of drugs Other treatments for depression suppress REM sleep, suggesting that REM sleep and mood may be correlated 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 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