Carlson (7e) Chapter 17: Schizophrenia and the Affective Disorders

1. Carlson (7e)Chapter 17: Schizophrenia and the Affective Disorders

2. Schizophrenia • Schizophrenia represents a disorder of thought and emotion but not a “split-personality” • Thought disorder (e.g., loose associations) • Hallucinations (e.g., auditory) • Delusions (e.g., paranoia) • Bizarre behaviors • The incidence of schizophrenia is about 1-2% • No clear gender differences in incidence 17.2

3. Symptoms of Schizophrenia • Positive symptoms include delusions, hallucinations and thought disorder • Delusions are beliefs that are contrary to reality • Delusions can involve control, grandeur, or persecution • Hallucinations are perceptions that occur in the absence of stimuli (often auditory and/or olfactory) • Thought disorder: disorganized and irrational • Negative symptoms involve a loss of normal behaviors, such as • Poverty of speech and low initiative • Social withdrawal and diminished affect • Anhedonia 17.3

4. Heritability of Schizophrenia • The heritability of schizophrenia is a strong indicator of a biological basis for schizophrenia • Adoption studies • Adult schizophrenics that were adopted as children are likely to have schizophrenic biological relatives. • Twin studies • Concordance rates for schizophrenia are higher for identical than for fraternal twins: • No single gene has been identified for schizophrenia • Genes may pass on a susceptibility to develop schizophrenia 17.4

5. The Dopamine Hypothesis of Schizophrenia • The “dopamine hypothesis” is that the positive symptoms of schizophrenia involve over activity of brain dopaminergic synapses • Chlorpromazine (CPZ) was identified as an effective antipsychotic (AP) agent • CPZ was later found to block DA receptors (D2 receptors) • D2 receptor blockade correlates with clinically effective dose of typical antipsychotic medications • Stimulants such as amphetamine that release DA can produce the positive symptoms of schizophrenia in “normals” and relapse in schizophrenics 17.5

6. Pharmacological Revolution in Treating Severe Mental Disorders

7. DA Activity in Schizophrenia • PET studies indicate greater activity of dopamine in the striatum of schizophrenics to a test dose of amphetamine • Amount of dopamine activity was related to the increase in positive schizophrenia symptoms • Studies of dopamine receptors in schizophrenic brain have provided mixed results (but generally supportive) • Postmortem studies suggest increased numbers of D2 receptors in striatum (but may be due to exposure to antipsychotic drugs) • The striatum is a motor control region: may be the wrong site • Schizophrenia may be related to D4 or D3 receptors • Clozapine is an effective (atypical) antipsychotic drug that interacts with D4 and not D2 receptors • strong effect on mesolimbic/mesocortical dopamine system (A10) • little effect on nigrostriatal dopamine system (A9) 17.7

8. Dopamine Augmentation & Schizophrenia • Psychomotor stimulants (e.g., amphetamine) • ‘normals’ develop paranoid psychosis • schizophrenics release -- subjectively indistinguishable for worsening of endogenous illness (cf. LSD) • L-DOPA (precursor loading) • little or no effect in ‘normals’ • worsening of psychotic symptoms in schizophrenics • schizophrenic symptoms in some Parkinson’s patients • Stress (increased dopaminergic activity) • precipitate relapse & perhaps even initiate disorder

9. Dopamine Attenuation & Schizophrenia • DA synthesis inhibitors (e.g., AMPT) abate schizophrenia • DA storage depleters (e.g., reserpine) abate schizophrenia • D2 receptor blockers (e.g., typical antipsychotics) abate schizophrenia • Even atypical antipsychotics (which do not effectively block D2 receptors) influence mesolimbic DA activity

10. Antipsychotic Medications • Antipsychotic medications diminish the thought disorder & disruptive behavior evident in schizophrenia • Side effects of antipsychotic medications include • Major • Extrapyramidal (Parkinsonism-like) side effects due to blockade of DA receptors • Tardive dyskinesia: facial tics and gestures due to an over stimulation of DA receptors (may be related to CNS sensitization and relapse) • Minor • Autonomic problems (dry mouth) • Skin-eye pigmentation • Breast development (increased prolactin release after blockade of dopamine neurons) 17.10

11. Brain Damage and Schizophrenia • The negative symptoms of schizophrenia may be related to brain damage • The neurological signs evident in schizophrenia include • Eye tracking problems • Catatonia • Problems with blinking, eye focusing, and visual pursuit • Schizophrenics exhibit enlarged brain ventricles, which suggests loss of brain cells • Regions of schizophrenic brain that are abnormal include • Prefrontal cortex • Medial temporal lobes • Medial diencephalon 17.11

12. Causes of Brain Damage in Schizophrenia • The neurological symptoms of schizophrenia may be caused by • Birth trauma (obstetrical issues) • Viral infections that impair neural development during the second trimester • Seasonality effects (schizophrenia is more likely for winter births) • Nutritional issues (Hunger Winter: female offspring were more likely to exhibit schizophrenia than male offspring) • Maternal stress may compromise the immune system of the mother and lead to a greater chance of contracting a viral infection 17.12

13. Seasonality and Schizophrenia • Children born during the late winter and early spring are more likely to develop schizophrenia • Seasonality effect occurs in cities but not the countryside • Seasonality effect may be related to the mother contracting a viral infection during the second trimester of fetal development (or astrological sign?) 17.13

14. Hypofrontality and Schizophrenia • Hypofrontality refers to the decreased activity of the dorsolateral prefrontal cortex • Damage to the prefrontal cortex • impairs behavioral flexibility (card sorting task) • may disinhibit mesolimbic dopamine system • Schizophrenics show decreased activity in the prefrontal cortex • Abuse of PCP produces positive and negative symptoms of schizophrenia • Positive: related to indirect actions of PCP on accumbens DA • Negative: related to decreased DA utilization in prefrontal cortex following PCP treatment • Data are less compelling that dopamine-agonist effect 17.14

15. Major Affective Disorders • Affect refers to emotions, moods, and feelings • Our affect is usually a reflection of our experiences • In the major affective disorders, our emotional reactions are at the extremes and may not be related to our actual experiences • The major affective disorders include • Bipolar disorder - alternating cycles of • Mania: euphoria, delusions • Depression: profound sadness, guilt, suicide risk • Unipolar depression: continuous, episodic 17.15

16. Biological Bases of Affective Disorder • Heritability of affective disorder (AD) has been established in twin studies and family studies • Bipolar disorder may be related to a single gene • Depression is amenable to physical treatments including • Pharmacological treatments • MAO inhibitors (e.g. iproniazid) • Noradrenergic reuptake inhibitors (desmethylimipramine) • Serotonin reuptake inhibitors (e.g. Prozac) • Electroconvulsive shock therapy (ECS) • Sleep deprivation 17.16

17. Monoamine Hypothesis of Depression • Depression results from reduced activity of brain monoamines • Reserpine depletes monoamines--> depression • Suicidal depression is related to a low level of 5-HIAA • Antidepressant medications increase either NE or 5-HT • Usually via blockade of monoamine reuptake • Tryptophan deletion procedure: • Reduces brain 5-HT levels • Reinstates depression in former depressed patients 17.17

18. Antidepressant Medication and 5-HT 17.18

19. REM Sleep and Depression • Sleep pattern is disrupted in depressed persons • Reduced REM latency, reduced stages 3 and 4 sleep • REM deprivation improves mood • Antidepressant drugs suppress REM sleep, and increase slow-wave sleep • Persons who have short REM sleep latency are more likely to develop depression • REM sleep deprivation is more effective than is total sleep deprivation (effects last longer) 17.19

20. Sleep Patterns in Depression 17.20

21. Mood and Sleep Deprivation 17.21

22. Seasonal Affective Disorder • SAD is a form of depression evident in winter months (short days/long nights) • SAD involves • Mood and sleep disturbances • Carbohydrate cravings and weight gain • Phototherapy for SAD: increased exposure to light improves mood in SAD (and also for unipolar depression) 17.22