ESSENTIAL PSYCHOPHARMACOLOGY, Neurobiology of Schizophrenia Carl Salzman MD Montreal

Transcription

1 ESSENTIAL PSYCHOPHARMACOLOGY, 2011 Neurobiology of Schizophrenia Carl Salzman MD Montreal

2 EVOLVING CONCEPTS OF SCHIZOPHRENIA Psychotic illness with delusions, hallucinations, thought disorder and deterioration; Redefinition into positive and negative symptoms ; identification of deficit syndrome Is a developmental disorder of genetic predisposition and environmental stress New data suggesting executive dysfunction is the core symptom complex suggesting frontal lobe dysregulation Has a prodrome, onset, and course.

3 THERAPEUTIC IMPLICATIONS OF EVOLVING CONCEPTS Classic psychotic (positive) symptoms due to hyperactive dopamine system (D 2 receptor) Requires dopamine receptor blockade Use of first generation antipsychotics (FGAs), especially high potency drugs: Haloperidol Fluphenazine Trifluoperazine, perphenazine etc.

4 THERAPEUTIC IMPLICATIONS OF EVOLVING CONCEPTS (continued) Positive and Negative symptoms Recognition that dopamine receptor blocking drugs are ineffective for negative symptoms and deficit syndrome Development of second generation antipsychotics (SGAs), also called atypical antipsychotics Initial data suggested more favorable improvement in negative symptoms with SGAs Occasional rebirth experiences with clozapine ( where have I been?)

5 THERAPEUTIC IMPLICATIONSOF EVOLVING CONCEPTS (concluded) Recognition that improvement in schizophrenic symptoms correlates with improvement in cognition and executive functions: Memory, concentration, planning, abstraction, sense of self/others Hypothesis: executive dysfunction in the primary defect in schizophrenia, not psychosis SGAs and augmentation strategies (e.g. cognitive enhancers) should be more therapeutic than FGAs

6 PROGRESSIVE CORTICAL THINNING IN SCHIZOPHRENIA Schizophrenic patients have thinner left orbitofrontal and right parahippocampal and superior temporal cortices Over time, excessive thinning of cortical bilaterally in temporal cortex and left frontal area Higher typical antipsychotic use was associated with more pronounced cortical thinning; atypicals were associated with less pronounced thinning Poor outcome was associated with more pronounced cortical thinning Van Haren 2011; ArchGenPsychiat 68:871

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8 DOPAMINE THEORY OF SCHIZOPHRENIA Mid 1950 s discovery that anti-dopaminergic drugs decreased SCH sx Early observations that dopamine agonists (amphetamines, cocaine) increased SCH sx Development of chlorpromazine (Thorazine) began decline in state hospital inpatient census

9 THREE DOPAMINE PATHWAYS Mesolimbic (and mesocortical): antipsychotic properties Nigrostriatal (extrapyramidal side effects) Tubero-infundibular (increased prolactin)

10 MULTIPLE DOPAMINE RECEPTORS DA 1 receptors responsible for cognition: Abstract reasoning Planning Integrating cognition with emotion DA 1 receptors are cortical; controlled by subcortical DA 2 receptors DA 2 receptors do not use 2 nd messenger; DA 1 receptors increase camp

11 PHARMACOLOGY OF DA RECEPTORS Classic (typical) neuroleptics block DA 2 Other blocked receptors: Alpha adrenergic (orthostatic blood pressure) Histamine (sedation, weight gain) Muscarinic (dry mouth, constipation) Typical neuroleptics vary in potency at DA and other receptors

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13 GLUTAMATE THEORY OF SCHIZOPHRENIA PCP (NMDA antagonist) causes schizophrenic-like symptoms; Ketamine (NMDA antagonist) increases positive symptoms of schizophrenia 3 genetic polymorphisms of glutamate receptors may increase risk for schizophrenia: Dysbindin Neuregulin G72

14 MULTIPLE GLUTAMATE RECEPTORS NMDA Ionophore: ion-gated entry of sodium and calcium into cell causing depolarization and neuronal firing: is stimulatory AMPA Associated receptor recognition site for glutamate: opens NMDA ionophore by removing magnesium plug Kainate Is also ion-gated; can be pre and post synaptic; may play a role in depression

15 MULTIPLE GLUTAMATE RECEPTORS-II: METABOTROPIC RECEPTORS Positive allosteric modulators (PAM) of the metabotropic glutamate receptor may have therapeutic properties: Decrease psychotic symptoms Enhance cognition mglu2/3 control presynaptic release of glutamate at NMDA synapse; mglu5 (pre- and postsynaptic) may also influence NMDA function Mutel, 2005

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17 ROLE OF GLIA Several myelin-related genes are lower in schizophrenia Excess excitatory neurotransmission may occur in schizophrenia Leads to significant decrease in oligodendrocytes in cortex May lead to defective routing of communication between cortico-cortical and thalamo-cortical pathways Would account for psychosis and cogntive deficits in schizophrenia

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19 DOES SCHIZOPHRENIA RUN IN FAMILIES? Parents and siblings of affected individuals are 10X more likely to develop schizophrenia; Children of schizophrenic parents are 15X more likely to develop schizophrenia Could be a result of faulty rearing

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21 CURRENT GENETIC THEORY Multiple genes of small to moderate effect confer compounding risk through interactions with each other and with non-genetic risk factors. Examples of candidate genes that may increase susceptibility to schizophrenia: D-amino oxidase; neuregulin-1; dysbindin; COMT; 5HT2a; D3; MAO-A;

22 GENETICS OF DOPAMINE METABOLISM DA metabolism in PFC is under rate limited step of COMT (catechol-o-methyl transferase) No DA uptake transporter in PFC Enzyme under genetic control: polymorphism with 2 alleles (Val158Met): Valine (val-val): more active metabolism, lower synaptic DA Methionine (met-met); slower metabolism, higher synaptic DA Heterozygote (val-met)

23 Neurotransmission (DA) DA COMT VAL-VAL VAL-MET MET-MET 2 Alleles: VAL MET DA DA DA DA DA DA DA DA High DA Metabolism DA Low DA Metabolism

24 7 NICOTINIC ACETYLCHOLINE RECEPTOR GENE IN SCHIZOPHRENIA Cortical 7nACh receptors modulate prefrontal glutamate release Gene has a common deletion in schizophrenia Decreases the expression of the receptor Are also found on cell bodies of inhibitory GABA interneurons Activation of these interneurons inhibit the overactive hippocampus in schizophrenia Activation may improve cognition and negative symptoms in schizophrenia

25 GENES AND WEIGHT GAIN FROM ANTIPSYCHOTICS 3 receptor gene polymorphisms are significantly related to olanzapine-induced weight gain Genetic variants of the post-synaptic serotonin receptors 5HT2 A and 5HT2 C : 102 T allele of 5HT2 A ; 23 Cys allele of 5HT2 C Also, a genetic variant of the post-synaptic ß adrenergic receptor: 64 Arg/arg genotype

26 GAMMA OSCILLATIONS Neurons synchronize with each other at a physiological frequency of 40 herz, known as a gamma oscillation Is impaired in schizophrenia (lower frequency oscillations) The stronger theses lower oscillations are, the greater the positive symptoms

27 CNS GAMMA OSCILLATIONS IN SCHIZOPHRENIA Abnormalities may be associated with: Impaired working memory (frontal cortex) Are most likely related to dysfunctional NMDA glutamate neurotransmission Woo 2010, Harvard Rev Psychiatry 18:173

28 ROLE OF GABA IN SCHIZOPHRENIA GABA interneurons play important role in inhibitory information processing in cortex Decreased density in anterior cingulate GABA release is under glutamate control Decreased GABA may be secondary to hypoglutamate function in schizophrenia

29 GLUTAMIC ACID DECARBOXYLASE 67 IN SCHIZOPHRENIA GAD 67 is the major GABA synthesizing enzyme Levels are significantly lower in patients with schizophrenia Deficit is seen in parvalbumin-containing GABA neurons These neurons are crucial to generation of gammaoscillations Leads to lower GABA synthesis in dorsolateral PFC Contributes to impaired cognition in schizophrenia Curley 2011; Am J Psychiatry 168:921

30 THERAPEUTIC IMPLICATIONS OF EVOLVING CONCEPTS Classic psychotic (positive) symptoms due to hyperactive dopamine system (D 2 receptor) Requires dopamine receptor blockade Use of first generation antipsychotics (FGAs), especially high potency drugs: Haloperidol Fluphenazine Trifluoperazine, perphenazine etc.

31 THERAPEUTIC IMPLICATIONS OF EVOLVING CONCEPTS (continued) Positive and Negative symptoms Recognition that dopamine receptor blocking drugs are ineffective for negative symptoms and deficit syndrome Development of second generation antipsychotics (SGAs), also called atypical antipsychotics Initial data suggested more favorable improvement in negative symptoms with SGAs Occasional rebirth experiences with clozapine ( where have I been?)

32 THERAPEUTIC IMPLICATIONSOF EVOLVING CONCEPTS (concluded) Recognition that improvement in schizophrenic symptoms correlates with improvement in cognition, executive and social functions: Memory, concentration, planning, abstraction, sense of self/others Ability to socialize and interact appropriately Hypothesis: executive dysfunction and social impairment are the primary defects in schizophrenia, not psychosis Non pharmacologic treatments in conjunction with medications are necessary