1 / 57

Schizophrenia

Schizophrenia. Features, Diagnosis, Epidemiology, Etiology, Treatment, Neurochemistry Jack Foust, MD Assistant Professor, Department of Psychiatry and Behavioral Sciences Medical University of South Carolina. Features of Schizophrenia - Positive Symptoms. Hallucinations

arleen
Download Presentation

Schizophrenia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Schizophrenia • Features, Diagnosis, Epidemiology, Etiology, Treatment, Neurochemistry • Jack Foust, MD • Assistant Professor, Department of Psychiatry and Behavioral Sciences • Medical University of South Carolina

  2. Features of Schizophrenia - Positive Symptoms • Hallucinations • Disorganized speech/thinking/behavior • Delusions

  3. (from The Hour of the Wolf, directed by Ingmar Bergman)

  4. Features of Schizophrenia - Negative Symptoms • Affective flattening • Alogia • Avolition • Anhedonia • Social Withdrawal

  5. Features of Schizophrenia - Cognitive Deficits • Attention • Memory • Executive functions (organization, planning)

  6. Schizophrenia - DSM Diagnostic Criterion “A” • Characteristic Sxs (2 + for 1 month) • delusions • hallucinations • disorganized speech • grossly disorganized or catatonic behavior • negative Sxs (flat affect, alogia, avolition) • (Only one element required if delusions bizarre, • or hallucinations commentary 2 voices conversing )

  7. Schizophrenia - DSM Diagnostic Criteria B - F • Social/occupational dysfunction (decline) • Duration - 6 months total, 1 month “A” Sxs • Exclusion - SAFD, mood d/o • Exclusion - sub abuse, gen med condition • PDD/Autism - at least 1 month delusions or hallucinations

  8. Schizophrenia - Comorbid Conditions • Depression • Anxiety • Aggression • Substance use disorder

  9. Schizophrenia: Who is at Risk? • Lifetime prevalence • Epidemiologic Catchment Area Study: 1.3% • National Comorbidity Survey: 0.7% • Demographic characteristics • Age - typical onset late teens/early twenties • Gender - earlier age of onset among men • Marital status - less likely to be married

  10. Schizophrenia: Who is at Risk? • Predisposing factors • Season of birth • Pregnancy and birth complications • Genetic background • Precipitating factors • Stress • Substance Abuse

  11. “In addition to interfering with normal brain development, heavy marijuana use in adolescents may also lead to an earlier onset of schizophrenia in individuals who are genetically predisposed” Dr Sanjiv Kumra, Albert Einstein College of Medicine

  12. “Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele.” Caspi A, et al. Biological Psychiatry.2005; 57:1117-1127.

  13. Genetic Risk Factors

  14. Etiology: Neurodevelopmental Hypothesis • Possible insult during gestation, environmental influences • Disturbance in normal brain maturation • Reduced size medial temporal lobe structures - amygdala, hippocampus • Disturbed cytoarchitecture in hippocampus, entorhinal cortex

  15. Treatment: Psychosocial Interventions • Supportive therapy • Behavioral family therapy • Family education • Social skills training • Community support • Lower relapse; improved functioning, compliance and social adjustment

  16. Treatment: Antipsychotics • Used to treat psychotic disorders, such as schizophrenia, mania, psychotic depression • Include both “typicals” (Haldol) and “atypicals” (Clozaril, Risperdal)

  17. Typical Antipsychotics • Chlopromazine (Thorazine) - prototype • Thioridazine (Mellaril) • Fluphenazine (Prolixin) • Haloperidol (Haldol)

  18. Typical Antipsychotics: Drug/Receptor Effects • Antidopaminergic (D2) • Anticholinergic • Antihistaminic • Anti-alpha 1

  19. Effects of Typical Antipsychotics • Four dopamine pathways • Mesocortical (negative symptoms) • Mesolimbic (positive symptoms) • Nigrostriatal (EPS, TD) • Tuberoinfundibular (hyperprolactinemia)

  20. Guillin O and Laruelle M. Cellscience Reviews. 2005; 2:79-107

  21. DA Receptor Distribution • D1- prefrontal cortex, striatum • D5 - hippocampus and entorhinal cortex • D2 – striatum, low concentration in medial temporal structures (hippocampus, entorhinal cortex, amygdala), thalamus, prefrontal cortex • D3 – striatum and ventral striatum • D4 - prefrontal cortex and hippocampus (have not been detected in the striatum)

  22. Guillin O and Laruelle M. Cellscience Reviews. 2005; 2:79-107

  23. Side Effects of Typical Neuroleptics • Extra-pyramidal syndrome (EPS) • Tardive dyskinesia (TD) • Neuroleptic malignant syndrome (NMS) • Prolactin elevation

  24. Extra-Pyramidal Syndrome (EPS) • Acute dystonia • Akathesia • Muscle rigidity • Bradykinesia • Treatment – typically treated with anticholinergic compounds (Cogentin, Benadryl, Artane), Beta-blockers

  25. Tardive Dyskinesia(TD) • 25-year continuous exposure risk: 68% in Yale Incidence Study • Annual incidence: 5% • Risk factors • Increased age • African-American race • Dose and duration of drug exposure • Early and severe EPS

  26. Neuroleptic Malignant Syndrome (NMS) • Potentially fatal complication of neuroleptic Tx • Temperature dysregulation: T >104°F/40°C • Muscle rigidity • Elevated CPK • Elevated WBC • Associated with TaqI A polymorphism in DRD2 • Tx: withdraw neuroleptics, cooling, dantrolene, bromocriptine (DA agonist)

  27. Summary: Limitations of Typical Antipsychotics • Limited efficacy against negative symptoms • A substantial portion of patients (25% to 40%) respond poorly to treatment • EPS occurs at clinically effective doses • Side effects other than EPS (such as NMS) • Liable to cause tardive dyskinesia • Serum prolactin elevation

  28. Advantages of Typical Antipsychotics • No blood monitoring • Efficacious for positive symptoms • Parenteral and depot preparations available • Low-cost

  29. Antipsychotics: Atypical • Clozapine (Clozaril) - prototype • Risperidone (Risperdal) • Olanzepine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidone (Geodon) • Aripiprazole (Abilify)

  30. Atypical Antipsychotics: Clinical and Drug/Receptor Characteristics • Clinically display less EPS, more effective against negative symptoms, some improvement in cognition • Balanced D2/D1 antagonism • Strong 5HT2 antagonists

  31. Serotonin-Dopamine Antagonists and TD: Hypothesized “Site-Specific” Neuromechanisms Psychosis EPS and TD Limbic Cortical Caudate/Putamen A10 A9 Ventral Tegmental Area Substantia Nigra Dopamine/5HT Antagonist Conventional Antipsychotic Agents

  32. Atypical Antipsychotics

  33. Antipsychotic Receptor Affinities • Haloperidol (Haldol)

  34. Antipsychotic Receptor Affinities • Clozapine (Clozaril)

  35. Antipsychotic Receptor Affinities • Risperidone (Risperdal)

  36. Antipsychotic Receptor Affinities • Olanzepine (Zyprexa)

  37. Antipsychotic Receptor Affinities • Quetiapine (Seroquel)

  38. Ziprasidone (Geodon) • High affinity (antagonist) for D2, D3, 5HT2a, 5HT2c, 5HT1d • High affinity (agonist) for 5HT1a • Inhibits re-uptake of 5HT and NE • Moderate affinity for H1, α1 • Low affinity for D1, α2 • Negligible affinity for M1

  39. Ziprasidone (Geodon), cont. • Positive symptoms improved (PANSS) • Negative symptoms improved (PANSS) • Depressive symptoms improved (MADRS) • Low EPS (5HT2a/D2, 5HT1a) • Low weight gain (H1) • Low sexual dysfunction • Minimal CYP450, CBC, LFT or CV effects (some QTc prolongation)

  40. Neurotransmitter Systems Implicated in Schizophrenia Dopamine Acetylcholine Serotonin Norepinephrine GABA Neuropeptides Glutamate

  41. Dopamine Hypothesis • Induction or worsening of psychotic symptoms with dopamine agonists • Amelioration of psychotic symptoms with antipsychotic drugs that are D2-receptor antagonists

  42. Serotonin (5HT) Hypothesis • M-CPP (m-chlorophenylpiperazine) selective 5HT receptor agonist worsens psychotic symptoms • Pretreatment with ritanserin (5HT antagonist) attenuates psychotic symptoms

  43. Glutamate Hypothesis • Psychotomimetic effects of phencyclidine (PCP), a potent N-methyl-D-aspartate (NMDA) type glutamate receptor antagonist - mimics negative, positive and disorganization symptoms • Possible beneficial effects of cycloserine, glutamate receptor agonist

  44. Glutamate, Dopamine, Ketamine • “Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia.” • “These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.” Moghaddam B et al. J Neurosci 1997; 17: 2921-2927.

  45. Aghajanian GK, Marek GJ. Brain Res Brain Res Rev 2000; 31:302-312.

  46. Neuronal Circuits in Schizophrenia • Thalamic nuclei relay sensory information to pyramidal neurons in limbic cortex and neocortex through glutaminergic excitatory afferents • Excessive response of pyramidal neurons is putative mechanism of psychosis (overstimulation) Freedman R. Schizophrenia. NEJM. 2003; 349:1738-1749.

More Related