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Overview of Psychosis and Antipsychotics in Psychiatry

Overview of Psychosis and Antipsychotics in Psychiatry. Fred Michel, MD June 9, 2003. Review of Terminology. Hallucinations – Sensory perceptions in absence of external stimuli Delusions – Firmly held false beliefs

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Overview of Psychosis and Antipsychotics in Psychiatry

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  1. Overview of Psychosis and Antipsychotics in Psychiatry Fred Michel, MD June 9, 2003

  2. Review of Terminology • Hallucinations – Sensory perceptions in absence of external stimuli • Delusions – Firmly held false beliefs • Thought Disorder – Disruption in form or organization of thinking – inchoerence, difficulty communicating, loose associations, thought blocking, clanging, echolalia,

  3. Hx of Diagnostic Classification of Schizophrenia • Kraeplin – 1896: • “Dementia Praecox” distinguished from “Manic Depressive Psychosis”. • Emphasized Chronic Deteriorating Course • Bleuler – 1911: • Schizophrenia as a splitting of psychic functions • Four A’s: Autism, Ambivalence, Loose Associations, Inappropriate Affect • Emphasis on NEGATIVE SYMPTOMS

  4. Hx of Diagnostic Classification of Schizophrenia • Schneider – 1970’s • First Rank Symptoms • Hallucinations, delusions, thought withdrawal, thought insertion, imposed feelings… • Emphasized POSITIVE SYMPTOMS

  5. DSM IV Dx of Schizophrenia • Essential Features • Psychotic Symptoms for at least 1 month (less if treated) • Functioning below the highest expected level • Duration of illness for at least 6 months ( including prodromal, residual phases)

  6. Active Phase • Requires bizarre delusions or • Hallucinations where • Two or more voices converse w/ eachother • Voice keeps a running commentary on a person’s thoughts or behaviors, or • Two or more of the following • Delusions, Hallucinations, Disorganized Speech, Grossly Disorganized or Catatonic Behavior or Negative Symptoms

  7. Prodromal or Residual Phase • Social Isolation, Withdrawal • Impairment of Functioning • Peculiar Behavior • Impaired Personal Hygiene • Blunted or Inappropriate Affect • Abnormal Speech • Odd Beliefs • Unusual Perceptual Experiences • Apathy

  8. DDX of Schizophrenia • Mood Disorders • Schizoaffective Disorder: Mood issues > Thought Issues when euthymic • Bipolar Disorder • Psychosis is present only during manic or depressive episodes • Psychotic Depression • Schizophreniform Disorder – Scz w < 6mo duration • Brief Reactive Psychosis- Psychotic sx ,1month • Schizotypal Personality Disorder – Fails to meet active phase of schizophrenia criteria • Delusional Disorder – persistent, non-bizarre delusions • Organic Etiologies

  9. Drugs of Abuse Neurological Disorders Alzheimer’s Disease Complex Partial Seizures Huntington’s Disease Hydrocephalus Lupus Parkinson’s Infectious Diseases Brain abscess Encephalitis Infectious Mononucleosis Meningitis Syphilis Endocrine Disorders Addison’s & Cushings Hypo/hyper Thyroidism Hypo/hyper Parathyroidism Organic Etiologies

  10. Nutritional Deficiencies Niacine (pellagra) Thiamine Deficiency Korsakoff’s psychosis Beriberi Vitamin B12 (pernicious anemia) Organic Etiologies (cont)

  11. Evaluation of Psychosis • Complete Physical and Neurological Exam • History – Subst Use, Past Psychosis, FHx, Medical Hx, Medications. • Mental Status Exam • Laboratory Screens: • Electrolytes, BUN, Cr, CA, Glucose, CBC, Thyroid Pannel, Liver enzymes, VDRL, B12, Folate, HIV when indicated • Tox Screen • Brain Imaging when indicated, or w/ neurological findings • EEG when suspicious of absence or partial seizures

  12. Theories of Etiology • Dopamine Hyperactivity • Schizophrenia and Acute Psycosis are associated with Increased Mesolimbic Dopamine Activity • Serotonin Dysfunction • LSD – 5HT agonist • Clozapine & other atypical antisycotics • Active at 5HT2 and 5HT1C receptors • Two Hit Model • 1st Hit: Genetic Predisposition • 2nd Hit: Environmental Stress or Injury - hippocampus

  13. Antipsychotic Medications • Classification • Conventional • Low Potency – Chlorpromazine (Thorazine), Thioridizine (Mellaril) • High Potency – Haloperidol (Haldol), Fluphenazine (Prolixin), Trifluoperazine (Stelazine), Pimozide (Orap) • Long Acting / Depot – Oil Based Injection • Prolixin or Haldol Decanoate

  14. Antipsychotic Medications • Novel or Atypical – • 5HT/DA Antagonists • Clozapine (Clozaril) • Risperidone (Risperdal) • Olanzapine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidione (Geodon) • Dopamine Partial Agonist/Antagonist • Aripiprazole (Abilify) • D2 Receptor Blockade • Essential for antipsychotic efficacy • 5HT2 Blockade

  15. Side Effects: Key Differentiator for Antipsychotics • Extrapyramidal Side Effects (EPS) • Common with Conventional Agents • High Potency >> Low Potency • Stiffness, shuffling gait, loss of automatic associated movements. PARKINSONIAN SX • Occur when > 80% of D2 Receptors are occupied • Therapeutic Antipsychotic Effects: 65-70% Blocked • “Minimal Effective Dosing” - Dose to block for tx of psychosis but avoid excessive blockaid to minimize EPS

  16. Side Effects: Key Differentiator for Antipsychotics • Acetyl choline neurons also exert INHIBITING effect on Striatal Dopamine Neurons • Minimizing effect of Cholinergic Neurons on Dopamine Neurons can alleviate Drug Induced EPS • Anticholinergic medications • Cogentin • Artane

  17. Side Effects: Key Differentiator for Antipsychotics • Serotonin (5HT) Neurons also exert INHIBITING effect on Striatal Dopamine Neurons • This may be why Serotonin-Dopamine Antagonists (Atypical Agents) cause less EPS than Conventional Antipsychotics

  18. Side Effects: Key Differentiator for Antipsychotics • Postural Hypotension – Low Potency Agents • Somnolence – Low Potency Agents • Akathisia – Sense of restlessness • “ants in pants” • Tx with decreased dose, beta blockers, BZD’s • Some try Cogentin, Artane, Benadryl

  19. Side Effects: Key Differentiator for Antipsychotics • Tardive Dyskinesia • Etiology:Supersensitivity of DA Receptors from chronic blockade • Frequency: • Conventionals – 4 %/yr • Atypical/Novel Agents – 0.5%/yr • Increased risk with: • higher potency • longer exposure • conventional, typical agents • Tx with: • decr dose • switch to novel agents, esp Clozapine

  20. Side Effects: Key Differentiator for Antipsychotics • Neuroleptic Malignant Syndrome • Fever • Muscle Rigidity • Two of following: • Diaphoresis, dysphagia, tremor, incontinence, tachycardia, labile BP, lecuocytosis, incr CPK • DDX: • Other causes of fever – infection • Heat Stroke, Malignant Hyperthermia • Parkinsons disease • Catatonia

  21. Side Effects: Key Differentiator for Antipsychotics • Prolactin Elevation • Conventional Antipsychotics – common • A consequence of D2 Receptor Blockade in Hypothalamus • Some used to titrate Conventionals up in dose till prolactin level elevated • Atypical Agents • Risperdal > Zyprexa >> Clozapine, Seroquel, Geodon > Abilify • Consequences of Prolactin Elevation: • Amenorrhea, Gynecomastia, Glactorrhea, Impotence, Decreased Bone Density

  22. Side Effects: Key Differentiator for Antipsychotics • Weight Gain • More common in Novel or Atypical agents than in Traditional/Conventional agents • Novel agents: • Zyprexa = Clozapine >> Risperdal > Seroquel • Weight Neutral: Geodon, Abilify • Diabetes – Increased risk with atypical antipsychotics! • Clozapine & Zyprexa – incr risk of DKA

  23. Side Effects: Key Differentiator for Antipsychotics • Agranulocytosis • Clozapine • Rare but occurs 0.5 – 1% • More rare with other atypicals • Requires WBC checks Q 1-2 weeks • Cardiac Side Effects • QT Elongation – incr risk of arrythmia • Most pronounced with: Mellaril (thioridizine), Inapsine (dorperidol) • Mild Increase with Geodon (Ziprasidone) • Minimal Increase with Risperdal, Haldol, Zyprexa

  24. Efficacy • Conventional Agents • Solid and Equal efficacy on POSITIVE SX • Limited efficacy on NEGATIVE SX • All Other Novel / Atypical Agents(except Clozapine) • Equal efficacy on POSITIVE SX • Better Efficacy on NEGATIVE SX • Clozapine • Better efficacy on POSITIVE SX • Better efficacy on NEGATIVE SX

  25. Treatment Resistance • When Positive Sx do not decrease: • Was trial adequate in terms of: • Dosing? • Duration? • If one antipsychotic fails another may work • Atypicals are tremendously different in terms of receptor affinity and diversity • If two antipsychotics fail chances for success diminish very rapidly • Clozapine offers best hope after 2 failures (30-50% Response) • Augmentation with mood stabilzers may improve response • Supplementation with another atypical is common practice but not evidence based

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