Schizophrenia
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  • 1. Schizophrenia Diagnosis and Pharmacotherapy Jason Cavolina Clerkship Internal Medicine I
  • 2. Epidemiology
    • Incidence: uncommon (~1%)
    • Prevalence: equal across cultures and sexes
    • Onset: usually during adolescence and early adulthood (Male~18-20) (Female~26-30)
    • Heredity: higher prevalence in 1st degree biologic relatives w/ schizophrenia
        • parents w/ schizophrenia have offspring w/ ~40% chance of schizophrenia
  • 3. Diagnosis
    • Characteristic psychotic symptoms: exhibited for at least 1 month during the active phase of illness
      • Lack of insight
      • Auditory hallucinations
      • Ideas of reference
      • Suspiciousness
      • Voices speaking to patient
      • Delusions
      • Thoughts spoken aloud
  • 4. Diagnosis
    • Functioning below previous level:
      • Work
      • Interpersonal relations
      • Self-care
    • Signs and symptoms last for at least 6 months: may include prodromal or residual symptoms
  • 5. Diagnosis
    • Must rule out:
      • Schizoaffective disorder
      • Mood disorder
      • Medical disorder (organic causes)
      • Substance abuse
  • 6. Core Symptom Clusters:
    • Positive Symptoms:
      • Delusions
      • Hallucinations
      • Disorganized speech
      • Catatonia
    • Do respond well to drug therapy (typical and atypical drugs); response to meds seen in ~7-14 days
    • Negative Symptoms:
      • Affective flattening
      • Alogia
      • Avolition
      • Anhedonia
    • Do not respond well to typical drugs ( do respond to atypical drugs ); response to meds seen in ~6 months
  • 7. Core Symptom Clusters:
    • Cognitive symptoms:
      • Attention
      • Memory
      • Executive functions
    • Mood symptoms:
      • Dysphoria
      • Suicidality
      • Hopelessness
    •  Social / Occupational Dysfunctions
  • 8. Favorable Prognostic Factors:
    • Female sex
    • Good social support network
    • High IQ
    • Abrupt onset of illness
    • Presence of positive symptoms
    • Presence of stressful precipitating events
    • Associated mood disturbances
    • Good insight
    • Fast tx after 1st episode
    • Good medication adherence
    • Good interepisode functioning
    • Absence of brain abnormalities
    • Family history + mood disorder and – schizophrenia
  • 9. Pharmacotherapy
    • Typical antipsychotics
    • 1 st generation
    • Low Potency:
      • Chlorpromazine [THORAZINE]: dose range 300-1000 mg/d
      • Thioridazine [MELLARIL]: dose range 100-800 mg/d; high doses lead to pigmentary retinopathy (need eye exams), and  QT interval
      • Mesoridazine [SERENTIL]: metabolite of thioridazine
  • 10. Pharmacotherapy
    • Typical antipsychotics
    • 1 st generation
    • High Potency:
      • Fluphenazine [PROLIXIN]: dose range 5-20 mg/d
        • Fluphenazin D: deconate ; long-acting IM form for maintenance therapy in non-compliant patients; dose range 6.25-50 mg IM/ 2-4 weeks
      • Haloperidol [HALDOL]: dose range 2-20 mg/d
        • Haloperidol D : dose range 50-200 mg/2-4 weeks
      • Thiothixene [NAVANE]: dose range 15-50 mg/d
      • Trifluoperazine [STELAZINE]: dose range 5-40 mg/d
  • 11. Pharmacotherapy
    • Typical antipsychotics
    • 1 st generation
    • High Potency:
      • Loxapine [LOXITANE]: dose range 50-150 mg/d
      • Molindone [MOBAN]: dose range 50-150 mg/d
      • Perphenazine [TRILAFON]: dose range 16-64 mg/d
  • 12. Pharmacotherapy
    • Atypical Antipsychotics
    • 2nd generation
    • 1st line therapy
      • Effective against: negative and positive symptoms
      • Treatment resistant patients
      • Less prolactin effect
      • Lower risk of EPS / TD
      • Do not  cognitive function
  • 13. Pharmacotherapy
    • Atypical Antipsychotics:
      • Clozapine [CLOZARIL]: dose range 300-900 mg/d (given BID 1/3 AM 2/3 PM); serum levels at doses >600 mg/d
        • Side Effects: agranulocytosis, seizures, myocarditis, anticholinergic effects,  salivation, weight gain
        • Usually reserved for tx resistant patients b/c of side effect profile
      • Olanzapine [ZYPREXA]: dose range 10-20 mg/d
        • Side Effects: weight gain and sedation (dosing given HS)
      • Quetiapine [SEROQUEL]: dose range 300-800 mg/d (given BID)
        • Side Effect: weight gain (monitor TG, cholesterol, LFT)
  • 14. Pharmacotherapy
    • Atypical Antipsychotics cont:
      • Risperidone [RISPERDAL]: dose range 2-6 mg/d (given HS or AM); > 6 mg/d lead to  EPS
      • Ziprasidone [GEODON]: dose range 80-160 mg/d (divided BID) [food can  absorption two-fold]
        • NO weight gain, orthostasis, or sedation are seen
      • Aripiprazole [ABILIFY]: dose range 10-30 mg/d (given QD)
        • Partial DA agonist: antagonist during high DAergic activity (mesolimbic DA, psychotic symptoms); agonist during low DAergic activity (low EPS or negative symptoms)
        • Partial serotonin agonist
        • No prolactin or anticholinergic effects
        • Minimal weight gain, hypotension and sedation
  • 15. Pharmacotherapy
    • Injectable Agents:
      • Acute Agitation: haloperidol, olanzapine, ziprasidone; (can use a lower dose if combined with a benzodiazepine)
      • Maintenance therapy: used for patients who exhibit poor compliance; risperdal consta (given q2w); haldol deconate (q4w); or prolixin deconate (q2-3w)
        • For patients who “cheek” their meds give risperdal M-tab (oral disintegrating tablet, ODT)
  • 16. Monitoring
    • Extrapyramidal Side effects: seen mostly in 1st generation (especially high potency) and w/ risperidone
      • Acute dystonia: can be life threatening
        • Includes: oculogyric crisis; torticollis; opisthotonus; trismus; and spasming of other muscles
        • Occurrence: seen usually in young males; 90% occurs w/in 72 hours of tx
        • Tx: parenteral anticholinergic agents (benztropine [Cogentin]; and/or  dose
      • Pseudoparkinsonism:
        • Includes: akinesia (rigidity, immobility, masklike expression, stooped posture, slow speech); and tremors (especially hands)
        • Occurrence: seen usually in elderly females; occurs ~3 months into therapy
      • Akathisia: least responsive to drug therapy
        • Includes: inability to sit still; restless movement; and tapping of feet
        • Tx: prevent with inderal; and/or  dose; and/or give BZD’s
  • 17. Monitoring
    • Tardive dyskinesia: 1st generation drugs
      • Includes:
        • Choreiform movements
        • Athetoid movements
        • Axial hyperkinesis
      • Abnormal Involuntary Movement Scale: (AIMS) measures progression of TD; performed every 6 months
      • Tx: mild to moderate change to 2nd gen drug; severe change to clozapine
  • 18. Monitoring
    • Neuroleptic Malignant Syndrome (NMS): potentially fatal and can occur at any time; seen more with 1st generation drugs
      • Includes: high fever;  WBC; muscular rigidity;  CPK
      • Tx: fluids; ICU; respiratory support; d/c drug
    • Sedation: seen mostly w/ low potency typical meds
    • Hyperprolactinemia: seen with typical meds and risperdidone
      • Signs and Symptoms: galactorrhea, gynecomastia, sexual dysfunction, and amenhorrhea
  • 19. Monitoring
    • Anticholinergic effects: seen mostly w/ low potency 1st generation drugs
    • Orthostatic Hypotension: seen mostly w/ low potency 1st generation drugs
    • QTc interval prolongation: > 0.44s seen with thioridazine
  • 20. Monitoring
    • Weight gain: most common with atypicals clozapine and olanzapine (not as common, but still seen, with risperidone, quetiapine and typical drugs)
    • Ophthalmic effects: thioridazine causes pigmentary retinopathy (atrophy and pigment infiltration)
    • Seizures: mostly seen with low potency typical drugs and clozapine; minimize with slow dose titration and use of lowest effective dose
  • 21. Monitoring
    • Sexual Dysfunctions: most common with thioridazine but can be seen with any typical or atypical agents
    • Agranulocytosis: seen with clozapine ~ 1-2%
      • Risk: seen @ 6-18 weeks;  in female, elderly, and cachectic patients
      • Do not start if: WBC <3.5 K/mm 3
      • D/C permanently if: WBC <2.0 K/mm 3
      • D/C temporarily if: WBC <3.0 K/mm 3
        • Warning signs: pharyngeal infections; fever
        • Monitoring: baseline, weekly, then every 4 weeks after D/C drug
  • 22. Monitoring
    • Drug Interactions:
      • Dopamine receptor antagonists +
        • Anticonvulsants: dopamine antagonists  anticonvulsant levels
        • Antihypertensives: dopamine antagonists potentiate hypotension
        • Barbiturates: long term use will  antipsychotic levels; short term use will  CNS depressant effects
        • Levodopa; mutual antagonism between levodopa and dopamine receptor antagonist
        • Pressor agents:
          • α-agonists: pressor effect is antagonized
          • β-agonists: marked hypotension
        • Sedative-Hypnotics: additive CNS depressant effects
  • 23. Monitoring
    • CYP450 Drug Interactions:
    • Clozapine: major 1A2; minor 3A4 and 2D6
      • Inhibited by: cimtidine; erythromycin; fluoxetine; paroxetine; fluvoxamine; and quinidine
      • Induced by: smoking; carbemazepine; and phenytoin
    • Olanzapine: major 1A2; minor 3A4 and 2D6
      • Inhibited by: fluvoxamine
      • Induced by: smoking
    • Quetiapine: major 3A4; minor 2D6
      • Inhibited by: cimetidine, erythromycin; fluconzaole; itraconazole; and ketoconazole
      • Induced by: carbamezapine and phenytoin
    • Risperidone: major 2D6
      • Inhibited by: fluoxetine; paroxetine; and quinidine
    • Ziprasidone: major aldehyde oxidase; minor 3A4 and 1A2
      • Induced by: carbemazepine
    • Aripiprazole: major 3A4; minor 2D6 ( see quetiapine above )
    • Thioridazine: avoid all drugs that inhibit 2D6 (  QTc interval)
  • 24. Monitoring
    • Efficacy:
    • Acute Phase:
      •  hostility and aggression; relieve acute symptoms to  functioning
    • Stabilization Phase: ~ 6+ months after onset of acute symptoms
      •  stress,  symptoms (see +/-)
    • Stable Phase: symptoms stable or not present or less severe
      • Pt may exhibit anxiety, tension, depression, and insomnia (add adjunctive tx)
  • 25. References
    • Lexi-interact Lexi-comp hand held reference, 2005
    • Lexi-onhand. Lexi-complete and specialties. Updated 8/05
    • http://www.clevelandclinicmeded.com/diseasemanagement/psychiatry/schizophrenia/table1schizo.htm , accessed 9/20/05
    • http://www.clevelandclinicmeded.com/diseasemanagement/psychiatry/schizophrenia/schizophrenia.htm#table1 , accessed 9/20/05
    • http://depts.washington.edu/stellalb/images/Schizophrenia.pdf , accessed 9/20/05
    • http://www.mentalhealth.com , accessed 9/20/05
    • http://www.psych.org/research/dor/dsm/index.cfm ,accessed 9/20/05
    • Micromedex Drugdex system 2005, accessed, 9/19/05