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