Review Primary Care

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  • 1. Antipsychotics Review
  • 2. Case  40 year old man with long hx of paranoid schizophrenia.  On perphenazine (Trilafon) 12 mg qhs, benztropine (Cogentin) 2 mg qhs x 15 years.  PMH notable for DM II on metformin, glyburide, accupril, last HgA1c of 7.9  Lives at B&C, smokes 2 packs per day, occ ETOH, remote hx of methamphetamines.
  • 3. Case  On MSE, overweight man with BMI 33, plain dress, adequate grooming, diminished spont movements, eye contact fixed, occ resting tremor in R hand noted and occ grimacing. Speech has slight delay with diminished tone but o/w fluent. Mood is “fine” Affect is constricted to blunted. TP generally linear, bit concrete, sparse details. TC of:
  • 4. Case  A) “I like what I’m taking.” Some mild paranoia of police but without evidence of overt delusions  B) “I know the B&C is poisoning me.”
  • 5. Antipsychotics  First antipsychotic was a phenothiazine (chlorpromazine) synthesized in 1950.  First Generation, also called “typical”  “Me too D2”  Second Generation, also called “atypical”  Starting in early 90’s
  • 6. How do Typical Antipsychotics work?  Dopamine Hypothesis  Targets for D2 blockade  Mesolimbic area: antipsychotic effect  Nigrostriatal tract: EPS  Tuberinfundibular area: prolactin elevation  76-80% D2 occupancy needed for effect for conventional antipsychotics  Problem:  Atypicals have varying occupancy requirements
  • 7. How do Atypical Antipsychotics work?  Leading Theories  May relate to DA receptors having subtypes D1-5 as well as other receptors playing a part to modulate dopamine receptors (such as 5-HT2A .)  Hypofunctional N-methyl-D-aspartate (NMDA) receptors in VTA leads to  hyperactive mesolimibic DA activity (via GABA interneuron)  hypoactive mesocortical DA activity
  • 8. First Generation Classified by Potency Equivalent Dose Sedation Autonomic (anti EPS (mg) andrenergic and anticholineric) SE’s haloperidol 2 + + +++ (Haldol) trifluoperazine 5 ++ + +++ (Stelazine) perphenazine 10 ++ ++ ++ (Trilafon) mesoridazine 50 +++ ++ + (Serentil) chlorpromazine 100 +++ +++ + (Thorazine)
  • 9. Acute EPS esp with high potency agents  Related to decreased DA activity in the basal ganglia  Akathisia: occurs in 2/3 of patients to some degree  Treat with beta blockers  Dystonia: occurs in 1/3 of patients  Treat with anticholinergics  Parkinsonism: occurs in 1/3 of patients treated long term  Treat with anticholinergics
  • 10. Neuroleptic Malignant Syndrome  Esp with high potency antipsychotics escalated quickly to high doses  Features are hyperthermia, severe muscular rigidity, autonomic instability, changing levels of consciousness.  Psychiatric emergency = emergency room
  • 11. Tardive Dyskinesia  Increased sensitivity of DA receptors in basal ganglia.  10-20% in one year, risk increases 4-5% per year.  Higher risk: include elderly women and schizoaffective disorder.
  • 12. Typical Antipsychotics Bottom Line  All work by blocking D2 receptor  High potency (haloperidol) = More EPS, TD, NMS  Low potency (chlorpromazine) = more sedation, anticholinergic side effects  All equally efficacious  High potency preferred by patients
  • 13. Atypical vs Typical Antipsychotics  Atypical antipsychotics advantages  greatly reduced to no propensity for EPS or TD  minimal elevation of prolactin (except risperidone)  Less impact on negative symptoms, cognition  broader spectrum of action  Typical antipsychotic advantages  depot formulations (except Consta)  cost  less severe metabolic impact
  • 14. How do Atypical Antipsychotics work?  Leading Theories  May relate to DA receptors having subtypes D1-5 as well as other receptors playing a part to modulate dopamine receptors (such as 5-HT2A .)  Hypofunctional N-methyl-D-aspartate (NMDA) receptors in VTA leads to  hyperactive mesolimibic DA activity (via GABA interneuron)  hypoactive mesocortical DA activity
  • 15. Are atypicals “better?”  Efficacy and effectiveness  Maybe  Side effects  Different  Cost effectiveness  Unknown
  • 16. Are atypicals “better?”  Improved efficacy based on short-term structured studies, mostly industry sponsored.  Meta-analyses have shown mixed results with risperidone and olanzapine edging typicals slightly.  NIMH sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was a randomized DB, flexible dose study with olanzapine, risperidone, quetiapine, ziprasidone, perphenazine, 18 months
  • 17. CATIE Points to Ponder  CATIE focused on “effectiveness” rather than “efficacy.”  Chronic schizophrenics have a high rate (>70%) of antipsychotic discontinuation over time.  Risperidone and especially olanzapine has comparatively better effectiveness compared to quetiapine and ziprasidone  Confirmed superior efficacy of clozapine  Typical antipsychotics (perphenazine) can be as effective as atypicals (except olanzapine)
  • 18. However…  Atypical Antipsychotics  olanzapine and clozapine: most cases of new onset DM, DKA, death, elevated triglyceride and LDL  ziprasidone and aripiprazole: fewest cases of new onset DM, DKA, death, elevated triglyceride and LDL  Weight gain over 1 year (pooled data from multiple trials)  olanzapine: > 13.2 lb, >22 lb with doses > 12.5 mg  quetiapine and risperidone: 4.4 - 6.6 lb  aripiprazole and ziprasidone: 2.2 lb
  • 19. Metabolic Impact (cont)  CATIE confirmed findings  Metabolic syndrome at baseline 42.7% (twice general population.  Olanzapine treatment:  30% gained > 7% weight compared to 7% (ziprasidone), 13% (risperidone, quetiapine)  Consistent increase in blood glucose (13.8 mg/dL), Hg A1c (0.97%), cholesterol (17.5 mg/dL), triglyceride (94.1mg/dL)
  • 20. ADA Consensus Position on Antipsychotics and Obesity, Diabetes, Dyslipidemia Drug Weight Gain DM Risk Dyslipidemia clozapine +++ + + olanzapine +++ + + risperidone + Discrepant Discrepant quetiapine + Discrepant Discrepant aripiprazole +/- No effect No effect ziprasidone +/- No effect No effect Diabetes Care 2004; 27:596-601
  • 21. Monitoring  At baseline, 1 month, 3 months  weight, BP, fasting glucose, fasting lipid panel  Yearly  weight, BP, fasting glucose  Every three years  fasting lipid panel  Looking for:  > 5-7% increase from initial weight or BMI > 25  Fasting glucose > 126  BP > 140/90  Cholesterol thresholds depends on risk factors
  • 22. clozapine (Clozaril)  Relatively low D2 blocker, significant 5-HT2A, H1, alpha1, alpha2, muscarinic receptor blocker.  Indications: treatment resistant schizophrenia, severe TD (may improve)  Dosage: titrated over weeks to 250-450 mg qd. If more than a 2-3 days of doses missed, should restart titration.  Common side effects: sialorrhea, orthostatic hypotension (can be severe, titration dependent), tachycardia, constipation, weight gain, sedation.
  • 23. clozapine (Clozaril)  Agranulocytosis  Overall risk < 1% with highest risk at week 6-18  Weekly CBC required for first 6 months then every other week  Discontinue if WBC < 3000 or granulocyte count < 1500  Bottom Line: most effective antipsychotic period but limited by side effects. Watch for metabolic side effects. You won’t be starting it.
  • 24. olanzapine (Zyprexa)  Antagonism at the 5-HT2A, DA, muscarinic, H1, alpha1 receptors  FDA approved for schizophrenia, acute bipolar mania and bipolar disorder maintenance.  Dosing: (PO) start at 5-10 mg qhs and increase by 5 mg qweek to target dose of 10-30 mg qhs. Max dose 40 mg qd.  Common side effects: weight gain, sedation, dry mouth, constipation,. May start seeing EPS at doses > 30 mg qd.  Bottom Line: Probably most effective (except clozapine) but metabolic effects limits use.
  • 25. risperidone (Risperdal)  Antagonism at 5-HT2A, D2, alpha1 and 2, H1 receptors  FDA approved for schizophrenia, acute bipolar mania  Dosing: start 1-2 mg qd, increase by 1-2 mg every 3-6 days with usual therapeutic dose of 4-6 mg qd. Max dose16 mg qd. Available in M-Tab and IM Consta.  Precautions: orthostatic hypotension, hyperprolactinemia  Common side effects: somnolence, dizziness, constipation, weight gain and dose dependent EPS (> 6 mg qd).  Bottom line: Popular first line agent, watch for EPS at > 6 mg and hyperprolactinemia in women.
  • 26. quetiapine (Seroquel)  Antagonist at 5-HT2A, D1, D2, H1, alpha1, alpha2 receptors  FDA approved for schizophrenia, bipolar mania and depression.  Dosing: start 25-50 mg bid, increase by 100-200 mg every few days to at least 200 mg bid. Max dose 400 mg bid  Common side effects: somnolence, dizziness, dry mouth, constipation, weight gain  Bottom Line: Sedating with no EPS liability at any dose,. Initially marketed with target dose too low, need to get to at least 200 mg bid. Don’t waste time at the low doses
  • 27. ziprasidone (Geodon)  Antagonist at D2, 5-HT2A, H1, agonist at 5-HT1A  Half life about 7 hours, metabolized by aldehyde oxidase and less so by 3A4. Absorption increased two fold in the presence of food.  FDA approved for schizophrenia and bipolar mania  Dosage: Dose with food usually bid. Start 40-60 mg bid, target dose 60-80 mg bid.  Common side effects: mild somnolence, dizziness, akathesia, nausea, agitation
  • 28. ziprasidone (Geodon)  Warnings: QTc prolongation (> 500 msec significant)  No documented cases of torsade although this is the presumed risk  Avoid with other QTc prolonging drugs, preexisting bradycardia, hypokalemia / hypomagnesemia, screen for congenital prolonged QTc syndrome. (hx of sudden death in family)  Bottom Line: Relatively nonsedating, but watch for agitation. QTc concern largely overblown but do screen above as indicated. Dose adequately.
  • 29. aripiprazole (Abilify)  “Modulates” DA: acts as DA2 agonist/antagonist, 5- HT1A agonist, 5-HT2A antagonist. FDA approved for schizophrenia and bipolar mania.  Dosing: start 10-15 mg qd. Most patients on 15-20 mg qd. For bipolar mania 30 mg qd  Common side effects: anxiety, insomnia, mild somnolence, akathesia, constipation, tremor.  Bottom Line: Like Geodon, not very sedating and a generally positive side effect profile. Some patient will complain of anxiety/akathesia initially.
  • 30. Which Antipsychotic?  With exception of clozapine, all considered first line.  Weight concern/DM: consider starting with something other than olanzapine.  Insomnia: consider olanzapine, risperidone, quetiapine.  EPS sensitivity or TD: consider quetiapine.
  • 31. Which Antipsychotic?  If you see an atypical antipsychotic on a clinic note.  Ask if the psychiatrist is checking lipids, glucose periodically. If they are not, get a fasting lipid panel and glucose. If the medication is new, check again in three months, then the glucose yearly, lipids q3-5 years.  Don’t forget monitoring increased weight > 7% from baseline while on antipsychotic.  Typical antipsychotic cause weight gain too although there is no mandatory monitoring of lipids or glucose. Do watch for TD.