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Antipsychotic Review

Antipsychotic Review. Jena L. Ivey, PharmD, BCPS, CPP. Objectives. Review different antipsychotic agents with regard to efficacy and safety Discuss adverse effect profiles of antipsychotic agents and learn how to pick the “best” one for your patient if needed.

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Antipsychotic Review

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  1. Antipsychotic Review Jena L. Ivey, PharmD, BCPS, CPP

  2. Objectives • Review different antipsychotic agents with regard to efficacy and safety • Discuss adverse effect profiles of antipsychotic agents and learn how to pick the “best” one for your patient if needed

  3. Antipsychotic Use in Older Adults • Decreased metabolism can lead to increased blood levels and increased side effects • Decreased absorption can lead to decreased blood levels and reduced effectiveness • Brain changes with aging can lead to heightened sensitivity to side effects (e.g. EPS) and reduced effectiveness • Cognitive impairment can lead to nonadherence

  4. Antipsychotics • Choice of traditional vs. new generation drugs • Side effect profiles often direct selection • EPS, TD, NMS less likely with newer agents • Efficacy against negative symptoms (when relevant) is higher with the new drugs (probably related to 5HT-2 antagonism) • 22% of Nursing home patients

  5. Traditional Antipsychotics • All have tendency to produce EPS/TD • Low potency drugs are usually highly sedating, highly anticholinergic and promote orthostasis • Orthostatic hypotension is related to alpha-1 blocking effects and correlates highly with hip FX • Low cost is an advantage

  6. Typical Antipsychotics • Chlorpromazine • Prototype typical antipsychotic • Only able to substantially improve positive symptoms, little effect on negative symptoms and many adverse effects • Equivalent doses of other typical antipsychotics based on 100 mg of chlorpromazine

  7. Low potency Chlorpromazine Thioridazine Mesoridazine Mid potency Molindone Loxapine Perphenazine High potency Haloperidol Fluphenazine Thiothixene Trifluoperazine Typical Antipsychotics

  8. Pharmacological Profile for Haloperidol • Affects alpha, dopamine-2 receptors • Oral, depot formulations • Oral • Start 0.5 mg daily, increase to 30 mg maximum per day in divided doses • Depot (haloperidol decanoate) • Given usually once monthly • Must been stable on oral dose first

  9. Why Use Depot? • Compliance • Once weekly dosing • Convenience • Side effects • Lacks peak concentrations • Gives lower but steady concentrations

  10. Perphenazine • Mid potency typical antipsychotic • Less EPS over high potency • Less affinity for muscarinic, alpha, and histaminic receptors over low potency • Max dose= 64 mg • Average dose in chronic schizophrenics • 32 mg/day

  11. Traditional Antipschotics

  12. Efficacy of Typical Antipsychotics • Most benefit seen with positive symptoms • Limited benefit with negative symptoms • May worsen negative or cognitive symptoms, especially in high doses • Have fallen out of favor as first-line agents

  13. Improve psychotic symptoms Improve or not worsen negative symptoms May improve cognition Cause less or no EPS Cause less or no tardive dyskinesia Effective in refractory patients Atypical Antipsychotics

  14. Decision of Antipsychotic • Atypical agents are now accepted to be first-line treatment • Considered ‘first-line’ now, but anticholinergic effects, orthostasis and COST are important factors in older adults • Treatment choice based on: • Past response or past side effects to individual agents and number of treatment failures • Patient or practitioner preference • Problems with EPS or tardive dyskinesia • Other concomitant disease states • Compliance issues

  15. Clozapine Risperidone Paliperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Available Atypical Antipsychotics

  16. Clozapine • Not a first-line agent • Must have failed at least two other trials of antipsychotics • Difficult to tolerate due to adverse drug effects Baseline work-up • CBC with diff (WBC, ANC) • Cardiac history • EKG • FLP • Weight/BMI • FPG and/or HgbA1c

  17. Clozapine – Adverse Effects • Black Box Warnings • Hypotension • Seizure • Agranulocytosis • Myocarditis • Risk of death in elderly demented patients with psychosis • Significant potential for metabolic dysregulations • Others: sedation, constipation, tachycardia

  18. Clozapine Agranulocytosis • 1% incidence • More frequently occurs early in therapy • Monitor CBC weekly for first 6 months, every two weeks for next 6 months, then every 4 weeks thereafter • Must be registered to receive clozapine • Do not rechallenge if patient has experienced agranulocytosis to clozapine in the past • ANC<1000

  19. Risperidone (Risperdal) • Mixed serotonin-dopamine antagonist activity • Also antagonizes alpha-2, histamine receptors Baseline work-up • Cardiac history • EKG • FLP • Weight/BMI • FPG and/or HgbA1c • Black Box • risk of death in elderly demented patients with psychosis

  20. Risperidone – Adverse Effects • Lower EPS than with typical antipsychotics like haloperidol • Risk of EPS higher with doses greater than 6 mg/day • Prolactin elevation • Orthostasis • Tachycardia

  21. Risperidone Decanoate • Only long-acting atypical antipsychotic injection • Compliance • Gluteal injection • Polymeric microspheres • Main release at 3 weeks • Single dose maintained for 4-6 weeks

  22. Paliperidone (Invega) • Major metabolite (9-OH) of risperidone • Innovative delivery system • Delivers smooth plasma levels over 24 hrs Baseline work-up • Similar to Risperidone • Black Box • risk of death in elderly demented patients with psychosis

  23. Paliperidone • Comparison to risperidone • Less peak/trough fluctuations, possibly less side effects due to fluctuations • “Once-daily” dosing • No CYP 2D6 interactions (e.g. paroxetine, fluoxetine, poor metabolizers) • Better choice for patients w/liver dysfunction • Phase II metabolism

  24. Olanzapine (Zyprexa) • Potent antagonist of several serotonin receptors, dopaminergic, muscarinic, histaminergic, and alpha Baseline work-up • Similar to risperidone PLUS • LFTS • Black Box • risk of death in elderly demented patients with psychosis

  25. Olanzapine – Adverse Effects • Significant potential for metabolic dysregulations • Sedation • Anticholinergic effects • Tachycardia • EPS less than with risperidone • monitor for akathisia at higher doses (>15mg)

  26. Olanzapine – IM • For control of acute agitation in schizophrenic and bipolar patients • Calming without oversedation • Can give Q 2-4 hours • Risk of bradycardia and orthostasis • Do not give within 1 hour of IM/IV lorazepam

  27. Quetiapine (Seroquel) • Antagonist of serotonin, dopamine receptors, some effect on histamine/alpha receptors Baseline work-up • Similar to risperidone PLUS: • CBC in pre-existing low WBC or h/o drug-induced neutropenia • Black Box • Risk of death in elderly demented patients with psychosis

  28. Quetiapine – Adverse Effects • EPS appears to be less due to less effect on dopamine (loose and transient binding to dopamine receptors) • Sedation/fatigue • Orthostasis • Anticholinergic effects at doses >300-400mg • Tachycardia • Increased LFTs (transient)

  29. Ziprasidone (Geodon) • High affinity for serotonin receptors, moderate dopamine/histamine, no affinity for alpha/beta Baseline work-up • Similar to risperidone PLUS • Electrolytes • Black Box • Risk of death in elderly demented patients with psychosis • Contraindicated • H/O arrhythmias or QTc prolongation • Uncompensated heart failure • Acute or recent myocardial infarction

  30. Ziprasidone – Adverse Effects • EPS versus “activation” • Minimal effects on metabolic profile • EKG changes • QTc prolongation

  31. Ziprasidone – Intramuscular • For acute psychotic agitation • Calming without oversedation • Can give Q 2-4 hours • Can give with IM/IV lorazepam

  32. Aripiprazole (Abilify) • Dopamine-2 partial agonist, partial serotonin-1A agonist Baseline work-up • Similar to risperidone • Black Box • Risk of death in elderly demented patients with psychosis • Risk of increased suicidal behavior similar to antidepressants labeling • FDA approval for adjunct therapy in MDD

  33. Aripiprazole – Adverse Effects • EPS initially presumed minimal • Akathisia versus anxiety, restlessness • Minimal effects on metabolic profile • Nausea • Headache

  34. Aripiprazole – IM • For acute agitation in patients with schizophrenia or bipolar d/o • Calming without oversedation • Can give Q 2 hours • Can give with IV/IM lorazepam

  35. Dosing

  36. Dosing ^ Max dose per Product Labeling; risk of EPS higher with doses > 6mg

  37. Dosing

  38. Antipsychotic Adverse Effects

  39. Orthostatic Hypotension • Vulnerability in older adults is increased because of decreased sensitivity of baroreceptors in the carotid and BP regulatory centers in the hypothalamus PLUS decreased alpha-1 adrenergic receptors • 30+% of institutionalized older adults display symptomatic orthostatic hypotension • Drugs cause this primarily by blocking alpha-1 receptors • TCAs, MAOIs, antipsychotics (including many of the new generation drugs) and lithium are all offenders • Benzodiazepines can cause falls by producing dysequilibrium rather than orthostasis

  40. Falls/Hip Fractures • 250,000 yearly • Most occur in women over age 65 • 90% are due to a fall from standing height! • 50-60% of FXs in this age group require Nursing Home placement and about 1/2 never leave • Mortality rate at the end of 1 year is 20% • Most falls are due to a combination of orthostasis, dizziness, EPS, sedation, decreased vision and dysequilibrium all of which can be caused or exacerbated by psychotropics

  41. Tardive Dyskinesia • Risk much higher in older adults • Incidence may be as high as 25% per year (versus 5% per year in younger patients) • Older adults have increased severity and lower spontaneous remission rates • Risk factors: AGE, F>M, early-onset EPS, length of neuroleptic exposure • TX: empiric. ?branched-chain amino acids, vitamin E, benzos

  42. Antipsychotic Comparison

  43. Atypicals and Weight Gain • Lots of ways to look at this issue (total average wt gain, number of patients with >10% initial body weight gain, length of weight gain, types of weight gain) • Risk of significant weight gain: • Clozapine, olanzapine and quetiapine, high • Risperidone, moderate • Ziprasidone, aripiprazole, low • Generally, thinner people gain more weight (lower BMI) • weight gain seems to plateau at 3 yrs or so, but average weight gain is in the 15 lb range • weight gain may be less of a problem in the elderly • However, even in low risk drugs like ziprasidone and aripiprazole, certain individuals gained large amounts of weight according to package insert date (7-8%)

  44. How Do Atypicals Cause Weight Gain? • Antihistamine effects (H1) : clozapine, olanzapine, quetiapine are strong inhibitors • 5HT2c blocking effects – Mice with this receptor ‘knocked out’ are all obese – all atypicals are 5HT2c blockers except aripiprazole • Endocrine effects such as hyperprolactinemia may contribute • Genetic susceptibility (receptor polymorphisms)

  45. Atypical Antipsychotics: Hyperglycemia • Hyperglycemia has been seen with olanzapine & clozapine • Good prospective studies are lacking; DM in schizophrenics increased dramatically after neuroleptics introduced in 1950’s • Schizophrenics may have impaired glucose tolerance • Insulin resistance may be the mechanism • Monitor Hgb A1c every 3 months; Chol & TGs every 6 months

  46. Monitoring Protocolab aBased on American Diabetes Association Consensus statetment bMore frequent assessments may be necessary based on clinical status

  47. Managing Side Effects • Anticholinergic Effects • fluids, sugarless gum, bowel regimen • EPS • lower dose of drug (esp. risperidone) • drug holiday • Hypotension • rise slowly from bed, divide doses, increase salt intake, TED hose, fludrocortisone in refractory cases • Sedation:lower dose, modafanil (Provigil), methylphenidate (Ritalin)

  48. Prolongation of QTc interval • QTc interval is time it takes the heart to repolarize, corrected for heart rate • 440 msec upper limits of nomal; >480 definitely prolonged • Tricyclics widen QRS & QTc intervals • Drugs which may significantly prolong QTc include: thioridazine , mesoridazine, ziprasidone, droperidol, pimozide & ketoconozole - often metabolized by P450-3A4 • Drugs which interfere with metabolism of these QTc prolongers such as: Nefazodone (SERZONE), fluvoxamine (LUVOX), cimetidine, erythromycin, ketoconazole, norfluoxetine can cause problems

  49. QTc Prolongation In Antipsychotics • 2+ Pimozide, Mesoridazine, Thioridazine, Droperidol • 1+ Ziprasidone, Clozapine, Loxapine, Thiothixene, …...Chlorpromazine, Trifluoperazine, Risperidone, …...Quetiapine • +/- Olanzapine, Haloperidol, Fluphenazine • RISK FACTORS: • Female sex • Congenital Long QT • Ischemic heart disease

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