Schizophrenia Consult Antipsychotics What’s the right dose? How low can it go? How much is too much? This Photo by Unknown Author is licensed under CC BY-SA Option 1 Schizophrenia Consult Sara Dugan, Pharm.D., BCPP, BCPS April 17, 2018

Objectives Identify biological, social, and psychological factors that affect psychotic illness Define the mechanisms or rationale for treatments appropriate for psychotic illness Integrate biological, social and psychological considerations when designing and implementing treatment of individuals affected by psychotic illness.

PORT Guidelines Treatment of acute positive symptoms in treatment-responsive people with schizophrenia: Acute antipsychotic medication dose Doses of first generation antipsychotics (FGA) 300 – 1000 chlorpromazine equivalents (CPZ) Recommend lower doses in first-episode schizophrenia patients Maintenance dose 300 – 600 CPZ Aripiprazole 10 – 30 mg Olanzapine 10 – 20 mg Paliperidone 3 – 15 mg Quetiapine 300 – 750 mg Risperidone 2 – 8 mg Ziprasidone 80 – 160 mg Maintenance dose for aripiprazole, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone should be dose found to be effective for reducing positive psychotic symptoms in the acute phase of treatment Fluphenazine Decanoate 6.25 – 25 mg q 2 weeks Haloperidol Decanoate 50 – 200 mg q 4 weeks Risperidone Long Acting Injection 25 – 75 mg q 2 weeks Kreyenbuhl J, et al. Schizophrenia Bulletin 2009.

A look at First Episode Prescribing Review of prescription data from Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) n=404 Drug # Prescriptions Median dose mg/day Mean dose mg/day Dose range mg/day Risperidone 108 3 2.9 0.25 – 7.0 Risperidone Long Acting 1 75 Olanzapine 51 15 16.5 2.5 – 40 Aripiprazole 35 10 2 – 20 Paliperidone 17 6 5.8 3 – 9 Paliperidone Long Acting 13 136.5 149.5 117 – 234 Quetiapine 28 300 309.7 20 – 800 Haloperidol 12 11.3 3 – 30 Haloperidol Long Acting 4 81.2 50 – 125 Ziprasidone 80 102.2 40 – 200 Lurasidone 40 66.7 40 – 120 Asenapine 2 Clozapine 250 200 – 300 Thiothixene 5 Fluphenazine Loxapine Perphenazine Robinson D, et al. Am J Psychiatry 2014.

Neuroprotective or Neurotoxic? Use of antipsychotics associated with decreased risk of relapse Relapses associated with reduced brain volume Longitudinal imaging suggest that greater intensity of antipsychotic treatment associated with smaller gray matter volumes Suzuki T, et al. Hum Psychopharm Clin Exp. 2014. Andreasen NC, et al. Am J Psychiatry 2013. Ho BC, et al. Arch Gen Psychiatry 2011.

Do low dose antipsychotics work? This Photo by Unknown Author is licensed under CC BY

Evaluating a range of risperidone doses Double-blind trial in patients with schizophrenia Treatment for 8 weeks 6 groups Risperidone 2 mg, 6 mg, 10 mg and 16 mg daily Haloperidol 20 mg daily Placebo Clinical Global Impression – Severity of Illness All medications superior to placebo Clinical Global Impression – Improvement All but Ris 2 mg superior to placebo Positive and Negative Syndrome Scale (PANSS) Total score Ris 6, 10, 16 mg and hal 20 mg superior to placebo Positive symptoms All Ris doses superior to placebo Dyskinesia with Ris 6, 10 and 16 mg Treatment for 8 weeks after single placebo wash out doses increased to maintenance doses in 1 week N=135 all inpatients- Canadian trial No difference seen in parkinsonism with ris although appeared to increase with dose but no different than placebo hal was greater than ris 2, 6 and 16 mg for parkinsonism Chouinard G, Jones B, Remington G, Bloom D, Addington D, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13(1):25-40. Chouinard G, et al. J Clin Psychopharmacol 1993

A look at Quetiapine doses Double-blind 6 week treatment of patients with schizophrenia Groups (n = 361) Quetiapine 75, 150, 300, 600 or 750 mg Haloperidol 12 mg Placebo Efficacy Brief Psychiatric Rating Scale (BPRS) MC R DB PC Initially had 1 week single blind placebo wash out then doses titrated up over the first week Patients were hospitalized with schizophrenia * P < 0.05 Arvanitis LA, et al. Biol Psychiatry 1997.

Can low doses also work for maintenance treatment of schizophrenia? This Photo by Unknown Author is licensed under CC BY-NC-ND

A look at long-acting injections Randomized, double-blind trial for 48 weeks Patients with schizophrenia n=41 Groups Haloperidol decanoate 60 mg IM every 4 weeks Placebo Significantly more relapses with placebo DB period preceeded by 15 week single blind run in phase treated with 60 mg hal dec (3.6 mg daily oral). Steady state hal levels reached at 11 weeks; mean ss level 6.3 nmol/L in placebo group 50% decrease in mean hal plasma concentration seen 8 weeks after withdrawal of hal- hal concentration seen as a predictor of relapse No difference in EPS- more hal pts on biperiden and more placebo pts on sedatives Eklund K, Forsman A. Minimal effective dose and relapse double blind trial: haloperidol decanoate vs. placebo. Clin Neuropharmacol 1991;14 Suppl 2:S7-12. Eklund K, Forsman A. Clin Neuropharmacol 1991

Suggested change in cognition Open label 28 week trial Patients (n=61) with schizophrenia with remission of positive symptoms and stable dose at least 3 months 25% dose reduction at baseline then again at week 4 Cognitive function evaluated by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Multicenter OL parallel group 28 wk randomized controlled trial at 6 psychiatric hospitals and clinics in Tokyo On at least 2 mg ris and 5 mg olz Maintained 50% of original dose for remaining 24 weeks Significant reductions in Total score RBANS, immediate memory, language No difference in PANSS total score or positive score but significantly greater decrease in PANSS negative score Takeuchi H, et al. Schizophrenia Bulletin 2013.

Standard dose vs. low dose antipsychotics Meta-analysis 13 studies, n=1395 Standard dose n=739 Low dose n=457 Very low dose n=199 Primary outcome Treatment failure Drug Defined Daily Dose PORT Dose Quetiapine 400 mg 300 – 750 mg Ziprasidone 80 mg 120 – 160 mg Olanzapine 10 mg 10 – 20 mg Risperidone long acting 25 mg q 2 weeks 25 – 75 mg q 2 weeks Fluphenazine Decanoate 14 mg q 2 weeks 6.25 – 25 mg q 2 weeks Haloperidol decanoate 92 mg q 4 weeks 50 – 200 mg q 4 weeks Treatment failure including d/c of treatment for any reason Study duration varied from 24 weeks to 104 weeks Uchida H, Suzuki T, Takeuchi H, Arenovich T, Mamo DC. Low dose vs. standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophrenia Bulletin 2011;37(4):788-799. Low dose ≥ 0.5 but <1 DDD Very low dose < 0.5 DDD Uchida H, et al. Schizophrenia Bull 2011.

Standard vs. Low dose antipsychotics * Uchida H, et al. Schizophrenia Bulletin 2011.

Revisit dosing to balance efficacy and safety Continuous treatment to prevent relapses Optimal antipsychotic dosing regimen may change over time Increased adverse effects or neurotoxicity This Photo by Unknown Author is licensed under CC BY-SA