Antipsychotics

1. 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 Schizophrenia Consult Sara Dugan, Pharm.D., BCPP, BCPS April 17, 2018

2. 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.

3. 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 Kreyenbuhl J, et al. Schizophrenia Bulletin 2009.

4. 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 Robinson D, et al. Am J Psychiatry 2014.

5. 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 PsychopharmClin Exp. 2014. Andreasen NC, et al. Am J Psychiatry 2013. Ho BC, et al. Arch Gen Psychiatry 2011.

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

7. 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 Chouinard G, et al. J ClinPsychopharmacol 1993

8. 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) * P < 0.05 Arvanitis LA, et al. Biol Psychiatry 1997.

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

10. 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 Eklund K, Forsman A. ClinNeuropharmacol 1991

11. 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) Takeuchi H, et al. Schizophrenia Bulletin 2013.

12. 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 Low dose ≥ 0.5 but <1 DDD Very low dose < 0.5 DDD Uchida H, et al. Schizophrenia Bull 2011.

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

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