Pharmacotherapy for schizophrenia: Side effect management
- Stephen Marder, MD
Stephen Marder, MD
- Section Editor — Psychotic Disorders
- Professor of Psychiatry
- Semel Institute of Neuroscience at UCLA
- T. Scott Stroup, MD, MPH
T. Scott Stroup, MD, MPH
- Professor of Psychiatry
- Columbia University
Schizophrenia is a severe disorder involving chronic or recurrent psychosis and long-term deterioration in functioning . It is among the most disabling and economically catastrophic disorders, ranked by the World Health Organization as one of the top 10 illnesses contributing to the global burden of disease .
Antipsychotic medications are first-line medication treatment for schizophrenia. They effectively reduce symptoms and behaviors associated with the disorder and also have significant side effects. Some of the side effects differ in likelihood and/or intensity across individual antipsychotic drugs (table 1).
This topic addresses the management of side effects during pharmacotherapy for schizophrenia. Pharmacotherapy for schizophrenia is reviewed separately. Side effects of individual medications are also reviewed separately for first-generation antipsychotic drugs, second-generation antipsychotic drugs, and for clozapine. (See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Side effects' and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Side effects' and "Guidelines for prescribing clozapine in schizophrenia", section on 'Adverse effects'.)
Patients receiving an antipsychotic should receive routine monitoring for manifestations of extrapyramidal symptoms (EPS), including akathisia, parkinsonism, and dystonias. All of the antipsychotic medications have the potential for causing EPS. They are common with some antipsychotics (eg, haloperidol, fluphenazine, thiothixene, and trifluoperazine), and uncommon with others (quetiapine, clozapine, and iloperidone).
Akathisia — Akathisia is the most common form of EPS. It usually presents as motor restlessness with a compelling urge to move and an inability to sit still. Individuals with milder akathisia may describe a subjective feeling of restlessness but not show restless motor behavior. If patients do not demonstrate restless behaviors, the examiner should inquire if they pace frequently or if they have difficulty sitting still.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, Washington DC 2000.
- Murray CJL, Lopez AD. The Global Burden of Disease, Harvard University Press, Cambridge, MA 1996. p.21.
- Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 2009; 70:627.
- Praharaj SK, Kongasseri S, Behere RV, Sharma PS. Mirtazapine for antipsychotic-induced acute akathisia: a systematic review and meta-analysis of randomized placebo-controlled trials. Ther Adv Psychopharmacol 2015; 5:307.
- Irwin M, Sullivan G, Van Putten T. Propranolol as a primary treatment of neuroleptic-induced akathisia. Hillside J Clin Psychiatry 1988; 10:244.
- Adler L, Duncan E, Angrist B, et al. Effects of a specific beta 2-receptor blocker in neuroleptic-induced akathisia. Psychiatry Res 1989; 27:1.
- Kramer MS, Gorkin R, DiJohnson C. Treatment of neuroleptic-induced akathisia with propranolol: a controlled replication study. Hillside J Clin Psychiatry 1989; 11:107.
- Adler LA, Peselow E, Rosenthal M, Angrist B. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull 1993; 29:283.
- Lima AR, Soares-Weiser K, Bacaltchuk J, Barnes TR. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2002; :CD001950.
- Tiihonen J, Mittendorfer-Rutz E, Torniainen M, et al. Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study. Am J Psychiatry 2016; 173:600.
- Fontanella CA, Campo JV, Phillips GS, et al. Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. J Clin Psychiatry 2016; 77:661.
- Rifkin A, Quitkin F, Kane J, et al. Are prophylactic antiparkinson drugs necessary? A controlled study of procyclidine withdrawal. Arch Gen Psychiatry 1978; 35:483.
- Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71.
- Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334.
- Tenback DE, van Harten PN, van Os J. Non-therapeutic risk factors for onset of tardive dyskinesia in schizophrenia: a meta-analysis. Mov Disord 2009; 24:2309.
- Sachdev P. Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study. Aust N Z J Psychiatry 2004; 38:445.
- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209.
- Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry 2000; 177:212.
- Baptista T, Kin NM, Beaulieu S, de Baptista EA. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002; 35:205.
- Stroup TS, McEvoy JP, Ring KD, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry 2011; 168:947.
- Ganguli R. Behavioral therapy for weight loss in patients with schizophrenia. J Clin Psychiatry 2007; 68 Suppl 4:19.
- Daumit GL, Dickerson FB, Wang NY, et al. A behavioral weight-loss intervention in persons with serious mental illness. N Engl J Med 2013; 368:1594.
- Bartels SJ, Pratt SI, Aschbrenner KA, et al. Pragmatic replication trial of health promotion coaching for obesity in serious mental illness and maintenance of outcomes. Am J Psychiatry 2015; 172:344.
- Green CA, Yarborough BJ, Leo MC, et al. The STRIDE weight loss and lifestyle intervention for individuals taking antipsychotic medications: a randomized trial. Am J Psychiatry 2015; 172:71.
- Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 2008; 165:352.
- Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008; 299:185.
- Jarskog LF, Hamer RM, Catellier DJ, et al. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry 2013; 170:1032.
- Baptista T, Rangel N, Fernández V, et al. Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial. Schizophr Res 2007; 93:99.
- Baptista T, Martínez J, Lacruz A, et al. Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial. Can J Psychiatry 2006; 51:192.
- Zhao J, Song X, Ai X, et al. Adjunctive Aripiprazole Treatment for Risperidone-Induced Hyperprolactinemia: An 8-Week Randomized, Open-Label, Comparative Clinical Trial. PLoS One 2015; 10:e0139717.
- Wu RR, Jin H, Gao K, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2012; 169:813.
- Wu CS, Wang SC, Yeh IJ, Liu SK. Comparative risk of seizure with use of first- and second-generation antipsychotics in patients with schizophrenia and mood disorders. J Clin Psychiatry 2016; 77:e573.
- Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185.
- Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225.
- Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death--how should we manage the risk? N Engl J Med 2009; 360:294.
- EXTRAPYRAMIDAL SYMPTOMS
- Parkinsonian syndrome
- TARDIVE DYSKINESIA
- METABOLIC SIDE EFFECTS
- Clinical management
- - Behavioral weight loss interventions
- - Metformin
- PROLACTIN ELEVATION
- OTHER SIDE EFFECTS
- Orthostatic hypotension
- Neuroleptic malignant syndrome
- QT prolongation
- Sudden death
- Anticholinergic effects
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS