How to Improve Treatment Adherence by Overcoming Antipsychotic Side Effects

What is the impact of antipsychotic side effects on medication adherence?


Approximately 50% of patients report nonadherence to antipsychotic treatment, shared Roger S. McIntyre, MD, FRCPC, at the 2022 NEI Congress.1 The most common reasons for intentional nonadherence of antipsychotics, McIntyre stated, are poor insight (55.6%), negative attitude toward medication (30.5%), and medication side effects (27.8%),2 the last of which became the focus of his presentation.

“Antipsychotic selection may be the single most powerful tool in a clinician’s armamentarium for reducing antipsychotic-induced adverse effects,” McIntyre said.

When trying to determine if a patient is in fact experiencing an adverse effect, McIntyre recommended asking yourself 4 questions3:

-Is there a plausible mechanism and time course?

-How far in time did the suspected adverse effect arise relative to last medication/dosage change?

-Can you differentiate the suspected drug effect from a symptom of the underlying condition?

-Is there restoration of normal function?

One of the major potential side effects with antipsychotics is weight gain/metabolic disturbances. Weight gain and metabolic problems are much more readily prevented than treated after the fact, McIntyre stated. Rapid weight gain of more than 5% in the first month of treatment is the best predictor for significant long-term weight gain. Furthermore, young patients are more susceptible than their adult counterparts to antipsychotic-induced weight gain.4,5 Drugs with the highest risk of weight gain are clozapine and olanzapine; those with the lowest risk include amisulpride, aripiprazole, brexpiprazole, cariprazine, lumateperone, lurasidone, pimavanserin, and ziprasidone.6-8 As a general rule, McIntyre shared that atypical antipsychotics are associated with more weight gain than typical antipsychotics. Metformin or olanzapine plus samidorphan show promise for preventing this weight gain. McIntyre specifically recommended using metformin when initiating treatment with either olanzapine or clozapine.6,9,10

Another major side effect are movement disorders. “Careful drug selection is key to avoiding motor side effects,” said McIntyre.

Movement disorders include drug-induced parkinsonism (DIP), akathisia, and tardive dyskinesia (TD), which are important to differentiate between, particularly as DIP and TD have opposite pharmacological mechanisms and different treatment options. Additionally, McIntyre added, while dose reduction may improve DIP and akathisia, it can make TD worse. Drugs with the highest risk of akathisia/DIP include paliperidone and risperidone; those with the lowest risk include clozapine, iloperidone, lumateperone, pimavanserin, and quetiapine.6,11,12

Across the board for movement disorders, McIntyre recommends using less anticholinergics. For treating akathisia, he advises using with beta-blockers, 5HT2A antagonists, and/or benzodiazepines. For treating DIP, he advises using more amantadine. As a general rule, you should not treat TD with anticholinergics, McIntyre said, as they could worsen symptoms.

“I think the message is loud and clear that we now have many, many new options,” concluded McIntyre.


1. Dibonaventura M, Gabriel S, Dupclay L, et al. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20.

2. Velligan DI, Sajatovic M, Hatch A, et al. Why do psychiatric patients stop antipsychotic medication? A systematic review of reasons for nonadherence to medication in patients with serious mental illness. Patient Prefer Adherence. 2017;11:449-468.

3. Goldberg JF, Stahl SM. Practical Psychopharmacology: Translating Findings From Evidence-Based Trials into Real-World Clinical Practice. Cambridge University Press; 2021.

4. Dayabandara M, Hanwella R, Ratnatunga S, et al. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017;13:2231-2241.

5. Vandenberghe F, Gholam-Rezaee M, Saigí-Morgui N, et al. Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015;76(11):e1417-1423.

6. Stahl SM, Sy S, Maguire GA. How and when to treat the most common adverse effects of antipsychotics: expert review from research to clinical practice. Acta Psychiatr Scand. 2021;143(2):172-180.

7. Citrome L, Norton JC, Chi-Burris K, Demos G. Pimavanserin for the treatment of Parkinson's disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed. CNS Spectr. 2018;23(3):228-238.

8. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(1):64-77.

9. Hiluy JC, Nazar BP, Gonçalves WS, et al. Effectiveness of pharmacologic interventions in the management of weight gain in patients with severe mental illness: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2019;21(6):19r02483.

10. Zhuo C, Xu Y, Liu S, et al. Topiramate and metformin are effective add-on treatments in controlling antipsychotic-induced weight gain: a systematic review and network meta-analysis. Front Pharmacol. 2018;9:1393.

11. Abbas A, Roth BL. Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmacother. 2008;9(18):3251-3259.

12. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951.