This website is made possible by third party financial support from Sage Therapeutics, Inc. and Biogen Inc.

This website is made possible by third party financial support from Sage Therapeutics, Inc. and Biogen Inc.

Cautious Use of Atypical Antipsychotics Due to Side Effect Profile

Cautious Use of Atypical Antipsychotics Due to Side Effect Profile

March 23, 2023

Editorially reviewed by Brooke Kempf, MSN, PMHNP-BC

Although many people do, not everyone who uses antipsychotics will experience side effects. Does that imply that patients no longer benefit from them?

Elder Pt Confused by Medication

This article has a corresponding quiz. Click the link to take quiz

The Food and Drug Administration (FDA) has approved atypical antipsychotic medications for the treatment of schizophrenia, bipolar disorder, and as adjunctive treatment for depression. In the United States, the use of atypical antipsychotic medications is rapidly increasing, with one study estimating an increase from 6.2 million to 14.3 million treatment visits between 1995 and 2008. Quetiapine, risperidone, aripiprazole, and olanzapine are the most prescribed adjunctive antipsychotic treatment medications for depression.1

Compared to dopamine, atypical antipsychotics bind to dopamine receptors with less affinity while also blocking serotonin 5-HT2A receptors.2 Weight gain, metabolic disturbance, QTc prolongation, neurologic adverse effects, and sedation are the most common risks of antipsychotic treatment when compared to placebo. Despite the magnitude of potential side effects, treatment strategies are available for many of them, making it beneficial to create a favorable risk versus benefit ratio during the first 1-2 years after a psychotic episode. The effectiveness of antipsychotics in preventing relapse in schizophrenia further supports the widely accepted notion that they maintain a favorable risk-benefit balance during this initial period.3

Beyond 1-2 years, clinical guidelines do not give systematic recommendations for treatment continuation or withdrawal, although they do warn about the risks of schizophrenia relapse associated with treatment discontinuation. Due to a lack of double-blind, placebo-controlled randomized clinical trials (RCTs), the effects of antipsychotic medication beyond the first two years of treatment are not well recognized.3

A meta-analysis of 65 placebo-controlled RCTs indicated an overall number needed to treat (NNT) of 3 favoring antipsychotics over placebo in avoiding relapse, although overall treatment effects tended to diminish as trial duration increased. Antipsychotics decreased the proportion of individuals who showed no improvement or worsened. However, this effect diminished over time and lost statistical significance in longer-term trials, mainly due to a higher likelihood of non-adherence with extended treatment durations.3

The number of patients who experienced at least one adverse event did not differ between antipsychotics and placebo, and it did not rise with time for antipsychotic users. Sedation did not change, although weight gain and at least one mobility issue were considerably more common following antipsychotic medication.3

Long-term antipsychotic treatment's metabolic and cardiovascular side effects have been a source of concern as potential contributors to an increase in morbidity and mortality, particularly in developed countries where most mortality in schizophrenia is related to the consequences of metabolic disturbance and cardiovascular disease.3 While the metabolic effects of long-term antipsychotic therapy are generally recognized, our knowledge of their contribution to morbidity and mortality in schizophrenia has changed in recent years.

Antipsychotics' contribution to lowering early mortality in schizophrenia is now better understood. Long-term antipsychotic medication is consistently associated with decreased mortality rates compared to no long-term treatment—but nonetheless higher rates than in people without schizophrenia—despite raising cardiovascular risk factors.3

A study discovered that— as compared to patients with schizophrenia who did not receive antipsychotic therapy, those who had extended antipsychotic treatment had lower mortality rates— including from cardiovascular causes. The same group looked at how cumulative antipsychotic dose over a 5-year period affected mortality in schizophrenia while accounting for a wide range of factors. They discovered that all antipsychotic cumulative dose — low, moderate, and high— were associated with decreased mortality rates versus no antipsychotic usage. Patients with schizophrenia who received low and moderate antipsychotic doses had lower rates of cardiovascular disease mortality, whereas those who received high doses had lower rates of suicide mortality.3

Long-term antipsychotic treatment is associated with significantly higher rates of metabolic and cardiovascular risk factors and disease3; however, patients treated with antipsychotics long-term appear to have significantly lower mortality rates, including death due to cardiovascular disease, at low and moderate doses, when compared to individuals with schizophrenia who do not receive antipsychotics. In terms of mortality reduction, data shows a favorable risk-benefit balance for the long-term use of antipsychotics for the treatment of schizophrenia.

1.    Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis [published correction appears in JAMA. 2012 Jan 11;307(2):147]. JAMA. 2011;306(12):1359-1369. doi:10.1001/jama.2011.1360
2.    Severance EG, Dickerson FB, Yolken RH. Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther. 2018;189:184-198. doi:10.1016/j.pharmthera.2018.05.005
3.    Correll CU, Rubio JM, Kane JM. What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry. 2018;17(2):149-160. doi:10.1002/wps.20516