Antipsychotics are FDA-approved as a primary treatment for schizophrenia and bipolar disorder and as adjunctive therapy for major depressive disorder. In the United States, approximately 26% of antipsychotic prescriptions written for these indications are for individuals age >65.1 Additionally, antipsychotics are widely used to treat behavioral symptoms associated with dementia.1 The rapid expansion of the use of second-generation antipsychotics (SGAs), in particular, has been driven in part by their lower risk for extrapyramidal symptoms (EPS) compared with first-generation antipsychotics (FGAs).1 However, a growing body of data indicates that all antipsychotics have a range of adverse effects in older patients. This focus is critical in light of demographic trends—in the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.2
In this context, psychiatrists need information on the relative risks of antipsychotics for older patients. This 3-part series summarizes findings and recommendations on safety and tolerability when prescribing antipsychotics in older individuals with chronic psychotic disorders, such as schizophrenia, bipolar disorder, depression, and dementia. This review aims to:
- briefly summarize the major studies and analyses relevant to older patients with these diagnoses
- provide a summative opinion on safety and tolerability issues in these older adults
- highlight the gaps in the evidence base and areas that need additional research.
Part 1 focuses on older adults with schizophrenia or bipolar disorder. Subsequent articles will focus on prescribing antipsychotics to older adults with depression and those with dementia.
Summary of benefits, place in treatment armamentarium. Individuals with schizophrenia have a shorter life expectancy than that of the general population mostly as a result of suicide and comorbid physical illnesses,3 but the number of patients with schizophrenia age >55 will double over the next 2 decades.4 With aging, both positive and negative symptoms may be a focus of treatment (Table 1).5,6 Antipsychotics are a first-line treatment for older patients with schizophrenia with few medication alternatives.7 Safety risks associated with antipsychotics in older people span a broad spectrum (Table 2).8
Clinical trials. Few studies have evaluated treatment of older adults with schizophrenia.7-13 Two Cochrane reviews found only a handful of randomized controlled trials (RCTs).10,11 The largest RCT was an 8-week prospective, multisite RCT of olanzapine vs risperidone in 175 older adults (age ≥60 years; mean age, 71 years) with schizophrenia.5 Before enrollment, just over one-half (53%) had been treated with FGAs. Both risperidone and olanzapine were flexibly dosed, with a target dose of 3 mg/d for risperidone and 20 mg/d for olanzapine. Median daily doses were 2 mg/d for risperidone and 10 mg/d for olanzapine. Both treatments were associated with symptom improvement, but there was no difference between groups. Approximately 70% of patients in each treatment arm experienced adverse events. The most common adverse effects (similar across groups) were somnolence, insomnia, dizziness, agitation, constipation, headache, and diarrhea. Rates of EPS were lower with both risperidone (9.2% EPS-related adverse effects) and olanzapine (15.9% EPS-related adverse effects) vs patients taking FGAs prior to starting the RCT. Drop-out rates were similar (risperidone, 19.3%; olanzapine, 27.6%). There was greater weight gain with olanzapine vs risperidone (P = .04).5
A 6-week prospective RCT evaluated paliperidone extended-release vs placebo in 114 older adults (age ≥65 years; mean age, 70 years) with schizophrenia.14 There was an optional 24-week extension of open-label treatment with paliperidone. Mean daily dose of paliperidone was 8.4 mg. Efficacy measures did not show consistent statistically significant differences between treatment groups. Discontinuation rates were similar between paliperidone (7%) vs placebo (8%). Serious adverse events occurred in 3% of paliperidone-treated vs 8% of placebo-treated patients. Elevated prolactin levels occurred in one-half of paliperidone-treated patients. There were no prolactin or glucose treatment-related adverse events or significant mean changes in body weight for either paliperidone-treated or placebo-treated patients. Safety findings in the 24-week, open-label extension group were consistent with the RCT results.
Howanitz et al15 conducted a 12-week, prospective RCT that compared clozapine (mean dose, 300 mg/d) with chlorpromazine (mean dose, 600 mg/d) in 42 older adults (mean age, 67 years) with schizophrenia. Drop-out rate prior to 5 weeks was 19% and similar between groups. Common adverse effects included sialorrhea, hematologic abnormalities, sedation, tachycardia, EPS, and weight gain. Although both drugs were effective, more patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients reported sedation.
There have been other, less rigorous studies.7,8 Most of these studies evaluated risperidone and olanzapine, and most were conducted in “younger” geriatric patients (age <75 years). Although patients who participate in clinical trials may be healthier than “typical” patients, adverse effects such as EPS, sedation, and weight gain were still relatively common in these studies.