Other clinical data. A major consideration in treating older adults with schizophrenia is balancing the need to administer an antipsychotic dose high enough to alleviate psychotic symptoms while minimizing dose-dependent adverse effects. There is a U-shaped relationship between age and vulnerability to antipsychotic adverse effects,16,17 wherein adverse effects are highest at younger and older ages. Evidence supports using the lowest effective antipsychotic dose for geriatric patients with schizophrenia. Positive emission tomography (PET) studies suggest that older patients develop EPS with lower doses despite lower receptor occupancy.17,18 A recent study of 35 older patients (mean age, 60.1 years) with schizophrenia obtained PET, clinical measures, and blood pharmacokinetic measures before and after reduction of risperidone or olanzapine doses.18 A ≥40% reduction in dose was associated with reduced adverse effects, particularly EPS and elevation of prolactin levels. Moreover, the therapeutic window of striatal D2/D3 receptor occupancy appeared to be 50% to 60% in these older patients, compared with 65% to 80% in younger patients.
Long-term risks of antipsychotic treatment across the lifespan are less clear, with evidence suggesting both lower and higher mortality risk.19,20 It is difficult to fully disentangle the long-term risks of antipsychotics from the cumulative effects of lifestyle and comorbidity among individuals who have lived with schizophrenia for decades. Large naturalistic studies that include substantial numbers of older people with schizophrenia might be a way to elicit more information on long-term safety. The Schizophrenia Outpatient Health Outcome (SOHO) study was a large naturalistic trial that recruited >10,000 individuals with schizophrenia in 10 European countries.21 Although the SOHO study found differences between antipsychotics and adverse effects, such as EPS, weight gain, and sexual dysfunction, because the mean age of these patients was approximately 40 years and the follow-up period was only 3 years, it is difficult to draw conclusions that could be relevant to older individuals who have had schizophrenia for decades.
Bipolar Disorder
Summary of benefits, place in treatment armamentarium. Up to 25% of bipolar patients are elderly,22 and that number is projected to increase over the next decade.23 Clinical considerations in older adults with bipolar disorder include medical comorbidity, depression burden, and possible cognitive decline (Table 3).24-27 Along with lithium and mood stabilizers, antipsychotics are a first-line treatment for bipolar disorder.28-30 Most FDA-approved antipsychotics for bipolar disorder are SGAs for bipolar mania. However, olanzapine-fluoxetine combination, quetiapine, and lurasidone are approved for bipolar depression. Aripiprazole, olanzapine, quetiapine, long-acting injectable risperidone, and oral ziprasidone are FDA-approved for longer-term use in adults with bipolar disorder. There are no head-to-head trials of antipsychotics for older persons with bipolar disorder.
Clinical trials: Bipolar depression. A post hoc, secondary analysis of two 8-week, double-blind, randomized, placebo-controlled studies in bipolar depression compared 2 dosages of quetiapine (300 mg/d and 600 mg/d) with placebo in mixed-age patients.31 In a subgroup of 72 patients, ages 55 to 65, remission occurred more often with quetiapine than with placebo. Study discontinuation rates were similar between older people and younger people (age <55 years): quetiapine, 300 mg/d, 29.2%; quetiapine, 600 mg/d, 48.1%; and placebo, 29.6% in older adults, compared with 37.1%, 45.8%, and 38.1%, respectively, in younger adults. In all patients, the most common reason for discontinuation was adverse events with quetiapine and lack of efficacy for placebo. Adverse event rates were similar in older and younger adults. Dry mouth and dizziness were more common in older adults. Proportions of adults experiencing clinically significant weight gain (≥7% of body weight) were 5.3%, 8.3%, and 0% in older adults receiving quetiapine, 300 mg/d, quetiapine, 600 mg/d, and placebo, respectively, compared with 7.2%, 10.1%, and 2.6% in younger adults. EPS and treatment-emergent mania were minimal.
A secondary analysis of mixed-age, RCTs examined response in older adults (age ≥55 years) with bipolar I depression who received lurasidone as monotherapy or adjunctive therapy.32 In the monotherapy study, these patients were randomized to 6 weeks of lurasidone 20 to 60 mg/d, lurasidone 80 to 120 mg/d, or placebo. In the adjunctive therapy study, they were randomized to lurasidone 20 to 120 mg/d or placebo with either lithium or valproate. There were 83 older adults (17.1% of the sample) in the monotherapy study and 53 (15.6%) in the adjunctive therapy study. Mean improvement in depression was significantly higher for both doses of lurasidone monotherapy than placebo. Adjunctive lurasidone was not associated with statistically significant improvement vs placebo. The most frequent adverse events in older patients on lurasidone monotherapy 20 to 60 mg/d or 80 to 120 mg/d were nausea (18.5% and 9.7%, respectively) and somnolence (11.1% and 0%, respectively). Akathisia (9.7%) and insomnia (9.7%) were the most common adverse events in the group receiving 80 to 120 mg/d, with the rate of akathisia exhibiting a dose-related increase. Weight change with lurasidone was similar to placebo, and there were no clinically meaningful group changes in vital signs, electrocardiography, or laboratory parameters.
A small (N = 20) open study found improvement in older adults with bipolar depression with aripiprazole (mean dose, 10.3 mg/d).33 Adverse effects included restlessness and weight gain (n = 3, 9% each), sedation (n = 2, 10%), and drooling and diarrhea/loose stools (n = 1, 5% each). In another small study (N = 15) using asenapine (mean dose, 11.2 mg/d) in mainly older bipolar patients with depression, the most common adverse effects were gastrointestinal (GI) discomfort (n = 5, 33%) and restlessness, tremors, cognitive difficulties, and sluggishness (n = 2, 13% each).34