Focus on Pharmacotherapy Studies in the Elderly

The NIMH-sponsored New Clinical Drugs Evaluation Unit (NCDEU) meeting is a favored venue for reports and reviews of NIH-funded psychopharmacological studies, and this was true of the recent annual meeting in Hollywood, Fla. The meeting included a workshop on new investigations of antidepressant use in Alzheimer disease and a panel session on the safety of pharmacotherapy in older adults.

Two studies were developed, in part, in response to growing concern about both safety and lack of efficacy of antipsychotics for behavior symptoms in patients with dementia. These were the Depression in Alzheimer’s Disease Study–2 (DIADS-2) sertraline (Zoloft) trial, the citalopram (Celexa) versus antipsychotics nested study in the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD), and the recently initiated Citalopram for the Treatment of Agitation in Alzheimer’s Disease (CitAD).

In describing the rationale and design of the CitAD study, Bruce Pollock, MD, Center for Addiction and Mental Health, questioned the premise for using antipsychotics in this population. “The neuropharmacologic rationale for using dopamine antagonists in elders with dopaminergic deficits is questionable,” Pollock indicated. “Agitation in Alzheimer disease is commonly derived from anxious, impulsive, and compulsive symptoms, which may be responsive to serotonergic agents.”

Pollock related that at the time of an earlier comparison of citalopram to antipsychotics in this population, risperidone (Risperdal) was commonly used and a placebo-controlled design was deemed unethical. In that 12-week trial with 103 nondepressed participants with moderate to severe behavioral and psychological symptoms of dementia, citalopram was better tolerated than risperidone and appeared to have comparable efficacy, including significant effect on agitation symptoms. These encouraging results led to the new placebo-controlled, multisite CITAD study, which will focus on the effect of citalopram for symptoms of agitation.

Lon Schneider, MD, University of Southern California Keck School of Medicine, presented an analysis from the CATIE-AD of the time to all-cause discontinuation between patients taking citalopram and those taking olanzapine (Zyprexa), quetiapine (Seroquel), or risperidone. In the initial randomized assignment of the CATIE-AD, patients received either an atypical antipsychotic or placebo; those who discontinued the initial treatment could be randomized in double-blind fashion to another atypical antipsychotic or to the antidepressant.

Schneider reported that there was no statistically significant difference in time to all-cause discontinuation between the antidepressant and antipsychotic groups, with 11.9 median weeks before discontinuing the citalopram treatment and 8.6 weeks for an antipsychotic. “Times to discontinuation due to lack of efficacy or intolerability also did not differ by treatment group,” Schneider noted.

In addition, there was mild improvement on rating scales with both antipsychotics and citalopram. Mean Brief Psychiatric Rating Scale (BPRS) total scores were reduced by 6 points with citalopram and 4.7 with an antipsychotic. “AD patients with psychosis or agitated/aggressive behavior who had previously discontinued treatment with an atypical antipsychotic medication or placebo for any reason fared similarly with either citalopram or a different antipsychotic as a next-step treatment,” Schneider concluded.

Daniel Weintraub, MD, University of Pennsylvania School of Medicine, described the DIADS-2 trial as a 12-week randomized, placebo-controlled trial with 131 patients, which assessed the safety of sertraline treatment in patients with Alzheimer disease to ascertain whether it is associated with improved mood outcomes. Remission from depressive symptoms was defined as a reduction in score on the modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression to 2 or less and to a score of not more than 6 on the Cornell Scale for Depression in Dementia.

Although the remission rate at 12 weeks was numerically greater with sertraline (33%) than with placebo (19%), the difference was not statistically significant. In addition, sertraline was associated with diarrhea, indigestion, dry mouth, and dizziness, and 4 patients treated with sertraline experienced an adverse pulmonary event.

Because of the lack of evidence of acute or long-term improvement in depressive symptoms, and because more adverse events occurred in the sertraline group than in the placebo group, Weintraub concluded that the antidepressant “cannot be recommended for treating patients with the syndrome of depression in Alzheimer disease.”

Jacobo Mintzer, MD, Medical University of South Carolina, shared the concerns expressed by Weintraub and elaborated on other adverse events with the SSRIs that have occurred across these trials. In addition to the adverse events reported in DIADS-2, Mintzer noted the occurrence of hyponatremia in some patients, possibly caused by inappropriate antidiuretic hormone secretion. Furthermore, Mintzer indicated, the question of whether SSRIs worsen cognitive impairment in patients with dementia remains unanswered.

Although antidepressants may offer a safer alternative to antipsychotics for behavioral symptoms in this population, Mintzer cautioned, “clinicians should be aware of safety concerns when using SSRIs to treat patients with dementia.”

Seeking safe psychopharmacotherapy

Jovier Evans, PhD, of the NIMH opened a panel session on safe psychopharmacotherapy and novel approaches to personalize treatments in older adults. He attributed the relative lack of information regarding tolerability, safety, and efficacy of psychotropics in this age-group to the few medication trials that have included elderly participants. He noted the concerns in recent years about negative long-term health effects of both antipsychotic and antidepressants, including increased risks of stroke and bone density loss.

“Given the advancing age of the population, more studies are examining the safety of psychotropic medications in older adults, and increasing our capacity to determine the best treatment choices for individual elderly patients based on safety and efficacy considerations,” Evans observed.

Wei Jiang, MD, Duke University Medical Center, described a study of sertraline in patients with depressive symptoms and heart failure, the Sertraline Antidepressant Heart Attack Trial (SADHART)-CHF, to determine whether antidepressant treatment can improve depressive symptoms and cardiovascular status and also reduce mortality.

In this 12-week, placebo-controlled study with 469 patients, sertraline was given in doses ranging from 25 to 200 mg daily. Depressive symptoms in the sertraline and placebo groups improved to a similar extent, which suggested to Jiang that “nurse-facilitated supportive measures have strong therapeutic impact.”

Although sertraline was not distinguished from placebo, the patients in both groups who achieved remission from depressive symptoms enjoyed significantly prolonged survival in comparison to nonremitters and to those who discontinued the trial at an early stage. “The finding emphasizes importance of future outcome studies of comorbid depression . . . aim[ing] at reaching remission and identifying characteristics of patients with specific responses to different antidepressant modalities,” Jiang indicated,

An NIMH-sponsored Consortium for Research in ECT (CORE) included a substantial number of elderly patients within a mixed-age adult cohort. Charles Kellner, MD, New Jersey Medical School, related that in the first of 2 CORE trials, which compared continuation ECT (a fixed schedule of 10 treatments over 5 months) with pharmacotherapy (a combination of nortriptyline and lithium), a subset of 253 patients aged 65 to 86 who completed the ECT course had a 90% remission rate, compared with 64.2% of all 531 completers.

“Age as a continuous variable positively influenced treatment response,” Kellner indicated. He noted that those with a diagnostic subtype of psychotic depression who completed the ECT course remitted at an even higher rate of 94%.

In the second CORE trial, which compared 3 electrode placements, Kellner reported that bifrontal, bitemporal, and right unilateral placements were associated with comparable antidepressant efficacy and cognitive outcomes. He also noted that there was a distinguishing outcome in older patients.

“Geriatric patients had higher remission rates than younger patients with right unilateral electrode placement,” Kellner noted, “a preliminary finding that is intriguing, but requires replication.” Kellner deemed ECT to be an effective and well-tolerated treatment for depression in adult age-groups.

In the NIMH-sponsored Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), patients treated with a combination of an atypical antipsychotic and an SSRI were compared with patients who received antipsychotic monotherapy in achieving remission. The study also compared the efficacy and tolerability of the treatments in both younger and older adults.

Anthony Rothschild, MD, University of Massachusetts Medical School, reported that in the 12-week trial with 259 subjects, the olanzapine/sertraline combination was associated with greater frequency of remission (41.9%) than the olanzapine/placebo combination (23.9%). He noted that the treatments were comparable in overall tolerability, although there were some age-related differences in specific side effects. Both age-groups had significant increases in cholesterol and triglyceride levels, but only the younger adult group had statistically significant increases in glucose levels. This younger age-group gained significantly more weight.

Rothschild noted that there have been few trials of combination pharmacotherapy in geriatric patients. However, he concluded from the STOP-PD results that “combination pharmacotherapy is more efficacious than antipsychotic monotherapy for the treatment of major depression with psychotic features.”