Response and remission rates with adjunctive aripiprazole in patients with major depressive disorder who exhibit minimal or no improvement on antidepressant monotherapy.

BACKGROUND: The efficacy of adjunctive aripiprazole in patients with major depressive disorder (MDD) with no improvement after 8 weeks of prior antidepressant monotherapy has not been evaluated. METHODS: A post hoc analysis of three similarly designed, randomised, double-blind, placebo-controlled, phase III studies was conducted investigating the efficacy and safety of aripiprazole adjunctive to standard antidepressant treatment (ADT) in MDD patients with a prior inadequate response to one to three ADTs. Minimal improvement to antidepressant monotherapy was defined as a Clinical Global Impressions - Improvement (CGI-I) score of 3 and non-improvement as a CGI-I of 4 at weeks 6 and 8 of antidepressant monotherapy. RESULTS: The end-point response rate for ADT minimal improvers receiving adjunctive aripiprazole was 38.8% vs. 26.6% for adjunctive placebo (p < 0.05; number needed to treat [NNT] = 9 [95% confidence interval: 4.8-27.7]), and for ADT non-improvers receiving adjunctive aripiprazole was 24.0% vs. 10.3% for adjunctive placebo (p < 0.05; NNT = 8 [95% confidence interval: 4.4-21.5]). ADT minimal improvers and non-improvers demonstrated significant improvements in response vs. ADT alone as early as after 1 and 2 weeks of adjunctive treatment, respectively. The end-point remission rate for ADT minimal improvers receiving adjunctive aripiprazole was 34.2% vs. 21.0% for adjunctive placebo (p < 0.05; NNT = 8), and for ADT non-improvers receiving adjunctive aripiprazole was 16.0% vs. 5.9% for adjunctive placebo (p < 0.05; NNT = 10). The most common adverse events for ADT minimal improvers and non-improvers receiving adjunctive aripiprazole were akathisia, restlessness and insomnia. CONCLUSION: Patients with minimal or no improvement after 8 weeks of antidepressant monotherapy significantly benefited from adjunctive aripiprazole treatment, supporting the efficacy of this treatment for MDD patients with all levels of response to ADT.

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice.

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.

Chronic administration of propranolol impairs inhibitory avoidance retention in mice.

Adrenergic systems are importantly involved in memory storage processes. As such, agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, the anxiety literature cautions that beta-adrenergic receptor antagonists, such as propranolol, may have different behavioral effects with acute vs chronic dosing. The effects of chronic propranolol specifically on memory modulation are unknown. This study was designed to evaluate the effects of chronic propranolol on retention for an aversive task, in which there is endogenous adrenergic activation. Adult male ICR mice were given daily injections of one of four doses of propranolol (2, 4, 8, and 12 mg/kg) or 0.9% NaCl vehicle for 15 days prior to, and continuing during, behavioral tests of exploration and retention. Exploratory behavior, as an index of anxiety level, was measured in a conventional elevated plus-maze, whereas retention of an aversive experience was measured in a step-through inhibitory avoidance apparatus. Sensitivity to aversive footshock was also evaluated. Compared to controls, propranolol-treated mice showed a dose-dependent decrease in retention for the inhibitory avoidance task, but no effect on anxiety on the plus-maze or on footshock sensitivity. Taken together with results from previous studies, it is apparent that propranolol can have different behavioral effects when administered acutely vs chronically, and its chronic effects significantly impair memory storage processes. Since these drugs are typically used chronically, and often in older adults, they could contribute to functional memory impairments.