Escitalopram in the acute treatment of depressed patients aged 60 years or older.

OBJECTIVE: The present study examined the efficacy and tolerability of acute escitalopram treatment in depressed patients aged 60 years or older. METHODS: Patients aged > or =60 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive disorder were randomized to 12 weeks of double-blind, flexible-dose treatment with escitalopram (10-20 mg/day; N = 130) or placebo (N = 134). The prospectively defined primary efficacy end point was change from baseline to week 12 in Montgomery-Asberg Depression Rating Scale (MADRS) total score using the last observation carried forward approach. RESULTS: A total of 109 (81%) patients in the placebo group and 96 (74%) patients in the escitalopram group completed treatment. Mean age in both groups was approximately 68 years. Mean baseline MADRS scores were 28.4 and 29.4 for the placebo and escitalopram treatment groups, respectively. Escitalopram did not achieve statistical significance compared with placebo in change from baseline on the MADRS (least square mean difference: -1.34; last observation carried forward). Discontinuation rates resulting from adverse events were 6% for placebo and 11% for escitalopram. Treatment-emergent adverse events reported by >10% of patients in the escitalopram group were headache, nausea, diarrhea, and dry mouth. CONCLUSIONS: Escitalopram treatment was not significantly different from placebo treatment on the primary efficacy measure, change from baseline to week 12 in MADRS. In patients aged 60 years or older with major depression, acute escitalopram treatment appeared to be well tolerated.

Double-blind comparison of escitalopram and duloxetine in the acute treatment of major depressive disorder.

BACKGROUND AND OBJECTIVE: Escitalopram is the most selective serotonin reuptake inhibitor antidepressant; in contrast, duloxetine inhibits both serotonin and norepinephrine reuptake. Double-blind comparison studies may help guide treatment decisions by revealing the relative benefits of different therapeutic approaches. This study evaluated the efficacy and safety of escitalopram versus duloxetine in the acute treatment of patients with moderate to severe major depressive disorder. METHODS: A 1-week, single-blind, placebo lead-in period followed by an 8-week, randomised, double-blind, multicentre, parallel-group comparison was conducted from 20 April 2005 to 10 March 2006 in independent psychiatric research facilities with principal investigators who were board certified in psychiatry. A total of 278 outpatients of 382 patients screened with Diagnostic and Statistical Manual of Mental Disorders (4th edition)-diagnosed major depressive disorder (Montgomery-Asberg Depression Rating Scale [MADRS] total score > or =26) were randomised to the two treatment groups. Eight patients received no medication and were excluded from the safety group. Patients were treated with either escitalopram 10-20 mg/day (fixed at 10 mg/day for the first 4 weeks) or duloxetine 60 mg/day. The primary efficacy variable was change from baseline at week 8 in MADRS total score using the last observation carried forward (LOCF) approach. Efficacy, safety and tolerability measures were prospectively defined in the statistical analysis plan prior to study initiation unless otherwise specifically noted as conducted post hoc. RESULTS: A significantly greater proportion of escitalopram-treated patients completed the 8-week study compared with duloxetine-treated patients (87% vs 69%, respectively; p < 0.01). Mean baseline MADRS total scores were 31.0 for the escitalopram group and 31.6 for the duloxetine group. At week 8, escitalopram treatment resulted in significantly greater improvement compared with duloxetine on the prospectively defined primary efficacy endpoint of mean change from baseline in MADRS total score using the LOCF approach (least-squares mean difference [LSMD] -2.42; 95% CI -4.73, -0.11; p < 0.05). There was no difference between treatment groups in the observed cases (OC) analysis (LSMD -0.32; 95% CI -2.71, 2.07; p = 0.79). Significantly fewer escitalopram-treated patients discontinued because of adverse events compared with duloxetine (2% vs 13%, respectively; p < 0.01). CONCLUSION: These findings suggest that escitalopram is better tolerated and at least as effective as the serotonin-norepinephrine reuptake inhibitor duloxetine in the treatment of major depressive disorder.

Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial.

BACKGROUND: Major depressive disorder is a recurrent illness that often requires maintenance antidepressant treatment. Escitalopram is a selective serotonin reuptake inhibitor (SSRI) that has shown efficacy in both acute and continuation treatment of major depressive disorder. The current trial examined the efficacy of maintenance escitalopram treatment in preventing depression recurrence in patients who responded to acute SSRI therapy. METHOD: Patients with recurrent DSM-IV-defined major depressive disorder (>or= 2 previous episodes; baseline Montgomery-Asberg Depression Rating Scale [MADRS] score >or= 22) who had responded (MADRS score or= 22 or insufficient therapeutic response during the double-blind phase. The study was conducted between October 16, 2000, and February 4, 2003. RESULTS: A total of 234 patients who responded to acute open-label treatment with 1 of 4 SSRIs received at least 1 dose of open-label escitalopram continuation treatment. Of 164 patients who completed escitalopram continuation treatment, 139 were randomly assigned to double-blind maintenance treatment with escitalopram (N = 73) or placebo (N = 66). Mean baseline MADRS scores at the start of the maintenance phase were < 5 for both the placebo- and escitalopram-treatment groups. Time to recurrence was significantly longer in patients who received maintenance treatment with escitalopram compared with patients switched to placebo (hazard ratio = 0.26, 95% CI = 0.13 to 0.52, p < .001). Long-term escitalopram treatment was well tolerated. CONCLUSION: Maintenance treatment with escitalopram was well tolerated and significantly reduced the risk for recurrence of depression. Patients with few residual symptoms following continuation treatment with escitalopram experienced a high rate of depression recurrence when switched to placebo, demonstrating the need for maintenance therapy of recurrent major depressive disorder beyond 4 to 6 months of initial symptom resolution even if few residual symptoms are present.

Individual differences in the expression of a "general" learning ability in mice.

Human performance on diverse tests of intellect are impacted by a "general" regulatory factor that accounts for up to 50% of the variance between individuals on intelligence tests. Neurobiological determinants of general cognitive abilities are essentially unknown, owing in part to the paucity of animal research wherein neurobiological analyses are possible. We report a methodology with which we have assessed individual differences in the general learning abilities of laboratory mice. Abilities of mice on tests of associative fear conditioning, operant avoidance, path integration, discrimination, and spatial navigation were assessed. Tasks were designed so that each made unique sensory, motor, motivational, and information processing demands on the animals. A sample of 56 genetically diverse outbred mice (CD-1) was used to assess individuals' acquisition on each task. Indicative of a common source of variance, positive correlations were found between individuals' performance on all tasks. When tested on multiple test batteries, the overall performance ranks of individuals were found to be highly reliable and were "normally" distributed. Factor analysis of learning performance variables determined that a single factor accounted for 38% of the total variance across animals. Animals' levels of native activity and body weights accounted for little of the variability in learning, although animals' propensity for exploration loaded strongly (and was positively correlated) with learning abilities. These results indicate that diverse learning abilities of laboratory mice are influenced by a common source of variance and, moreover, that the general learning abilities of individual mice can be specified relative to a sample of peers.

Calcium 'leak' through somatic L-type channels has multiple deleterious effects on regulated transmitter release from an invertebrate hair cell.

Using an identified synapse in the nervous system of the mollusc Hermissenda, the influence of somatic calcium accumulation on regulated synaptic transmission was investigated. Hair cells in Hermissenda project onto postsynaptic B photoreceptors where they mediate inhibitory postsynaptic potentials (IPSPs). Intracellular recordings in combination with bath perfusion of calcium channel modulators indicated that L-type channels were present on the hair cell soma but not on the terminal branches. In contrast, P/Q and an unidentified channel type (similar to N-type channels) contributed additively to transmitter release from the hair cell. Antibodies raised against rat brain channel proteins detected L- (alpha1(C)) and P/Q-type (alpha1(A)) channels in lysates of the Hermissenda nervous system, indicating a homology between the Hermissenda channels and their mammalian counterparts. To mimic somatic calcium channel 'leak', hair cells were exposed to the L-type channel agonist +/-BAY K 8644. Exposure to +/-BAY K 8644 resulted in a rapid (<2 min) increase (40%) in the amplitude of the spike after-hyperpolarization in the hair cell, and was associated with a reduction in evoked firing frequency. This reduction in rate of discharge induced a proportional decrease in the amplitude of compound IPSPs recorded in the postsynaptic B photoreceptors. From Fura-2 emissions we determined that +/-BAY K 8644 induced a rapid (<2 min) and persistent increase (70%) in somatic calcium concentration, followed by a slower elevation of calcium in the medial axon (>30 min) and subsequently in the terminal branches (>40 min), suggesting that excessive somatic calcium had diffused or induced a propagation along the axon. Corresponding with a 56% rise in terminal calcium (50-60 min post agonist), postsynaptic potentials declined to 70% of baseline amplitude. These results suggest that prolonged somatic L-channel 'leak' can interfere with regulated transmitter release, both by reducing the rate of presynaptic discharge and by promoting terminal calcium accumulation that may oppose transmitter release. Such effect may have implications for the age-related learning deficits that often accompany somatic calcium 'leak'.

Hippocampal function during behaviorally silent associative learning: dissociation of memory storage and expression.

In laboratory studies, the assessment of memory is typically associated with overt behavioral responses. Thus, it has been difficult to determine whether the enhancement of hippocampal sensory-evoked potentials that often accompany memory formation are the neurophysiological manifestation of a memory "trace" or are a secondary product of the behavioral expression of the memory. We addressed this issue by examining changes in evoked hippocampal field potentials during sensory preconditioning, a form of behaviorally silent relational learning that requires an intact hippocampus for execution. Rats were exposed to presentations of a white noise (S1) that terminated with a tone (S2). These pairings of ostensibly "neutral" stimuli supported no change in the behavior elicited by the noise. However, if the tone was subsequently paired with mild footshock (US), suppression of ongoing licking behavior (indicative of fear) was elicited by the noise, indicating that the animal had associated the noise with tone (S1-S2), and had represented the noise-tone-shock (S1-S2-US) relationship. Pre-training neurotoxic lesions of the hippocampus had no effect on conditioned suppression to tone after tone-shock (S2-US) pairings, but disrupted the expression of continued suppression to noise (S1) after tone-shock pairings. In a second experiment, sensory-evoked field potentials in the dorsal hippocampus were recorded with extracellular electrodes. No changes in the hippocampal response evoked by white noise were observed after pairings of noise and tone, i.e., no evidence for a memory trace could be detected. In contrast, after tone was paired with footshock, two short-latency negative potentials within the noise-evoked field response increased in amplitude, a response often presumed to reflect a neurophysiological correlate of memory storage. In total, these results suggest that although the hippocampus critically contributes to the processing of a behaviorally silent associative memory, there may be no role for changes in the amplitude of hippocampal sensory-evoked field potentials in storing representations of the relationships between sensory experiences.