Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate.

It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults. Fifty-four participants, of mean age 23.1 years (sd 4.68), 29 male, were randomised into three parallel groups. Each group received one of the three drugs, dosed incrementally over a 3-week period to reach daily doses of 150 mg/day venlafaxine and 200 mg/day pregabalin. Blood pressure sphygmomanometer measurements, heart rate measurements, and orthostatic challenges recorded continuously beat-to-beat were performed weekly over this period and 5 days after treatment cessation. Results showed resting systolic blood pressure (SBP) and resting and standing diastolic blood pressure (DBP) and heart rate (HR) were significantly raised by venlafaxine compared with the pregabalin and placebo groups. SBP drop on standing was larger, the resulting overshoot was smaller, and recovery was slower on venlafaxine. HR recovery was significantly impaired by venlafaxine. CV changes were observed after only 1 week of dosing at 112.5 mg/day. These effects of venlafaxine are likely to be due to its action of noradrenergic reuptake inhibition.

Combined NK1 antagonism and serotonin reuptake inhibition: effects on emotional processing in humans.

BACKGROUND: Synergistic effects of NK1 receptor antagonism combined with serotonin reuptake inhibition have been reported in preclinical models. GSK424887 is a selective competitive antagonist of the human NK1 receptor and inhibitor of the serotonin transporter. However, its actions in human models of depression have not been assessed. METHODS: This study explored the effects of acute administration of GSK424887 compared to placebo in healthy male volunteers. The selective serotonin reuptake inhibitor (SSRI) citalopram was used as a positive control. A battery of emotional processing tasks was given at the peak time of drug effect. RESULTS: GSK424887 enhanced attentional vigilance in the dot-probe task to both positive and negative stimuli. By contrast, citalopram enhanced perception of angry, sad and happy facial expressions and increased positive bias in the facial expression recognition task. Neither drug significantly affected emotion potentiated startle responses or emotional memory. CONCLUSIONS: These results suggest that acute administration of GSK424887 modulated some aspects of emotional processing but these effects were not similar to those seen previously with antidepressant agents. This was the first use of the battery of emotional processing tasks in a Phase 1 study. Repeated administration of the test and active control drugs may be needed to reliably characterise their effects.

The effect of a clinically effective and non-effective dose of lorazepam on 7.5% CO2-induced anxiety.

Symptoms of anxiety induced by 7.5% CO2 inhalation can be attenuated by acute administration of GABA(A) receptor anxiolytics such as lorazepam and alprazolam. This study investigated if these effects are dose-related, by comparing a 0.5 mg dose (considered non-clinically effective) and a 2 mg dose of lorazepam (clinically effective) on 7.5% CO2 inhalation. Eighteen healthy males (mean age 20.6 years, SD 1.29), judged physically and mentally fit, attended three visits, each one week apart, to take each treatment in a randomised double-blind crossover design. Drugs were given 60 min prior to 20 min air inhalation, followed by 20 min 7.5% CO2 inhalation. The order of gas presentation was single blind. Subjective ratings using visual analogue scales (VAS) and questionnaires were recorded before and after each inhalation. Blood pressure (BP), heart rate (HR), respiration rate (RR) and expired CO2 were recorded during each inhalation. Inhalation of 7.5% CO2 significantly raised BP, HR, RR and expired CO2. Ratings of feeling like leaving the room were significantly lower on 2 mg compared with 0.5 mg and placebo, and dose-dependent trends were seen in scores for VAS fearful, anxious, stressed, tense, and worried. Results may be indicative of dose-dependent effects of lorazepam in a CO2 model of anxiety.

Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.

The alpha5 subunit of the GABA(A) receptor is localized mainly to the hippocampus of the mammalian brain. The significance of this rather distinct localization and the function of alpha5-containing GABA(A) receptors has been explored by targeted disruption of the alpha5 gene in mice. The alpha5 -/- mice showed a significantly improved performance in a water maze model of spatial learning, whereas the performance in non-hippocampal-dependent learning and in anxiety tasks were unaltered in comparison with wild-type controls. In the CA1 region of hippocampal brain slices from alpha5 -/- mice, the amplitude of the IPSCs was decreased, and paired-pulse facilitation of field EPSP (fEPSP) amplitudes was enhanced. These data suggest that alpha5-containing GABA(A) receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus.