Enric Álvarez

Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment

BACKGROUND Major depression affects more than 5% of the population and is a serious health and economic problem. Antidepressants have a slow onset of action and are effective in less than two-thirds of patients. The biochemical effects of selective serotonin reuptake inhibitors may be limited by the negative feedback from serotonin autoreceptors. Pindolol is an antagonist of both serotonin autoreceptors and beta-adrenoceptors. We studied the effect of the addition of pindolol to fluoxetine antidepressant treatment. METHODS Of 132 eligible patients with major depression, 111 were randomly assigned to treatment with fluoxetine (20 mg daily) and either placebo or pindolol (7.5 mg daily). Patients were assessed twice a week for the first 3 weeks of active treatment and then once a week until the end of the study (42 days). Hamilton and Montgomery-Asberg depression-rating scales were used to assess depression severity. FINDINGS The proportion of patients who responded to treatment with fluoxetine and pindolol was greater than that with fluoxetine and placebo (41/55 [75%] vs 33/56 [59%], [90% CI 1.1-30.1], p = 0.04). The proportion of patients who achieved a sustained response was also greater in the fluoxetine and pindolol group than in the fluoxetine and placebo group (38/55 [69%] vs 27/56 [48%] [5.9-35.9], p = 0.03). The number of days to reach a sustained response was lower in the fluoxetine and pindolol group than in the fluoxetine and placebo group (median 19 vs 29 days, p = 0.01), however, there was no difference in the time-to-onset of clinical improvement when stringent conditions were used (15 vs 18 days, p = 0.20). INTERPRETATION The addition of pindolol to fluoxetine antidepressant treatment increases the effectiveness of fluoxetine therapy. Further work is needed to resolve whether the time to clinical improvement benefits from this combination and whether the increase in efficacy occurs with other antidepressants.

A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

SPECT mapping of cerebral activity changes induced by repetitive transcranial magnetic stimulation in depressed patients. A pilot study

Repetitive transcranial magnetic stimulation (rTMS) is being investigated as an alternative treatment for depression. However, little is known about the clinical role and the neurophysiological mechanisms of the action of rTMS in these patients. In this study, 99mTc-HMPAO single photon emission computed tomography (SPECT) was used to map the effects of left dorsolateral prefrontal rTMS on prefrontal activity in seven patients who met DSM-IV criteria for major depression resistant to pharmacological treatment. rTMS consisted of 30 trains of 2-s duration stimuli (20 Hz, 90% of motor threshold), separated by 30-s pauses. Each patient underwent three SPECTs: at baseline; during the first rTMS; and 1 week after 10 daily sessions of rTMS. Regional cerebral blood flow (rCBF) of each cerebral region was normalized to the rCBF value in the cerebellum and relative changes in normalized rCBF were addressed using a region-of-interest analysis. The Hamilton Depression Rating Scale (HDRS) was used for clinical evaluation before and after rTMS. A significant rCBF increase after the 10 sessions of rTMS was found in the left prefrontal region (MANOVA F=5.29, d.f.=2,10, P=0.027), but no significant rCBF changes were found during the first rTMS session. The remaining cerebral regions showed no significant rCBF changes at any time. Only two patients showed a clinical improvement after rTMS, with 50% reduction of the initial HDRS score. The study was repeated under placebo conditions (identical design but addressing coil discharges to the air) in these two patients, who failed to show any rCBF increase during sham-rTMS. No relationship was found between the percentage of left prefrontal rCBF change and the clinical findings. In conclusion, rTMS of the left prefrontal cortex induces a significant rCBF increase in this region, despite the limited clinical effect in our sample of depressed patients. Cerebral perfusion SPECT is a useful tool to map cerebral activity changes induced by rTMS.

Increased plasma free serotonin but unchanged platelet serotonin in bipolar patients treated chronically with lithium

The effect of lithium salts administered chronically to bipolar patients on peripheral measures of the serotoninergic system has been studied. Plasma free serotonin (5HT), whole blood 5HT, plasma 5-hydroxyindoleacetic acid (5HIAA) and plasma total tryptophan (TP) have been analyzed in 22 patients treated with lithium carbonate (mean daily dose: 1280 mg, mean serum concentration: 0.73 mmol/l) and compared to 14 healthy controls and 11 patients treated chronically with antipsychotic drugs. Lithium salts induced significant increases in plasma free 5HT (+159% with respect to control values) and in plasma 5HIAA (+39%) without affecting 5HT contained in platelets. Plasma TP was also unchanged by chronic lithium treatment. The ratio between 5HT stored in platelets and 5HT free in plasma, a variable reduced after uptake inhibitors like clomipramine, was decreased in lithium-treated patients (-50%). These results are compatible with an enhanced synthesis of 5HT in the periphery (mainly enterochromaffin cells) as well as with an inhibition of platelet 5HT uptake (or increased 5HT efflux from intracellular stores) induced by lithium. The lack of effect of several antipsychotic drugs upon these variables is consistent with their predominant effect on the dopaminergic system and reinforces the specificity of the effect observed with lithium salts. Taken together, these results support the usefulness of using this “in vivo” 5HT peripheral model for the study of the actions elicited by drugs acting on the presynaptic components of the 5HT system.

Effects of the antidepressant drug tianeptine on plasma and platelet serotonin of depressive patients and healthy controls.

We have examined the effects of a single 12.5 mg dose and of 12 weeks treatment up to 37.5 mg daily with tianeptine, a new antidepressant drug that potentiates in vivo the uptake of serotonin (5-HT). On day 0, tianeptine reduced plasma 5-HT concentration. This acute effect occurred also on subsequent examination days. However, long-term treatment tended (P < 0.06) to increase basal plasma 5-HT concentrations, in covariation with decreases of MADRS (Montgomery-Asberg Depression Rating Scale) and HARS (Hamilton Anxiety Rating Scale). Platelet 5-HT increased only in elderly patients, probably due to the higher plasma concentration of the drug in this group than in younger patients. These results show that the acute effects of therapeutic doses of tianeptine are consistent with an enhancement of the 5-HT uptake. However, long-term treatment does not result in a decreased plasma 5-HT, as might be expected from the acute effects of the drug.