Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis was conducted to assess the use of pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitor (SSRI) therapy. METHODS: A comprehensive search of PubMed, Cochrane, Embase, Web of Science, and PsychINFO databases from 1970 through December 2013 was conducted. Only randomized controlled trials (RCTs) studied on unipolar SSRI-resistant depressed adults were included. The primary outcome was mean change scores of depressive symptom on the depression rating scales, assessed with standardized mean differences. RESULTS: Five RCTs consisting of 154 patients met all inclusion and exclusion criteria. The overall pooled effect size in the primary and secondary efficacy analysis showed no significant effects of pindolol plus SSRI therapy (standardized mean difference = -0.43, p = 0.24; OR = 1.92, p = 0.39, respectively). In terms of acceptability, there was no statistical difference in either tolerability or safety between the two groups (OR = 0.46, p = 0.40; OR = 0.90, p = 0.94, respectively). These estimates remained robust through several sensitivity and subgroup analyses, except 7.5 mg-qd pindolol augmentation did show a significant benefit over 2.5-mg tid pindolol augmentation. CONCLUSIONS: Pindolol augmentation may not be suitable for treatment-resistant depression patients with SSRI-resistant depression. However, once-daily high-dose pindolol (7.5 mg qd) appears to show a promising benefit in these patients.

Beta blockers for peripheral arterial disease.

BACKGROUND: Beta (ß) blockers are indicated for use in coronary artery disease (CAD). However, optimal therapy for people with CAD accompanied by intermittent claudication has been controversial because of the presumed peripheral haemodynamic consequences of beta blockers, leading to worsening symptoms of intermittent claudication. This is an update of a review first published in 2008. OBJECTIVES: To quantify the potential harmful effects of beta blockers on maximum walking distance, claudication distance, calf blood flow, calf vascular resistance and skin temperature when used in patients with peripheral arterial disease (PAD). SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched March 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 2). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the role of both selective (ß1) and non-selective (ß1 and ß2) beta blockers compared with placebo. We excluded trials that compared different types of beta blockers. DATA COLLECTION AND ANALYSIS: Primary outcome measures were claudication distance in metres, time to claudication in minutes and maximum walking distance in metres and minutes (as assessed by treadmill).Secondary outcome measures included calf blood flow (mL/100 mL/min), calf vascular resistance and skin temperature (ºC). MAIN RESULTS: We included six RCTs that fulfilled the above criteria, with a total of 119 participants. The beta blockers studied were atenolol, propranolol, pindolol and metoprolol. All trials were of poor quality with the drugs administered over a short time (10 days to two months). None of the primary outcomes were reported by more than one study. Similarly, secondary outcome measures, with the exception of vascular resistance (as reported by three studies), were reported, each by only one study. Pooling of such results was deemed inappropriate. None of the trials showed a statistically significant worsening effect of beta blockers on time to claudication, claudication distance and maximal walking distance as measured on a treadmill, nor on calf blood flow, calf vascular resistance and skin temperature, when compared with placebo. No reports described adverse events associated with the beta blockers studied. AUTHORS' CONCLUSIONS: Currently, no evidence suggests that beta blockers adversely affect walking distance, calf blood flow, calf vascular resistance and skin temperature in people with intermittent claudication. However, because of the lack of large published trials, beta blockers should be used with caution, if clinically indicated.

Fetal cardiac function after labetalol or pindolol for maternal hypertension in a sheep model of increased placental vascular resistance.

OBJECTIVE: We hypothesized that labetalol and pindolol have no detrimental effects on fetal cardiac function and pulmonary hemodynamics when administered for norepinephrine-induced maternal hypertension in a chronic sheep model of increased placental vascular resistance. Specifically, we investigated the effects of labetalol and pindolol on fetal cardiopulmonary responses to acute hypoxemia. STUDY DESIGN: Twenty chronically instrumented near-term ewes with increased placental vascular resistance after placental embolization were anesthetized and randomized to receive labetalol or pindolol for norepinephrine-induced hypertension. Thereafter, maternal inspiratory oxygen fraction was decreased to induce fetal hypoxemia. At the end of each phase, fetal hemodynamics were assessed by Doppler ultrasonography. The data were analyzed using repeated measures ANOVA. RESULTS: Maternal administration of norepinephrine had no effect on fetal hemodynamics. Pindolol decreased fetal heart rate and weight-indexed left ventricular cardiac output and increased pulmonary vascular impedances, while labetalol had no effect on these parameters. During hypoxemia, fetal heart rate increased to baseline in the pindolol group and pulmonary vascular impedances increased in the labetalol group, with no changes in fetal cardiac outputs. CONCLUSION: Pindolol decreased fetal left ventricular cardiac output and induced vasoconstriction in the pulmonary vasculature, but neither pindolol nor labetalol significantly modified fetal cardiopulmonary responses to acute hypoxemia.

[Drug-induced tremor]. / Medikamentös-induzierter Tremor.

Drug-induced tremor is an important differential diagnosis for tremor syndromes. In view of a constantly ageing population and increasingly frequent polypharmacotherapy, identification of potentially tremor-inducing drugs may help generating risk profiles for individual patients. Drug-induced tremor has often been seen as a complication of antipsychotic therapy, but its occurrence has also been described in response to a great diversity of compounds such as antidepressants, sympathomimetics, antiarrhythmics, antiepileptics and other drugs. The present article presents a synopsis of the most prevalent tremor-inducing drugs as well as strategies to overcome drug-induced tremor, either by replacement of the causative drug or by symptomatic therapies.

Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression.

OBJECTIVE: Since depression entails not only dramatic personal disruption but also a huge amount of medical and socioeconomic burden, slowness of antidepressant action and difficulties to attain remission are entangled issues to be solved. Given the controversial previous findings with enhancing strategies such as pindolol, we examined whether the speed of selective serotonin reuptake inhibitor (SSRI) action can be truly accelerated with optimized pindolol dosage. Additionally, we aimed at elucidating whether pindolol benefits emerge, particularly in a population with nonresistant depression. METHOD: Thirty outpatients with major depressive disorder (DSM-IV criteria) recruited between December 2002 and November 2005 were randomly assigned to receive citalopram + pindolol (5 mg tid) or citalopram + placebo for 6 weeks in a double-blind randomized clinical trial. A meta-analysis of randomized controlled trials of pindolol augmentation in patients with nonresistant depression was also performed. Outcome criteria were based on the 17-item Hamilton Depression Rating Scale. For the meta-analysis, efficacy was assessed by the number of treatment responders at 2 weeks and 4-6 weeks. RESULTS: Clinical trial outcomes: Repeated-measures analysis of variance showed a significant group-by-time interaction (P = .01). Cumulative percentage showed a trend for sustained response (odds ratio [OR] = 2.09; 95% CI, 0.914-4.780; P = .08) and a well-defined increased likelihood of sustaining remission (OR = 5.00; 95% CI, 1.191-20.989; P = .03) in pindolol receivers. Median survival time until first response was 65% less in the pindolol group (22 days vs 30 days; P = .03). The negative binomial regression model yielded different rates of response per person-day for pindolol and placebo groups (7.6% vs 4.7%, respectively; P = .03). Meta-analysis: Outcome favored pindolol at 2 weeks' time (relative risk [RR] = 1.68; 95% CI, 1.18-2.39; P = .004) and also at 4-6 weeks' time (RR = 1.11; 95% CI, 1.02-1.20; P = .02). CONCLUSIONS: Present findings represent further evidence of the acceleration and enhancement of efficacy with pindolol administered together with SSRIs, displaying a quicker and more pronounced decrease of symptoms in patients with nonresistant major depressive disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00931775.

Pindolol augmentation enhances response outcomes in first depressive episodes.

Effectiveness of Pindolol addition to SSRIs is still a matter of debate. Recently, Geretsegger et al. [Geretsegger, C., Bitterlich, W., Stelzig, R., Stuppaeck, C., Bondy, B. and Aichhorn, W. (2008) Paroxetine with Pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. Eur. Neuropsychopharmacol. 18, 141-146.] have found that never-medicated depressed patients showed a significant sustained response with Paroxetine + Pindolol treatment. Also, patients with a first depressive episode displayed a trend for higher sustained response rates with Pindolol co-administration. Re-analysing the data of a previous clinical trial of Fluoxetine + Pindolol [Pérez, V., Gilaberte, I., Faries, D., Alvarez, E. and Artigas, F. (1997). Randomised, double-blind, placebo-controlled trial of Pindolol in combination with Fluoxetine antidepressant treatment. Lancet 349, 1594-1597.], we have found that first depressive episodes are associated with a significant higher percentage of sustained responses when administering Fluoxetine + Pindolol (70.3%) compared to Fluoxetine + Placebo (44%). Moreover, based on a survival analysis, among the patients with a first depressive episode, those who received Fluoxetine + Pindolol achieved a sustained response significantly earlier (19 days) than those on Fluoxetine + Placebo (35 days). Interestingly, none of these effects were observed in the subsample of recurrent patients. The results suggest that Pindolol augmentation accelerates and enhances the action of SSRI at the beginning of the illness.

Placental and fetal hemodynamics after labetalol or pindolol in a sheep model of increased placental vascular resistance and maternal hypertension.

We investigated the effects of labetalol and pindolol on uterine, placental, and fetal hemodynamics following norepinephrine-induced maternal hypertension in a sheep model of increased placental vascular resistance. Also, we examined fetal and placental hemodynamic responses to acute hypoxemia after antihypertensive medication. Norepinephrine increased maternal heart rate (HR), mean arterial pressure (MAP) and uterine vascular resistance (R(UtA)), and decreased uterine volume blood flow (Q(UtA)). Both labetalol and pindolol decreased maternal HR, MAP, and R(UtA), but did not restore Q(UtA). Fetal MAP was unaffected while fetal HR and placental volume blood flow (Q(UA)) decreased and placental vascular resistance increased. During hypoxemia, which was induced by decreasing maternal inspiratory oxygen fraction, all these parameters remained unchanged in the labetalol group while fetal HR increased and Q(UA) further decreased in the pindolol group. We conclude that labetalol and pindolol may compromise uterine and placental hemodynamics. Hypoxemic stress provokes divergent hemodynamic responses in fetuses exposed to these differently acting adrenoceptor antagonists.

Glomerular filtration rate after tramadol, parecoxib and pindolol following anaesthesia and analgesia in comparison with morphine in dogs.

OBJECTIVE: To compare the effects of morphine, parecoxib, tramadol and a combination of parecoxib, tramadol and pindolol on nociceptive thresholds in awake animals and their effect on glomerular filtration rate (GFR) in dogs subjected to 30 minutes of anesthesia. ANIMALS: Eight adult mixed breed experimental dogs. STUDY DESIGN: Randomized, controlled trial. METHODS: Dogs received 0.05 mg kg(-1) acepromazine subcutaneously (SC) as anaesthetic pre-medication. Thirty to sixty minutes later, they received either tramadol 3 mg kg(-1) intravenously, (IV), parecoxib (1 mg kg(-1) IV), a combination of tramadol 3 mg kg(-1) (IV), parecoxib 1 mg kg(-1) (IV) and pindolol 5 microg kg(-1) (SC), morphine (0.1 mg kg(-1) (IV) or 0.9% saline (2 mL). Anaesthesia was then induced with IV propofol to effect (2.9 +/- 0.8 mg kg(-1)) and maintained with halothane in oxygen for 30 minutes. Systolic arterial blood pressure was maintained above 90 mmHg with IV fluids and by adjusting the inspired halothane concentration. Post-treatment nociceptive thresholds to mechanical stimuli, expressed as percent of pre-treatment values, were compared between the treatments to assess the analgesic efficacy of the drugs. Plasma iohexol clearance (ICL), a measure of GFR, was estimated both before and 24 hours after induction of anaesthesia to study the drugs' effects on renal perfusion. Nociceptive threshold and GFR data were compared using mixed model analysis in SAS 9.1. RESULTS: Both tramadol and parecoxib produced similar analgesia, which was less than that of morphine. Their combination with pindolol produced analgesia comparable with morphine. None of the test drugs, either alone or in combination, reduced GFR. CONCLUSION: Tramadol and parecoxib (either alone or in combination) can increase nociceptive thresholds in awake dogs and have minimal effects on renal perfusion in normotensive dogs subjected to anaesthesia.

Once-daily high-dose pindolol for paroxetine-refractory premature ejaculation: a double-blind, placebo-controlled and randomized study.

PURPOSE: To evaluate the efficacy and safety of pindolol 7.5 mg/d in delaying of ejaculation in paroxetine-refractory patients. MATERIALS AND METHODS: Eighty-six married men (mean age, 33 years) with premature ejaculation unresponsive to paroxetine 20 mg/d given for 2 months or longer were randomized to receive 7.5 mg pindolol (n = 44) (group 1) (PXT + POL) or placebo (n = 42) (group 2) (PXT + PBO) for 6 weeks, while continuing paroxetine. After 6 weeks, all patients received paroxetine and placebo and were followed for 3 further weeks in a single-blind manner. Pretreatment evaluation included history and physical examination, mean intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and Meares-Stamey test. The efficacy of 2 treatments was assessed every 1 week during treatment and, at the end of study, using responses to IIEF, IELT evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes, and adverse drug effects. RESULTS: Seventy-seven (89.5%) completed the whole treatment schedule. At the end of 6-week treatment period, the IELT after paroxetine-pindolol and paroxetine-placebo gradually increased from mean 48 and 41 seconds to approximately 188 and 58 seconds, respectively (P = 0.001). The mean weekly intercourse episodes increased from pretreatment values of 1.5 and 1.5 to 2.7 and 1.7, for groups PXT + POL and PXT + PBO, respectively (P = 0.01). Baseline mean intercourse satisfaction domain values of IIEF 12 and 11 reached to 16 and 11 at 6-week treatment in PXT + POL and PXT + PBO groups, respectively (P = 0.01). Upon discontinuing pindolol, all outcome measures returned to baseline values rapidly. The incidence of side effects with paroxetine-pindolol was significantly higher (P = 0.04). CONCLUSIONS: These findings support that a single high dose of pindolol (7.5 mg) is an effective augmentation strategy in paroxetine-refractory patients.

Open trial of pindolol in the treatment of fibromyalgia.

BACKGROUND: Evidence suggests that fibromyalgia is related to both chronic sympathetic hyperactivity and decreased levels of serotonin. OBJECTIVE: To examine the efficacy of pindolol, a mixed serotonin (5-HT)(1A) presynaptic autoreceptor/beta-adrenergic receptor antagonist, in the treatment of fibromyalgia. METHODS: An open trial was conducted using 20 female patients who met the American College of Rheumatology criteria for fibromyalgia. Treatment was initiated with pindolol 7.5 mg/day and titrated to a maximum dose of 15 mg/day for a total of 90 days. Primary outcome measures were tender point analysis and the Fibromyalgia Impact Questionnaire (FIQ). Anxiety and depression were measured with the Hamilton Depression and Anxiety Scales and Beck Depression Inventory. RESULTS: There was significant improvement in primary outcome measures, including Tender Point Count (mean +/- SD, 16.3 +/- 2.2 vs 12.3 +/- 5.0; F = 8.9; p < 0.001), Tender Point Score (24.4 +/- 5.7 vs 17.5 +/- 9.4; F = 7.8; p < 0.001), and FIQ (45.3 +/- 10.8 vs 35.0 +/- 15.0; F = 5.6; p < 0.005). The depression and anxiety scores did not change significantly among women who completed the study, while the impact on cardiovascular parameters was clinically insignificant. CONCLUSIONS: While the current results are encouraging, further studies are needed to determine whether pindolol might be effective in the treatment of fibromyalgia. Limitations of this study include small group size and lack of placebo control.

Noradrenergic activity is associated with response to pindolol in aggressive Alzheimer's disease patients.

Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer's disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 +/- 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 +/- 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 microg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.

Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials.

BACKGROUND: Contradictory results on the efficacy of pindolol associated with selective serotonin reuptake inhibitors (SSRIs) in depressive illness have been published and no former review has produced an overall figure of its efficacy. This study aims to review the efficacy and tolerability of pindolol plus SSRIs in depressive illness. METHODS: A meta-analysis of randomised controlled trials (RCTs) comparing pindolol plus SSRIs with placebo plus SSRIs. RESULTS: Nine RCTs met inclusion criteria. Outcome favoured pindolol at 2 weeks time (N=5; OR=2.8; 95% CI 1.4-5.7), but not at four to 6 weeks (N=7; OR=1.4; 95% CI 0.8-2.7). Results for early outcome studies were robust to sensitivity analysis. Nineteen more studies, averaging null results, would be needed to change the overall probability (P=0.0001) to a non-significant figure. CONCLUSIONS: Pindolol seems to hasten the response to SSRIs in depression with a timing window circumscribed to the first weeks of treatment.

Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial.

BACKGROUND: Studies of pindolol augmentation of antidepressants in major depressive disorder have produced mixed results, and data in treatment-resistant patients are limited. Here, we report on a double-blind, randomized, controlled 6-week study of pindolol augmentation of selective serotonin reuptake inhibitors (SSRIs) in depressed outpatients resistant to SSRI monotherapy. METHOD: Forty-two outpatients with DSM-IV major depressive disorder who had an insufficient response to an adequate trial of an SSRI (fluoxetine, paroxetine, or sertraline) were randomly assigned to pindolol, 2.5 mg t.i.d., or sham augmentation, in addition to continued SSRI administration. For separate analysis, the control group underwent a single-blinded switch to pindolol, 2.5 mg t.i.d., from week 4 through week 6, while the active group was continued on pindolol augmentation (hemi-crossover design). Change in Hamilton Rating Scale for Depression (HAM-D) score from baseline to the end of week 3 was the primary outcome measure. Data were gathered from February 1994 to August 1998. RESULTS: Thirty-eight patients completed at least 1 week on protocol, with 21 and 17 randomly assigned to the pindolol and control groups, respectively. After 3 weeks on protocol, partial response rates (i.e., minimum 50% decrease from baseline in HAM-D score and maximum absolute score of 15) for the pindolol (19% [4/21]) and control (24% [4/17]) groups were comparable. At 3 weeks, the pindolol and control groups demonstrated mean +/- SD decreases in HAM-D scores of 6.5 +/- 9.8 and 9.7 +/- 7.2, respectively. There were no significant differences in antidepressant response or side effects between the 2 groups. CONCLUSION: These results do not support the efficacy of pindolol in augmenting clinical response to SSRIs in treatment-resistant depressed patients.

Milnacipran and pindolol: a randomized trial of reduction of antidepressant latency.

BACKGROUND: New, better tolerated and faster treatments for depression are needed. Patients are understandably unhappy with having to wait 3 to 4 weeks for a response to an antidepressant, while experiencing side effects almost immediately. This frequently has an adverse effect on compliance and engagement with treatment. AIMS: The primary objective was to assess the activity of pindolol on the onset of antidepressive response of milnacipran. The secondary objective was to assess the number of responders among the patients who received milnacipran and pindolol versus patients who received milnacipran and placebo. The tertiary objective was to evaluate the safety of milnacipran and pindolol versus milnacipran and placebo. METHOD: Randomized, double-blind, placebo-controlled study over 42 days. SETTING: Inner city London community mental health teams. PARTICIPANTS: 80 patients were selected and gave written consent to treatment, 78 were randomized (39 in each group) and evaluated for safety (intention-to-treat, ITT, safety data set), 77 (ITT efficacy data set), and 64 (per protocol, PP, data set) were evaluated for efficacy. The mean age was 31.9 for the pindolol group and 32.3 for the placebo. INTERVENTION: All patients received milnacipran 50 mg twice a day plus either pindolol 2.5 mg (the 'pindolol group') or matching placebo (the 'placebo group') three times a day. OUTCOME MEASURES: The main efficacy variable was the Montgomery-Asberg depression rating scale (MADRS) score at days 0, 4, 7, 10, 14, 21, 28, 42 on PP data set in an observation carried (OC) approach. Secondary efficacy variables were clinical global impression (global improvement) and Hamilton depression rating scale (HDRS). RESULTS: Improvement in MADRS total score was greater in the pindolol group than in the placebo group from day 7 (p=0.03). Responder rates in the clinical global impression were 97.2% for the pindolol group and 60.6% for the placebo group. The treatment was well tolerated with the most common side effects being nausea (28.2%; 35.9%), vomiting (7.7%; 23.1%), hot flushes (15.4%; 5.1%) and sweating (12.8%; 12.8%). CONCLUSION: The milnacipran and pindolol combination is safe, well tolerated and efficacious in major depression, and represents a rational strategy for the possible acceleration or potentiation of antidepressant action.

EEG effects of buspirone and pindolol: a method of examining 5-HT1A receptor function in humans.

RATIONALE: An involvement of 5-HT(1A) receptors is postulated in the pathophysiology of affective disorders and mechanism of action of antidepressants. Methods for studying their functional integrity in humans are, however, limited. Preliminary data suggests that activation of somatodendritic 5-HT(1A) receptors cause a negative shift in the EEG frequency spectrum. Animal research suggests that pindolol is an agonist at these receptors but an antagonist at postsynaptic 5-HT(1A) receptors. OBJECTIVE: We postulated that while pindolol would antagonise known postsynaptic mediated neuroendocrine responses to the 5-HT(1A) agonist buspirone, both drugs would have a similar effect on the EEG frequency spectrum. METHODS: Fourteen healthy men were administered placebo or pindolol (20 mg orally) 90 min before placebo or buspirone (30 mg orally) in a double blind cross-over study. Plasma prolactin and growth hormone were assayed and EEGs recorded before and after drug administration. RESULTS: A significant negative shift in the EEG frequency spectrum was found for both buspirone and pindolol, with the combination producing a similar effect to each drug alone. In contrast, the neuroendocrine response to buspirone was significantly attenuated by pindolol. CONCLUSIONS: The data obtained are consistent with the EEG effects of buspirone and pindolol being mediated by somatodendritic 5-HT(1A) receptors, in contrast to the neuroendocrine response, which is known to be mediated by postsynaptic receptors. The development of this novel method of assessing somatodendritic 5-HT(1A) receptors in humans is a potentially important advance which may allow the testing of hypotheses of its involvement in depression and response to antidepressants.

Effects on sleep architecture of pindolol, paroxetine and their combination in healthy volunteers.

RATIONALE: The combination of pindolol with a serotonergic antidepressant has been used to speed up the antidepressant response and to augment in cases of resistant depression. Animal studies have suggested that this increased response occurs because of 5HT(1A) antagonist properties of pindolol, which in combination with a serotonergic antidepressant produces a synergistic increase in 5HT in the synapse. OBJECTIVES: To test whether the combination of pindolol with a serotonergic antidepressant produces a synergistic increase in synaptic 5HT by examining the effects on measures of sleep, psychomotor performance and ratings of anxiety. METHODS: Twelve healthy male volunteers took part in randomised crossover study in which they received paroxetine 20 mg/day (or its placebo) for 9 days with a washout period of 5 days between. On day 7 and 9 of each treatment they also received pindolol 2.5 mg (or its placebo) three times a day. Sleep EEG recordings were made on each of the nights on pindolol (or its placebo) and ratings of saccadic eye movement parameters, subjective sleep, anxiety and other adverse events recorded on the following days. Four drug conditions were therefore tested: placebo, pindolol alone, paroxetine alone and paroxetine+pindolol. RESULTS. The combination of paroxetine+pindolol produced an increase in REM suppression and a reduction in SWS compared with other drug combinations. There were no significant effects on the other measures of 5HT function recorded in this study. CONCLUSIONS: REM suppression by the combination was approximately equal to the sum of REM suppression by each drug individually and thus does not show a synergistic effect. However, there was a significant reduction in SWS produced by only the combination treatment, which may suggest a specific effect of the combination on non-REM sleep mechanisms.

Pindolol augmentation of selective serotonin reuptake inhibitors: PET evidence that the dose used in clinical trials is too low.

OBJECTIVE: Positron emission tomography (PET) was used to examine whether the dose of pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT(1A)) autoreceptor in depressed patients receiving medication. METHOD: The authors examined eight depressed patients on one of two regimes of pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635. RESULTS: The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT(1A) autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy. CONCLUSIONS: The dose of pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of pindolol's efficacy will necessitate doses higher than those used in present clinical trials.

Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression.

BACKGROUND: It has been recently reported that the short variant of the serotonin transporter (5-HTT) gene-linked functional polymorphic region (5-HTTLPR) influences the antidepressant response to certain selective serotonin reuptake inhibitors. The aim of the present study was to test this finding in a sample of major and bipolar depressives, with or without psychotic features. METHODS: One hundred fifty-five inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Allelic variation of 5-HTTLPR in each subject was determined using a polymerase chain reaction-based technique. RESULTS: 5-HTTLPR short variant was associated with a poor response to fluvoxamine treatment, independently from the recorded clinical variables. More specifically, the diagnosis, the presence of psychotic features, and the severity of depressive symptomatology did not influence this association. Conversely, pindolol augmentation may ameliorate the rate of response in 5-HTTLPR short variant subjects, thus reducing the difference in the response rate among the genotype variants. CONCLUSIONS: If confirmed, these results may improve patient care by helping the clinician to individualize treatment according to the patient's genetic 5-HTTLPR pattern.