Time course for blood pressure lowering of beta-blockers with partial agonist activity.

BACKGROUND: Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA). OBJECTIVES: To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device. MAIN RESULTS: Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.

Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis.

OBJECTIVE DATA: Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension. STUDY: Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. RESULTS: Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery. CONCLUSION: Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.

Effect of single doses of pindolol and d-fenfluramine on flumazenil-induced anxiety in panic disorder patients.

The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean ±â€¯SD, 32.9 ±â€¯8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90 and 45 min before a challenge test with flumazenil (1.5 mg, i.v., in 10 min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo-flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects.

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.

No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation.

The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg), with or without pindolol (20 mg), oxytocin nasal spray (40 IU+16 IU) or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18-26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg) selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors. Trial registration: MDMA & PSB NTR 2636.

Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats.

BACKGROUND: Clinical trials have shown promising results with the use of subcallosal cingulate gyrus deep brain stimulation (DBS) for treatment-resistant depression. However, strategies to manage patients who do not respond to this therapy have not been explored in detail. In rats, DBS in the ventromedial prefrontal cortex (vmPFC) induces a significant antidepressant-like response in the forced swim test (FST). We have used this test to investigate potential interactions between DBS and clinically used augmentative regimens. METHODS: Rats undergoing the FST were treated with vmPFC DBS along with different augmentative drugs, namely buspirone, risperidone and pindolol. Locomotor activity was tested in an open field. RESULTS: DBS induced a significant reduction in immobility scores as compared to saline treated controls. These antidepressant-like effects, however, were not potentiated by the co-administration of buspirone, risperidone or pindolol. LIMITATIONS: Despite having good predictive validity, animal models are limited from a translational perspective. CONCLUSIONS: Our results indicate that that the antidepressant-like effects of vmPFC DBS in the FST are not enhanced by augmentative therapies.

Serial blood serotonin levels in a randomized controlled trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in patients with chronic tension-type facial pain.

BACKGROUND: Patients often present with chronic facial pain despite normal nasal endoscopy and sinus computerized tomography. Such pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension headache in the face. Descending serotonergic neuronal projections are known to modulate pain and intra-platelet serotonin levels are an accepted model reflecting central intra-neuronal serotonin. OBJECTIVES: 1.To determine whether low-dose amitriptyline significantly changes whole blood serotonin compared to a surrogate placebo in patients with chronic MFP 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties further alters blood serotonin. METHODOLOGY: Sixty-two patients were randomized to three treatment groups a) amitriptyline , b) amitriptyline with pindolol, and c) loratadine as surrogate placebo. Whole blood serotonin was taken before and after 8 weeks of treatment. Serotonin was also measured in 40 age-matched healthy controls. RESULTS: There was a significant reduction in blood serotonin levels in the amitriptyline with pindolol group. A non-significant reduction was seen in the amitriptyline group, with no change in serotonin levels in the surrogate placebo group. A comparison of change in serotonin with change in pain frequency and intensity scores is presented. Women in the control group had significantly higher serotonin levels than men. Women with tension-type facial pain who failed to respond to treatment had significantly lower blood serotonin than women in the control group. CONCLUSION: When linked to the clinical response this study provides evidence that the serotonergic system is involved in the modulation of chronic MFP. Serotonin levels are sex-dependent and related to treatment response.

A Randomized Controlled Trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in the treatment of chronic tension-type facial pain.

BACKGROUND: Patients often present to otolaryngologists with chronic facial pain, presumed to be of sinus origin despite normal nasal endoscopy and sinus CT. This pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension-type headache affecting the midface. PRIMARY OUTCOME MEASURES: 1. To determine whether low-dose amitriptyline reduces pain scores compared to surrogate placebo in patients with chronic MFP. 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties hastens onset of action or improves efficacy of amitriptyline. SECONDARY OUTCOME MEASURE: to determine whether amitriptyline or amitriptyline with pindolol significantly reduces analgesic consumption. METHODOLOGY: Sixty two patients were randomized to three treatment groups (a) amitriptyline 10mg daily (b) amitriptyline 10mg daily with pindolol 5mg twice daily and (c) loratadine 10mg daily. Daily pain scores using a facial pain diary were recorded over eight weeks. RESULTS: At 8 weeks, pain frequency and intensity were significantly reduced in patients treated with amitriptyline and in those receiving amitriptyline with pindolol compared to surrogate placebo. Patients on the combination therapy showed significantly improved clinical outcome and significantly reduced analgesic intake compared to those on amitriptyline alone. CONCLUSION: Low dose amitriptyline is effective in the management of MFP and is enhanced by the addition of pindolol.

A short-term double-blind randomized controlled pilot trial with active or placebo pindolol in patients treated with venlafaxine for major depression.

BACKGROUND: Pindolol has been widely investigated as an augmenter of antidepressant drug response. Results have been inconsistent. In this study, we used pindolol together with venlafaxine because of its ability to achieve a rapid onset of serotonin transporter blockade. AIMS: The object of this study was thus to investigate if pindolol augments the antidepressant response to venlafaxine. METHODS: Patients with major depression were randomized to either active or placebo pindolol 20 mg retard daily dosage and concomitantly treated with venlafaxine for 19 days. Depression severity was evaluated at four visits. Plasma concentrations of venlafaxine and its major metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) and pindolol were analysed. The ratio of ODV/venlafaxine was calculated. A low ratio corresponds to patients being poor metabolizers and a high ratio corresponds to patients being extensive metabolizers. RESULTS: No statistically significant difference in depression outcome was found between treatment groups. A statistically significant effect was, however, found of the ratio of ODV/venlafaxine on depression outcome, showing an augmenting effect of pindolol in patients with a low ratio, and the reverse in patients with a high ratio. CONCLUSION: The differential effect of pindolol, on depression outcome, in patients with varying degrees of venlafaxine metabolism into ODV, corresponds to patients being poor or extensive metabolizers of venlafaxine. From this finding, we conclude that only patients who are poor metabolizers of venlafaxine might benefit from pindolol augmentation. This mechanism might explain some of the variability of outcome in pindolol augmentation studies.

Pindolol potentiates the panicolytic effect of paroxetine in the elevated T-maze.

AIMS: the ß-adrenergic and 5-HT(1A) receptor antagonist pindolol has been used in combination with antidepressant drugs, to shorten the time of onset of clinical efficacy and/or increase the proportion of responders in depressive and anxiety disorders. The aim of this study was to examine the interaction between pindolol and the selective serotonin reuptake inhibitor (SSRI), paroxetine in rats submitted to the elevated T-maze (ETM). MAIN METHODS: for assessing the drug combination effect, rats were administered with pindolol before paroxetine, using oral or intraperitoneal (i.p.) routes of acute administration, and were submitted to the ETM model. KEY FINDINGS: the highest dose of pindolol used (15.0mg/kg, i.p.) increased both inhibitory avoidance and escape latencies in the ETM, probably due to nonspecific motor deficit, since locomotion in a circular arena was also significantly decreased. The highest dose of paroxetine (3.0mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0mg/kg, i.p.) with an ineffective dose of paroxetine (1.5mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0mg/kg) nor pindolol (5.0mg/kg) alone were effective, but the combination treatment had a marked panicolytic effect, again indicating drug potentiation. SIGNIFICANCE: the present results show that the combination of the ineffective doses of pindolol and paroxetine significantly increased escape latency, indicating a selective panicolytic effect. These findings give preclinical support for the use of this drug combination in the treatment of panic disorder (PD).

Cardiovascular drugs in human mechanical nociception: digoxin, amlodipine, propranolol, pindolol and atenolol

Calcium channel blockers, β adrenergic receptor blockers and Na/K ATPase inhibitors are widely used drugs, mainly for cardiovascular diseases. Their pharmacological targets are not restricted to the cardivascular tissue, nociceptive system structures also express similar targets, which strongly suggests a direct effect on pain sensation. To evaluate the pain intensity changes in outpatient groups, who receive these drugs as a therapy, a cross-sectional sampled, randomized patient groups receiving the calcium channel blocker amlodipine for blood hypertension (n=45), β adrenergic receptor blockers (propranolol, atenolol or pindolol; n=40) for blood hypertension, or digoxin (n=40) for heart failure, were compared to an aparently healthy volunteers control group (n=60). A calibrated noxious pressure of 890 g/mm² was applied for 5 seconds on the patient’s sternum. Subjective pain intensity was reported by the visual analog scale (VAS, 0 to 10). Pain modulation system was evaluated by the application of a second stimulus with a 5 minutes delay. The analgesic effect of the β blockers group (propanolol, atenolol, pindolol) was dosage-dependant (-36.8 percent; P=0.0000003), without differences among them. The calcium channel blocker amlodipine showed lower pain scores (-50.6 percent; P=0.0000003) than β-receptor blockers (P=0.0000003). Digoxin presented the highest pain scores (+56.5 percent; P=0.0000003). All pain scores for the second stimulus were lower than the first stimulus and were differentially affected by β-blockers (atenolol, pindolol and propanolol) and calcium channel blocker (amlodipine), but not by digoxin. These results suggest the influence of widely clinically used cardiovascular drugs on nociception.

Los bloqueadores de los canales de calcio, los bloqueadores de los receptores β adrenérgicos y los inhibidores de la ATPasa Na/K son medicamentos ampliamente usados en enfermedades cardiovasculares. Sus blancos farmacológicos no se restringen al tejido cardiovascular, el sistema nervioso nociceptivo expresa blancos similares, lo que sugiere fuertemente un efecto directo en la sensación del dolor. El objetivo del presente estudio fue evaluar los cambios en la intensidad del dolor en grupos de pacientes ambulatorios que reciban estos medicamentos como terapia. Grupos aleatorios de pacientes que reciben el bloqueador de canales de calcio amlodipina contra la hipertensión arterial (n=45), bloqueadores de receptores β adrenérgicos (propranolol, atenolol or pindolol; n=40) contra la hipertensión arterial o digoxina (n=40) por insuficiencia cardíaca fueron comparados con un grupo control de voluntarios aparentemente sanos (n=60). A todos los grupos se les aplicó una presión nociva calibrada de 890 g/mm² durante 5 segundos sobre el esternón. El paciente reportó la intensidad subjetiva del dolor mediante la escala visual análoga (VAS). El sistema de modulación descendente del dolor fue evaluado mediante la aplicación del mismo estímulo 5 minutos después del primero. Se determinó un efecto analgésico en el grupo de β bloqueantes (propanolol, atenolol, pindolol) dosis dependiente (-36,8 por ciento; P=0,0000003) sin mostrar diferencias entre ellos. El bloqueador de canales de calcio amlodipina mostró un efecto analgésico (-50,6 por ciento; P=0,0000003) que fue mayor que el de los β bloqueantes (P=0,0000003). El grupo con digoxina expresó un efecto hiperalgésico (+56,5 por ciento; P=0,0000003). Todos los valores de dolor para el segundo estímulo fueron menores que para el primero y fueron diferencialmente afectados por los β bloqueantes (atenolol, pindolol and propanolol) y por la amlodipina pero no por la digoxina. Estos...

A short duration of untreated illness (DUI) improves response outcomes in first-depressive episodes.

BACKGROUND: Few studies have addressed the implication of the duration of untreated illness (DUI) on the clinical outcome of mood disorders. Although not focusing on DUI, previous findings suggest that the longer it takes to start appropriate treatment, the worse will be the evolution of depressive disorder. We sought to determine the effect of the duration of untreated episode (DUE) on 1) rates of response to treatment, 2) time to attain a sustained response and 3) rates of remission of MDD, dealing specially with first-depressive episodes. METHODS: 141 patients with MDD were grouped into long DUE (>8 weeks) and short DUE (< or =8). Statistical analyses were performed to determine differences in outcome variables. The same analyses were repeated by splitting the sample between first-episode and recurrent depression. RESULTS: The percentage of patients who achieved a sustained response was significantly higher in the group with a short DUE [OR=2.6; 95% CI 1.3-5.1]. Survival analyses showed that patients with a long DUE delayed longer time to attain a sustained response [39 vs. 20 days, p=0.012]. Once the sample was split, these results were even more pronounced in the subsample of first-depressive episode patients. LIMITATIONS: Given that the sample was originally recruited for two clinical trials, the follow-up period of this study is only six weeks long. CONCLUSIONS: Our results indicate that response to antidepressant treatments is faster when the no-treatment interval is reduced. The earliest treatment of first-depressive episodes seems to be crucial since a shorter duration of untreated illness implies better response outcomes.

Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review.

UNLABELLED: Adding pindolol to serotonergic antidepressant treatment offers a potential strategy for producing a more rapid onset of action and an enhanced antidepressant effect. This review investigated whether pindolol enhances the efficacy of serotonergic antidepressant treatment in adult patients with depressive disorders at sequential time points up to 6 weeks. SEARCH STRATEGY: Cochrane Collaboration Depression, Anxiety and Neurosis-Controlled Trials Register plus unpublished trial data. STUDY SELECTION: Randomised trials including depressed patients, comparing serotonergic antidepressants + pindolol with serotonergic antidepressants + placebo and using depressive symptom clinical outcomes scales. DATA EXTRACTION: Clinical response at time points up to 6 weeks as defined by >50% depression scale score reduction was extracted for each trial as possible. Eleven studies were identified including unpublished data. The pooled odds ratios for dichotomous response to treatment at time points from 1 to 6 weeks were 2.39 (95% CI 1.40-4.06), 2.39 (1.74-3.29), 1.94 (1.46-2.58), 1.59 (1.16-2.18), 1.42 (0.87-2.31) and 1.28 (0.91-1.81). Time-to-event analysis showed a greater response with pindolol augmentation versus placebo (P = 0.04). There was significant heterogeneity between studies at some time points. Dropout rates did not significantly differ between treatment arms. This review suggests an overall beneficial clinical effect of pindolol augmentation, most clearly up to 4 weeks of treatment.

Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

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 due to the presumed peripheral haemodynamic consequences of beta blockers, leading to worsening symptoms of intermittent claudication. OBJECTIVES: To quantify the potential harm 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 STRATEGY: The Cochrane Peripheral Vascular Diseases (PVD) Group searched for publications describing randomised controlled trials (RCTs) of beta blockers in PAD in their Trials Register (last searched 6 May 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2008, Issue 2). We handsearched relevant journals and conference proceedings. SELECTION CRITERIA: Randomised controlled trials evaluating the role of both selective (beta1) and non-selective (beta1 and beta2) beta blockers compared with placebo. We excluded trials comparing different types of beta blockers. DATA COLLECTION AND ANALYSIS: Primary outcome measures were claudication distance in metres, and the time to claudication in minutes, and maximum walking distance in metres and minutes (as assessed by treadmill).Secondary outcome measures were calf blood flow (ml/100 ml/min), calf vascular resistance, and skin temperature (degrees C). MAIN RESULTS: We included six RCTs fulfilling the above criteria, with a total of 119 patients. The beta blockers studied were atenolol, propranolol, pindolol, and metoprolol. None of the trials showed a statistically significant worsening effect of beta blockers on either the primary or secondary outcomes. There were no reports of any adverse events with the beta blockers studied. AUTHORS' CONCLUSIONS: There is currently no evidence that beta blockers adversely affect walking distance in people with intermittent claudication. However, due to the lack of large published trials beta blockers should be used with caution if clinically indicated.

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.

An index of 5-HT synthesis changes during early antidepressant treatment: alpha-[11C]methyl-L-tryptophan PET study.

The antidepressant selective serotonin transporter inhibitors (SSRIs) are clinically active after a delay of several weeks. Indeed, the rapid increase of serotonin (5-HT) caused by SSRIs, stimulates the 5-HT(1A) autoreceptors, which exert a negative feedback on the 5-HT neurotransmission. Only when autoreceptors are desensitized, can SSRIs exert their therapeutic activity. The 5-HT(1A) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback. Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography (PET), the goal of the present double-blind, randomized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping, an index of serotonin synthesis, in patients suffering from unipolar depression treated with the SSRI citalopram (20 mg/day) plus placebo versus patients treated with citalopram plus pindol (7.5 mg/day). PET and Hamilton depression rating scale (HDRS-17) were performed at baseline, and after 10 and 24 days of antidepressant treatment. Results show that the combination citalopram plus pindol, compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex (BA 9). This research is the first human PET study demonstrating that, after 24 days, the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex, an area associated to depressive symptoms.