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Current Drug Targets Feb 2006Pindolol, a partial beta-adrenoceptor/5-HT1A receptor antagonist was first used to accelerate the onset of action of antidepressant drugs in 1994. Since then, it has... (Review)
Review
Pindolol, a partial beta-adrenoceptor/5-HT1A receptor antagonist was first used to accelerate the onset of action of antidepressant drugs in 1994. Since then, it has been used in more than a dozen controlled trials to examine whether it can reduce the lag to clinical improvement, and/or improve the clinical response in treatment-resistant patients. A recent metaanalysis concluded that pindolol accelerates the antidepressant response but does not increase the effectiveness of SSRIs in unresponsive patients. Several studies have examined the pharmacology of pindolol to clarify the neurobiological basis of its clinical action. Pindolol was initially used due to its ability to block 5-HT1A receptor-mediated responses and to enhance the neurochemical effects of SSRIs. In transfected cells, however, pindolol is a weak (20-25%) partial agonist at 5-HT1A receptors and, as such, its actions greatly depend on the system used. In line with this, other reports have also shown that pindolol can reduce serotonergic cell firing when given alone. Positron emission tomography (PET) scan studies have shown that pindolol displays a preferential occupancy of pre- vs. postsynaptic 5-HT1A receptors, although the overall occupancy is lower than desirable, which suggests that higher doses (e.g., 15 mg/day) may be more effective than the currently used 7.5 mg daily dosage. However, given the complex pharmacology of pindolol, it is hoped that new developments in this field can proceed through the use of a) selective and silent 5-HT1A receptor antagonists in combination with SSRIs, or b) dual action agents (SSRI+5-HT1A receptor blockers).
Topics: Brain; Depression; Humans; Pindolol; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome
PubMed: 16475955
DOI: 10.2174/138945006775515446 -
American Heart Journal Aug 1982Beta-adrenoceptor blockade is responsible for the therapeutic action of beta-adrenoceptor-blocking drugs in the treatment of hypertension and angina pectoris. Many... (Comparative Study)
Comparative Study Review
Beta-adrenoceptor blockade is responsible for the therapeutic action of beta-adrenoceptor-blocking drugs in the treatment of hypertension and angina pectoris. Many aspects of their effects can therefore be studied in relatively simple clinical pharmacologic experiments. Cardiac beta-adrenoceptor blockade can be measured in terms of the reduction of isoprenaline-induced and exercise-induced tachycardia. Based on these experimental procedures pindolol is, on a weight-for-weight basis, about 20 times more potent than propranolol. The duration of action of pindolol, measured by the reduction in exercise-induced tachycardia, is longer than that of many other beta-adrenoceptor-blocking drugs such as propranolol, alprenolol, and slow-release oxprenolol tested at equipotent beta-adrenoceptor-blocking doses. Pindolol is a beta-adrenoceptor-blocking drug with partial agonist activity (intrinsic sympathomimetic activity [ISA]). Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as drugs devoid of this property, but unlike the latter they produce some stimulation of beta adrenoceptors. The ISA of pindolol is sufficient to counterbalance the diminution in resting sympathetic tone that results from beta-adrenoceptor blockade. In hemodynamic studies pindolol does not alter or only slightly reduces normal cardiac output. This is in contrast to drugs lacking ISA, which consistently depress cardiac output. In addition, propranolol has been shown to markedly reduce blood flow in the calf, whereas pindolol and placebo do not differ from one another in their effect on this parameter. A linear correlation exists between the logarithm of plasma concentrations of pindolol and cardiac beta-adrenoceptor blockade expressed as a reduction of exercise-induced tachycardia. The high systemic availability of pindolol after oral administration, due to good oral absorption and low first-pass effect, is revealed not only in pharmacokinetic studies but also in pharmacodynamic experiments; beta-adrenoceptor blockade 75 minutes after intravenous administration was equivalent to that observed 2 hours after the same doses given orally.
Topics: Adrenergic beta-Agonists; Cardiac Output; Depression, Chemical; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Humans; Hypertension; Physical Exertion; Pindolol; Propranolol; Regional Blood Flow; Vascular Resistance
PubMed: 6125094
DOI: 10.1016/0002-8703(82)90125-9 -
The Australian and New Zealand Journal... Feb 2000To critically review the literature on clinical trials in which pindolol, a 5HT1A receptor antagonist, has been used to augment the effects of antidepressants in... (Review)
Review
OBJECTIVE
To critically review the literature on clinical trials in which pindolol, a 5HT1A receptor antagonist, has been used to augment the effects of antidepressants in patients with depression and to examine the pharmacodynamics and pharmacokinetics that may underlie such augmentations.
METHOD
The available literature from the previous 10 years relating to the clinical use of pindolol in combination with antidepressants was critically examined. This was placed in the context of its pharmacodynamic rationale, and evidence supporting its use was critically reviewed.
RESULTS
A number of open-label and placebo-controlled, double-blind trials on patients with depression showed conflicting results as to the value of adding pindolol to various antidepressant regimens in reducing latency or in augmenting the antidepressant effect in treatment-resistant cases. While pre-clinical studies using electrophysiological and microdialysis techniques suggest utility in terms of increases in extracellular concentration of 5-hydroxy-tryptamine (5HT) in serotonergic projection areas, few studies have examined the possibility of drug-drug interactions and subsequent elevated plasma levels of antidepressant.
CONCLUSIONS
Pre-clinical studies suggest possible advantages of pindolol augmentation of antidepressant regimens and the achievement of faster acting antidepressants. The results of investigations in patients with depression have so far been conflicting. There exists the possibility of drug-drug interaction in pindolol/antidepressant augmentation strategies which remains to be examined.
Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Drug Synergism; Drug Therapy, Combination; Humans; Pindolol
PubMed: 11185947
DOI: 10.1046/j.1440-1614.2000.00681.x -
Human Psychopharmacology May 2015This systematic review and meta-analysis was conducted to assess the use of pindolol augmentation in depressed patients resistant to selective serotonin reuptake... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Adult; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Humans; Pindolol; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 25689398
DOI: 10.1002/hup.2465 -
Pharmacotherapy 1982Pindolol is a new noncardioselective beta adrenergic blocking agent with intrinsic sympathomimetic activity. In the treatment of mild to moderate hypertension, pindolol... (Comparative Study)
Comparative Study Review
Pindolol is a new noncardioselective beta adrenergic blocking agent with intrinsic sympathomimetic activity. In the treatment of mild to moderate hypertension, pindolol provides effective control of blood pressure in a large majority of patients when administered alone or, more commonly, when combined with a thiazide diuretic. Pindolol is approximately as effective as propranolol in the therapy of hypertension, but in some crossover trials central nervous system side effects were more frequent with pindolol. A "ceiling effect" may be observed as dosages are titrated upward above approximately 20 to 30 mg per day, such that further blood pressure reductions may not be achievable. Some patients will exhibit a paradoxical increase in blood pressure with an increase in dosage. In patients who respond to modest doses of pindolol, twice or even once daily dosing is often adequate. This prolonged duration of hypotensive activity, while not suggested by the kinetics of this or similar drugs, is probably common to most beta blockers. Investigations in small numbers of patients with angina pectoris have reported variable but generally beneficial results with pindolol.
Topics: Adrenergic beta-Antagonists; Angina Pectoris; Arrhythmias, Cardiac; Brain; Cardiac Output; Chemical Phenomena; Chemistry; Drug Interactions; Female; Glaucoma; Headache; Heart Rate; Humans; Hypertension; Hypotension, Orthostatic; Kinetics; Methyldopa; Metoprolol; Pindolol; Pregnancy; Propranolol; Renin-Angiotensin System; Sodium; Thyroid Diseases; Tremor; Vascular Resistance
PubMed: 6133267
DOI: 10.1002/j.1875-9114.1982.tb04521.x -
Clinical Neuropharmacology Oct 1987
Clinical Trial
Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Humans; Hypertension; Male; Pindolol; Propranolol; Random Allocation; Tremor
PubMed: 3332615
DOI: 10.1097/00002826-198710000-00007 -
British Journal of Clinical Pharmacology 19821 Pindolol is a beta-adrenoceptor antagonist equally effective on beta 1- and beta 2-adrenoceptors which has a relatively long duration of action. It is practically... (Review)
Review
1 Pindolol is a beta-adrenoceptor antagonist equally effective on beta 1- and beta 2-adrenoceptors which has a relatively long duration of action. It is practically completely absorbed and, unlike most other beta-adrenoceptor blockers, is only metabolized to a small extent during the first passage through the liver. 2 Pindolol possesses partial agonist activity (intrinsic sympathomimetic activity, ISA). This means that apart from blocking beta-adrenoceptors it produces some stimulation. Pindolol therefore only slightly influences normal sympathetic drive at rest but effectively reduces the effects of elevated sympathetic activity. 3 Various therapeutic advantages have been attributed to the partial agonist activity of pindolol: no or only slight alterations in normal cardiac output, heart rate and peripheral blood flow occur. Peripheral resistance is reduced during chronic oral therapy. No alteration of HDL/LDL cholesterol ratio has been observed. Rebound phenomena on sudden withdrawal of therapy and bronchoconstriction in susceptible patients are less likely than with drugs devoid of ISA.
Topics: Adrenergic beta-Agonists; Animals; Heart Rate; Hemodynamics; Humans; Lung; Pindolol; Substance Withdrawal Syndrome
PubMed: 6125169
DOI: 10.1111/j.1365-2125.1982.tb01909.x -
Trends in Pharmacological Sciences May 2001Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as... (Review)
Review
Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as the selective 5-HT reuptake inhibitors (SSRIs), that act primarily on 5-HT-containing neurones. Pindolol was initially thought to act by preventing the inhibition of 5-HT release, elicited by SSRIs and other 5-HT-acting drugs, as a result of its ability to antagonize the action of 5-HT at midbrain raphe 5-HT(1A) autoreceptors that control the activity of ascending 5-HT-mediated pathways. However, the partial agonist properties of pindolol at 5-HT(1A) receptors and beta-adrenoceptors suggest that other explanations for its action are also possible. In this article, recent controversial data on the mechanism of action of pindolol, which are crucial for the development of more rapid and efficient antidepressant therapies, will be discussed.
Topics: Adrenergic beta-Antagonists; Animals; Antidepressive Agents; Humans; Pindolol; Receptors, Serotonin; Serotonin Receptor Agonists
PubMed: 11339972
DOI: 10.1016/s0165-6147(00)01682-5 -
American Heart Journal Aug 1982The antihypertensive effect of pindolol has been demonstrated in several hundred clinical trials performed in many countries. The results of several representative... (Clinical Trial)
Clinical Trial Comparative Study Review
The antihypertensive effect of pindolol has been demonstrated in several hundred clinical trials performed in many countries. The results of several representative trials will be reviewed in this article. In a cooperative study of pindolol by Swiss internists, blood pressure (BP) normalization was achieved in 76% of the patients and a fair response in 9%. In a French trial, BP reduction was found to correlate with the initial pressure level. Pindolol was also found effective in treating renal hypertension (Germany) and was considered particularly useful in hypertensive patients with coexistent angina pectoris (South Africa). A favorable effect on the BP profile registered during the whole day was demonstrated by means of BP telemetry (Germany). A Swedish long-term study showed pindolol to have a sustained antihypertensive effect over 16 months associated with a progressive decrease in systemic vascular resistance. In a study conducted in New Zealand, pindolol compared favorably with drugs previously used for hypertension, (methyldopa, diuretics, rauwolfia, guanethidine, etc.). It proved slightly less effective than methyldopa in a Canadian trial but significantly more effective than this drug in a South African study. Danish investigators found pindolol equivalent to chlorthalidone in lowering the resting BP but more effective than the diuretic in reducing the pressure and pulse response to exercise. Of particular interest are comparisons of pindolol with other beta-blockers performed in Germany, Sweden, Australia, and New Zealand. BP reductions obtained with pindolol did not differ significantly from those obtained with the other beta-blockers, whether they were cardioselective (metoprolol, atenolol) or not (propranolol, timolol, nadolol); however, pindolol produced less slowing of resting heart rate than these five other drugs, which are devoid of intrinsic sympathomimetic activity (ISA). Pindolol proved somewhat more effective than other nonselective beta-blockers with ISA (i.e., oxprenolol), although both produced less bradycardia than propranolol (New Zealand). In resistant cases, the combination of pindolol with diuretics, methyldopa, or hydralazine was found to significantly increase the responder rate.
Topics: Adrenergic beta-Antagonists; Adult; Aged; Antihypertensive Agents; Clinical Trials as Topic; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Pindolol
PubMed: 6125096
DOI: 10.1016/0002-8703(82)90129-6 -
American Heart Journal Aug 1982
Clinical Trial Comparative Study Review
Topics: Adult; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Pindolol; Pulse; Random Allocation
PubMed: 7048877
DOI: 10.1016/0002-8703(82)90128-4