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the sorts Share 4 +1 1 Pin 1 Stumble Reddit Shares 6 Pindolol is a beta blocker initially synthesized by the pharmaceutical company Sandoz in the 1960s. As of 1977 it received FDA approval for the management of hypertension and was sold under the brand name Visken. Pharmacologically, pindolol acts as a non-selective beta blocker, meaning it competitively binds to all 3 beta-adrenergic receptor sites (Beta-1, Beta-2, Beta-3) as an antagonist, thereby buffering receptor activation induced by endogenous catecholamines and stress hormones (e.g. epinephrine and norepinephrine). The inhibition of beta-adrenergic receptor site activation prevents [catecholamine-induced] upregulation in sympathetic nervous system tone, as well as corresponding constriction of blood vessels implicated in hypertension. Upon administration of standard doses of pindolol, parasympathetic nervous system is thought to remain dominant, allowing for vasodilation of blood vessels and reduced blood pressure. Based on these peripheral effects, pindolol is sometimes administered for the treatment of conditions such as angina pectoris, arrhythmias, and acute stress reactions. Interestingly, pindolol is also utilized as an antidepressant adjunct among individuals who fail to derive sufficient relief from conventional antidepressant monotherapies. Its mood enhancing properties may be related to its ability to antagonize 5-HT1A autoreceptors for increased serotonin signaling. Moreover, pindolol scavenges nitric oxide and reduces sympathetic outflow, each of which may contribute to its therapeutic antidepressant effect. How Pindolol May Treat Depression (Mechanisms of Action) There are numerous mechanisms by which pindolol may alter neurobiology and physiology to treat major depression. Arguably the most relevant mechanism by which pindolol may treat symptoms of depression is via its antagonism of the 5-HT1A autoreceptors. The effect of pindolol upon 5-HT1A autoreceptors is understood to facilitate the release of serotonin into the extracellular space, thereby stimulating the postsynaptic neuron to improve mood. When combined with an SSRI , it is the 5-HT1A autoreceptor antagonism of pindolol that is responsible for accelerating (and possibly potentiating) onset of antidepressant effects. Although pindolol-induced modulation of the 5-HT1A autoreceptor likely accounts for a majority of its antidepressant effect, other mechanisms may play a smaller role. Other proposed mechanisms by which pindolol may treat depression include: reducing sympathetic activation and scavenging nitric oxide. 5-HT1A autoreceptor antagonism : Experts suspect that the therapeutic antidepressant properties of pindolol are associated with its antagonism of 5-HT1A autoreceptors in the stomatodendritic region of the serotonergic neuron. Antagonizing 5-HT1A autoreceptors leads to desensitization, and thereafter, downregulation of 5-HT1A autoreceptors. Downregulation in 5-HT1A autoreceptors is understood to disinhibit the serotonergic neuron, resulting in an increased neuronal firing rate. The expedited firing rate of the serotonergic neuron leads to a greater amount of serotonin being released from the serotonergic neuron into the synaptic cleft. Intrasynaptic elevations in serotonin ultimately generate increased stimulation of postsynaptic serotonin receptors. Continuous stimulation of postsynaptic serotonin receptors results in desensitization and downregulation of these postsynaptic receptor sites. Once the postsynaptic receptor sites are adequately desensitized and downregulated, a person s depression lifts. Among a subset of individuals with depression, it is theorized that low serotonin in the synaptic cleft leads to hypersensitivity of the postsynaptic receptor sites. Administration of pindolol would could effectively reverse postsynaptic hypersensitivity by promoting greater release of serotonin into the synaptic cleft. More serotonin in the synaptic cleft increases the amount of postsynaptic stimulation. When combined with an SSRI [which blocks presynaptic reuptake], the postsynaptic stimulation should be even more substantial. This should explain why some individuals report faster onset of SSRI action, as well as a bolstered antidepressant effect as a result of pindolol. Beta-adrenergic antagonism : Although pindolol s beta-adrenergic receptor antagonism facilitates peripheral vasodilation [making it highly useful in reducing blood pressure], beta-adrenergic antagonism may also account for some of its antidepressant effect. Though not all individuals with depression will experience mood improvement from the beta-adrenergic receptor antagonism elicited by pindolol, a subset of individuals may benefit from this exact mechanism. The benefits to be attained from pindolol s beta-adrenergic receptor antagonism may be most significant among depressed individuals in which peripheral catecholamine concentrations are elevated. Elevated peripheral catecholamine concentrations is associated with agonism of peripheral beta-adrenergic receptors, possibly leading to chronic overactivation of the sympathetic nervous system. Chronic activation of the sympathetic nervous system generates an uncomfortable state in which an individual may experience depression, as well as severe anxiety. The anxious feelings may lead to avoidance of socialization and/or isolation, which in turn may exacerbate the underlying depression. Additionally, overactivation of the sympathetic nervous system may lead to: further production of catecholamines, alterations in hormone secretion, and modifications in bidirectional signaling between the peripheral nervous system and the brain sustaining a person s depression. Research by Moleman et al. (1992) reports that epinephrine and norepinephrine are hypersecreted in depressed patients. A study by Potter and Manji (1994) documented elevated norepinephrine excretion among melancholic depressives than non-depressed controls. Another report by Lechin, Van der Dijs, and Benaim (1996) suggests that individuals with depression exhibit abnormalities in peripheral catecholamines, NA/Ad ratio, and cortisol. Since pindolol competes with catecholamines for beta-adrenergic receptor binding and acts as an antagonist, it interferes with perpetuation of sympathetic overactivity. This should decrease upregulate parasympathetic function, thereby reversing sympathetic-induced neurobiological and physiological abnormalities implicated in depression. Source: http://www.ncbi.nlm.nih.gov/pubmed/1627048 Source: http://www.ncbi.nlm.nih.gov/pubmed/8313609 Source: http://www.ncbi.nlm.nih.gov/pubmed/8888102 Reactive nitrogen species modulation : Research suggests that pindolol is capable of modulating concentrations of reactive nitrogen species (RNS). A study by Fernandes et al. (2005) discovered that pindolol is a potent scavenger of reactive nitrogen species in animal models. Specifically, administration of pindolol efficiently scavenges: nitric oxide (NO), peroxynitrite (ONOO-), nitrogen dioxide radical (NO2), and carbonate radical anion (CO3-). Researchers speculate that the scavenging of reactive nitrogen species may be a critical mechanism by which pindolol decreases latency and/or potentiates efficacy of SSRI antidepressants. Evidence suggests that modulation of reactive nitrogen species such as by inhibiting nitric oxide synthesis, results in anxiolytic and antidepressant effects. Chronically high levels of reactive nitrogen species (RNS) may deleteriously affect central nervous system function, contributing to depression. A report by Lee et al. (2013) outlines the therapeutic potential of reducing reactive nitrogen species (RNS) and reactive oxygen species (ROS) among those with depression. In this report, it was hypothesized that elevated RNS and ROS may wreak havoc upon lipids, proteins, mitochondria, and neurons within the brain to cause and/or exacerbate depression. Specifically, both RNS and ROS may induce micro-alteration, micro-dysfunction, and degeneration of neurons. Since a subset of those with depression likely exhibit abnormally high concentrations of RNS, the RNS-scavenging properties of pindolol may facilitate an antidepressant effect. Assuming pindolol scavenges RNS (reactive nitrogen species) to a sufficient extent, this may reverse RNS-induced neuronal dysfunction for mood enhancement. Though pindolol-induced modulation of reactive nitrogen species warrants further investigation in humans, it may be an overlooked mechanism by which the drug treats depression. Source: http://www.ncbi.nlm.nih.gov/pubmed/15916777 Source: http://www.ncbi.nlm.nih.gov/pubmed/23022673 Benefits of Pindolol for Depression (Possibilities) Perhaps the most significant benefit associated with using pindolol for the treatment of depression is its ability to expedite therapeutic to first-line antidepressants [when used as an adjunct]. Other advantages associated with using pindolol include its: low cost, lack of side effects and favorable tolerability, as well as ability to target comorbidities such as hypertension and/or anxiety. Moreover, in a subset of patients, pindolol may potentiate the therapeutic effect of conventional antidepressants and could be effective as a monotherapy. Acceleration of antidepressant action : Individuals with major depression are typically prescribed antidepressants such as SSRIs or SNRIs to improve mood. These drugs function primarily by inhibiting the reuptake of serotonin to increase extracellular concentrations. That said, one complaint issued by patients is that antidepressants take too long to work or fully kick-in. This is because the 5-HT1A autoreceptors in the stomatodendritic region haven t been desensitized. Administration of adjunctive pindolol rapidly desensitizes 5-HT1A autoreceptors to accelerate the onset of antidepressant action. Rather than waiting between 4 and 8 weeks for antidepressants to take effect, users may only need to wait around 2 weeks. Adjunctive option : Some psychiatrists will prescribe pindolol as an adjunct to an SSRI or SNRI due to the fact that it is not contraindicated nor does it cause interaction effects. Studies show that adjunctive administration of pindolol is as well tolerated as a placebo indicating that it doesn t exacerbate side effects. Additionally, pindolol is useful as an adjunct in that it dramatically accelerates the onset of SSRI action, and in some cases, amplifies SSRI efficacy. Anxiety reduction : Many individuals with depression suffer from comorbid anxiety. In fact, the occurrence of comorbid anxiety may exacerbate depressive symptoms by causing functional impairment at school, work, and/or in relationships. As a nonselective beta blocker, pindolol is able to block beta-adrenergic receptors to prevent catecholaminergic agonism and the corresponding upregulation in sympathetic tone. Decreased sympathetic tone should significantly reduce physical symptoms of anxiety similar to other beta blockers. Additionally, psychological anxiety may be reduced via 5-HT1A autoreceptor antagonism and/or scavenging of reactive nitrogen species. The overall anxiety reduction may indirectly improve a person s mood or neuropsychiatric functioning. Moreover, many individuals have success using beta blockers for anxiety as off-label therapies. Cost : Most patients would consider the cost of pindolol to be reasonable, making it favorable to other more expensive antidepressant adjuncts. The reason pindolol is sold for a low price is a result of its generic availability the patent for Visken has long expired. A total of 60 pindolol pills can be attained for between $23 and $40 (depending on the pharmacy that you use). At the cheapest this equates to around $0.38 per pill, and at the most expensive, this equates to around $0.66 per pill. By most standards, pindolol is an affordable drug. Effective : Most well designed studies using proper doses of pindolol (7.5 mg to 10 mg) have demonstrated its efficacy as an antidepressant adjunct. The 5-HT1A autoreceptor antagonism exerted by pindolol is able to accelerate antidepressant onset of action, and possibly even potentiate antidepressant efficacy. Furthermore, although it hasn t been investigated as a standalone agent in the treatment of depression, there s a possibility that it may be effective as a monotherapy. It is possible that increased release of serotonin from the serotonergic neuron as a result of pindolol-induced disinhibition (via 5-HT1A antagonism) would be enough to improve mood especially in mild cases of depression. Few side effects : Individuals taking pindolol under medical supervision as an adjunct treatment for depression aren t likely to notice significant unwanted side effects. Studies show that when pindolol is administered along with a serotonergic antidepressant, it is as well tolerated as a placebo. In other words, there are no substantial differences in side effects among those who receive pindolol compared to a placebo adjunct. Other than side effects associated with reductions in blood pressure, pindolol is favorably well-tolerated. Medical conditions : In addition to the usefulness of pindolol as an antidepressant [adjunct], it may treat comorbid medical conditions such as hypertension, angina pectoris, arrhythmias, and prophylaxis of acute stress reactions. Evidence suggests that uncontrolled hypertension is common among patients with depression, and other studies have found links between angina pectoris and depression, as well as arrhythmias and depression. Based on these findings, pindolol may be useful in that it is able to treat depression plus comorbidities. Potentiation of antidepressant effect : Studies suggest that pindolol potentiates the effect of antidepressants, especially over the short-term. The short-term potentiation of antidepressant effect is largely a result of its antagonism at 5-HT1A autoreceptors, allowing for greater release of serotonin [from the disinhibited serotonergic neuron] into the synaptic cleft. Most speculate that after 4 to 8 weeks of using a conventional antidepressant, similar effects are observed rendering pindolol somewhat useless over a long-term. However, it may continue to potentiate antidepressant effect over a longer-term through alternative mechanisms such as scavenging of reactive nitrogen species (RNS) and/or minimizing sympathetic nervous system (SNS) activation. Premature ejaculation : There s some evidence suggesting that pindolol can potentiate the efficacy of an SSRI for the treatment of premature ejaculation. Adjunctive administration of pindolol along with an SSRI significantly increases latency of ejaculation, especially among those who insufficiently respond to SSRI monotherapy. Those treating depression and premature ejaculation simultaneously may find pindolol useful in that it is likely to improve both conditions. Drawbacks of Pindolol for Depression (Possibilities) Despite the possible benefits to be attained from using pindolol in the treatment of depression, possible drawbacks warrant discussion. Arguably the most prominent drawback associated with using pindolol for the treatment of depression is that it may be totally ineffective. Other drawbacks include: contraindications, interactions, and/or individual intolerability. Moreover, it isn t known as to whether long-term adjunctive pindolol administration is safe, nor if whether upon discontinuation, severe withdrawal symptoms will occur. Adverse reactions : As a beta-adrenergic receptor antagonist, pindolol is capable of lowering blood pressure. Reduced blood pressure may benefit someone with hypertension, but could be problematic for those with normative and/or slightly-below-normal blood pressure. Administration of pindolol to those without preexisting hypertension may cause hypotension and adverse reactions including cardiac abnormalities and fainting. Other adverse reactions that have been reported among pindolol users include: shortness-of-breath, swelling of ankles/feet, fever, and depression. Contraindications : Pindolol is contraindicated among those with numerous health conditions due to the fact that it may exacerbate associated symptoms. Examples of such conditions in which pindolol is contraindicated include: myasthenia gravis, cardiac blockages, sinus bradycardia, kidney disease, diabetes, bronchospasm, liver disease, and more. These contraindications may interfere with a person s ability to safely use pindolol as an antidepressant adjunct. Interactions : Assuming you re taking pindolol under medical supervision, likelihood of unnecessary interaction effects can be minimized. Nonetheless, interactions could occur if you use any other substances (e.g. alcohol, drugs, supplements) along with pindolol. Examples of such drugs that may interact with pindolol include: alcohol, asthma medication, cold medicine, diet pills, digoxin, heart medications, insulin, thioridazine, and psychostimulants. Interaction effects may be serious and could lead to death. Long-term effects : It is possible that taking a non-selective beta blocker every day to help manage depression (or even hypertension) may take a toll on your brain and/or body over the long-term. At this time, it is unknown as to whether any deleterious long-term effects resulting from pindolol usage may occur. Some speculate that long-term usage of beta blockers may increase your risk for future cardiac abnormalities. Short-term : Though pindolol may be effective for enhancing the efficacy of antidepressants over a short-term, enhancement of efficacy may be unsustainable over the long-term. This is likely due to the fact that after 4 to 8 weeks of administering a serotonergic antidepressant, the 5-HT1A autoreceptor downregulation induced by pindolol is no longer required for therapeutic benefit. Within 8 weeks of administration, serotonergic antidepressants will have modified 5-HT1A autoreceptors on their own to disinhibit serotonergic neurons. This suggests that pindolol may only be useful for up to 8 weeks. Side effects : Even if you aren t at risk for serious adverse effects or contraindications, pindolol may provoke unwanted side effects. Common side effects of pindolol include: cold sensations, dizziness, fatigue, heartburn, lightheadedness, muscle pain, sleep disturbances, and tiredness. Pindolol can also cause brain fog (cloudy thinking), cognitive deficits, and/or drowsiness each of which could affect your ability to operate a motor vehicle or perform in academic or occupational settings. Superior options : Although pindolol is an effective for accelerating responses to antidepressant treatment, there may be superior alternatives. Utilizing a different 5-HT1A autoreceptor antagonist may be safer and/or more efficacious for some individuals than pindolol. Pindolol exerts a potent effect upon beta-adrenergic receptors which may be unnecessary and/or unfavorable for certain subtypes of depression. By using a standalone 5-HT1A autoreceptor antagonist without peripheral beta blocking action, side effects may be reduced and tolerability may improve. Tolerance : Long-term beta blockade with pindolol may increase your reliance on the drug and could lead to onset of physiological and/or neurobiological tolerance. As tolerance occurs, you may need to increase your pindolol dosage to derive the same initial therapeutic effects that were attained in the early stages of treatment. That said, increasing your pindolol dosage may increase likelihood of adverse reactions and/or unwanted side effects. Some individuals will need to discontinue pindolol as a result of tolerance, however, discontinuation may be associated with unwanted withdrawal symptoms. Treatment-resistant depression : Among those diagnosed with treatment-resistant depression and/or individuals that already have tried at least one serotonergic antidepressant for up to 8 weeks without symptomatic improvement, pindolol may be less useful. There s evidence to suggest that pindolol is highly effective in patients naïve to antidepressant therapy, but relatively useless among those with treatment-resistant depression. Individuals with treatment-resistant depression may not respond to pindolol due to the fact that serotonergic abnormalities are not implicated in their particular neurochemical depressive footprint. Unnecessary : Using pindolol as an antidepressant adjunct may be entirely unnecessary, especially for those that respond quickly to conventional antidepressants. A subset of users report that antidepressants work immediately , which is due to the fact that serotonergic reuptake is inhibited on the first day of administration. Among quick responders, additional 5-HT1A autoreceptor antagonism to facilitate additional release of intrasynaptic serotonin may be unnecessary. Pindolol may also be unnecessary among those that have recently taken an SSRI for over 4 weeks, largely due to the fact that using SSRIs for over a month will have desensitized 5-HT1A autoreceptors; it is unlikely that additional benefit will be attained from pindolol. Unproven : Some may argue that the efficacy of pindolol as an accelerator and/or potentiator of antidepressant effect isn t well-established in medical literature. Due to its lack of established efficacy in large-scale, randomized controlled trials a subset of professionals may recommend avoiding pindolol as an adjunct. Furthermore, pindolol monotherapy for the treatment of depression hasn t undergone any randomized controlled evaluation. For this reason, it remains unclear as to whether standalone pindolol may effectively treat depression. Withdrawal symptoms : A subset of individuals taking pindolol as an antidepressant adjunct report that it eventually stops working and/or becomes intolerable as a result of side effects. If you re no longer deriving any therapeutic effect from pindolol or struggling with unwanted side effects you may end up discontinuing treatment. Upon cessation of pindolol, you may experience severe withdrawal symptoms. Examples of possible pindolol withdrawal symptoms include: heart rate increases, headache, hypertension, palpitations, and tremor. Withdrawal symptoms may last several weeks [or longer] and interfere with your quality of life. Pindolol for Depression (Review of Evidence) Studies published in the early 1990s were among the first to suggest that pindolol may be efficacious as an antidepressant adjunct. Research of pindolol as an adjuvant intervention to antidepressants has continued from the 1990s throughout the 2000s and 2010s, with some evidence indicating that it serves as an effective mood enhancer. That said, other research suggests that pindolol may be ineffective as an antidepressant adjunct. The efficacy of pindolol as an antidepressant adjunct be contingent upon the dosage administered, as well as the individual receiving it. Investigators highlight the fact that some studies in which pindolol is tested as an SSRI adjunct may have administered suboptimal pindolol doses. At too low of a pindolol dose, the 5-HT1A autoreceptor isn t bound sufficiently as to yield a mood enhancing effect. Additionally, like any antidepressant adjunct, not everyone receiving pindolol will respond favorably to its administration. Although adjunctive pindolol administration appears as safe and tolerable as standalone SSRIs, its efficacy may be less among those with non-serotonergic neurobiological depressive subtypes. Moreover, there doesn t appear to be any research in which pindolol is tested as a standalone monotherapy for the treatment of depression. 2015 : Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis. Researchers Liu et al. (2015) conducted a systematic review and meta-analysis to determine the efficacy of pindolol as an antidepressant augmentation strategy specifically among populations for whom SSRIs were therapeutically ineffective. For the systematic review, researchers scoured databases such as PubMed, Cochrane, Embase, and others and compiled data published between 1970 and 2013. To be included in their review, trials were required to implement a randomized controlled design while examining the effect of pindolol on adults with SSRI-resistant depression. The primary outcome taken into consideration was change in scores on depression rating scales from baseline to post-treatment. A total of 5 randomized controlled trials with 154 participants met inclusion criteria. Pooling the effect size revealed that administration of pindolol as an SSRI adjunct failed to significantly improve mood. That said, addition of pindolol to SSRI therapy had no effect on tolerability nor safety, suggesting that the combination is likely safe and tolerable. Furthermore, a subset of evidence suggested that administration of a single high-dose of pindolol (7.5 mg) was efficacious as an adjuvant intervention to an SSRI for mood enhancement. Researchers concluded that while standard-dose pindolol appears ineffective as an adjuvant among non-responders to SSRIs, high-dose pindolol may be useful. It is unclear as to why higher doses of pindolol may be therapeutically helpful among non-responders to SSRIs, but it may be related to pindolol s altered pharmacodynamics at elevated doses. A high single dose of pindolol is understood to exert a sympathomimetic effect similar to epinephrine, somewhat in opposition to its effect at lower doses. It is reasonable to hypothesize that individuals who are unresponsive to SSRIs may require enhancement of catecholaminergic [rather than serotonergic] signaling, and the high dose of pindolol yields this effect. Source: http://www.ncbi.nlm.nih.gov/pubmed/25689398 2011 : 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. A study conducted by Portella et al. (2011) sought to determine whether it was possible to accelerate and enhance the antidepressant effect of SSRIs with administration of pindolol. Prior to the study, authors discussed the fact that major depression is a burden upon the healthcare system as well as economy. A big problem associated with treating depression is that conventional FDA-approved antidepressants often require treatment for 4 to 8 weeks before they actually improve mood. In other words, there s significant lag time between when a patient initiates antidepressant treatment and when the therapeutic effect fully kicks in. Another problem associated with antidepressant treatment is that even if a patient waits a couple of months in hopes that an antidepressant will uplift mood, the drug is not guaranteed to be effective or tolerable. Researchers noted evidence suggesting that speed and efficacy of conventional antidepressants may be bolstered with adjunct administration of pindolol, a nonselective beta blocker. For this reason, researchers organized a randomized controlled trial incorporating 30 outpatients diagnosed with major depression (in accordance with DSM-IV criteria). The 30 outpatients were assigned to receive citalopram plus pindolol (5 mg, t.i.d.) OR citalopram plus a placebo for 6 weeks. In addition to the aforestated randomized controlled trial, researchers conducted a meta-analysis of randomized controlled trials (RCTs) documenting the efficacy of pindolol as an adjunct among those with refractory depression. In the randomized controlled trial, the efficacy of pindolol as an adjunct was determined based on changes in scores on the 17-item Hamilton Depression Rating Scale (HDRS) from baseline through 6 weeks. In the meta-analysis, the effectiveness of pindolol was evaluated based on the number of responders after 2 weeks, as well as 4 to 6 weeks. Results from the randomized controlled trial documented significantly quicker onset of antidepressant effect and greater likelihood of remission among those that received pindolol as an adjunct compared to the placebo. On average, those that received pindolol responded to treatment within ~22 days, whereas the non-pindolol responded within ~30 days. Results from the meta-analysis suggested that treatment with pindolol yielded superior antidepressant efficacy after 2 weeks and 4-6 weeks compared to a placebo. It was concluded that pindolol expedites the onset of SSRIs antidepressant effect and provides more substantial symptomatic relief from depressive symptoms among individuals with resistant-depression. Source: http://www.ncbi.nlm.nih.gov/pubmed/21034693 2010 : Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review. A systematic review was conducted by Whale et al. (2010) to gauge the antidepressant efficacy of pindolol as an adjuvant to SSRIs. Prior to this review, preliminary evidence suggested that addition of pindolol to selective serotonin reuptake inhibitors appeared to expedite onset of antidepressant action and potentiate antidepressant efficacy. Evidence for this review was compiled from Cochrane Collaboration Depression and Anxiety and Neurosis-Controlled Trials Register. Inclusion criteria for this review consisted of randomized controlled trials that compared the efficacy SSRIs plus pindolol to that of SSRIs plus a placebo. The goal was to determine whether pindolol augmentation enhanced SSRI efficacy over a 6-week span among adults diagnosed with major depression. A total of 11 studies met inclusion criteria for the review and data was pooled. Results suggested that individuals taking SSRIs plus pindolol responded quicker to treatment than those taking SSRIs plus a placebo. There were no differences in discontinuation rates between each group, suggesting that pindolol was well-tolerated. Authors concluded that using pindolol as an antidepressant adjunct is of therapeutic benefit. Source: http://www.ncbi.nlm.nih.gov/pubmed/18832428 2005 : Pindolol augmentation of selective serotonin reuptake inhibitors: accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression. Segrave and Nathan (2005) discussed the fact that administration of pindolol with SSRIs is said to accelerate and enhance antidepressant responses. Despite the fact that the combination of SSRIs plus pindolol have been tested in clinical trials for the treatment of depression, results are conflicting. Some data suggests that the combination of an SSRI plus pindolol is effective, while other data suggests no additional benefit is attained from adjunctive administration of pindolol. Authors of this report highlight some variables that may help explain why data has been conflicted. One reason as to why data is conflicted is related to the fact that only a subset of patients with depression respond well to pindolol, whereas others derive no benefit. This is likely due to the fact that pindolol responders exhibit dissimilar neurochemistry from non-responders. Those who respond well may benefit from its 5-HT1A antagonism which increases serotonin signaling. Researchers also speculate that individual differences in neurophysiology and genotype may be responsible for mixed data. Furthermore, it is possible that methodological differences such as: measures of antidepressant response and timing of pindolol administration could account for some of the contradictory results. Even the dosing of pindolol may have been problematic in much of the research in that a suboptimal quantity was administered. A subset of pindolol trials for depression involved administration of 2.5 mg (t.i.d.). What s problematic is that neuroimaging scans reveal that 5-HT1A autoreceptors remain unoccupied at doses of 2.5 mg (t.i.d.). Since the majority of pindolol s antidepressant effect is derived from its occupancy of 5-HT1A autoreceptors as an antagonist, lack of 5-HT1A binding as a result of suboptimal dosing is likely a significant reason as to why some studies documented no benefit of pindolol as an antidepressant adjunct. Further research should investigate the effects of larger pindolol doses in randomized controlled trials. In theory, larger doses should sufficiently occupy 5-HT1A autoreceptors to enhance serotonin signaling and improve mood. Source: http://www.ncbi.nlm.nih.gov/pubmed/15648095 2004 : Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. A meta-analysis con of one


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