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Pindolol For Depression: A Useful Antidepressant Adjunct?

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 conducted by Ballesteros and Callado (2004) assessed randomized controlled trials in which pindolol plus SSRIs was compared to a placebo plus SSRIs for the treatment of major depression.  The impetus for this meta-analysis was based on the fact that trials of pindolol plus SSRIs have been conducted, but results were conflicting.  In other words, some trials documented significant benefit of the combination compared to standalone SSRI monotherapy, whereas others found no advantages of the combined treatment approach.

Researchers were able to find 9 randomized controlled trials (RCTs) that met inclusion criteria for their meta-analysis.  Results suggested that the antidepressant efficacy of the pindolol plus SSRI was significantly greater than a standalone SSRI after 2 weeks’ time.  Despite the enhanced efficacy after 2 weeks of treatment, there were no differences in efficacy between the combination therapy (pindolol plus SSRI) and the monotherapy (standalone SSRI) after 4-6 weeks.

In conclusion, the addition of pindolol to an SSRI expedited onset of antidepressant response.  Rather than patients waiting 4 to 6 weeks to attain symptomatic relief with a standalone monotherapy, pindolol appears to reduce the time to onset of antidepressant effect – by approximately half.  Those that are unable to wait 4 to 6 weeks for relief from depressive symptoms would likely benefit from augmenting their SSRI with pindolol.

It should be hypothesized that pindolol may serve as nothing more than an expediter of antidepressant effect.  After 6 weeks of treatment, the antidepressant effect of an SSRI doesn’t appear to be enhanced by pindolol.  Perhaps pindolol could be used as a short-term agent to expedite onset of antidepressant action and discontinued after 6-weeks of treatment.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15023488

2004: Once-daily high-dose pindolol for SSRI-refractory depression.

Researchers Sokolski et al. (2004) acknowledge that pindolol, a 5-HT1A antagonist, may be useful in augmenting SSRIs for the treatment of depression.  Data from neuroimaging studies involving PET scans indicate that, in order to sufficiently block 5-HT1A autoreceptors and enhance mood, large doses of pindolol would need to be administered.  Since many trials involved administering small doses of pindolol as an adjunct, and discovered it to be ineffective, it may be that the small dose was to blame.

It was speculated that a single high dose of pindolol would be capable of occupying 5-HT1A autoreceptors and augmenting antidepressant efficacy among individuals with refractory depression.  Sokoloski et al. tested this hypothesis on 9 individuals with major depression that were previously resistant to SSRI monotherapy.  A total of 4 participants were randomly assigned to receive pindolol (7.5 mg), whereas the remaining 5 participants received a placebo – as an adjunct to paroxetine.

To track the therapeutic efficacy of adjunctive pindolol (7.5 mg), neuropsychiatric scales such as the: Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), Bech-Rafaelsen Melancholia Scale, and Zung Depression Inventory – were administered at baseline, as well as after Week 1, Week 2, Week 3, and Week 4.  Results indicated that adjunctive pindolol significantly improved scores on all rating scales after Week 2 compared to the placebo control.  These statistically significant improvements in neuropsychiatric scores were maintained throughout Week 4.

Based on these results, it seems as though larger single doses of 7.5 mg pindolol are more effective in accelerating SSRI antidepressant onset than a placebo.  Furthermore, it appears as though a single large dose of pindolol is more efficacious than smaller divided doses (e.g. 2.5 mg, t.i.d.).  Since this was a small trial with just 9 participants, it is necessary to conduct a larger-scale follow-up to confirm preliminary findings.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15006431

2004: Preferential 5-HT1A autoreceptor occupancy by pindolol is attenuated in depressed patients: effect of treatment or an endophenotype of depression?

A study by Rabiner et al. (2004) utilized PET scan (positron emission tomography) neuroimaging to investigate the effect of pindolol on 5-HT1A autoreceptors among those with major depression.  In healthy volunteers, researchers discovered that the 5-HT1A receptor radioligand [11C]WAY100635 exhibits preferential occupancy of the 5-HT1A autoreceptors whereas pindolol occupies postsynaptic receptor sites.  It was hypothesized that preferential receptor occupancy may be relevant in acceleration of SSRI effect onset with adjunct pindolol.

To elucidate how pindolol bound to receptor sites to expedite onset of antidepressant effect, researchers devised 3 protocols of pindolol administration including: 10 mg (single dose), 2.5 mg (t.i.d.), and 5 mg (t.i.d.).  A total of 15 individuals taking SSRIs for major depression were assigned to one of the 3 protocols and analyzed via neuroimaging.  The neuroimaging data collected from the 15 participants with depression was compared to neuroimaging data from 7 healthy volunteers after taking a single 10 mg dose of pindolol.

It was discovered that a single 10 mg dose of pindolol in healthy volunteers occupied ~22.6% of the 5-HT1A autoreceptor compared to ~2.9% among those with depression.  Unexpectedly, researchers discovered a substantial negative correlation between extent of preferential 5-HT1A occupancy and severity of depression as measured by the HAM-D (Hamilton Depression Rating Score).  Researchers believe that alterations in 5-HT1A sites within midbrain raphe autoreceptor areas may: be a biomarker of depression, result from SSRI treatment, or a combination of both.

Accounting for these findings, it is logical to suspect that pindolol could accelerate onset of antidepressant effect among naïve patients, but is less likely to bolster antidepressant efficacy.  In short, 5-HT1A autoreceptors will be affected by pindolol upon commencement of treatment to facilitate a quicker antidepressant response.  However, among those that have been using an SSRI for awhile, 5-HT1A autoreceptor alterations will have occurred [from the SSRI].

The effect of pindolol, even at high doses (e.g. 10 mg) will no longer preferentially occupy the 5-HT1A autoreceptors.  For this reason, we would not expect any additional mood enhancement to be derived from the pindolol among someone that’s taken SSRIs for several months.  In summary, pindolol is likely useful to accelerate the onset of antidepressants and is speculated to be most therapeutic among those with less severe cases of depression (as measured by preferential 5-HT1A autoreceptor occupancy).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15127080

2004: Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial.

Perry et al. (2004) noted that studies assessing the efficacy of pindolol as an adjunct in the treatment of depression have yielded inconsistent data.  For this reason, researchers organized a double-blind, randomized, controlled 6-week trial of pindolol administration as an adjunct to SSRIs among depressed outpatients.  A total of 42 outpatients were recruited to participate in the trial, all of whom failed to derive sufficient therapeutic benefit from SSRI monotherapy.

The participants were assigned to receive an SSRI along with either: pindolol (2.5 mg, t.i.d.) OR a placebo.  Additionally, the individuals initially assigned to receive the placebo were transitioned to pindolol (2.5 mg, t.i.d.) from Week 4 to Week 6 of the trial – and the active group continued receiving pindolol.  To determine efficacy of the pindolol as an adjunct, researchers recorded changes in scores on the Hamilton Rating Scale for Depression (HAM-D) from baseline to Week 3.

Results suggested that after 3 weeks of treatment, response rates to the pindolol plus SSRI were comparable to those of the SSRI monotherapy.  This randomized controlled trial suggests that pindolol provides no significant benefit as an SSRI adjunct.  That said, it is possible that the dosing of pindolol at 2.5 mg (t.i.d.) was problematic in that this dosing quantity fails to sufficiently occupy 5-HT1A autoreceptor sites.  Larger single doses (e.g. 10 mg) of pindolol may have produced different results.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15003079

2003: Interest of the use of pindolol in the treatment of depression: review.

French researchers Brousse et al. (2003) conducted a review in which the usage of pindolol as an adjunct intervention for depression was evaluated.  They note that pindolol has been tested as a potential accelerator of antidepressant onset, as well as a potentiator of antidepressant effect – likely by antagonizing somatodendritic presynaptic 5-HT1A receptors.  The team of researchers discovered 12 controlled studies, as well as 6 open label studies that had documented the adjunctive antidepressant effect of pindolol.

The first open-label pilot study discovered that pindolol not only expedited response to antidepressants, but it bolstered its efficacy.  Thereafter, a total of 5 additional open-label studies were carried out and similarly reported that pindolol accelerates onset of serotonergic antidepressant activity.  That said, in the 5 follow-up trials, there was no data to suggest that pindolol enhanced antidepressant efficacy, especially among those with resistant forms of depression.

In the 12 controlled trials: 4 investigated how pindolol affects both onset and efficacy of SSRIs; 3 investigated solely how pindolol affects onset of SSRI activity; 3 investigated solely how pindolol affects SSRI efficacy; 1 documented the efficacy of pindolol as an adjunct to sleep deprivation for the treatment of depression; and 1 assessed how pindolol affects onset of ECT (electroconvulsive therapy) action – among depressed individuals.  A total of 6 studies were comprised of patients diagnosed with treatment-resistant depression.

Findings indicate that just 1 study suggests that pindolol accelerates antidepressant activity and another 1 study suggests that pindolol enhances antidepressant efficacy.  An additional 2 trials concluded that pindolol may hasten onset of antidepressant action and boost efficacy.  Oppositely, 3 trials found no significant effect associated with administration of pindolol as an adjunct.

Researchers note that that pindolol’s antidepressant effect is unlikely associated with its beta-adrenergic antagonism due to the fact depressive symptoms improved from pindolol plus the SSRI, whereas anxiety levels remained the same.  It was also noted that high doses of pindolol may be more beneficial compared to low doses as a result of greater 5-HT1A receptor occupancy.  Moreover, was associated with favorable tolerability and few unwanted adverse effects.

Variation in results of controlled studies were discussed by researchers and may have been a result of criterion of “resistant depression” used in each trial, as well as the finding that individuals with a long history of depression tend to respond poorly to SSRIs with pindolol.  By agreeing on simple criteria for “resistant depression” and studying pindolol as an adjunct among naïve depressives, therapeutic outcomes of SSRIs plus pindolol may differ.  At one point, researchers noted that pindolol may be worth investigating as an alternative treatment for all conditions in which SSRIs are primarily used.

It was also recommended to investigate how genetic variants associated with the 5-HT transporter gene may influence responsiveness to pindolol and serotonergic antidepressants.  Based on this extensive analysis of the data, researchers concluded that pindolol is able to accelerate and sometimes potentiate the action of antidepressants.  Although adjunctive pindolol may be less beneficial among those with long-term refractory depression, larger doses (than previously used) necessitate investigation.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/14615704

2001: Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression.

It is understood that genetic polymorphisms (variants) can affect mood, as well as individual responses to psychopharmacological treatments.  Research by Zanardi et al. (2001) highlighted that the short variant of the serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) significantly affects responsiveness to serotonergic antidepressants such as SSRIs.  They organized a study to analyze how the efficacy of various antidepressants was influenced by 5-HTTLPR expression.

A total of 150 inpatients diagnosed with either major depression or bipolar depression were recruited for the study.  A polymerase chain reaction-based technique was used to determine allelic variation in 5-HTTLPR expression in each participant.  Participants were assigned at random to receive fluvoxamine (300 mg) and either: pindolol OR a placebo – for a duration of 6 weeks.

Efficacy of the pharmacological interventions was determined based upon changes in Hamilton Rating Scale for Depression (HAM-D) scores from baseline throughout 6 weeks.  Results indicated that individuals with the short variant of 5-HTTLPR responded poorly to standalone fluvoxamine.  Interestingly, administration of adjunct pindolol appeared to enhance antidepressant responses to fluvoxamine among those with short variants of 5-HTTLPR.

Based on this finding, researchers suspect that pindolol may be an especially useful adjunct among those with short variant 5-HTTLPR expression.  They suspect that pindolol may reduce genotype-mediated suboptimal antidepressant responses, thereby improving clinical outcomes.  Follow up studies are necessary to confirm preliminary evidence suggesting that pindolol may be of greater benefit among those expressing short variants of 5-HTTLPR.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11543734

2000: Pindolol augmentation of antidepressants: a review and rationale.

Olver et al. (2000) sought to conduct a review of literature to investigate the clinical value of pindolol as an antidepressant adjunct.  Researchers attempted to elucidate ways in which the pharmacodynamics and pharmacokinetics of pindolol may yield therapeutic benefit among those with depressive disorders.  The review included studies published over a 10-year span throughout the 1990s, each of which tested the adjunctive effectiveness of pindolol for major depression.

Assessment of data revealed inconsistent findings in that some results highlighted therapeutic augmentation value associated with pindolol, whereas other results indicated zero value from augmentation of antidepressants with pindolol.  It was concluded that there may be some advantages associated with pindolol augmentation, one of which is a faster onset of action.  Nevertheless, authors emphasize further research to confirm potential therapeutic value of adjunctive pindolol, as well as to rule out potentially deleterious interactions [between pindolol and the antidepressant].

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11185947

1999: The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

In the introductory section of their publication, Berman et al. (1999) mention that concurrent administration of pindolol with SSRIs appears to significantly accelerate onset of antidepressant response.  Researchers reflect upon results from a double-blind, placebo-controlled, randomized trial in which pindolol was administered as an adjunct to fluoxetine (Prozac) for the treatment of major depression.  In the aforestated trial, individuals experiencing a major depressive episode were assigned to receive fluoxetine (20 mg/day) and either: pindolol (7.5-10 mg) OR a placebo.

Following 6 weeks of treatment, participants were assessed for an additional 3 weeks in a single-blind modality – on fluoxetine and placebo.  Researchers discovered that after 2 weeks, there were no differences in responses between the groups [based on changes in depression rating scores from baseline].  Specifically, 16% of those receiving adjunctive pindolol and 19% of those receiving a placebo adjunct – experienced significant improvements in depression.

At the end of the 6-week study term, approximately 67% of those receiving adjunctive pindolol and 80% of those receiving the adjunctive placebo – exhibited improvement in depressive symptoms.  There were no differences in onset of antidepressant action, overall efficacy, nor tolerability among the groups.  Authors concluded that these results do not support the clinical usage of adjunctive pindolol for the treatment of unremitting depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10331109

1999: Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial.

A study conducted by Smeraldi et al. (1999) aimed to determine whether sleep deprivation and pindolol would be therapeutically effective in mitigating depressive symptoms among patients diagnosed with bipolar depression.  It is understood that total sleep deprivation (TSD), defined as the deprivation of sleep for an entire night, serves as a highly effective short-term antidepressant.  Furthermore, it is thought that pindolol (a nonselective beta-blocker) is able to potentiate the antidepressant effect exerted by SSRIs through blockade of the 5-HT1A autoreceptor.

In this study, researchers evaluated the combination of total sleep deprivation plus pindolol for reversal of acute bipolar depression.  A total of 40 individuals diagnosed with bipolar depression were assigned at random to receive either: pindolol (7.5 mg/day) or a placebo for 9 days in conjunction with 3 consecutive cycles of total sleep deprivation.  It was discovered that pindolol substantially enhanced antidepressant effects of total sleep deprivation.

What’s more, administration of pindolol prevented short-term relapse into depression that can occur with standalone total sleep deprivation.  Results noted that 15 of the 20 individuals receiving pindolol as an adjunct to total sleep deprivation experienced significant reduction in depressive symptoms.  By comparison, just 3 out of the 20 individuals receiving a placebo as an adjunct to total sleep deprivation experienced significant reduction in depression.

Perhaps most intriguing is the finding that, following treatment of bipolar depression with total sleep deprivation plus pindolol, ongoing treatment with standalone of lithium salts was sufficient to sustain symptomatic remission for up to 6 months [for 65% of patients].  It was concluded that total sleep deprivation likely modulates serotonergic transmission to reverse depressive symptoms.  Moreover, while administration of pindolol may amplify therapeutic antidepressant effects of total sleep deprivation [via blocking 5-HT1A autoreceptors], it is reasonable to hypothesize that pindolol may function as an effective standalone antidepressant.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10088139

1999: Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance.

A study by Maes et al. (1999) compared the therapeutic efficacy of pindolol to that of mianserin as an adjunct to fluoxetine among individuals diagnosed with resistant depression.  Researchers specifically sought to determine whether pindolol and/or mianserin would be able to enhance the therapeutic efficacy of fluoxetine and/or expedite the onset of its antidepressant action.  A total of 31 inpatients with major depression were recruited for the study and assigned at random to receive: standalone fluoxetine (20 mg/day), fluoxetine (20 mg/day) plus pindolol (7.5 mg/day), or fluoxetine (20 mg/day) plus mianserin (30 mg/day) – for a duration of 5 weeks.

Therapeutic efficacy was determined based on changes in 17-item Hamilton Rating Scale for Depression (HAM-D) scores from baseline through the 5-week treatment term.  Analysis of the results suggested that groups receiving either pindolol or mianserin experienced significantly greater antidepressant effect compared to the group receiving standalone fluoxetine.  Around 60% of patients receiving mianserin or pindolol (adjuncts) with fluoxetine experienced reductions in HAM-D scores by 50%.

By comparison, just 9% of patients receiving standalone fluoxetine experienced HAM-D score reductions by 50%.  What’s more, the group receiving mianserin plus fluoxetine experienced significant HAM-D score reductions within 1 week of treatment.  In other words, adjunctive mianserin administration was able to reduce latency of fluoxetine’s antidepressant action, but pindolol was not.  In summary, although both adjuncts appear equally efficacious, mianserin may be preferred in that it expedites onset of antidepressant effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10211920

1997: Pindolol augmentation of treatment-resistant depressed patients.

Moreno et al. (1997) conducted a study evaluating the efficacy of pindolol augmentation among patients with treatment-resistant cases of depression.  A major reason for conducting the study was to replicate findings from uncontrolled reports in which adjunctive pindolol appeared to potentiate and accelerate the antidepressant effects of SSRIs and MAOIs.  Researchers recruited 10 patients diagnosed with major depressive disorder for a randomized, placebo-controlled, double-blind trial.

It was noted that all 10 patients had previously undergone at least one full trial of antidepressant monotherapy, but failed to attain sufficient symptomatic relief.  The participants were assigned to receive either: pindolol (2.5 mg, t.i.d.) OR a placebo – as an adjunct to their current antidepressant for a duration of 2 weeks.  After each week of treatment, the clinical outcomes, vital signs, and behavioral ratings of patients were recorded.

Upon comparison of measures for 2 weeks, results indicated that there were no significant differences in alleviation of depressive symptoms among those that received pindolol compared to those that received the placebo.  Both the pindolol and placebo were considered well-tolerated and neither exacerbated depressive symptoms.  Nonetheless, this trial was unable to replicate findings of previous uncontrolled studies in which pindolol augmentation appeared to facilitate fast and substantial antidepressant effects.

It is important to consider that the results from this randomized controlled trial may be erroneous for multiple reasons including: dosing, prior treatment with an SSRI, as well as the specific sample (of those with resistant-depression).  The dosing in this study was problematic in that, for pindolol to adequately bind to 5-HT1A autoreceptors (the mechanism by which it treats depression), it necessitates administration at a single large dose such as 7.5 mg.  This study involved administration of pindolol three times per day at 2.5 mg per dose, an amount insufficient for 5-HT1A binding [to enhance mood].

Another notable problem with this study was that all participants had previously undergone SSRI treatment.  Prior treatment with an SSRI will have altered 5-HT1A autoreceptors (as well as serotonergic transmission) in such a way that pindolol administration will exhibit less preferential binding to these receptors.  So not only was the dose of pindolol too low for sufficient binding, but 5-HT1A autoreceptors were altered as a result of prior SSRI treatment – making pindolol unlikely to work even if administered at an optimal dose.

Finally, it is problematic that only patients with treatment-resistant depression were included in this study.  Later reports would discover that pindolol is significantly less effective among patients with treatment-resistant depression.  Due to the methodological flaws as well as study limitations (e.g. small sample, short duration, etc.) – results from this study are irrelevant.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9375594

1996: Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression.

Maes, Vandoolaeghe, and Desnyder (1996) mention that fluoxetine (an SSRI) and trazodone (an atypical antidepressant) are effective for the treatment of major depressive disorder (MDD), as well as treatment-resistant depression (TRD).  Ongoing treatment with either agent is understood to increase extracellular concentrations of serotonin by inhibiting serotonin reuptake, as well as by desensitizing 5-HT1A autoreceptors.  The mechanism of serotonin reuptake inhibition occurs immediately after antidepressant administration.

However, it is known that most individuals require at least 4 to 8 weeks of treatment before a substantial antidepressant effect is attained.  This is likely due to the fact that when using a serotonergic antidepressant, it takes between 4 and 8 weeks to fully desensitize the 5-HT1A autoreceptor.  Desensitization of 5-HT1A autoreceptors leads to 5-HT1A autoreceptor downregulation, which in turn allows the serotonergic neuron to release a greater amount of serotonin into the synaptic cleft.

The greater the quantity of serotonin available within the synaptic cleft, the more pronounced the serotonergic signaling – as well as corresponding mood improvements.  Since individuals with depression dislike and/or struggle to wait between 4 and 8 weeks for mood improvement, researchers sought to determine whether they could expedite onset of antidepressant effect with adjunct administration of pindolol.  Pindolol functions as a 5-HT1A autoreceptor antagonist and is theorized to expedite 5-HT1A autoreceptor downregulation for a hastened antidepressant response.

A total of 33 inpatients with major depression were recruited to participate in the study and were initially treated with trazodone (100 mg/day) starting 10 days after hospitalization.  After 1 week of trazodone treatment, patients were assigned at random to receive one of the following adjuncts: placebo, pindolol (7.5 mg/day), fluoxetine (20 mg/day) – for an additional 4 weeks.  To measure efficacy of each adjunct, scores on the 17-item Hamilton Depression Rating Scale (HDRS) were collected at baseline and compared to post-treatment.

Criteria for symptomatic improvement was defined as: [at least] 50% reduction in Hamilton Depression Rating Scale (HDRS) scores from baseline.  Results indicated that 72.5% of patients receiving adjunct pindolol, 75% of those receiving adjunct fluoxetine, and 20% of those receiving the adjunct placebo – experienced significant symptomatic improvement.  This suggests that adjunctive pindolol is as effective as adjunctive fluoxetine, as well as that both interventions are more effective than the placebo.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8988452

1994: Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.

Researchers Artigas, Perez, and Alvarez (1994) were among the first to highlight the rapid onset of antidepressant effect associated with administration of pindolol as an adjunct to SSRIs.  In their article, it was documented that repeated administration of antidepressants (SSRIs and MAOIs) enhance serotonergic transmission to improve mood.  However, upon inhibition of serotonin synthesis, individuals treated with antidepressants tend to experience exacerbation of depression.

Exacerbation of depression associated with inhibited serotonin synthesis is likely related to decreased serotonergic activity and signaling in the synaptic cleft.  Administration of pindolol as an SSRI adjunct is understood to antagonize 5-HT1A autoreceptors.  Antagonism of 5-HT1A autoreceptors may lead to 5-HT1A autoreceptor downregulation, which in turn enhances serotonergic release into the synaptic cleft, thus explaining the rapid mood improvement among those receiving pindolol adjuncts.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8122960

Limitations associated with research of pindolol for depression

There are a multitude of limitations associated with the research of pindolol as an antidepressant adjunct.  Likely the most significant limitation is that most trials of pindolol administered the drug at too low of a dose for users to attain any therapeutic value.  Other limitations include the lack of research investigating pindolol as a monotherapy, as well as a paucity of research comparing its therapeutic value to that of other antidepressant adjuncts.

  • Antidepressant specifics: Researchers haven’t considered that the specific antidepressant administered along with pindolol may alter the therapeutic effects of pindolol. Although most research investigating pindolol as an adjunct involves pairing it with an SSRI, we should consider that the specific SSRI with which it is paired may make a difference in its efficacy.  Certain SSRIs may be more compatible with pindolol compared to others.  Moreover, researchers haven’t considered evaluating whether pindolol may be a superior adjunct when paired with a particular class of antidepressants (e.g. MAOI) compared to another (e.g. TCA).
  • Depressive subtypes: It is known that there are a myriad of neurobiological footprints associated with depression, and each specific footprint may signify a different depressive subtype. Like any pharmacological intervention, pindolol may be better suited for individuals with a particular depressive subtype compared to others.  For example, those with depression caused by lack of serotonergic signaling would be more likely to benefit from pindolol than someone with suboptimal dopaminergic transmission.  Researchers haven’t taken the time to pinpoint the ways in which neural biomarker expression among depressives may determine the efficacy of pindolol.
  • Dosage: The most substantial limitation in the research of pindolol for depression is the dosage administered. In most early randomized controlled trials, pindolol was administered at a dose of 2.5 mg, three times per day.  While this adds up to a total dose of 7.5 mg per day, division of 7.5 mg into 3 distinct administrations (hours apart) results in insufficient binding of pindolol to 5-HT1A autoreceptors.  Only when pindolol is administered in the form of a large single dose such as between 7.5 mg and 10 mg – does it actually bind to 5-HT1A autoreceptors for a therapeutic effect.
  • Comparative efficacy: Only one study compared the adjunctive efficacy of pindolol to that of another agent. In the comparative study, the adjunct of pindolol was compared to the adjunct of fluoxetine while paired with mirtazapine as the primary antidepressant.  Pindolol and fluoxetine were of comparable efficacy as adjuncts to mirtazapine.  That said, no other research was conducted to determine how pindolol compares to other established SSRI adjuncts.  It may turn out that pindolol is more/less therapeutically valuable when compared to other adjuncts.
  • Monotherapy: Another limitation associated with research of pindolol for depression is the lack of research investigating its value as an antidepressant monotherapy. Some suspect that pindolol could be effective as a standalone antidepressant, thus eliminating the need for conventional, first-line options (e.g. SSRIs).  Perhaps a subset of depressed patients would benefit from the intrasynaptic serotonin release (as induced by pindolol) without additional reuptake inhibition.  As of current, the efficacy of pindolol as a monotherapy remains unknown.
  • Study designs: To accurately determine whether pindolol is effective as an antidepressant adjunct or as a monotherapy, further studies are warranted. Many of the published studies investigating the therapeutic value of pindolol fail to implement robust randomized controlled designs (RCTs) with large sample sizes.  Others may be of insufficient duration to determine whether pindolol potentiates antidepressant efficacy over a long-term.  Optimizing the design of future studies and correcting methodological flaws (e.g. suboptimal dosing) should yield more accurate results than are currently available.

Verdict: Pindolol may be a useful antidepressant adjunct for some patients

Based on the available scientific literature, it seems as though adjunct pindolol is an effective accelerator of antidepressant action, particularly SSRIs.  For example, a randomized controlled trial by Portella et al. (2011) documented significant acceleration of citalopram action as a result of pindolol (5 mg, t.i.d.) compared to a placebo.  Researchers in the aforementioned trial by Portella et al. also noted that patients receiving pindolol were more likely to attain symptomatic remission compared to those receiving the placebo adjunct.

Additional evidence to support the usefulness of pindolol as an antidepressant adjunct can be derived from a systematic review conducted by Whale et al. (2010).  The review pooled data from 11 studies and discovered that administration of an SSRI plus pindolol (as an adjunct) expedited onset of antidepressant action to a greater extent than an SSRI plus a placebo (adjunct).  Rather than waiting between 4 and 8 weeks for an antidepressant to deliver its therapeutic effect, adjunctive pindolol is able to expedite delivery of the therapeutic effect to a time of less than 3 weeks.

The expedited onset of antidepressant efficacy as a result of pindolol administration is due to its antagonism [and corresponding desensitization] of the 5-HT1A autoreceptor, which disinhibits the serotonergic neuron.  Disinhibition of the serotonergic neuron results in greater serotonin release through the presynaptic membrane to stimulate postsynaptic receptor sites.  Although SSRIs also desensitize the 5-HT1A autoreceptor, they take much longer to do so (usually up to 8 weeks – hence the delay in onset of effect).

In addition to accelerating the onset of antidepressant action, some evidence suggests that pindolol may be an effective potentiator of an antidepressants effects – over an extended duration.  Though there’s less evidence to support potentiation of antidepressant effect from pindolol, it is reasonable to assume that this could occur.  Not only could its 5-HT1A antagonism sustain enhanced serotonergic firing, but other mechanisms such as scavenging reactive nitrogen species (RNS) and reducing sympathetic nervous system (SNS) tone could augment the antidepressant effect of SSRIs.

Maximizing the Therapeutic Potential of Pindolol for Depression

It is clear that not all patients will benefit from administration of adjunct pindolol as a treatment for depression.  Furthermore, it is apparent that not all administration protocols of pindolol are successful for mood enhancement.  For this reason, it is necessary that psychiatrists are cognizant of patients for whom pindolol is most likely to prove efficacious, as well as the dosage necessary to facilitate a therapeutic antidepressant effect.

  • High, single dose: Administration of pindolol at either too low of a dose, or in small divided doses may be ineffective as an adjunct. One study discovered that administration of 5 mg pindolol (t.i.d.) was therapeutically effective as an adjunct.  Other studies have shown that single doses of 7.5 mg and 10 mg pindolol are effective adjuncts.  However, administration of 2.5 mg pindolol (t.i.d.) appears ineffective.  Larger single doses are likely to work better than smaller and/or divided dosing protocols.
  • Treatment-naïve patients: Pindolol appears most useful among those that haven’t already taken an SSRI or serotonergic antidepressant. Treatment-naïve patients are therefore most likely to find pindolol useful, especially in regards to accelerating the onset of antidepressant action.  A non-naïve patient (or someone that’s already been treated with an antidepressant) will have undergone 5-HT1A downregulation and neuronal disinhibition and are less likely to benefit from pindolol’s mechanism.
  • Non-refractory depressives: While a subset of individuals with refractory depression may benefit from pindolol administration, evidence suggests that most are unlikely to derive much benefit. Refractory depressives may fail to benefit from pindolol due to the fact that they’ve already tried serotonergic agents and haven’t responded.  Perhaps their underlying neurochemical abnormalities have little or nothing to do with serotonin signaling.
  • Psychiatric oversight: Since pindolol is not officially approved by the FDA as an antidepressant adjunct, it should be used cautiously and only when hypothesized to be of therapeutic benefit to a particular patient. For this reason, it is likely best administered under supervision of a psychiatrist and/or psychopharmacologist.  Psychiatrists and psychopharmacologists are professionally trained to determine whether a drug such as pindolol is likely to benefit a particular patient.  They will also be able to determine whether it is safe to administer given an individual’s current medication regimen and medical conditions.  Furthermore, a psychiatrist should be able to calibrate dosing and administration parameters to enhance efficacy and/or tolerability for on a patient-by-patient basis.  For example, some users may find that dosing with 10 mg (q.d.) is more effective and/or tolerable than 7.5 mg (b.i.d.), whereas others may report the opposite.
  • Serotonergic underpinnings: Pindolol is most likely to benefit individuals with neurobiological signatures of depression characterized by serotonergic abnormalities. This is because administration of pindolol antagonizes and consequently downregulates 5-HT1A autoreceptors to disinhibit serotonergic neurons.  Upon disinhibition of the neuron, serotonin release into the synaptic cleft increases, and postsynaptic receptor sites are stimulated for mood enhancement.  This corrects the underlying low serotonin signaling (and possibly other abnormalities) that lead to onset of depressive symptoms.  That said, individuals with depression in which aberrant serotonin signaling isn’t implicated may not benefit much from pindolol.

Have you tried Pindolol for depression?

If you’ve used pindolol as an adjunct to an antidepressant (or tested it as an experimental monotherapy), share your experience in the comments section below.  To help others get a better understanding of your situation, provide details such as: dosage of pindolol and administration frequency (e.g. 7.5 mg, b.i.d.), the duration over which you’ve been using it, as well as any co-administered medications and/or substances.  Based on your anecdotal experience, do you believe that pindolol was therapeutically valuable as an antidepressant adjunct – or do you believe that it was relatively useless?

Assuming you derived therapeutic benefit from pindolol, document the specific ways in which it may have helped during treatment such as by: accelerating the onset of antidepressant action and/or potentiating antidepressant effects.  If you believe that pindolol expedited the onset of antidepressant action, mention the amount of time it took for your mood to improve following initiation of treatment.  Did you continue taking pindolol over an extended duration or discontinue after 6 to 8 weeks (e.g. once an SSRI had sufficient time to also downregulate 5-HT1A autoreceptors)?

For those that eventually discontinued adjunctive pindolol, did you experience a worsening of mood or reduction in antidepressant efficacy upon cessation?  Among those that have taken adjunct pindolol over a long-term, did it remain therapeutically effective over the extended duration? Or did depressive symptoms reemerge once your neurochemistry and physiology developed a tolerance?

It is important to recognize that not all individuals are likely to find pindolol helpful in the management of depressive symptoms, especially those with non-serotonergic and/or treatment-resistant depression.  That said, pindolol appears to be extremely valuable as an adjunct in that it accelerates onset of antidepressant action, and may potentiate overall mood improvement.  Those stuck in a state of depression who dislike the idea of waiting up to 8 weeks for an SSRI to take full effect may wish to discuss pindolol augmentation with a professional.

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