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Buspar (Buspirone) is a drug of the azapirone chemical classification that was engineered and patented in the 1970s by Mead Johnson.  It was later acquired by the pharmaceutical company Bristol-Myers Squibb and approved by the FDA in 1986 for the treatment of generalized anxiety disorder (GAD).  What’s unique about buspirone compared to other anxiolytics such as benzodiazepines is that it isn’t associated with serious risks of abuse, dependence, nor protracted discontinuation symptoms.

Furthermore, despite the fact that buspirone exhibits a relatively delayed onset of therapeutic action, studies have shown that its anxiolytic efficacy is analogous to that of other FDA-approved anxiolytic medications.  While buspirone is most commonly used for the treatment of generalized anxiety disorder (GAD), it is sometimes prescribed off-label as an intervention for conditions such as: cerebellar ataxia, insomnia, and obsessive-compulsive disorder (OCD).  By happenstance, some individuals taking Buspar realize that it alleviates their symptoms of depression.

Although not formally approved as an antidepressant, research from STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trials support the usefulness of buspirone as an adjunct among those with major depression.  When administered along with a first-line serotonergic antidepressant, buspirone may potentiate therapeutic mood enhancement, as well as counteract SSRI-induced side effects such as sexual dysfunction.  Moreover, while not everyone with major depression will benefit from buspirone, it is a relatively low-risk off-label adjunct to test.

How Buspar May Treat Depression (Mechanisms)

There are numerous potential mechanisms by which buspirone may function to enhance mood.  Since it functions predominantly as a 5-HT1A receptor partial agonist, most speculate that its modulation of serotonin receptor activity is the primary mechanism by which it enhances mood.  Buspirone is also understood to modulate oxytocin release, influence the firing rate of noradrenergic neurons within the locus coeruleus, plus reduce neroinflammation and oxidative stress.  Though its 5-HT1A partial agonism may constitute a majority of its effect, a combination of mechanisms may contribute to its antidepressant action.

5-HT1A partial agonist: It is known that partial agonism of 5-HT1A receptors facilitates an anxiolytic effect, and in some cases also yields an antidepressant effect.  Buspirone functions as a full agonist of presynaptic 5-HT1A autoreceptors, whereby it inhibits synthesis of serotonin and firing of serotonergic neurons.  It also acts as a partial agonist upon 5-HT1A heteroreceptors located within the hippocampal and frontal regions to correct dysfunctional transmission of serotonin often implicated in major depression.

Modulation of 5-HT1A receptor activity is likely the primary means by which buspirone enhances mood.  A report by Blier and Ward (2003) questioning whether 5-HT1A agonists may be useful interventions for depression, mentions that alterations in 5-HT1A receptor activity is associated with response to antidepressant and anxiolytic medications.  The report cites evidence suggesting that buspirone’s full agonism at 5-HT1A autoreceptors and partial agonism at 5-HT1A postsynaptic receptors delivers its antidepressant effect.

Researchers Blier and Ward concluded by noting that 5-HT1A receptor agonism is a useful pharmacological target for the treatment of major depression.  This supports previous research by Sargent et al. (1997) documenting that mood enhancement derived from conventional antidepressants is associated with adaptations in functionality and/or sensitivity of presynaptic and postsynaptic 5-HT1A receptor sites.  Since buspirone modulates 5-HT1A receptor activity, it is reasonable to assume that ongoing buspirone administration corrects 5-HT1A abnormalities to reduce depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12559651/
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9292630/
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2198303/

Oxytocin release: Another means by which buspirone may reduce symptoms of depression [plus anxiety] is by enhancing the release of oxytocin, a neuropeptide that’s associated with antidepressant-like effects.  Though buspirone doesn’t directly deliver oxytocin nor does it act upon oxytocin receptors, it is speculated that buspirone’s agonism of the 5-HT1A receptor triggers a downstream release of oxytocin.  Evidence to support the idea that 5-HT1A agonism of buspirone may increase oxytocin secretion was initially reported by Bagdy and Kalogeras (1993).

In their study, Bagdy and Kalogeras administered buspirone to animal models and tracked changes in plasma oxytocin concentrations.  Results suggested that buspirone, as well as other 5-HT1A receptor agonists, facilitated dose-dependent increases in plasma oxytocin concentrations.  Conversely, deliberate blockade of 5-HT1A receptors [with antagonist drugs] significantly inhibited 5-HT1A agonist-induced secretion of oxytocin, providing evidence that 5-HT1A agonism is a critical mechanism by which buspirone enhances oxytocin release in animal models.

Another study by Chiodera et al. (1996) assessed the effect of buspirone (15 mg) on serum oxytocin and vasopressin concentrations in humans during hypoglycemia.  Results suggested that, while in a hypoglycemic state, agonism of 5-HT1A receptors interacts with hypoglycemia to enhance the release of oxytocin secretion.  Although further research is warranted to confirm preliminary speculation that 5-HT1A agonism may enhance oxytocin secretion in non-hypoglycemic humans, it should be recognized that any buspirone-induced oxytocin release may reduce depressive symptoms in a subset of patients.

While not all individuals with major depression exhibit dysfunction in secretion and/or concentrations of oxytocin, studies have reported lower plasma oxytocin concentrations among depressed individuals compared to euthymic (non-depressed) controls.  What’s more, it is known that certain subtypes of depression may be caused (at least in part by) exposure to early life stressors, detached parenting styles, and/or chronic long-term stress – all of which can disrupt oxytocin systems.  Knowing this, it is reasonable to assume that some cases of major depression are caused directly by an inability to regulate oxytocin.

A study by Cyranowski et al. (2008) reported irregular peripheral oxytocin release among women with depression.  Research suggests that irregular release of oxytocin is associated with HPA-axis (hypothalamic pituitary adrenal) dysfunction.  Enhanced release of oxytocin is understood to attenuate HPA-axis abnormalities that are commonly exhibited among individuals with depressive disorders.

Other evidence suggesting a possible role of oxytocin in depression comes from a report by Neumann and Landgraf (2012).  In this report, researchers note that oxytocin and vasopressin levels require a delicate balance to maintain euthymic mood and mental health.  In particular, when vasopressin concentrations are high and oxytocin levels are low, individuals are prone to bouts of anxiety and depression.

When previously-deficient oxytocin concentrations are increased to counteract high vasopressin, mood improves and anxiety diminishes.  Clearly there’s a complex relationship between oxytocin and mood disorders.  Though buspirone’s downstream influence on oxytocin systems may be less important than its principal impact on serotonin systems, downstream modulation of oxytocin should be considered as possibly contributing to buspirone’s antidepressant effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8334526
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8771561
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19005082
  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033976/
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5-HT2B agonist: Although its affinity for agonizing 5-HT2B receptors is 7.5-fold lesser than its affinity for agonizing 5-HT1A receptors, buspirone-induced agonism of 5-HT2B may be another mechanism by which it treats depression.  Research by Diaz et al. (2012) presents evidence to suggest that 5-HT2B receptor agonism significantly contributes to the therapeutic antidepressant effect of SSRIs.  Furthermore, direct activation of 5-HT2B receptors with a 5-HT2B agonist generates an antidepressant response analogous to SSRIs.

Oppositely, when 5-HT2B receptors are blocked with an antagonist, any initial mood enhancement derived from SSRIs is attenuated.  The blockade of 5-HT2B receptors leads to a return in behavioral and neurochemical patterns associated with depression.  Other research presented by Peng et al. (2014) assessed the neurochemical mechanisms by which SSRIs improve mood.

In laboratory tests, 5-HT2B receptor agonism was as noted as a critical target by which SSRIs facilitated mood enhancement.  Akin to previous findings, Peng et al. discovered that SSRIs lost their antidepressant efficacy when 5-HT2B receptors were intentionally inactivated (with an antagonist) or knocked-out (genetically).  With this evidence, it becomes obvious that 5-HT2B activation is instrumental for mitigation of depressive symptoms.

Though buspirone doesn’t exert a strong effect upon 5-HT2B receptors, its effect may just enough to contribute to an antidepressant effect.  Perhaps among individuals who find high-dose buspirone to be effective for depression are using high doses (as an adjunct or monotherapy).  At higher doses, buspirone may activate 5-HT2B receptors enough to lift mood.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22158014
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25342944

Locus Coeruleus modulation: Buspirone is known to enhance activity in the locus coeruleus of the brain, leaving some to suspect that this may be a mechanism by which it treats depression.  The locus coeruleus is considered a nucleus within the pons (located within the brainstem) implicated in generating physiological responses to stressors.  It is the primary region of the brain in which norepinephrine is synthesized, and is involved in regulation of: arousal, attention, balance, cognitive function, emotion, and neuroplasticity.

Abnormalities in locus coeruleus function are thought to cause clinical depression in a subset of individuals.  Researchers Weiss et al. (1994) report stress-induced depression as a result of dysregulated locus coeruleus activity.  The dysregulation of locus coeruleus activity may provoke stress-induced depression by reducing the firing rate of noradrenergic neurons.

This may explain the link between low norepinephrine and depression, as well as the therapeutic efficacy of noradrenergic modulators (e.g. NRIs, NDRIs, SNRIs) for certain cases of depression.  Research by Klimek et al. (1997) analyzed norepinephrine and norepinephrine transporter (NET) activity in the locus coeruleus of depressed individuals and discovered reductions in noradrenergic activity compared to euthymic controls.  Sanghera et al. (1982) documented the fact that, unlike benzodiazepine compounds which reduce noradrenergic activity in the locus coeruleus, buspirone increases noradrenergic activity in this region.

The primary metabolite of buspirone known as 1-PP (1-(2-pyrimidinyl-piperazine)) antagonizes alpha-2 receptors, which activates neurons within the locus coeruleus.  Increases in noradrenergic activity within the locus coeruleus appear to be dose-dependent – the larger the buspirone dose administered, the greater the noradrenergic activation.  Knowing that norepinephrine levels are often reduced in the locus coeruleus among those with depression, and that buspirone bolsters noradrenergic tone within the locus coeruleus, we can speculate that buspirone attenuates depressive symptoms [in part] through its effect upon the locus coeruleus.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7859114
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9334417
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/6130954

Oxidative stress reduction: Research suggests that, in some cases of depression, there are more oxidants in circulation than antioxidants, causing damage via oxidative stress.  A systematic review and meta-analysis by Black et al. (2015) documented levels of biomarkers among individuals with major depression compared to euthymic controls.  Results of the review indicated that depressive disorders were associated with abnormally high concentrations of biomarkers 8-OHdG and F2-isoprostanes, signifying increased oxidative stress.

Oxidative stress may damage or kill brain cells, as well as induce morphological alterations throughout various regions.  It is hypothesized that counteracting excessive oxidative stress with administration of antioxidants may enhance mood among individuals with depression – particularly those with high levels of oxidative stress.  A means by which buspirone could improve mood and offset depressive symptoms is by counteracting oxidative stress.

Evidence to suggest that buspirone acts as an antioxidant was noted in research by de Freitas et al. (2010).  Researchers deliberately induced seizures in rats by administering pilocarpine, which significantly increased oxidative stress within the hippocampal region of the brain.  It was discovered that pre-treatment with buspirone was able to offset all increases in oxidative stress resulting from pilocarpine.

Specifically, buspirone significantly increased superoxide dismutase (47%) and catalase (40%) while simultaneously decreased lipid peroxidation (60%) and nitrite content (44%) within the hippocampus.  Additional research by Kumar, Kaur, and Rinwa (2014) documented that buspirone plus melatonin significantly reduced oxidative damage in animal models of stress.  The buspirone appeared to reduce lipid peroxidation and nitrite concentrations, yet upregulated glutathione and catalase activity.

Researchers suspect that the serotonergic mechanism of buspirone may facilitate downstream increases in antioxidant activity.  Regardless as to how buspirone manages to increase antioxidant activity and decrease oxidative stress, these actions may be therapeutic among those with depression.  Although oxidative stress reduction is unlikely the chief antidepressant mechanism of buspirone, it should be mentioned as a possible contributor.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25462890
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19800952
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25156283

Inflammation reduction: A study by Sharifi et al. (2015) assessed the effect of ongoing buspirone and fluoxetine administration on expression of proinflammatory cytokines in animal models with 6-OHDA (6-hydroxydopamine)-induced lesions.  Lesions resulting from 6-OHDA are associated with significant abnormalities in proinflammatory biomarkers.  Following the 6-OHDA-induced lesions, researchers monitored cerebrospinal fluid (CSF) concentrations of biomarkers: TNF-α, IL-1β, and IL-6.

Three weeks later, the animal models received buspirone plus fluoxetine for 10 consecutive days.  After 10 days of buspirone and fluoxetine administration the cerebrospinal fluid (CSF) samples were reassessed and compared to pre-treatment baseline.  Results indicated that buspirone and fluoxetine ameliorated biomarker abnormalities resulting from 6-OHDA-induced lesions.

In particular, the combination treatment significantly reduced concentrations of TNF-α, yet increased concentrations of IL-1β and IL-6.  Researchers concluded that administration of buspirone plus fluoxetine appears to modulate and normalize levels of proinflammatory cytokines.  The normalization of proinflammatory cytokines may play a role in facilitating its antidepressant effect, especially among depressed individuals with high levels of neuroinflammation.

A report by Zunszain, Hepgul, and Pariante (2013) highlights links between inflammation and depressed mood.  It has been observed that patients with major depression often exhibit heightened concentrations of proinflammatory cytokines.  Since these cytokines affect neurotransmitter metabolism, neuroendocrine processes, as well as regional activity – there’s reason to suspect that they may be liable for induction and/or exacerbation of depression.

Researchers Brites and Fernandes (2015) mention that chronic inflammation often results in onset of depressive symptoms.  Analyses of patients with depression reveal high concentrations of cytokines compared to euthymic individuals.  Although the anti-inflammatory effect of buspirone hasn’t been well-researched in humans, the combination of buspirone plus an SSRI appear to reduce inflammation in animal models.  The reduction in inflammation with an SSRI plus buspirone combination may favorably influence mood.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24782287
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22553073
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26733805

HPA-axis activity: There’s evidence indicating that HPA (hypothalamic pituitary adrenal) axis is overactive among certain individuals with major depression.  A review of literature by Varghese and Brown (2001) suggested that HPA-axis activation is typical among those with depression.  This activation leads to elevations in cortisol, corticotropin-releasing hormone (CRH), reduced adrenocorticotropic (ACTH) response to CRH, and lower volume within the hippocampus.

In addition, results from their review documented an increased suicide risk associated with HPA axis activation.  Other research by Swaab, Bao, and Lucassen (2005) reports that the HPA-axis interacts with concentrations of the neuropeptides vasopressin and oxytocin, and that HPA-axis dysfunction is implicated in depression.  Researchers agree that medications targeting the HPA axis to reduce activation and/or dysfunction may improve mood among those with depression.

Interestingly, evidence from a study by Malmkvist, Hansen, and Damgaard (2003) indicates that buspirone reduces HPA-axis activity in fearful mink.  Fearful mink generally exhibit higher cortisol and lower ACTH secretion compared to confident mink.  When buspirone is administered, differences in HPA-axis activity are similar to those of the more confident mink.

It could be that the 5-HT1A agonism elicited by buspirone enhances oxytocin secretion, and this enhancement of oxytocin secretion counteracts vasopressin to normalize HPA-axis activity.  Normalization of HPA-axis activity may improve anxiety and depression simultaneously, especially if the depression was induced by chronic stress.  Though this mechanism of buspirone hasn’t been confirmed in humans, it’s reasonable to assume that it could reverse HPA-axis dysfunction seen in depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15014598
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15996533
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12576120

Note: It is also understood that buspirone has a moderate effect upon 5-HT2A receptors as an agonist.  Though this mechanism could enhance downstream oxytocin release, most evidence suggests that 5-HT2A agonism has unfavorable effects upon mood.  Perhaps 5-HT2A agonism of buspirone limits or reduces the antidepressant effect of 5-HT1A agonism.

The binding profile of buspirone also reveals that it has a negligible affinity for 5-HT2C receptors as an agonist.  Agonism of 5-HT2C agonism is associated with reductions in appetite and increased anxiety.  Since the effect at this receptor site is extremely low, it is likely overshadowed by therapeutic effects resulting from binding to the 5-HT1A receptor and modulation of activity within the locus coeruleus.

Although buspirone has an affinity for D4, D3, and D2 receptors (respectively) as an antagonist, its antagonism at these receptors is unlikely to improve mood.  In fact, some would argue that dopamine receptor antagonism may exacerbate depressive symptoms and/or offset any therapeutic antidepressant effects attained from 5-HT1A receptor antagonism.  Animal model studies indicate that dopamine receptor antagonists reverse antidepressant action.

Benefits of Buspar for Depression (Possibilities)

Included below is a list of possible benefits to be attained from utilizing buspirone as an intervention for the treatment of major depression.  Arguably the most obvious benefit associated with using buspirone is that it should help alleviate cases of depression in which anxiety is causing depressed mood.  Other possible advantages associated with using buspirone include: few side effects, limited withdrawal symptoms, and its ability to offset SSRI-induced sexual dysfunction.

  • Adjunctive option: Anecdotal clinical reports and data from STAR*D trials suggests buspirone is a useful antidepressant adjunct. At doses of 20 to 60 mg per day, buspirone appears to bolster therapeutic efficacy of first-line antidepressant medications (e.g. SSRIs, SNRIs, TCAs, etc.) in certain patients.  Any enhancement of first-line antidepressant efficacy is considered especially helpful among those with refractory depression who respond partially or insufficiently to treatment.  Furthermore, when administered at recommended doses, risk of contraindications and interaction effects from adjuvant buspirone is low.
  • Anxious-depression: Buspirone may be an ideal intervention for those with “anxious-depression” or types of depression in which high anxiety is also present. In anxious-depression, it is suspected that excessive anxiety may exacerbate and/or lead to the depressed mood.  There appears to be a bidirectional relationship between the anxiety and depression in that, when anxiety increases, depression also becomes more severe – and vice-versa.  By using buspirone to counteract the anxiety, some may find that their mood improves synonymously with the reduction of anxiety.  Some studies have discovered that among patients with depression and comorbid moderate anxiety, buspirone was an effective standalone monotherapy for treating both conditions.  Moreover, a related compound known as Gepirone ER is slated to be approved for “anxious depression” or atypical depression.
  • Comorbid conditions: As was already mentioned, those with depression and comorbid anxiety may benefit significantly from taking buspirone. Limited evidence suggests that buspirone may also prove useful for reducing symptoms of neuropsychiatric comorbidities such as: ADHD (attention-deficit/hyperactivity disorder) and certain eating disorders such as bulimia nervosa.  Additionally, those struggling with depression plus sexual dysfunction such as anorgasmia and/or impotence may find that buspirone reduces these unwanted sexual consequences.
  • Few side effects: Contrary to most neuropsychiatric medications, buspirone isn’t associated with frequently-occurring unwanted side effects and adverse reactions.  The most common side effects associated with buspirone include: dizziness, lightheadedness, and somnolence – most of which are easy to manage.  Unlike other anxiolytics and antidepressants, buspirone doesn’t appear to cause: brain fog/cognitive deficits, changes in body weight, or sexual dysfunction.  At low to moderate doses, buspirone is regarded as being among the most tolerable psychiatric drugs on the market.
  • Limited withdrawal: Literature from clinical trials and research suggests that buspirone is associated with zero discontinuation symptoms. In other words, the experts currently suggest that buspirone can be taken for an extended duration and users can quit without experiencing troublesome withdrawal symptoms.  While those that have taken buspirone know that the literature is slightly misleading regarding discontinuation, it is easier to discontinue than most other antidepressant and anxiolytic medications.
  • Long-term: A concern with many psychiatric medications is that their therapeutic efficacies tend to wane over an extended duration of administration. Compounding the problem of diminished therapeutic efficacies is the finding that, over a long-term of administration, many patients experience an emergence of treatment-related adverse long-term effects.  Most research of buspirone indicates that it is likely to sustain its therapeutic efficacy and tolerability over an extended duration.  Research suggests that among those who find buspirone effective, it appears to sustain its therapeutic efficacy and tolerability over an extended duration (up to a full year).
  • Low cost: Compared to many other medications, buspirone is an advantageous pharmaceutical based on its extremely low cost. The patent for the brand name “Buspar” is long-expired and the drug can be attained on the cheap.  As of current, around 60 tablets of generic buspirone can be purchased for approximately $10.  Even at higher doses such as 30 mg, 60 tablets can generally be purchased for between $20 and $35.  Since many patients struggle to afford psychiatric medications and/or may end up discontinuing due to high prices, having access to low-cost medications like buspirone is critical.
  • Monotherapy: Another benefit associated with using buspirone for depression is that it may be an efficacious monotherapy. A controlled trial by Rickels et al. (1991) documented that standalone buspirone (at doses up to 90 mg/day) significantly reduced symptoms of depression plus anxiety – compared to a placebo control.  In this trial, it was concluded that buspirone was highly effective regardless of the baseline severity of a person’s depression and/or anxiety symptoms.  While certainly not all cases of depression will respond to buspirone monotherapy, there’s reason to believe that some will.  Furthermore, buspirone as a monotherapy may be preferred among those who fail to benefit from conventional antidepressants and/or are unable to tolerate first-line antidepression pharmacology.
  • Sexual enhancement: It is widely understood that sexual dysfunction is a common side effect of serotonergic antidepressants, as well as a symptom of major depression. Although most patients are more concerned about their mood than sexual performance, some may become depressed if their sexual performance suffers.  When administered as an antidepressant adjunct, buspirone is effective for reducing the anorgasmia and impotence that often result from SSRIs.  Research by Landén et al. (1999) noted that flexibly-dosed buspirone (20 to 60 mg/day) reverses SSRI-induced sexual dysfunction in nearly 60% of users.  Those struggling to cope with sexual dysfunction resulting from their primary antidepressant may benefit significantly from buspirone.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/10350034).
  • Safety: Most would not contest the idea that buspirone is among the safest psychiatric drugs on the market. Dissimilar to many of the more dangerous psychiatric drugs, buspirone isn’t associated with: abuse/addiction potential, psychological/physical dependence, rapid tolerance onset, nor serious long-term effects (e.g. dementia from benzodiazepines).  When compared to other psychiatric drugs, buspirone doesn’t appear to exhibit an extensive list of unfavorable contraindications nor interaction effects.  Moreover, the withdrawal symptoms associated with discontinuing buspirone are considered minimal compared to those associated with first-line antidepressants (e.g. SSRIs/SNRIs).
  • Treatment-resistant depression: There’s some data indicating that buspirone may be a useful option for patients with refractory or treatment-resistant depression.  It is well-documented that individuals with difficult-to-treat depression often fail to respond to first-line pharmacological interventions.  Among patients with treatment-resistant depression, there’s generally a need for adjunctive interventions and/or atypical pharmacological strategies.  Evidence from the STAR*D trial presented by Trivedi et al. (2006) supports the efficacy of buspirone (up to 60 mg/day) for treatment of unremitting major depression.  A randomized controlled trial (RCT) by Appelberg et al. (2001) also documented the efficacy of adjunctive buspirone (20-60 mg/day) for severe depression.  Based on these findings, it is reasonable to consider that buspirone may serve as a useful adjunct among those with extreme and/or treatment-resistant depression.
  • Unique mechanism of action: Compared to most antidepressant medications, buspirone exhibits unique pharmacodynamics. It is understood to modulate serotonergic transmission by agonizing receptors such as 5-HT1A and 5-HT2B – each of which may contribute to its mood-enhancing effect.  Additionally, agonism of 5-HT1A receptors results in the downstream secretion of oxytocin which may improve mood by reducing HPA-axis activity.  Other mechanisms by which buspirone could reduce depression include: upregulating noradrenergic tone in the locus coeruleus, decreasing inflammation, and/or minimizing oxidative stress.  Although certain antidepressants share a subset of pharmacodynamic commonalities with buspirone, they do not function the exact same – possibly making buspirone a favorable intervention for some users.

Drawbacks of Buspar for Depression (Possibilities)

Though there may be benefits associated with using buspirone for the treatment of depression (as an adjunct or monotherapy), it is important to understand all potential drawbacks.  The most obvious drawback of administering buspirone for depression is the paucity of quality evidence [from randomized controlled trials] to support its efficacy.  Other possible drawbacks of using buspirone as an antidepressant include its: comparative efficacy (to other adjuncts and monotherapies), delayed onset of action, side effect profile, as well as that it may worsen depressive symptoms for some individuals.

  • Delayed onset of action: Buspirone itself is among the slowest-acting agents on the market for the management of depression and anxiety. Some speculate that buspirone takes between 4 and 8 weeks to fully deliver its therapeutic antidepressant and/or anxiolytic effect.  This delay in onset of action is a problem, especially for those who are suffering from severe depression and are in-need of immediate symptomatic reduction.  Not only is buspirone slow-acting in its own right, but there’s evidence to suggest that when administered as an SSRI adjunct, it may delay the antidepressant action of the SSRI.  The delay is thought to result from increased stimulation of postsynaptic 5-HT1A receptors.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/12943952).
  • Efficacy (unproven): Compared to first-line antidepressant monotherapies, evidence to support the usage of buspirone is scarce. For this reason, most would not consider buspirone to exert as substantial of an antidepressant effect as conventionally-recommended options.  Even as an adjunctive intervention, it is believed that buspirone may be an inferior choice to drugs such as bupropion and pindolol.  Bupropion has proven itself in randomized clinical trials to be an effective monotherapy and SSRI adjunct, and is able to offset side effects of weight gain and sexual dysfunction.  Additionally, using adjunctive pindolol for depression may be favorable over buspirone in that 5-HT1A somatodendritic autoreceptors are antagonized, resulting in enhanced firing of serotonergic neurons.  This accelerates onset of antidepressant action with pindolol, whereas buspirone may delay activity.  Comparatively, there appear to be numerous other medications that may be more effective and/or useful than adjunct buspirone.
  • Gepirone comparison: A similar drug to buspirone (also of the azapirone classification) known as gepirone (Travivo ER) is slated to receive FDA approval for the treatment of atypical depression. While buspirone and gepirone are analogous in that they are of the same chemical classification and function by agonizing the 5-HT1A receptor, gepirone differs from buspirone in that it lacks affinity for the D2 receptor.  Antagonizing the D2 receptor is understood to cause depression rather than alleviate it, possibly making gepirone the favorable intervention to buspirone.  Moreover, gepirone is also manufactured in an extended-release format, eliminating many pharmacokinetically-mediated adverse effects resulting from sharp peaks in plasma concentration from immediate-release buspirone formats.
  • Interactions: Although the interactions associated with buspirone aren’t any more alarming than other psychiatric medications, interaction effects may be a problem for individuals taking other medications. Since buspirone is subject to hepatic metabolism through CYP3A4 (cytochrome P450 3A4) isoenzymes, the metabolism speed and corresponding plasma concentrations of buspirone may be affected by a concurrently administered medication.  Altered metabolism speed and plasma concentrations may detrimentally affect the efficacy and safety of buspirone.  Inhibitors of CYP3A4 (such as Cobicistat, Indinavir, Itraconazole, and Ketoconazole) should interfere with buspirone metabolism, whereas inducers of CYP3A4 (such as Carbamazepine, Glucocorticoids, Modafinil, and Phenytoin) should expedite its metabolism.  Buspirone is known to interact with MAOIs by causing hypertension and cannot be administered as an MAOI adjunct.  Furthermore, some suspect that high doses of buspirone may interact with other antidepressants by causing “serotonin syndrome.”
  • Lack of extended-release: Most suspect that the tolerability and efficacy of buspirone could be improved by reengineering the drug in an extended-release format. As a result of its immediate-release format and functionality, it is quickly absorbed and rapidly eliminated.  This rapid absorption/elimination increases odds that low-dose users may find the drug ineffective, whereas high-dose users may find the drug intolerable.  Buspirone is generally administered twice per day (b.i.d.) and yields unforgiving, abrupt peaking of plasma concentrations.  If the drug were manufactured in an extended-release format, plasma concentrations would remain steady, thereby enhancing tolerability of [the arguably more effective] higher doses.
  • Potency: Many anecdotal reports suggest that the potency of standard-dosed buspirone is too low to deliver a pronounced antidepressant effect. Assuming buspirone is capable of treating select cases of depression, an important mechanism may be its agonism of 5-HT2B receptors.  Due to its extremely low affinity for 5-HT2B receptor sites (compared to other serotonin receptors), buspirone may require a very high dose to improve mood.  While potency increases at high doses, so does likelihood of adverse effects.
  • Side effects: While buspirone may have few side effects compared to other psychiatric medications, some individuals may find that in their experience, the side effects of buspirone are intolerable. Examples of some general buspirone side effects include: blurred vision, dizziness, drowsiness, headache, nausea, and sleep disturbances.  If you are unable to get a good night’s sleep and/or are constantly drowsy from buspirone, you may wish to test another antidepressant.  The side effects associated with buspirone usage among individuals treating depression may be more pronounced than suspected.  This is because doses of buspirone necessary for treating depression may exceed those required to manage anxiety; as dose increases, so does the severity of side effects.
  • Unknown long-term: Though literature suggests that buspirone is well-tolerated by long-term users, in most cases, “long-term” is classified as a duration of 3 months to 1 year. For this reason, it is unclear as to whether buspirone may lose its therapeutic antidepressant efficacy when used for a duration exceeding 1 year.  It is possible that like most cases of long-term pharmaceutical administration, users develop tolerance to the effect of twice-daily buspirone.  This tolerance may require an individual to increase their dosage (resulting in more side effects) or to discontinue the medication (for a tolerance reset – but the unfavorable resurgence of depressive symptoms).  Since no multi-year studies have been conducted to analyze efficacy and buspirone dosing over a long-term, it remains unclear as to whether it’s a favorable long-term intervention for depression.
  • Withdrawal symptoms: Despite some literature suggesting that buspirone is associated with zero discontinuation effects, those that have taken the drug understand that Buspar withdrawal symptoms often occur. Among the most common symptoms of withdrawal from buspirone include: dizziness, insomnia, anxiety, drowsiness, and lightheadedness.  Other discontinuation such as nausea, headache, and fatigue have been reported.  Even more concerning is that these symptoms may persist for a duration ranging from several weeks to several months, possibly impairing your ability to function at work and/or to maintain social relationships.
  • Worsening of depression: Among a subset of individuals taking buspirone, it is possible that the drug could exacerbate preexisting depressive symptoms and/or provoke suicidal thoughts. Not everyone using buspirone will find its action on serotonergic receptors to be therapeutic.  Some individuals with depression do not exhibit serotonergic abnormalities and would be better suited to a non-serotonergic medication.  Others may necessitate serotonergic reuptake inhibition from an SSRI, but are not guaranteed to benefit from the 5-HT1A agonism of buspirone.  Furthermore, actions as a 5-HT2A and 5-HT2C agonist, plus an antagonist of dopamine receptors (D2, D3, D4) antagonist – may attenuate antidepressant effects via other mechanisms and/or induce depression.

Buspar (Buspirone) for Depression (Review of Evidence)

Though we know that Buspar is considered effective for the management of anxiety, it is less clear as to whether it is useful for the treatment of depression.  Included below are studies that directly test and/or discuss the therapeutic value of buspirone as an antidepressant.  Keep in mind that some studies lack randomized, placebo-controlled designs – making it difficult to interpret the accuracy of findings.

It is also necessary to realize that buspirone monotherapy hasn’t been subject to much evaluation for the treatment of depression.  There is preliminary evidence suggesting that buspirone monotherapy (at doses greater than administered for anxiety) could alleviate depressive symptoms.  The majority of studies focus on investigating the therapeutic efficacy buspirone as an adjunct to conventional SSRI antidepressants among those with major depression.

1990: Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression.

An analysis conducted by Robinson et al. (1990) documented the clinical effects of 5-HT1A partial agonists among those with depression.  In a section of their analysis, they discussed the antidepressant efficacy of buspirone, an azapirone anxiolytic.  Researchers reflected upon the fact that buspirone had undergone evaluation in 5 placebo-controlled, parallel group trials encompassing 382 participants meeting DSM-III criteria for major depression plus anxiety.

In these 5 trials, buspirone was administered at a dose of 15 mg/day and titrated [on an individual basis] to a maximum dose of 90 mg/day.  Results suggested that buspirone at a dose of 15 mg to 90 mg per day significantly improved symptoms of both depression and anxiety.  Improvements were evidenced by statistically significant (p < 0.05) reductions in scores on the HAM-D, HAM-A, and CGI-GI scales – compared to those receiving a placebo.

Researchers highlighted that hallmark symptoms of major depression such as: depressed mood, fatigue, guilt, mood swings, etc. – significantly improved with buspirone treatment.  Interestingly, individuals with the most severe depressive symptoms (based on HAM-D scores) and those with melancholic subtypes of depression attained better responses with buspirone than others.  Analysis of the dosing revealed that substantial mood improvements were more likely to be attained at a dose of 40 mg/day.

At the time of this publication (1990), another azapirone referred to as “Gepirone” was in clinical trials and demonstrated preliminary efficacy as an antidepressant.  Gepirone is an analogue of buspirone that is highly selective for 5-HT1A receptors and as of 2016, was approved by the FDA for the treatment of major depression in an “extended-release” (ER) format.  Based on this report from the 1990s, there’s reason to believe that buspirone effectively treats depression as a monotherapy when administered at 40 mg/day.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2198303

1991: Buspirone in major depression: a controlled study.

A study conducted by Rickels et al. (1991) tested the therapeutic efficacy of buspirone among 155 outpatients diagnosed with major depression and anxiety.  The study was double-blinded, placebo-controlled, and involved assigning participants to receive either: buspirone (up to 90 mg/day) OR a placebo control – for a duration of 8 weeks.  It was noted 34% of buspirone recipients and 41% of placebo recipients dropped out of the trial prior to its completion.

To gauge the efficacy of buspirone, researchers measured physician-rated and patient-rated symptomatic severity of each participant before the trial, as well as after the 8-week treatment period.  Results indicated that patients receiving buspirone experienced significant reductions in symptoms of depression compared to those receiving the placebo control.  It was noted that 70% of buspirone recipients “moderately” or “markedly” improved after the 8 weeks (p < 0.01) compared to just 35% of placebo recipients.

Researchers concluded that buspirone (at doses up to 90 mg/day) is an effective, safe, and tolerable intervention for the simultaneous treatment of depression plus anxiety.  What’s more, the severity of a person’s baseline depression and anxiety had zero influence upon degree of symptomatic improvement resulting from treatment.  Clearly, this study supports the usage of buspirone for the treatment of major depression and comorbid anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1988416

1998: Buspirone augmentation of antidepressant therapy.

Dimitriou and Dimitriou (1998) conducted a study assessing the efficacy of buspirone as an adjunct to first-line antidepressants.  For this study, researchers recruited 30 individuals with major depression (in accordance with DSM-III-R / DSM-IV diagnostic criteria) to participate.  All 30 participants had previously undergone treatment with a properly-dosed antidepressant for a minimum of 6 weeks, yet failed to experience symptomatic improvement.

Thereafter, these individuals were assigned to receive adjunct buspirone at dosages between 20 mg/day and 30 mg/day – for a duration of 4 to 5 weeks.  Of the 30 participants, 22 patients were using an SSRI and the remaining 8 patients were using a TCA.  To determine the efficacy of buspirone as an adjunct, researchers compared scores on the CGI (Clinical Global Impressions) scale before and after treatment.

Results indicated that 13 of the 22 SSRI users (59%) and 5 of the 8 TCA users (63%) experienced full or partial symptomatic remission as a result of adjunct buspirone.  Average scores on the CGI dropped from ~4.7 (pre-Buspar) to ~1.7 (after 4-5 weeks of Buspar).  A follow-up analysis was conducted 4 months after the trial and 11/14 (79%) of responders sustained clinically significant reductions in depressive symptoms.

It was concluded that antidepressant augmentation with buspirone appears to significantly reduce depressive symptoms among non-responders to conventional antidepressant monotherapy.  Based on these findings, we can also deduce that the efficacy of buspirone as an adjunct is not contingent upon the classification of antidepressant with which it is administered.  Moreover, it is promising that therapeutic antidepressant benefits were maintained for an additional 4 months post-trial [in a majority of responders].

Despite results of this trial supporting the efficacy of buspirone as an antidepressant adjunct, it is necessary to discuss the trial’s problematic design.  The design of the trial lacks randomization, controlling, and blinding – and also presents a small sample (just 30 participants).  Though buspirone may be a legitimately effective antidepressant adjunct, the evidence from this trial to support its efficacy is weak.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9864079

1998: A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression.

Landén, Björling, Agren, and Fahlén (1998) mentioned that, based upon data from open-label and case studies, the addition of buspirone to an SSRI appeared effective for the treatment of refractory depression.  However, open-label and case studies are limited in that they do not incorporate randomization or placebo-controls, making it difficult to trust the results.  For this reason, Landén et al. opted to conduct the first ever placebo-controlled trial to assess the efficacy of an SSRI plus buspirone for the treatment of resistant depression.

A total of 119 patients that met DSM-IV diagnostic criteria for major depressive episodes were recruited for participation.  It was noted that all participants previously had failed to respond to administration of a standalone SSRI (citalopram or paroxetine) for a 4-week duration.  Participants were assigned at random to receive either: an SSRI plus buspirone (58 patients) OR an SSRI plus placebo (61 participants) for 4 weeks.

To determine whether buspirone was an efficacious adjunct, researchers documented changes in CGI-I (Clinical Global Impressions-Improvement) scale scores – both before and after the 4-week study duration.  Results indicated that there were no significant differences in responses to the buspirone adjunct compared to the placebo adjunct.  Specifically, 50.9% of buspirone recipients experienced symptomatic improvement, whereas 46.7% of placebo recipients experienced symptomatic improvement.

This suggests that buspirone offers no additional benefit as an adjunct for the management of depressive symptoms.  There appeared to be no differences in adverse effects, suggesting that buspirone was as tolerable as the placebo.  Of some interest was the fact that researchers conducted an optional follow-up evaluation in which 97 individuals agreed to participate.

The follow-up evaluation revealed that 69.4% of individuals receiving an SSRI plus buspirone experienced significant reduction of depressive symptoms, suggesting that buspirone may have taken longer than 4 weeks to fully deliver a therapeutic effect.  Some have suggested that an abnormally strong placebo response may have affected the results of this study.  Moreover, while it appears as though buspirone isn’t effective as an SSRI adjunct, this finding may be limited based upon the short study duration and strong placebo response.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9921700/

2001: Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study.

Researchers Appelberg et al. (2001) sought to determine the efficacy of buspirone as an adjunct to SSRIs for the treatment of severe depression.  Prior to their research, it was noted that case reports and open-label trials suggested the therapeutic usefulness of buspirone among those with refractory depression when combined with SSRIs.  However, no randomized, placebo-controlled, double-blinded trials had been able to prove superiority of adjunct buspirone to that of an adjunct placebo when administered with SSRIs.

Appelberg et al. set-up a trial including 102 outpatients meeting diagnostic criteria for major depressive episodes.  All 102 outpatients had failed to derive sufficient therapeutic relief from at least 6 weeks of treatment with an SSRI (fluoxetine or citalopram).  Initially, the depressed outpatients participated in a single-blinded placebo wash-in period of 2 weeks while they continued their SSRI.

Following the single-blinded wash-in phase, participants were assigned at random to receive either: buspirone 10-30 mg (b.i.d.) OR a placebo – for a duration of 6 weeks.  To determine whether the adjunct buspirone was more effective than the adjunct placebo, researchers compared severity of depressive symptoms before and after the trial.  Changes in severity of depressive symptoms were tracked using the: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions scale (CGI), and visual analogue scales.

It was noted that within the first week of treatment, those receiving the adjunct buspirone exhibited significant reductions in MADRS scores compared to individuals receiving the adjunct placebo.  Despite the significant reduction in depressive symptoms (based on MADRS scores) after 1 week among buspirone recipients, there were no significant differences in symptomatic severities between buspirone and placebo groups following the entire 6-week trial duration.  Of interest, however, was the fact that patients with high baseline scores on the MADRS (30+) experienced statistically significant reductions in depressive symptoms with adjunct buspirone compared to with adjunct placebo.

At first glance, it appears as though buspirone is an ineffective SSRI adjunct for the treatment of major depression.  However, a closer look reveals that adjunct buspirone significantly reduced depressive symptoms among those with the severest cases of depression (MADRS scores of 30+) compared to the adjunct placebo.  Researchers concluded that patients with severe cases of major depression may derive therapeutic antidepressant effects from adjunct administration of buspirone (10 to 30 mg, b.i.d.).

Moreover, based on the finding that depression was significantly reduced after 1 week among those receiving buspirone (adjunct) compared to the placebo (adjunct), authors hypothesize that buspirone may expedite onset of antidepressant action.  Other agents that modulate activity at 5-HT1A receptors appear to accelerate antidepressant effects by disinhibiting serotonergic neurons.  Whether buspirone facilitates a similar effect to accelerate onset of SSRI action warrants further research.

Results of this study can be considered fairly reliable in that: a reasonable sample size was utilized (102 participants), a randomized controlled design (RCT) was implemented, and duration was sufficient to detect an antidepressant response (6 weeks).  Additionally, dosing of buspirone administered (10 to 30 mg, b.i.d.) is consistent with previous evidence suggesting greatest antidepressant benefit from ~40 mg/day.  Overall, the results of this study support the therapeutic usefulness of adjunct buspirone among those with the severest cases of depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11465522

2003: Faster response in depressive patients treated with fluoxetine alone than in combination with buspirone.

Onder and Tural (2003) set up a trial to compare the efficacy of conventional antidepressant monotherapy to that of an antidepressant plus adjunct buspirone.  For their trial, researchers recruited 120 patients diagnosed with unipolar depression (based on DSM-IV criteria).  All patients were assigned to receive either: fluoxetine (20 mg or 40 mg per day) OR fluoxetine (20 mg/day) plus buspirone (20 mg/day).

Prior to treatment (at baseline), researchers measured severity of depressive symptoms using the Hamilton Depression Rating Scale (HDRS).  Efficacy of each treatment strategy was assessed based upon the number of individuals that experienced at least a 50% reduction in HDRS total scores from pre-treatment to post-treatment (weeks thereafter).  Results indicated that the number of responders didn’t differ between the “fluoxetine-only” and the “fluoxetine plus buspirone” groups.

This suggests that there is no significant benefit associated with administration of adjunct buspirone for the treatment of depression.  Not only did adjunct buspirone fail to offer additional mood enhancing benefit, but it appeared to delay onset of antidepressant efficacy.  A survival analysis documented significantly quicker reduction in symptoms of depression among individuals receiving standalone fluoxetine compared to those receiving fluoxetine plus buspirone.

Researchers noted that the sample of participants was devoid of individuals with treatment-resistant depression.  Since buspirone is generally reserved for adjunctive usage among those with treatment-resistant depression, this was reported as a limitation.  That said, data from this study suggests that buspirone is ineffective as an SSRI adjunct for the treatment of depression, and may actually be problematic in that it appears to prolong onset of antidepressant action.

Besides a lack of individuals with treatment-resistant depression, other limitations of this study include: lack of 40 mg fluoxetine dose among adjunct recipients and the low dosage of buspirone administered.  Perhaps one reason the fluoxetine-only group responded quicker to treatment was related to more participants taking 40 mg (compared to 20 mg).  If the buspirone group would’ve been given 40 mg fluoxetine, speed of symptomatic reduction may have been similar.

It is also reasonable to consider that the adjunct buspirone dosage may have been too low to deliver a mood enhancing effect.  If adjunct buspirone would’ve been administered at a higher dose (e.g. 40 mg/day), adjunct efficacy may have been greater.  Despite evidence from this study suggesting that buspirone is a poor adjunctive intervention, limitations necessitate addressing in future research.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12943952

2006: Medication augmentation after the failure of SSRIs for depression.

Some estimates suggest that up to 1 in every 3 patients with major depression respond insufficiently to antidepressant monotherapy.  For this reason, it is common for medical professionals to prescribe a secondary agent as an adjunct with the hope that it will potentiate the antidepressant effect of the first-line, primary agent.  Despite the regular practice of prescribing adjuncts to improve therapeutic outcomes among the depressed populace, effectiveness of adjuncts remained unclear until the STAR*D trial.

Trivedi et al. (2006) reported upon results from the STAR*D trial in which buspirone was evaluated.  A total of 565 adults with major depression (that had undergone nearly 12 weeks of treatment with citalopram) were assigned to receive either: Buspirone (up to 60 mg/day) OR Bupropion (up to 400 mg/day) – as an adjunct to their SSRI.  Efficacies of each intervention were determined based on change in HRSD-17 (Hamilton Rating Scale for Depression) and QIDS-SR-16 (Quick Inventory of Depressive Symptomatology) scores.

Results suggested that adjunctive Buspirone and Bupropion significantly reduced depressive symptoms (as evidenced by changes in HRSD and QIDS scores).  Of interest to researchers was the fact that, QIDS scores revealed that adjunctive bupropion was more effective than buspirone.  Furthermore, dropout rates suggested that bupropion was likely better tolerated than buspirone.

Though adjunct bupropion may be advantageous over adjunct buspirone for the treatment of depression, both were effective interventions and neither differed from the other in regards to the primary outcome measure of change in HRSD scores.  Overall, this STAR*D trial supports the usage of buspirone among those with treatment-resistant depression.  Although this was a large trial with hundreds of participants, and it appears as though adjunct buspirone is therapeutically effective as an adjunct, the lack of a control (e.g. placebo) is problematic.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16554526/

2006: An Evidence-Based Approach to Augmentation and Combination Strategies for: Treatment-Resistant Depression.

Barowsky and Schwartz (2006) discuss evidence-based pharmacological approaches for the management of treatment-resistant depression (TRD).  Authors reflect upon published literature dating from 1989 through 2005, noting that buspirone may be a therapeutically effective antidepressant adjunct.  It was mentioned that, analogous to the beta-blocker pindolol, buspirone acts upon the 5-HT1A receptor, a mechanism which may disinhibit neurons to release serotonin.

Assuming buspirone facilitates additional release of serotonin into the intrasynaptic space, this enhancement of serotonergic transmission may complement the presynaptic reuptake inhibition provided by SSRIs.  It may be that this desensitizes postsynaptic receptors at a faster rate (to accelerate antidepressant action) or potentiates antidepressant efficacy.  In their report, authors discuss results from the STAR*D trial in which using buspirone as an SSRI adjunct was superior in therapeutic efficacy to a standalone SSRI [among those with refractory depression].

Results from several distinct open-label trials were also discussed in which adjunct buspirone (20-30 mg/day) significantly alleviated depressive symptoms among partial and insufficient responders to a standalone SSRI or TCA.  Furthermore, follow-up data documented that antidepressant efficacy of adjunct buspirone was maintained for upwards of 3 months post-trial.  Contrarily, data from multiple randomized controlled trials suggested that buspirone as ineffective as an SSRI adjunct among those with resistant-depression.

That said, in one of the randomized controlled trials in which ineffectiveness of adjunct buspirone was noted, a clinically significant reduction in depressive symptoms was observed for individuals with severe depression.  What’s more, data from the STAR*D trial suggests that 20-30 mg/day buspirone are effective for the treatment of major depression.  Since the data are still somewhat mixed regarding buspirone’s antidepressant efficacy, authors of this report recommend further randomized controlled research.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20975817

Limitations of research associated with Buspar for depression

There are some obvious limitations associated with the research of Buspar as a treatment for depression.  Perhaps the most notable limitation is the lack of randomization and controlling in a majority of studies.  Other limitations that warrant discussion include short trial duration and strong placebo responses.  At this time, the overall lack of research investigating the antidepressant efficacy of buspirone makes it difficult to know whether it’s legitimately effective [as an adjunct or monotherapy] for the management of depression.

  • Depressive subtypes: It is largely understood that not all individuals with major depression exhibit the same neurochemical and physiological abnormalities. A subset of depressed individuals appears to benefit more from serotonergically-acting medications, whereas others derive greater benefit from non-serotonergic agents.  Knowing that certain depressive subtypes may respond better to buspirone than others, studies in which a majority of the the participants present a neurochemical mismatch [to benefit from buspirone] may have yielded flawed results.  While at this time it is impossible to pinpoint who may be likely to respond to buspirone compared to others, this may warrant future consideration if the technology becomes available.  As of now, evidence suggests that buspirone may be more effective among individuals with melancholic or anxious features.
  • Designs: The biggest problem with research of buspirone as an antidepressant is the lack of randomized controlled designs. In the current literature, there are only 2 randomized controlled trials assessing the efficacy of buspirone as an adjunct – and just 1 randomized controlled trial assessing its efficacy as a monotherapy.  Most of the evidence supporting the usefulness of buspirone in the management of depression comes from open-label and pilot studies.  Any future research should focus on implementing only randomized controlled designs.
  • Duration: It is understood that buspirone exhibits a delayed onset of action, often taking 4 to 8 weeks to deliver its full therapeutic effect. The fact that some studies only tested the efficacy of buspirone over a 4-week duration is problematic in that the drug may have lacked sufficient time to improve mood.  Knowing that buspirone’s effect isn’t always seen within 4 weeks, studies should be designed to evaluate changes in mood from baseline through a minimum of 6 weeks – but preferably 8 weeks.  A longer duration (for randomized controlled trials) should help researchers understand whether buspirone is legitimately effective as an antidepressant.
  • Follow-ups: There are some concerns as to whether buspirone’s antidepressant efficacy and tolerability (as an adjunct) are sustained over an extended or long-term duration. Some studies have implemented follow-up evaluations that occurred months after a trial, many of which documented favorable outcomes.  Nevertheless, there may be a need for longer-term follow-up evaluations such as after 6-months or 1-years of its administration.
  • Lack of research: Only 5 studies investigating the antidepressant effect of buspirone have been published from 1990 to 2006. Of these 5 studies, 3 appear to be randomized controlled trials – with several flaws.  The overall paucity of research, as well as quality research, makes it nearly impossible to know whether buspirone is a legitimately-effective antidepressant intervention.  Results from quality trials need to be published before we can fully understand whether buspirone is helpful in treating depression.
  • Monotherapeutic efficacy: There is a single randomized controlled trial by Rickels et al. (1991) documenting the antidepressant potential of buspirone monotherapy, however, it appears as though no follow-up studies were published. Although the results from this single trial suggest that Buspar (up to 90 mg/day) could effectively treat depression, more research is needed to support its usage as a standalone antidepressant.  Intriguing may be the fact that Gepirone (a spinoff of Buspar) may be approved as an antidepressant.
  • Placebo responses: In one of the randomized controlled studies, there was a strong response to administration of an adjunct placebo control. Since nearly half of all patients experienced significant symptomatic reductions as a result of the placebo, authors reported that the placebo response was “unusually strong.”  The strong response to the adjunct placebo may have been reason as to why buspirone was reported as ineffective.

Is Buspar effective for the treatment of depression?

It remains questionable as to whether buspirone should be used in the treatment of depression.  While no professional would consider prescribing buspirone as a standalone, monotherapeutic intervention for mood enhancement – many have prescribed it as an antidepressant adjunct.  Its usage as an adjunct is justified among depressed patients with comorbid anxiety is justified on the basis that it is FDA-approved for the treatment of generalized anxiety disorder.

When considering that excessive anxiety can impair functioning in numerous areas of life (e.g. relationships, occupational productivity, etc.) – it becomes obvious that failure to treat anxiety could lead to onset or exacerbation of depression.  By using buspirone to treat anxiety [that may have been culpable for induction of depression], it is possible that both anxiety and depression OR “anxious depression” may clear up.  It is also possible that high-dose buspirone might be effective as a standalone treatment for depression.

A placebo-controlled, double-blinded trial by Rickels et al. (1991) documented that administration of buspirone (up to 90 mg/day) significantly reduced depression and anxiety among those with depression plus anxiety.  Despite promising results from the aforestated trial, no further research investigated standalone buspirone for treatment of depression.  For this reason, there’s insufficient evidence to support standalone clinical usage of buspirone for depression.

Of the 2 randomized controlled trials that tested buspirone’s therapeutic efficacy as an SSRI adjunct, neither found it to be more effective than a placebo.  Based on these findings, it doesn’t appear that buspirone is a useful intervention among individuals with major depression.  While data from open-label trials, case reports, and the STAR*D study suggests buspirone is effective as an antidepressant adjunct – none of these implemented a placebo control, making results highly questionable.

In 1 randomized controlled trial, it was discovered that adjunct buspirone may have accelerated the onset of antidepressant action [as evidenced by significant reductions in depressive symptoms within 1 week compared to a placebo adjunct].  That said, in successive weeks (beyond the first week), there were no statistically significant differences in depressive symptoms between the buspirone recipients and placebo recipients.  Furthermore, the finding that adjunct buspirone may have accelerated action of an SSRI remains unsubstantiated in the literature.

In fact, opposing evidence from Onder and Tural (2003) suggests that, when administered as an SSRI adjunct, buspirone appears to delay onset of antidepressant action.  At this time, the only quality evidence to support the usage of buspirone as an antidepressant adjunct is from a RCT by Appelberg et al. (2001).  Although Appelberg et al. discovered zero differences in the efficacies of buspirone and placebo adjuncts among their entire sample of individuals with depression, statistically significant differences in efficacies were observed in a subset of participants.

Only the subset of participants that exhibited the severest depressive symptoms derived statistically relevant therapeutic benefit from buspirone as an antidepressant adjunct.  This finding was evidenced by the fact that depressive symptoms significantly improved among individuals with scores of at least 30 points on the MADRS (Montgomery-Asberg Depression Rating Scale).  From this information, we can conclude that while adjunctive buspirone may reduce depression among those with severe cases, it is unlikely to benefit individuals with mild-to-moderate cases.

In summary, while preliminary research suggests that buspirone may be of benefit to those with depression plus comorbid anxiety (i.e. “anxious depression”) and/or among individuals with the severest cases depression, follow-up studies are warranted to confirm these findings.  At this time, there’s a lack of data to support usage of buspirone among those with major depression (especially if devoid of comorbid anxiety).  For a drug that’s been FDA approved since 1986, it’s somewhat surprising that there isn’t more research evaluating its efficacy as an adjunct and monotherapy among those with depression.

What dosage of buspirone is effective for depression?

Although there’s currently insufficient evidence to support the usage of buspirone for the treatment of depression (as a monotherapy or adjunct), this doesn’t mean it’s automatically ineffective for all users.  Additionally, many psychiatrists continue prescribing it as an antidepressant adjunct among individuals with treatment-resistant depression based on results from the STAR*D trial.  A psychiatrist or psychopharmacologist is most qualified to determine optimal dosing of buspirone for the treatment of depression.  Below is what the available research suggests regarding dosing strategies of buspirone for depression.

  • Adjunct: When administered as an adjunct to an SSRI (or along with other antidepressants), likelihood of side effects and/or interaction effects increases at high doses. For this reason, it may be a smart option to keep the dose of buspirone as low as possible without compromising its adjunctive efficacy.  Research indicates that administration of 20 mg to 60 mg buspirone per day may be useful as an antidepressant adjunct.
  • Monotherapy: It is highly unlikely that any professional would prescribe buspirone as an antidepressant monotherapy. That said, it has undergone some testing as a monotherapeutic intervention for depression and dosages were documented.  When used as a monotherapy, buspirone appears to deliver greatest antidepressant benefit at around 40 mg per day.  In the research, buspirone wasn’t introduced at high doses, rather it was initially administered at 15 mg per day and titrated upwards to a maximum dose of 90 mg per day.  It is possible that a slow titration may improve tolerability and responses of patients.

Who is most likely to benefit from using Buspar for depression?

There’s no definitive way to know who is likely to benefit most from administration of buspirone for the treatment of depression.  Since buspirone is an effective anxiolytic, it should be suspected that most benefit will be attained from individuals in which anxiety influences severity of depressive symptoms.  Anyone with depression plus comorbid anxiety (i.e. “anxious depression”) should stand to benefit more from buspirone than others.  There is modest evidence suggesting that individuals with the most severe symptoms of depression may benefit from adjunctive buspirone.

  • Depression with anxiety: Those with simultaneously occurring depression and anxiety often report a bidirectional relationship between depressed mood and anxious symptoms. When the anxiety flares up, they isolate themselves from others and it makes them depressed.  The depression leads them to think poorly of themselves and their abilities, causing increased future anxiety – it’s a vicious circle.  It is known that buspirone is effective for the treatment of anxiety and preliminary evidence suggests it could improve mood.  Evidence suggests that it is an effective option among those with “anxious depression.”
  • Severe depression: Analysis of data from a standalone randomized controlled trial indicated that adjunct buspirone may help individuals with severe depression. The “severe depression” was classified as MADRS scores exceeding 30.  In the event that a person exhibits severe depression to the extent that they’re scoring at least 30 (or above) on the MADRS (Montgomery-Asberg Depression Rating Scale), adjunct buspirone may be helpful.

Have you tried Buspar for depression?

If you suffer from major depression and have taken buspirone, share whether you found it to be a useful antidepressant in the comments section below.  In your anecdotal experience, rate the antidepressant efficacy of buspirone on a scale of 1 to 10 (with 1 being completely ineffective, and 10 being highly effective).  To help others get a better understanding of your situation, provide some additional details including your: dosage (e.g. 20 mg, b.i.d.), duration of administration (e.g. 6 months), and whether you used it as a standalone monotherapy or antidepressant adjunct.

Assuming you utilized buspirone as an adjunct, document the first-line antidepressant medication with which it was administered (as well as its dosage).  In the event that you found buspirone effective for the enhancement of mood, how long did it take for a substantial mood change to emerge after initiation of buspirone treatment?  Since buspirone is understood to be effective for the treatment of anxiety, and anxiety/stress can cause depression, do you believe that buspirone may have improved your mood mostly by reducing anxiety?

In summary, it is clear that buspirone is a potentially-useful intervention for the treatment of major depression – especially among patients with depression plus generalized anxiety disorder (or those with “anxious-depression”).  It is also possible that buspirone may be useful among those with treatment-resistant depression, however, evidence from randomized controlled trials to support its usage remains insignificant (even as an adjunct).  Most would agree that, by comparison, many antidepressant monotherapies and adjuncts are superior choices to buspirone.

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