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Travivo (Gepirone ER) For Depression & Anxiety

Travivo (Gepirone ER) is a pharmaceutical medication of the “azapirone” classification exhibiting a combination of anxiolytic, antidepressant, and libido-enhancing properties, similar to the drug Buspar (Buspirone).  It was originally synthesized in 1986 by the company Bristol-Myers Squibb, and its licensing rights were acquired by the company Fabre-Kramer in 1993.  In 1998, Fabre-Kramer out-licensed Gepirone to Organon International for further development and commercialization.

Thereafter, Gepirone underwent clinical trials to evaluate its therapeutic potential as a treatment for anxiety and depression.  Its favorable safety profile and efficacy throughout Phase III of clinical trials lead Organon to submit a new drug application for Gepirone in 2002 and 2004, but the FDA rejected its approval on both accounts.  Fabre-Kramer reacquired licensing rights of Gepirone in 2005, partnered with GSK and eventually resubmitted the drug for FDA approval in 2007 to be sold under the brand name “Velexity.”

Despite additional data being included in the resubmission, the FDA panel remained dubious of its efficacy, predictably rejecting it.  Clinical trial data was revised again by Fabre-Kramer and the Gepirone was resubmitted for yet another reevaluation in 2015, however, the FDA remained skeptical of its ability to treat neuropsychiatric disorders and gave it a negative review.  In an unexpected 2016 plot-twist, the FDA rescinded its negative opinion of Gepirone and paved the way for its imminent approval.

Travivo (Gepirone ER) for Anxiety & Depression (Mechanism of Action)

The mechanism of action associated with Travivo (Gepirone ER) primarily involves partial agonism of the 5-HT1A receptor.  Partial agonism of the 5-HT1A receptor is the principal means by which the drug appears effective as a treatment for certain types of anxiety, depression, and/or anxious depression.  Another potentially useful effect of Gepirone is its stimulation of oxytocin release within the paraventricular nucleus (as an indirect effect of agonizing 5-HT1A receptors).

Though 5-HT1A partial agonism accounts for the bulk of the drug’s therapeutic effect, its major metabolite known as 1-PP (1-(2-pyrimidinyl)piperazine) might play a role.  The 1-PP metabolite functions by binding to α2-adrenergic receptors as an antagonist, which may also modulate sensitivity of these receptors and norepinephrine turnover – each of which may enhance mood and/or decrease anxiety.  Moreover, Gepirone alters activity in the HPA axis, plus may reduce markers of oxidative stress and inflammation.

5-HT1A partial agonist: Analogous to other azapirones, Gepirone functions predominantly as a partial agonist of the 5-HT1A receptor to reduce anxiety and uplift mood.  A study by Söderpalm, Hjorth, and Engel (1989) was among the first to assess the effect of Gepirone and its metabolite (1-PP) in hypersensitive animal models, with results showing profound anxiolytic reactions after administration.  At the time, researchers attributed the anxiolytic responses to agonism of 5-HT1A receptors by Gepirone.

Studies in humans would later confirm that Gepirone delivers a bulk of its anxiolytic and antidepressant effect through the 5-HT1A receptor as a partial agonist.  When compared to the related drug Buspirone, Gepirone exerts a stronger partial agonist effect upon 5-HT1A receptors, possibly yielding more pronounced anxiolytic and/or antidepressant responses among users.  Specifically, Gepirone is suspected to function as a: 5-HT1A heteroreceptor partial agonist (in frontal and hippocampal regions), presynaptic 5-HT1A autoreceptor agonist (in the somatodendritic region), and postsynaptic 5-HT1A receptor partial agonist.

There’s little disputing that 5-HT1A agonism is capable of reducing anxiety and enhancing mood.  Evidence to support the idea that 5-HT1A partial agonism may treat anxiety and depression is derived from research by Blier and Ward (2003).  In their paper, Blier and Ward assessed individuals who respond favorably to antidepressants and anxiolytics, noting that responders exhibited significant changes in 5-HT1A receptor activity compared to non-responders.

Blier and Ward are not alone in their findings, previous research suggested that antidepressant efficacy may be associated with changes in the functioning and/or sensitization of 5-HT1A pre- and post- synaptic receptors.  Humans with panic disorder tend to exhibit impairments in 5-HT1A receptor function, and multiple neuroimaging studies have showed reduced 5-HT1A binding among patients with untreated anxiety.  Since Gepirone binds to 5-HT1A receptors, this mechanism may reverse impaired 5-HT1A function implicated in anxiety, ultimately attenuating anxious feelings.

Among patients with depression, research shows downregulation of 5-HT1A receptors and/or dysfunction of their activity.  It is thought that many FDA-approved antidepressants improve mood as a result of their ability to enhance signaling of the postsynaptic 5-HT1A receptor.  Knowing that the 5-HT1A receptor abnormalities are implicated in anxiety and depression, as well as that Gepirone chiefly targets these receptors, explains why it may be effective for some individuals.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2567524
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Oxytocin release: Another possibly important means by which Gepirone may alleviate symptoms of depression and anxiety is by enhancing the secretion of oxytocin.  Though Gepirone doesn’t contain exogenous oxytocin nor does it act directly on oxytocin receptors, there’s a connection between 5-HT1A receptors and oxytocin release.  As a byproduct of agonizing 5-HT1A receptors, some oxytocin may get released in certain regions of the brain.

Specifically, a subset of 5-HT1A receptors located in certain regions of the brain happen to be positioned directly atop oxytocin-containing neurons.  When Gepirone agonizes a portion of the 5-HT1A receptors, the oxytocin-containing neurons release their oxytocin into the central nervous system.  The increase in oxytocin concentrations may contribute partially to Gepirone’s anxiolytic and antidepressant efficacy.

Oxytocin is a neuropeptide capable of affecting cognitive function, emotional states, and social behaviors.  In optimal amounts, oxytocin boosts mood, increases feelings of comfort (or reduces anxiety) in social situations, and is implicated in partner bonding.  It is understood that various subtypes of depression and/or anxiety are caused in part by deficits and/or dysfunction of oxytocin systems.

Research by Cyranowski et al. (2008) documented abnormal peripheral oxytocin release among women with major depression compared to non-depressed women.  Other evidence suggesting a possible role of oxytocin in depression comes from a report by Neumann and Landgraf (2012), noting that when oxytocin and vasopressin levels were imbalanced, mental health was poor.  The role of oxytocin in anxiety has been documented in multiple studies, including one by Hoge, Pollack, Kaufman, et al. (2008) in which severity of social anxiety was inversely correlated with level of plasma oxytocin.

A paper by Neumann and Slattery (2016) mentions imbalances in oxytocin among individuals with many types of anxiety disorders, especially social anxiety.  Gepirone may reverse and/or ameliorate oxytocin dysfunction as a result of the 5-HT1A receptor agonist-mediated secretion.  Evidence to support that 5-HT1A agonists enhance oxytocin secretion comes from a study by Bagdy and Kalogeras (1993).  These researchers administered azapirones (like Gepirone) to animals and measured plasma oxytocin levels pre- and post-administration to determine whether there was any change.

It was discovered that the azapirones markedly increased plasma oxytocin levels, and that the increases were contingent upon the dose; the greater the dose, the more substantial the increase.  Another interesting finding was that if 5-HT1A receptor antagonists (blockers) were administered prior to 5-HT1A receptor agonists (stimulators), oxytocin increases were negligible.  This provides clear evidence that 5-HT1A receptor activation is capable of upregulating oxytocin levels in animal models.

It’s fairly unclear as to whether 5-HT1A agonism upregulates oxytocin in humans, however, many suspect that it does.  Research by Chiodera et al. (1996) administered 15 mg Buspirone to patients [with hypoglycemia] and documented significant increases in oxytocin secretion.  That said, this effect hasn’t been well-researched among patients with normative glucose levels, meaning further research is warranted to confirm the hypothesized effect.  Nevertheless, since Gepirone exerts a more potent effect upon 5-HT1A receptors than Buspirone, its 5-HT1A receptor-mediated oxytocin secretion should be predictably more substantial.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8334526
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HPA axis modulation: Another mechanism by which Gepirone might attenuate symptoms of anxiety, depression, and/or anxious-depression is through modulation of activity in the HPA (hypothalamic pituitary adrenal) axis.  Activation of the HPA axis is shaped based on a person’s genetics, early childhood development, and exposure to stressors.  If the HPA axis becomes dysregulated by genes and excessive environmental stress, a person may experience anxiety, depression, and increased vulnerability to addictive behaviors.

Research by Du and Pang (2015) notes that dysregulation of the HPA-axis is implicated in the pathology of major depression.  When a person responds favorably to antidepressant therapy (e.g. an SSRI), activity in the HPA-axis is altered, possibly contributing to mood enhancement.  Other research by Faravelli, Lo Suaro, Lelli, et al. (2012) mentions dysfunctional HPA axis activity as being associated with many types of anxiety disorders including: PTSD, panic disorder, generalized anxiety disorder, OCD, and social phobia.

What’s more, Cameron (2006) reports that among individuals with “anxious depression” (comorbid anxiety and depressive disorders), HPA reactivity was elevated compared to persons with standalone disorders (e.g. anxiety-only OR depression-only).  If left dysregulated, HPA activation may lead to heightened cortisol and corticotropin-releasing hormone (CRH), reduced adrenocorticotropic (ACTH) response to CRH, reduced hippocampal volume, and increased suicide risk.

There’s modest evidence to support the idea that Gepirone modulates HPA axis activity to exert its therapeutic anxiolytic-antidepressant combination effect.  Work by Matheson, Knowles, Gage, et al. (1997) discovered that Gepirone modulated HPA activity in a dose-dependent manner among rats.  Another study by Malmkvist, Hansen, and Damgaard (2003) mentioned that administration of Buspirone (a similar drug to Gepirone) normalized HPA axis activity among fearful mink, which lead to more confident behaviors.

Activity in the HPA axis influences function of the adrenal cortex, hypothalamus, pituitary gland, as well as the secretion of neuropeptides such as: ACTH, oxytocin, vasopressin, beta-endorphin, epinephrine, and norepinephrine.  Assuming Gepirone modulates activity within the HPA axis, it may normalize activation of unfavorable feedback loops (e.g. associated with stress), thereby reducing anxiety and improving mood.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25806005
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Alpha-2 receptor antagonist: The chief metabolite of Gepirone is 1-PP (1-(2-pyrimidinyl-piperazine) which functions as an alpha-2 receptor antagonist.  Alpha-2 receptor antagonists are understood to enhance norepinephrine, dopamine, and serotonin signaling, while simultaneously inducing secretion of insulin and lowering blood sugar concentrations.  Various drugs with alpha-2 antagonist properties have been used for the treatment of major depression, including: mianserin and mirtazapine, although it remains unclear as to whether this particular mechanism contributed to mood enhancement.

Some have speculated that alpha-2 receptor activation may be abnormal among persons with anxiety and/or depression.  A study by Karege, Bovier, and Widmer (1992) documented altered densities and sensitivities of alpha-2 receptors among persons with major depression compared to euthymic individuals.  While a subset of individuals might benefit more from agonism (stimulation) of the alpha-2 receptor, others are thought to respond better to its antagonism (blockade).

Blocking the alpha-2 receptor is understood to enhance sexual function which is often suboptimal among those with depression and/or anxiety.  Research by Invernizzi and Garattini (2004) notes that co-administration of alpha-2 receptor antagonists augment SNRI, NDRI, and/or NRI-induced increases in extracellular norepinephrine throughout various regions of the brain.  If deficient noradrenergic signaling was implicated in a person’s depression and/or anxiety, Gepirone’s 1-PP metabolite may prove therapeutic through its alpha-2 receptor antagonism.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1359596
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/3021082
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15363606

Locus Coeruleus modulation: Azapirones such as Gepirone are understood to upregulate activity within the locus coeruleus, possibly a means by which they treat depression.  The locus coeruleus is located in the pons portion of the brainstem and alters physiology when faced with fear or stress by synthesizing norepinephrine.  In fact, the locus coeruleus is the predominant subregion of the brain responsible for norepinephrine synthesis.

In addition, the locus coeruleus can influence our arousal, attention, balance, cognition, and emotion.  Those with suboptimal locus coeruleus activation may experience a combination of depression and anxiety.  Though it may not seem as though enhancing noradrenergic activity [in the locus coeruleus] would help anxiety, research by Weiss et al. (1994) showed that increased firing of locus coeruleus neurons resulted in decreased anxious behavior among mice, whereas impaired firing increased anxiety.

The combination of anxiety and depression (or stress-related depression) is associated with suboptimal firing rate of noradrenergic neurons in the locus coeruleus.  Work by Klimek et al. (1997) documented deficient norepinephrine and norepinephrine transporter (NET) activity in the locus coeruleus among persons with major depressive disorders – compared to those without depression.  Since research by Piercey, Smith, and Lum-Ragan (1994) supports the idea that Gepirone increases firing rates of norepinephrine in the locus coeruleus, this may be yet another mechanism by which it treats anxious depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8138943
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Note:  It is known that 5-HT1A partial agonism, and corresponding downstream effects of this agonism are responsible for the bulk of Gepirone’s therapeutic effect.  That said, there may be other neurological targets contributing [slightly] to its anxiolytic and/or antidepressant effect that haven’t been formally reported in the literature (e.g. oxidative stress and/or inflammation reduction).  Additionally, though gepirone may have a modest affinity for various dopamine receptor sites (e.g. D2) as an antagonist, its antagonism of dopamine receptors is unlikely to deliver any therapeutic effect among those with anxiety and/or depression.

Benefits of Travivo (Gepirone ER) for Depression and Anxiety (Possibilities)

There are numerous possible benefits associated with Travivo (Gepirone ER) for depression and/or anxiety.  While the drug is certainly capable of treating depression, anxiety, and “anxious depression” as a standalone, perhaps the drug’s most significant benefit is unrelated to its effect on mood.  Research shows that Gepirone ER significantly enhances sexual function and desire among men and women with major depression.  Other potential benefits to be attained from Gepirone ER include its: tolerability, safety, extended-release format, and advantage over Buspirone.

  • Adjunct (SSRI) intervention: Though Gepirone ER hasn’t been clinically evaluated as an antidepressant adjunct, based on its similarity to Buspar (a drug commonly used as an SSRI adjunct), most would predict that Gepirone ER is likely to be tolerable and efficacious. Like Buspar, Gepirone as an adjunct may potentiate the antidepressant effect of first-line interventions (e.g. SSRIs) and combat unwanted SSRI effects (e.g. sexual dysfunction).  Additionally, Gepirone isn’t associated with significant interaction effects and seems to be tolerable over an extended duration.
  • Anxiety treatment: Gepirone ER is an analogue of Buspar (Buspirone), and each medication forms the same 1-PP metabolite. Buspar is FDA approved for the treatment of generalized anxiety disorder, but is often used for many other types of anxiety.  Knowing the similar function of Gepirone and Buspirone, it is likely that Gepirone ER is equally as capable of treating anxiety as Buspirone.  A study in 1997 shows that 10-45 mg/day of Gepirone significantly alleviates symptoms of anxiety compared to a placebo, and other research documents its ability to reduce comorbid anxiety among persons with depression.
  • Depressive subtypes: It is thought that Gepirone ER will prove useful for the treatment of various subtypes of depression including: atypical depression, non-melancholic depression, mild depression, and anxious depression. Developers of the drug hope to sell Gepirone specifically for the treatment of major depression with comorbid anxiety (i.e. “anxious depression”).  It is known that individuals with anxious depression are less responsive to antidepressant monotherapy than those with non-anxious, standalone major depression.  Using a 5-HT1A agonist like Gepirone ER is capable of correcting symptoms of anxiety and depression simultaneously.
  • Extended-release (ER) format: A major advantage associated with Travivo (Gepirone ER) is its extended-release format. The extended-release format ensures that the drug is absorbed and eliminated at a steady pace.  This should enhance efficacy of Gepirone at lower doses and minimize some of the side effects that would likely occur at higher doses if the drug were not an extended-release.  Moreover, if the drug weren’t extended-release, it may require administration multiple times per day (b.i.d.) at precise times like Busprione.
  • Efficacy: There is moderate evidence to support the efficacy of Gepirone ER as a treatment for major depressive disorder, as well as anxiety disorders. Several reasonably-sized randomized controlled trials (RCTs) have reported that Gepirone ER significantly reduces symptoms of depression and anxiety compared to a placebo control over an 8-week duration.  Other research shows that it’s an efficacious libido-enhancer and preventative for relapse of depressive symptoms.
  • Minimal abuse potential: Like other first-line antidepressants (SSRIs, SNRIs, etc.), Gepirone ER exhibits low abuse potential. Many anxiolytics such as benzodiazepines are associated with high abuse potential, making Gepirone ER a favorable option.  Research by Balster (1990) documents a lack of reinforcing effect upon administration of Gepirone ER to rhesus monkeys.  Human studies also show that Gepirone ER is extremely unlikely to be a drug of abuse.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/1973938).
  • Modest withdrawal: Since most people do not like the idea of taking an antidepressant and/or anxiolytic every day for the rest of their lives, they may inevitably transition off and/or attempt to live drug-free. Data from clinical trials suggests that Gepirone ER is associated with zero significant withdrawal symptoms.  This is advantageous over many other antidepressants and anxiolytics (e.g. SSRIs, SNRIs, benzodiazepines, etc.) that are associated with severe, protracted withdrawal symptoms.  Though it is unlikely that Gepirone ER has “zero” withdrawal, the discontinuation symptoms are likely more tolerable than many other medications.
  • Monotherapy: Another obvious benefit of Gepirone ER is that it is a single pill capable of treating multiple neuropsychiatric conditions simultaneously. Theoretically, a person experiencing major depression with comorbid anxiety plus sexual dysfunction may find that the drug treats all three at a dose between 40 mg and 80 mg per day.  Using a single Gepirone ER pill each day to manage multiple conditions is likely preferred over taking several medications which might yield deleterious effects and/or unexpected interactions.
  • Refractory depression: Individuals with major depression and comorbid anxiety are often extremely difficult to treat. They often don’t respond well to standalone monotherapies and may find that an agent helpful for depression exacerbates anxiety – and vice-versa.  Gepirone ER may prove useful for difficult-to-treat refractory cases of depression that don’t respond to currently available pharmacology.
  • Relapse prevention: It is understood that many individuals respond to first-line interventions, but eventually experience tachyphylaxis in which their antidepressant stops working or “poops out.” A large-scale, long-term trial showed that Gepirone ER effectively treats cases of recurrent depression and is able to prevent symptomatic relapse for up to 44 weeks in around 77% of initial responders.  This means that persons with recurrent depression responding to Gepirone ER will likely attain long-lasting symptomatic relief.
  • Safety: There don’t appear to be any major safety issues associated with Gepirone ER at doses up to 80 mg per day. No serious adverse effects were reported in any of the clinical trials and the drug was noted as being extremely well-tolerated.  Additionally, it is understood that the related drug Buspar is one of the safest psychiatric medications.  Like Buspar, Gepirone ER isn’t associated with: abuse/addiction, rapid tolerance onset, serious long-term effects (e.g. dementia from benzos), or serious discontinuation symptoms.  Moreover, Gepirone ER is thought to have few contraindications and/or interactions with other medications.
  • Sexual enhancement: Major depression, as well as antidepressant medications are associated with decreased libido and sexual dysfunction. The lack of libido and sexual dysfunction (e.g. impotence) are likely unwanted by most and may inevitably lead a person to feel depressed as a result of inability to maintain intimacy with a partner.  Data from large randomized controlled trials (RCTs) in men and women show that Gepirone ER significantly enhances sexual performance and desire.  It may also prove effective to counteract SSRI-induced sexual dysfunction or low libido resulting from depression.  After all, the closely-related drug Buspar is able to alleviate SSRI-induced sexual dysfunction in around 60% of users.
  • Tolerability: A benefit associated with using Gepirone ER for the treatment of depression and/or anxiety is its tolerability. Compared to most medications, side effects are modest and the drug is very well tolerated over a long-term.  Unlike SSRIs, Gepirone isn’t associated with sexual dysfunction, reduced sexual desire, or low energy.  Additionally, unlike benzodiazepines Gepirone doesn’t cause cause brain fog, cognitive deficits, or sedation [that may impair your ability to operate a motor vehicle or heavy machinery].
  • Unique mechanism of action: Unless compared to Buspar, this drug functions different than most antidepressants. It doesn’t inhibit reuptake of monoamines (e.g. 5-HT, NE, DA), rather, it partially agonizes the 5-HT1A receptor.  This is thought to enhance release of oxytocin and affects activity in the HPA axis and locus coeruleus of the brain.  Some individuals may benefit more from this 5-HT1A partial agonism than reuptake inhibition and/or modulation of activity at multiple receptor sites.  For individuals that don’t respond well to currently-available antidepressants, there’s a chance that the pharmacodynamics of Gepirone ER may prove useful.
  • Upgraded buspirone (Buspar 2.0): There’s a lot more to like about Gepirone ER than Buspar (Buspirone). Perhaps the most notable advantage of Gepirone ER is it’s extended-release formatting.  A major problem with Buspar is its formatting as an immediate release medication.  Buspar is rapidly absorbed and released, making it relatively ineffective at the lower end of the dosing spectrum, and difficult-to-tolerate at higher doses.  Many patients have a tough time finding an optimal “sweet spot” with Buspar – plus it necessitates twice-daily dosing.  Gepirone ER only needs to be administered once daily, and the extended release should yield steadier plasma concentrations – rather than abrupt peaks and valleys.  While Buspar could be improved with extended-release formatting, it still would be pharmacodynamically inferior to Gepirone ER.  Gepirone ER exerts a stronger effect upon 5-HT1A receptors (which helps depression and anxiety), but lacks affinity for antagonism of the D2 receptor (likely favorable for depression).

Drawbacks of Travivo (Gepirone ER) for Depression and Anxiety (Possibilities)

There may be some significant drawbacks associated with Gepirone ER for depression and/or anxiety.  A major drawback is that the medication may be ineffective for a bulk of patients with standalone cases of major depressive disorder.  Other drawbacks associated with Gepirone ER include: its high price, similarity to Buspar, and perhaps inferiority to other medications.  Moreover, Gepirone ER may be considered disadvantageous for usage among those in need of immediate symptomatic relief as the drug requires between 2 and 6 weeks to take effect.

  • Buspar “knock-off”: There are many similarities between Travivo (Gepirone ER) and Buspar including: azapirone classification, 5-HT1A partial agonist mechanism of action, and identical primary metabolite (1-PP). Travivo differs from Buspar based on its: extended-release format, lower D2 antagonism, and slightly greater 5-HT1A agonism.  Due to the limited differences, some may argue that Travivo (Gepirone ER) is nothing more than a Buspar “knock off” drug, perhaps engineered solely to cash in after a Buspar patent expiration.  Moreover, although Travivo appears favorable to Buspar on paper, it may turn out to be less effective as a treatment for neuropsychiatric conditions.
  • Delayed onset of action: Data from clinical trials suggests that Travivo (Gepirone ER) exhibits a slow onset of action, seemingly as slow as SSRIs (possibly slower). On average, it takes between 2 and 6 weeks for Gepirone ER to fully alleviate symptoms of depression and/or anxiety.  The delayed onset of action may be problematic for those who are severely depressed and/or anxious, requiring immediate symptomatic reduction.  It is thought that a delayed onset of action results from the principal mode of action implicating 5-HT1A receptor agonism. (Source: http://www.ncbi.nlm.nih.gov/pubmed/12943952).
  • High cost: Though some may be excited about the release of Travivo (Gepirone ER) as an antidepressant and/or anxiolytic, most won’t be too thrilled with the cost. Anyone with a poor insurance plan will likely end up paying a significant amount of money for a 30-day Travivo prescription.  Most newer antidepressant and/or anxiolytic medications cost upwards of $300 for a 30-day prescription, equating to around $10 per pill.  Even if you respond well to Gepirone ER, discontinuation may be necessary on the basis of unaffordability.
  • Interactions: Though Travivo (Gepirone ER) may be well-tolerated when administered as an adjunct to other medications (SSRIs, SNRIs, etc.), it is not devoid of contraindications nor interaction effects. Anyone using other substances such as pharmaceutical drugs or supplements along with Gepirone ER may experience interaction effects.  It is understood that Gepirone undergoes extensive hepatic metabolism mediated by CYP3A4 enzymes (95%) and to a lesser extent, CYP2D6 (5%).  Any agents that induce enzymatic activity of CYP3A4 (butalbital, carbamazepine, phenobarbital, phenytoin, St. John’s wort, etc.) will expedite Gepirone metabolism, possibly causing adverse interaction effects.  In addition, any agents that inhibit enzymatic activity of CYP3A4 (e.g. Cobicistat, Indinavir, Itraconazole, Ketoconazole, etc.) may prolong metabolism, leading to prolonged elimination and corresponding side effects.  Gepirone is understood to interact with MAOIs (monoamine oxidase inhibitors) in that it may cause a hypertensive crisis.  Moreover, administering high doses of Travivo with other antidepressants could lead to “serotonin syndrome.”  (Keep in mind that there are more interactions than were briefly discussed here).
  • Mechanism of action: Most would argue that Travivo (Gepirone ER) doesn’t exhibit a breakthrough mechanism of action that is needed in the antidepressant industry. Furthermore, its mechanism of action is similar to Buspar (Buspirone), so much so that it may be no more effective than Buspar as a treatment.  Each drug functions primarily as a 5-HT1A receptor partial agonist.  Some research suggests that Gepirone may agonize the 5-HT1A receptor slightly more than Buspirone, however, this isn’t well-substantiated.  Furthermore, it is possible that Gepirone ER’s mechanism may prove less efficacious than that of Buspirone.  Though Gepirone has a lower affinity for the D2 receptor as an antagonist than Buspirone (perceived as a favorable attribute for treating depression by many), it is possible that this may make Gepirone less effective as a neuropsychiatric intervention.  Travivo will differ from many current-market medications in how it works, however, it is nearly a replica of Buspar that has been around since the 1980s – its mechanism of action wasn’t engineered to incorporate the latest in neuroscientific discovery.  Moreover, a subset of antidepressants already target the 5-HT1A receptor as partial agonists including: Brintellix (Vortioxetine), Viibryd (Vilazodone), and Trazodone.
  • Questionable efficacy: A reason as to why Travivo (Gepirone ER) isn’t already on the market is related to its questionable efficacy for the treatment of depression and anxiety. As was already mentioned, there’s a chance that the drug is less effective than its predecessor Buspar (Buspirone) based on certain attributes such as lower dopamine receptor antagonism.  If Gepirone was highly effective for the treatment of anxiety and/or depression, most would predict that it would’ve been approved between the 1990s and 2000s.  The drug has undergone testing in 10 to 20 clinical trials since the 1980s, with a majority yielding unfavorable results.  When considering the myriad of unfavorable outcomes from clinical trials outnumber the favorable outcomes, FDA evaluators remain skeptical of Gepirone ER’s efficacy.
  • Side effects: For the most part, Travivo (Gepirone ER) isn’t associated with severe unwanted side effects. Most users are able to tolerate it extremely well over the long-term, especially after the preliminary titration phase.  That said, not everyone will experience zero or minimal side effects from the drug.  A subset of users will experience prominent, unwanted side effects that make it difficult to continue treatment.  Some of the most common Travivo side effects include: diarrhea, dizziness, headaches, insomnia, lightheadedness, nausea, restlessness, and vertigo.
  • Unknown long-term outcomes: There appears to be just one study investigating the long-term efficacy, safety, and tolerability of Gepirone ER. This study included individuals with recurrent depression that responded to Gepirone ER in an open-label phase, then tracked them in a randomized controlled phase lasting 40 to 44 weeks.  It was noted that around 77% of Gepirone ER recipients tolerated the drug well and experienced no adverse long-term effects for the 44-week duration.  Though this study shows that Gepirone ER is effective and tolerable for around a full year of administration, it is a standalone study warranting replication.  Furthermore, it is reasonable to consider that like many antidepressants, Gepirone ER stops working after a longer duration (e.g. 2 to 3 years), ultimately requiring replacement and/or increased dosage.  The full scope of long-term health problems resulting from Gepirone ER remains unclear, but may be similar to Buspar.
  • Withdrawal symptoms: Most literature associated with Gepirone and Buspirone suggests zero discontinuation symptoms from either medication. Unfortunately, most of this information is collected from studies in which the drugs were administered over an extremely short-term.  Anyone that’s actually taken an azapirone medication for an extended duration knows that discontinuation symptoms can occur.  The brain doesn’t automatically immediately revert back to homeostasis easily and/or without consequences after daily administration of a drug like Gepirone ER for a long-term.  For this reason, we should expect that Gepirone ER discontinuation will yield withdrawal symptoms, however, it is reasonable to suspect that they may be easier to manage than those associated with other medications (likely due to the drug’s highly-targeted pharmacodynamics).
  • Worsening of symptoms: As evidenced by clinical trial data, not everyone with anxiety and/or depression will respond favorably to Travivo (Gepirone ER). There are many subtypes of depression and/or anxiety disorders in which Gepirone is unlikely to facilitate any benefit.  Furthermore, certain individuals taking Gepirone ER may experience worsening of depression and/or suicidality as a result of 5-HT1A partial agonism and its downstream effects.  Targeting the 5-HT1A receptor with partial agonists is only ideal in a subset of persons.  Some individuals may benefit more from outright inactivation of the 5-HT1A receptor with an antagonist (e.g. Pindolol) or from using a non-serotonergic antidepressant (e.g. bupropion).

Travivo (Gepirone ER) for Depression & Anxiety (Research)

It is important to examine the research of Travivo (Gepirone ER) to determine whether it is likely to be safe and/or effective for the treatment of depression and anxiety.  Keep in mind that upwards of a dozen clinical trials have been conducted with Gepirone and only a subset of those trials were actually published.  It would be useful to have access to the unpublished trial data to assess whether there were legitimate methodological flaws OR if the trials were deliberately concealed to enhance the perception of Gepirone’s efficacy.  Below are studies conducted with Gepirone examining its effect among persons with depression and/or anxiety.

2012: The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men.

Fabre, Clayton, Smith, et al. (2012) noted that sexual dysfunction is a common occurrence among persons with clinical depression.  Medications used to treat depression such as SSRIs are effective for improving mood, but often exacerbate underlying sexual dysfunction.  In some cases, the lack of libido and/or suboptimal sexual performance associated with conventional antidepressants may lead to frustration followed by a worsening of mood, hence the need for unique pharmacological interventions such as Gepirone.

Researchers suspect that Gepirone ER might treat depression plus combat sexual dysfunction simultaneously through partial agonism of the 5-HT1A receptor.  For this reason, trial was organized to test the effect of Gepirone ER on sexual function of men diagnosed with clinical depression.  The aim of the study was to specifically determine whether Gepirone ER might enhance sexual function – regardless of its antidepressant and/or anxiolytic effects.

A total of 181 men were assigned at random to receive either: Gepirone ER, fluoxetine, or a placebo – over a duration of 8 weeks.  Primary outcome measures of the study included the Hamilton Depression Rating Scale (HAM-D) and the Changes in Sexual Functioning Questionnaire (CSFQ).  Analysis of data suggested that Gepirone ER significantly enhanced sexual function among the men with depression within 4 weeks and the enhancement stayed significant [compared to the placebo and fluoxetine] through the remainder of the trial (through Week 8).

Remarkably, every aspect of sexual function as measured by the CSFQ improved, especially the ability to orgasm.  What’s more, even those who failed to derive antidepressant or anxiolytic benefit from Gepirone ER experienced enhancement of sexual function compared to the placebo and fluoxetine interventions.  As may have been expected, those receiving the SSRI (fluoxetine) compromised sexual function compared to the placebo on the CSFQ.

It was concluded that Gepirone ER is capable of enhancing sexual function in men with depression, regardless of whether the drug improves mood or reduces anxiety.  Though the study was designed to specifically test Gepirone’s effect on sexual function of men with depression, it would’ve been helpful to know how its efficacy compared to fluoxetine and the placebo as an antidepressant – solely on mood improvement.  Based on the results, one might speculate that Gepirone ER might be more effective for enhancing sexual function than improving mood.

It would be interesting to test Gepirone ER for the treatment of sexual dysfunction among euthymic persons (devoid of neuropsychiatric issues).  Another possibility would be to determine whether Gepirone ER enhances sexual function among those without any prior dysfunction.  Moreover, it is reasonable to suspect that Gepirone could be used as an adjunct medication among SSRI responders to mitigate SSRI-induced sexual dysfunction.  Finally, one must consider that improving sexual function may be a standalone mechanism by which mood improves for a subset of those with depression; especially if the sexual dysfunction was an underlying cause of their low mood.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22240272

2011: Gepirone-ER treatment of low sexual desire associated with depression in women as measured by the DeRogatis Inventory of Sexual Function (DISF) fantasy/cognition (desire) domain–a post hoc analysis.

It is known that many women with depression report decline in sexual desire as a result of either low mood and/or treatment with conventional serotonergic antidepressants (e.g. SSRIs).  The drug Gepirone appears to possess antidepressant, anxiolytic, and sexual enhancing properties – making it a favorable drug for testing among women with depression.  Fabre, Smith, and DeRogatis (2011) evaluated results of multiple trials to determine whether Gepirone ER could combat low sexual desire among women with depression.

Specifically, researchers wanted to know whether Gepirone ER was effective for enhancement of sexual desire irrespective of its antidepressant and/or anxiolytic effects.  A total of 334 women with atypical depression were recruited to participate in the two trials of Gepirone ER – one 8-week trial (shorter-term) and a 24-week trial (longer-term).  In each of the trials, participants were assigned at random to receive either: Gepirone ER (40-80 mg/day) or a placebo control.

The effectiveness of Gepirone ER was determined based on changes in measures of mood, anxiety, and sexual desire from pre-treatment baseline to post-treatment.  Mood and anxiety were assessed using the Hamilton Depression Rating Scale (HDRS), whereas sexual desire was assessed with the DeRogatis Inventory of Sexual Function (DISF).  Upon comparison of pre- and post- treatment measures, results indicated that Gepirone ER significantly improved sexual desire in the short-term (8 weeks) and over the long-term (24 weeks) among women with depression – compared to the placebo.

Despite favorable enhancement of sexual desire, Gepirone ER failed to improve mood or reduce anxiety in each of the trials, indicating that it may be ineffective as an antidepressant or anxiolytic intervention.  Nonetheless, a subset of the women with atypical depression were noted to have derived antidepressant and/or anxiolytic benefit from Gepirone ER plus enhanced sexual function.  Based on these results, it seems as though Gepirone ER may be a superior treatment for sexual dysfunction among women with depression than an anxiolytic or antidepressant.

Among the subset of women that experienced an antidepressant effect from Gepirone ER, perhaps a portion of this effect was a direct result of their improved sexual desire.  Although Gepirone ER is able to enhance sexual desire among women with depression over the short-term (8-week) and long-term (24-week), it seems to exhibit lackluster efficacy for treating anxiety and/or depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21707926

2011: Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women.

Fabre, Brown, Smith, and Derogatis (2011) reflected upon the fact that there are no FDA-approved interventions for the treatment of Hypoactive Sexual Desire Disorder (HSDD), a condition characterized by lack of sexual fantasy and/or activity.  Multiple agents such as Flibanserin and testosterone have shown preliminary efficacy in treating HSDD, however, Flibanserin was denied by the FDA for approval and testosterone is thought to have safety risks.

Another promising pharmacological intervention that may prove effective for the treatment of HSDD is Gepirone ER.  For this reason, researchers conducted a series of studies to test the effect of Gepirone ER among 161 women who met diagnostic criteria for HSDD.  The women received either: Gepirone ER (20-80 mg/day), an SSRI (fluoxetine 20-40 mg/day OR paroxetine 10-40 mg/day), or a placebo control.

The primary outcome measure was the number of patients who no longer met diagnostic criteria for HSDD after receiving treatment.  Results suggested that Gepirone ER was significantly more effective for attenuating HSDD than the SSRIs and placebo control.  It was concluded that Gepirone ER was an effective intervention for treating HSDD among women (some of which were diagnosed with depression).

Though this study doesn’t prove that Gepirone ER improves mood and/or reduces anxiety, it shows that the drug is capable of mitigating symptoms of HSDD.  It’s reasonable to suspect that HSDD may cause and/or be associated with depression in some women, as well as speculate that attenuation of HSDD may lead to (at least modest) mood enhancement.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21324094

2008: Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study.

Bielski, Cunningham, Horrigan, et al. (2008) organized a randomized, double-blinded, placebo-controlled, parallel group trial testing the effect of Gepirone ER as a treatment for depression.  For the trial, researchers recruited adult outpatients diagnosed with moderate-to-severe major depression.  Participants in the study were assigned at random to receive either: Gepirone ER (titrated from 20 to 80 mg/day) or a placebo control.

Prior to the trial, mood assessments were conducted the Hamilton Rating Scale for Depression (HAM-D), Bech Six-Item Scale, Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions Scale (CGI-S).  The primary outcome measure for the trial was change in HAM-D score from baseline through 8 weeks.  Results indicated that patients receiving Gepirone ER exhibited significant reductions in depressive symptoms within 4 weeks compared to patients receiving the placebo control.

Statistically significant mood improvement reported by Week 4 was maintained through Week 6 and Week 8 (the final week) of the trial.  It was noted that secondary outcome measures also showed significant improvement among those receiving Gepirone ER compared to the placebo.  Investigators concluded that Gepirone ER significantly reduced symptoms of major depressive disorder and was favorably tolerated by patients.  This research supports the idea that Gepirone (at doses up to 80 mg) is an effective antidepressant.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18373383

2005: Relapse prevention with gepirone ER in outpatients with major depression.

A trial conducted by Keller, Ruwe, Janssens, et al. (2005) analyzed the efficacy and tolerability of Gepirone ER as a prophylactic agent for the prevention of symptomatic relapse among patients with major depressive disorder.  Researchers organized a randomized, placebo-controlled trial and recruited 420 patients diagnosed with recurrent major depression, each of which exhibited a HAM-D 17 score exceeding 20.

The trial began with a washout period in which patients received a placebo for a duration of 3 to 14 days.  Next, all participants were slated to receive Gepirone ER for an 8-week or 12-week duration, starting at doses of 20 mg/day titrated upwards within the range of 40 to 80 mg/day.  Thereafter, a subset of patients (250 of the initial 420) that experienced symptomatic remission from the Gepirone ER participated in a randomized, double-blinded trial involving: continuation of Gepirone (40-80 mg/day) OR a placebo – for a duration of 40 to 44 weeks.

The primary outcome of the study was comparison of relapse rates among those receiving Gepirone ER to those taking a placebo.  Results indicated that the relapse rate among those receiving Gepirone ER (23%) was significantly lower than those receiving the placebo (34.7%).  Authors concluded that Gepirone ER is effective for preventing symptomatic relapse among individuals with recurrent forms of depression.

The drug appears safe, well-tolerated, and effective over an extended duration (approximately a full year) among those with recurrent depression.  Obviously, this study supports the idea that Gepirone ER is a useful pharmacological intervention for a subset of those with major depressive disorder.  That said, perhaps the biggest weakness associated with this study is the immediate transition of 124 patients (of the 250 responders) from Gepirone ER to the placebo upon completion of the open-label phase.

Relapse of depressive symptoms among patients assigned to receive the placebo may have been inevitable, especially when considering that a subset may have experienced [potentially severe] withdrawal symptoms from abrupt (i.e. “cold turkey”) discontinuation of Gepirone ER (40-80 mg/day).  Perhaps discontinuation symptoms in the randomized, double blinded phase explain the greater rates of depression relapse among those receiving the placebo.  Though Gepirone ER might be useful to prevent symptomatic relapse, one should be skeptical of these results.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15643103

2004: Gepirone extended-release treatment of anxious depression: evidence from a retrospective subgroup analysis in patients with major depressive disorder.

Many individuals with neuropsychiatric disorders experience a debilitating combination of anxiety plus depression, sometimes referred to as “anxious depression.”  Anxious depression is often regarded as being more difficult to treat than standalone depression without anxiety, and vice-versa.  A major problem associated with treating anxious depression is that many medications that help improve anxiety often exacerbate depression, and vice-versa.

Furthermore, combination treatments are often administered, but tolerability issues may be reported as a result of interaction effects.  For this reason, using a standalone agent capable of reducing anxiety while simultaneously enhancing mood would be preferred.  Though SSRIs are capable of targeting both anxiety and depression, not everyone with anxious depression responds to their mode of serotonergic action.

A novel, unapproved agent of the azapirone class known as Gepirone ER is suspected to be a viable SSRI alternative for treating cases of anxious depression.  To test the efficacy of Gepirone ER on patients with anxious depression, Alpert, Franznick, Hollander, and Fava (2004) organized a double-blind, placebo-controlled trial over an 8-week term.  Patients were assigned at random to receive either: Gepirone ER (20-80 mg/day) or a placebo control.

The effectiveness of Gepirone ER was determined based on change in Hamilton Depression Rating Scale (HDRS) from baseline through the 8-week trial period.  More specifically, since the patients were dealing with anxious depression, changes in: HDRS total scores, anxiety/somatization scores, and anxiety/psychic scores were documented.  Analyzing the results indicated that treatment with Gepirone ER significantly reduced: HDRS total scores, anxiety/somatization scores, and anxiety/psychic scores – compared to the placebo throughout 8 weeks.

No significant differences in side effects or adverse reactions were observed among the Gepirone ER recipients compared to placebo recipients, suggesting that Gepirone ER is well-tolerated.  Researchers concluded that Gepirone ER was an efficacious intervention for persons dealing with “anxious depression.”  When considering Gepirone’s similarity to Buspirone, this finding isn’t very surprising.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15323591

2003: Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder.

A trial conducted by Feiger, Heiser, Shrivastava, et al. (2003) documented the tolerability and effectiveness of Gepirone ER for the treatment of depression.  For the trial, researchers recruited individuals who met diagnostic criteria for moderate-to-severe major depressive disorder (MDD) – as evidenced by a 17-item Hamilton Depression Rating Scale score exceeding 20.  At the start of the trial, a washout phase was implemented for 4 to 7 days in which all participants received a placebo.

Following the initial washout period, 209 participants were assigned at random to receive either: Gepirone ER (20-80 mg/day) OR a placebo control – for an 8-week duration.  Results suggested that Gepirone ER significantly reduced symptoms of depression over an 8-week duration compared to the placebo control – as evidenced by changes in Hamilton Depression Rating Scale scores from pre-treatment baseline to post-treatment.  This trial supports the idea that Gepirone ER is effective (and favorably-tolerated) for the treatment of major depressive disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12716264

1997: Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

A randomized, double-blinded trial was conducted by Rickels, Schweizer, DeMartinis, Mandos, and Mercer (1997) testing the therapeutic efficacy of Gepirone and diazepam (trade name “Valium”) for the treatment of generalized anxiety disorder (GAD).  In addition, researchers sought to document the occurrence of discontinuation symptoms upon abrupt cessation of each treatment.  A total of 198 patients with GAD diagnoses were recruited for participation and assigned at random to receive either: Gepirone (10-45 mg/day), diazepam, or a placebo control – for a duration of 8-weeks.

After the 8-week treatment phase, all participants underwent immediate transition to receiving a placebo for 2 weeks and monitored for withdrawal symptoms.  It was noted that diazepam recipients experienced significant reductions in anxiety within just 1 week of administration, whereas recipients of Gepirone experienced significant reductions in anxiety within 6 weeks of administration.  This suggests that diazepam is a fast-acting anxiolytic whereas Gepirone exhibits a delayed onset of anxiolytic action.

It would’ve been interesting if researchers monitored longer-term diazepam and Gepirone usage to determine whether one yields a more robust long-term anxiolytic effect over the other and/or is more tolerable.  Despite the faster-acting onset of diazepam, a significant worsening of anxiety and/or rebound effect was noted among diazepam users during the 2-week post-trial placebo period, suggestive of withdrawal symptoms.  Gepirone recipients didn’t experience worsening of anxiety during the post-trial placebo period, suggesting zero discontinuation symptoms.

This trial shows that low dose (10 to 45 mg/day) Gepirone is able to alleviate symptoms of generalized anxiety within 6 weeks of treatment onset.  It is unknown as to whether larger doses (e.g. 40 to 80 mg/day) would’ve resulted in quicker onset of Gepirone’s action.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9241006

1994: Gepirone in Depression and Anxiety Disorders

Fitton and Benfield (1994) appraised the clinical potential of Gepirone in the early 1990s.  In their report, it was noted that Gepirone is similar to Buspirone in that it functions as a 5-HT1A receptor agonist, but differs in that it has negligible affinity for the D2 receptor.  It was also mentioned that Gepirone appears to exhibit antidepressant and anxiolytic effects in animal models.

Authors discuss the fact that Gepirone appears more effective than a placebo intervention for the treatment of generalized anxiety disorder (at doses up to 60 mg/day) and atypical major depression (at doses up to 90 mg/day).  Fitton and Benfield propose that Gepirone is primarily an anxiolytic with secondary antidepressant properties, another similarity with Buspirone.  Furthermore, it seems that Gepirone is extremely tolerable without prompting sedative nor anticholinergic effects.

It was hypothesized that Gepirone may be most useful for cases of mild, non-melancholic depression; anxious depression; atypical depression; and generalized anxiety disorder.  Keep in mind that this wasn’t an actual trial, just a reflection of the currently available literature at the time.  Though it seems authors were correct with their predictions, the creators of Gepirone chose to test the drug primarily as an antidepressant (likely due to a bigger market potential) as opposed to an anxiolytic.

  • Source: http://link.springer.com/article/10.2165%2F00023210-199401050-00009

1993: Gepirone and the treatment of panic disorder: an open study.

Pecknold, Luthe, Scott-Fleury, and Jenkins (1993) conducted a 6-week open-label study testing the effect of Gepirone on 21 individuals diagnosed with generalized anxiety disorder (GAD) plus panic disorder with agoraphobia.  Participants were initially monitored for 2 weeks without any medication and initiated treatment with Gepirone at 2 mg/day.  Dosage of Gepirone was titrated upwards to 12 mg/day over a 3-week duration.

Investigators noted that 3 patients dropped out of the trial in Week 1 and another patient failed to follow proper protocol, resulting in the exclusion of 4 patients from final analysis.  A total of 12 of 17 patients (70.6%) experienced significant reductions in panic attacks within 6 weeks, whereas 9 patients (52.9%) experienced significant reductions within 3 weeks.  Interestingly, 10 patients (58.8%) reported zero panic attacks by Week 6.

Within the first week of treatment, 11 of 17 patients (64.7%) experienced significant reductions in total anxiety scores based on the Hamilton Anxiety Scale.  Few adverse effects were noted and Gepirone was considered tolerable.  This open-label study provided proof of concept that Gepirone may be useful for the treatment of panic disorder.

Not much can be concluded from this study other than Gepirone could work for anxiety.  Since there was no placebo control, randomization, or blinding – no conclusions can be made here regarding Gepirone’s anxiolytic efficacy.  Results from the trial may also be flawed when considering the modest (arguably subtherapeutic) dosage of Gepirone used, as well as the fact that the sample size was extremely small (just 17 people).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8096526

1989: Serotonergic anxiolytics and treatment of depression.

Gepirone was synthesized in the mid-1980s, assessed in animal models as an intervention for neuropsychiatric disorders, and shortly thereafter, tested in human trials.  Among the first reports to discuss the effect of Gepirone was written by Robinson, Alms, Shrotriya, et al. (1989).  The report mentioned that 5-HT1A receptor agonists such as Gepirone and Buspirone modulate serotonergic transmission through presynaptic and postsynaptic receptors.

Through 5-HT1A receptor-mediated serotonergic modulation, Gepirone and Buspirone induce a combination of antidepressant and anxiolytic effects.  Ongoing long-term administration of Gepirone is understood to downregulate 5-HT2 receptors in analogous fashion to a majority of conventional antidepressant therapies.  Authors of this report discussed early placebo-controlled trials of Gepirone in patients with clinical depression, noting that Gepirone facilitated a significant antidepressant and anxiolytic effect over an 8-week duration.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2657837

1987: Gepirone in anxiety: a pilot study.

In the 1980s, Csanalosi, Schweizer, Case, and Rickels (1987) conducted a pilot study to test the effect of Gepirone in anxiety.  For the study, a total of 10 patients with generalized anxiety disorder (GAD) were recruited and given a placebo for a 1-week washout period.  After the washout phase, participants received Gepirone for 6 weeks.

Changes in average Hamilton Anxiety scores from pre-treatment baseline to post-treatment were assessed.  Results indicated that treatment with Geprione for 6 weeks yielded significant improvements in average anxiety scores from ~24.8 (at baseline) to ~7.1 (post-treatment).  Various physician and patient ratings confirmed improvement in anxious symptoms throughout treatment.

The average dosage of Gepirone used in this study was around 40 mg and it appeared to be favorably tolerated by users.  It was concluded that Gepirone seems to be a promising anxiolytic medication.  Despite the favorable effect of Gepirone, nothing can be definitively concluded here because the trial lacked a placebo control, randomization, blinding, and implemented an extremely small sample size (just 10 patients).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2880873

Limitations associated with trials of Travivo (Gepirone ER) for depression and anxiety

Despite the therapeutic potential of Gepirone ER as an intervention for anxious depression, as well as distinctive anxiety and depressive disorders, there are some serious limitations associated with the clinical trial data.  It is these limitations that lead to the FDA panel rejecting approval of Gepirone ER on several accounts.  Arguably the most prominent limitation is that upwards of a dozen clinical trials have assessed the efficacy of Gepirone ER for the treatment of depression, yet only a few showed that it was effective.  Other limitations include the: paucity of long-term trials, lack of adjunct testing, untargeted participants, and unknown comparative efficacy.

  • Adjunct efficacy unknown: It is understood that 5-HT1A partial agonists are favorable antidepressant augmentation strategies, especially when prescribed with SSRIs. Many suspect that 5-HT1A partial agonism bolsters the SSRI-induced antidepressant effect, as well as offsets unwanted side effects such as sexual dysfunction.  Though the azapirone medication Buspirone is a useful SSRI adjunct, it is unknown as to whether Gepirone ER would prove equally or more effective by comparison.  At this time, nearly all trials have assessed the efficacy of Gepirone ER as a monotherapeutic intervention for depression and anxiety.  Testing is warranted to determine the safety, tolerability, and efficacy of Gepirone ER as an adjunct.
  • Comparative efficacy: In most clinical trials of Gepirone ER, its efficacy was compared to that of a placebo control. Though a placebo is certainly a legitimate control, it would be useful to understand how Gepirone ER compares with already-approved agents (e.g. SSRIs, SNRIs, etc.) for the treatment of depression and anxiety.  It may turn out that Gepirone ER is significantly more effective than a placebo – plus more effective and/or tolerable than other first-line options.  On the other hand, it could be that Gepirone ER is more effective than a placebo, yet effective and/or tolerable than other conventional pharmacology.  Some may argue that Gepirone ER should at least be compared to Buspirone, as there’s some evidence to suggest that using Buspar for depression is effective at high doses.
  • Participant populations: Allegedly, numerous trials of Gepirone ER tested its efficacy on populations who were unlikely to derive any therapeutic benefit from its administration. Upwards of a dozen trials were conducted and it took awhile before researchers figured out which patients were likely to achieve symptomatic remission from Gepirone ER.  It turns out that the drug is most beneficial for those with atypical depression or “anxious depression,” but not necessarily standalone major depressive disorder.  Failure to recruit participants with atypical or “anxious depression” may have yielded suboptimal results, making the drug seem ineffective.  More trials may be needed to confirm that Gepirone ER is effective among populations diagnosed specifically with anxious depression.
  • Mixed results: In regards to Gepirone ER’s efficacy for treating anxiety and depression, the data are mixed. Some studies suggest that the drug is likely effective, whereas others suggest ineffectiveness.  In fact, there appear to be more trials in which the drug was ineffective for the treatment of anxiety and depression than trials showcasing its efficacy.  These conflicting trial results have lead some to question whether the drug is truly an effective option.  That said, it should be noted that mixed results have occurred while testing other (FDA-approved) medications.
  • Trial duration: Most trials of Gepirone ER last approximately 8 weeks, making it difficult to know whether Gepirone ER remains effective over a longer-term. In the trials that last 8 weeks, Gepirone ER usually doesn’t deliver the therapeutic effect until between Week 2 and Week 4 of treatment, meaning a majority of patients will have only derived significant benefit for a duration of 4 to 6 weeks in the trial.  Longer trial duration is necessary to know whether Gepirone ER remains safe and effective for an extended duration (e.g. 6 months, 1-year, etc.).  Although one trial tested Gepirone ER for 40 to 44 weeks, some of the methods in the trial may have been suboptimal.
  • Unpublished data: It’s no secret that there is a considerable amount of unpublished data from Gepirone ER trials. While the data may remain unpublished for good reason such as suboptimal: dosing, methods, recruitment of participants, etc. – this data should be available for public review.  Apparently upwards of a dozen trials have been conducted investigating the efficacy of Gepirone ER for the treatment of anxiety and depression, and a majority found Gepirone ineffective.  The FDA is aware of these trials and rejected Gepirone on three accounts as a result.  Unless the unpublished data are released for critique, it may seem as though creators are attempting to manipulate the perception of Gepirone ER’s efficacy to attain approval and cash in on over $1B (billion) in sales per year.

Based on the research, should Travivo (Gepirone ER) be used for depression, anxiety, or “anxious depression”?

The FDA has every reason to be skeptical of the therapeutic efficacy of Travivo (Gepirone ER).  When considering that Gepirone is closely related to the FDA-approved medication Buspar (Buspirone), a drug many consider to be downright useless, it may turn out that Gepirone isn’t as effective as was hoped by developers.  Assessing the literature, only a few randomized controlled trials (RCTs) show that Gepirone is significantly more effective than a placebo control for the treatment of depression.

In 2008, results from an RCT by Bielski, Cunningham, Horrigan, et al. were published indicating that Gepirone ER (20-80 mg/day) was more effective than a placebo for the treatment of moderate-to-severe depression.  Results from an earlier RCT published in 2004 conducted by Alpert, Franznick, Hollander, and Fava documented Gepirone ER as being significantly more effective than a placebo for “anxious depression.”  Data published in 2003 from an RCT by Feiger, Heiser, Shrivastava, et al. also supports the idea that Gepirone ER is an efficacious antidepressant.

Other evidence supporting the usefulness of Gepirone ER for depression is derived from a study by Keller, Ruwe, Janssens, et al., published in 2005.  Though there may have been some methodological flaws, it was discovered that Gepirone ER was more effective than a placebo for preventing symptomatic relapse among those with major depression.  A trial by Rickels, Schweizer, DeMartinis, Mandos, and Mercer also showcases the efficacy of Gepirone as an anxiolytic agent.

When considering that 4-5 studies support the antidepressant (and/or anxiolytic) efficacy, safety, and tolerability of Gepirone, one might think that it deserves FDA approval.  That said, we must consider that numerous studies have discovered Gepirone ER to be no more effective than a placebo for depression.  A trial by Fabre, Clayton, Smith, et al. published in 2012 noted that Gepirone ER improved sexual function of depressed men, but it wasn’t reported whether the drug significantly improved depressive symptoms compared to a placebo.

What’s more, results from an earlier RCT by Fabre, Smith, and DeRogatis were published in 2011 and documented that Gepirone ER failed to improve depressive and anxious symptoms among 334 women with atypical depression.  Knowing that individuals with atypical depression are the intended demographic for Gepirone treatment, yet they failed to significantly benefit is suggestive that Gepirone may be ineffective.  Moreover, over a dozen clinical trials have been conducted – yet many remain unpublished due to lack of significant results.

The FDA argues that the large number of clinical trials conducted may have yielded favorable results in a subset of studies by sheer chance.  Developers of Gepirone ER argue that they simply targeted the wrong demographics for treatment, thus leading to unfavorable outcomes.  Whether Gepirone ER should receive FDA approval is a somewhat a matter of opinion and perspective.

The drug has demonstrated safety and seems to be extremely well tolerated with few discontinuation symptoms [compared to other agents].  It appears as though Gepirone ER can be effective for a subset of individuals with depression, anxiety, and anxious depression – plus the drug is able to counteract sexual dysfunction.  Based on the fact that alternative pharmacological approaches are needed in the management of depression and anxiety, it is of personal opinion that Gepirone ER should receive a reluctant nod of approval by the FDA.

A Brief History of Travivo (Gepirone ER)

The azapirones are a class of drugs that were first synthesized in the 1980s and intended to be used for the treatment of many neuropsychiatric conditions.  It was suspected that azapirones would be novel alternatives to benzodiazepine anxiolytics and tricyclic antidepressants.  In a report entitled “Azapirones: History of Development” by Eison (1990), it was discussed that azapirones exhibit anxiolytic and antidepressant properties and function principally by acting upon the 5-HT1A receptor.

Their unique mechanism of action through 5-HT1A agonism was thought to yield fewer adverse effects compared to older benzodiazepines (developed in the 1950s).  Gepirone was synthesized in the mid-1980s by chemists at the pharmaceutical company Bristol-Myers Squibb.  Licensing rights were attained by the company Fabre-Kramer in 1993, and by Organon International in 1998.  The drug was sold from Organon International back to Fabre-Kramer in 2005 as a result of its rejection for approval by the FDA in both 2002 and 2004.

Fabre-Kramer partnered with GSK and resubmitted the drug for FDA approval in 2007, but received another rejection.  Between 10 and 20 clinical trials for Gepirone have been conducted, spanning over the course of 20+ years.  There are currently just 2 positive trials showing that Gepirone is effective, yet the FDA panel argued Gepirone’s inefficacy and/or negative results were shown in a number of other trials.  Ambiguity of Gepirone’s efficacy based on trial data makes it difficult to know whether the drug is sufficiently effective, hence the lack of FDA approval.  Fabre-Kramer challenged the FDA’s decision by stating various Gepirone studies were “uninterpretable” as a result of short duration and/or the wrong patient population.

It is reasonable to suspect that Fabre-Kramer may have been correct based on the fact that azapirones often require an extended duration to “kick in” – short trials were likely to compromise study findings.  Furthermore, targeting the wrong subset of individuals for treatment is very likely to yield poor results.  If a meta-analysis were performed on the valid studies of Gepirone, it seems as though the drug may be effective for the treatment of anxious depression.

Still, throughout 2015 the FDA believes that the 2 positive trials may have occurred by chance.  Conducting a large number of trials (e.g. 12+) is bound to produce a couple of (potentially false) positive trials.  That said, it is clear that Gepirone appears extremely safe with few side effects compared to existing medications.  Moreover, there is some data suggesting that it could be useful among a subset of persons with neuropsychiatric disorders.

Fabre-Kramer also argues that many psychiatric patients need alternative treatments to currently available drugs because they suffer from intolerable side effects.  The FDA may think that Fabre-Kramer is simply pushing hard for Gepirone approval because annual sales may reach $1.6 billion per year if it receives approval.  Despite the unfavorable review of Gepirone in 2015, the FDA panel had a change of heart in 2016 and replaced the negative review with a positive one.

Suddenly, it seems as though Gepirone is on the verge of hitting the market.  It will be sold in an extended-release (ER) tablet and marketed under the brand name Travivo for the treatment of anxious depression.  It may also be used as an adjunct to first-line antidepressant therapies and/or to reverse sexual dysfunction.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1973936

Would you try Travivo (Gepirone ER) for depression and/or anxiety?

If Travivo (Gepirone ER) hits the market for the treatment of depression with comorbid anxiety, will you give it a try? Leave a comment explaining why (or why not).  In the event that you’ve participated in a clinical trial of Gepirone (ER), feel free to share your experience.  Mention whether you found it helpful for the treatment of depression, anxiety, or sexual dysfunction – and document any unwanted side effects that you experienced.

Assuming you’ve read the literature for Gepirone ER and reviewed the clinical trial data, do you believe that it should receive FDA approval as Travivo?  It’s relatively easy to argue that the drug should receive approval on the basis of its safety, tolerability, efficacy in multiple RCTs, and the desperate need for newer pharmacological treatments.  Some have argued that if Gepirone ER isn’t approved, it may discourage pharmaceutical companies from future development of antidepressants in fear that they may get rejected by the FDA.

Other reasons for Gepirone approval include its pharmacodynamic and pharmacokinetic superiority to Buspar as a result of its lack of dopamine antagonism and extended-release format, respectively.  That said, the drug was rejected for FDA approval on three accounts for legitimate reason, one of which is questionable efficacy.  Though you may want a new antidepressant-anxiolytic to hit the market like Gepirone ER, you probably wouldn’t want it to get approval if it wasn’t actually effective.

We could argue that the positive findings in clinical trials resulted from probabilistic chance rather than efficacy of the drug; trials have been conducted since the 1980s with more yielding negative than positive outcomes.  Some believe that Fabre-Kramer pharmaceuticals are pushing for Gepirone ER approval without solid data just to cash in on upwards of a billion dollars per year in sales of their shiny, new drug.  If Travivo is approved, it may lower FDA approval criteria and set the stage for lower standards in the future; not something most should want.

In addition, Gepirone may be no more effective than current-market options.  It may turn out to be less effective than Buspar (Buspirone), an anxiolytic which also has proven effective for depression at high doses.  Regardless of whether Travivo (Gepirone ER) is approved, the final decision will go down as being controversial.  Those responding well to 5-HT1A partial agonists may want to keep their fingers crossed that Gepirone ER hits the market.

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