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New antidepressant gepirone (EXXUA) compared to buspirone (BUSPAR)

Gepirone (Exxua) is the latest antidepressant, approved by the FDA in September 2023 with availability expected in 2024. Given that gepirone is a structural analogue of buspirone (Buspar), it is surprising that gepirone is much less benign.

comparing buspirone (Buspar) vs gepirone (Exxua)
Mascots, nicknames, ballicules, and chemical structures of gepirone and buspirone

Similarities between gepirone and buspirone:

❖ Nearly identical chemical structure

❖ Azapirone drug class (the only two azapirones available in the US)

❖ Both are 5-HT1A partial agonists (anxiolytic effects, likely anti-aggression effects)

❖ Both are metabolized to 1-pyrimidinylpiperazine (1-PP), which is an Alpha-2 antagonist--the principal antidepressant action of mirtazapine (Remeron)

❖ Both can enhance sexual functioning

❖ Both are weight neutral

❖ Neither are addictive or abusable

❖ Neither are sedating at regular doses

❖ Both are sensitive CYP3A4 substrates (fish). Blood levels of both drugs are increased by strong 3A4 inHibitors (H for high and hurried) and decreased by strong 3A4 inDucers (D for down and delayed)

❖ They both have a do-not-combine with MAOI warnings and serotonin syndrome warnings, but they do NOT cause a life-threatening serotonin syndrome (Foong et al, 2018)--signs of mild serotonin toxicity at worst.

❖ Neither is approved for pediatric use.

Differences between gepirone and buspirone:

❖ Gepirone is approved for major depression. Buspirone is approved for generalized anxiety.

EXxua is EXtended release, intended for once daily dosing (vs BID-TID dosing of buspirone).

❖ Gepirone can cause QT prolongation, making it more dangerous in overdose than buspirone, which is nearly benign in overdose.

❖ The gepirone label instructs "correct electrolyte abnormalities and perform electrocardiogram (ECG) prior to initiating treatment with EXXUA. Do not initiate EXXUA if QTc is > 450 msec". Monitoring electrolytes or ECG with buspirone is unnecessary.

❖ Gepirone is to be taken with food. Buspirone is to be taken consistently either with food or without food. Taken with food, the amount of buspirone reaching the bloodstream is increased by 100%, compared to only a 37% increase with gepirone.

❖ Although the two drugs were not compared head-to-head, subjects were much more likely to report side effects from gepirone: 49% dizziness (vs 12% buspirone), 35% nausea (vs 8% buspirone), and 31% headache (vs 6% buspirone).

❖ Buspirone is compatible with most any other psychotropic medication, although dose adjustment of buspirone is needed when co-administered with CYP3A4 inHibitors and inDucers. Co-prescribing buspirone with either with vilazodone (Viibryd) or vortioxetine (Trintellix) would be redundant because those two antidepressants have built-in 5-HT1A partial agonist action. Gepirone, on the other hand, is contraindicated with strong CYP3A4 inHibitors or inDucers and with other QT-prolonging medications.

❖ Gepirone is expected to be much more expensive than buspirone, which is available for $4 with GoodRx coupons.

❖ The 1-PP metabolite (Alpha-2 antagonist) appears to play a more prominent role in the action of gepirone, making it suitable monotherapy for depression (although buspirone which can enhance the antidepressant effect of serotonin reuptake inhibitors).

❖ Buspirone, but not gepirone, blocks D2 (very low affinity), D3, and D4 dopamine receptors. As we know, D2 blockade can result in extrapyramidal side effects, but in the case of buspirone this would only occur at extreme high dose. Besides, blocking D3 and D4 appears to have the opposite locomotor effects as blocking D2.

❖ Owing to D3 and D4 blocking effects, buspirone (but not gepirone) may be useful in preventing relapse on cocaine (Winhusen et al, 2013).

❖ By virtue of being approved for depression, gepirone (but not buspirone) has the usual warning of "increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants."

Gepirone (Exxua)

Pronunciation: GE pi rone / EKS shoo uh

Mascot: Jeeper (which resembles the buspirone "Bus spear" mascot)

Mnemonic phrase: “(Ex, you a) Jeeper”

Interaction mnemonic: Fish (CYP3A4 substrate)

Anticipated availability: 2024

Strengths: Extended-release tablets: 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg

Approved for: Major Depressive Disorder

❖ Structural analogue of buspirone (Buspar)

❖ 5-HT1A partial agonist

❖ Alpha-2 antagonist (via active metabolite)

gepirone qt prolongation check ecg ekg and do not start if QTc >450
From Urban Dictionary: JEEPER - a medication no one is going to prescribe because of onerous warning about QT prolongation and requirement for screening ECG, considering the FDA previously declined to approve it x3 for doubtful efficacy, and considering similarities to buspirone which is ultra-cheap and ultra-safe

Mechanism of Action of Gepirone

An active metabolite of gepirone, 1-pyrimidinylpiperazine (1-PP) is an α2-adrenergic receptor antagonist. Blocking α2 receptors is the principal antidepressant action of mirtazapine (Remeron)--that's why I depicted a variation of the mir"Taz"apine mascot tagging along behind the gepirone mascot.

gepirone mechanism of action in Stephen Stahl style molecule ballicule binding affinities
Ballicule representing the receptor binding affinities and other characteristics of gepirone, including the mechanism of its metabolite 1-PP. I made the QT-prolongation peg large because gepirone has stricter requirements regarding QT interval than anything psychiatrists routinely prescribe.
Stahl-style chemical binding affinity ballicule explanation of Gepirone binding to 5-HT1A serotonin receptor
Gepirone binding to 5-HT1A serotonin receptor

History of Gepirone

Gepirone is not a new chemical. It was brought before the FDA in 2004, 2007, and 2015 and was not approved due to lack of substantial evidence of effectiveness. Positive studies suggested a true antidepressant effect, rather than improvement reflecting relief of anxiety symptoms alone. The FDA is reviewing gepirone for a generalized anxiety disorder indication.

Side Effects of Gepirone

7% of patients treated with gepirone discontinued treatment due to an adverse reaction (vs 3% placebo). Side effects were common, however. 49% reported dizziness (vs 10% placebo), 35% nausea (vs 13% placebo), 31% headache (vs 20% placebo), 7% abdominal pain (vs 3% placebo), and 6% dyspepsia (vs 3% placebo).

QT Prolongation with Gepirone

The label instructs "correct electrolyte abnormalities and perform electrocardiogram (ECG) prior to initiating treatment with EXXUA. Do not initiate EXXUA if QTc is > 450 msec". What?!! I am unaware of any other psychotropic with this specific and strict of a guideline. Even thioridazine (Mellaril), which has a Boxed Warning about QT prolongation, does not define QTc > 450 as a contraindication. The thioridazine guideline is to "avoid in combination with other drugs that are known to prolong the QTc interval and in patients with congenital long QT syndrome or a history of cardiac arrhythmias". Ziprasidone (Geodon), which is known to prolong QT interval, does not require an ECT prior to starting it. Considering that a 460 msec QTc interval is far from dangerous, my initial impression is that gepirone is either subject to a wildly inappropriate guideline or the drug itself is too dangerous to be prescribing, especially given its questionable efficacy as an antidepressant. The largest mean increase in QTc interval with 2-fold max dosage of gepirone was about 18 msec, which is a lot. The label also instructs "perform ECGs during dosage titration and periodically during treatment". Not many doctors are going to be prescribing this medication.

Gepirone Overdosage

While buspirone is benign in overdose, gepirone appears to be dangerous due to QT prolongation. In clinical studies, no one was known to have taken more than 454 mg (6.25 times the maximum recommended dose), and that individual experienced vomiting and transient incomplete bundle branch block. An unknown dosage of gepirone produced altered level of consciousness and a 60-second convulsion. This is especially concerning given that gepirone is a sensitive CYP3A4 substrate (fish) with exposure quickly increased ~5-fold by strong CYP3A4 inHibitors (bobbers, H for "High" and "Hurried").

Gepirone is Not Recommended for Bipolar Depression

The label recommends screening patients for a personal or family history of bipolar disorder, mania, or hypomania prior to initiating treatment with gepirone. This is a general antidepressant warning, because medications with mechanisms of action similar to gepirone (e.g., buspirone and some antipsychotics) are not associated with destabilization of bipolar disorder or activating mania/hypomania.

Pharmacodynamic interactions of gepirone:

❖ Serotonin modulator

❖ QT prolongation

❖ Alpha-2 antagonist-- may oppose antihypertensive effect of α2 agonists like clonidine

❖ Sedative (minimal)

Pharmacokinetic interactions of gepirone:

CYP3A4 substrate (fish) - major

➤ Strong CYP3A4 InHibitors (bobbers, H for "High" and "Hurried") increase gepirone exposure by ~ 5-fold (contraindicated)

➤ Moderate CYP3A4 InHibitors increase gepirone exposure by ~ 2.5 fold (dose adjustment warranted)

Strong CYP3A4 inDucers (anvils, D for "Down" and "Delayed") decrease gepirone exposure by 20- to 29-fold ! (contraindicated)

pharmacokinetic interaction gepirone cafer
Gepirone is a CYP3A4 substrate -- "fish" -- as is buspirone

Dosing of gepirone:

❖ The recommended starting dose is 18.2 mg QD with food. The dosage may be increased to 36.3 mg QD on Day 4, to 54.5 mg once daily after Day 7, and to 72.6 mg once daily after an additional week.

Do not escalate dosage if QTc > 450 msec (which is really strict and applicable to no other commonly prescribed psychotropic)

Geriatric patients or Renal Impairment (creatinine clearance < 50 mL/min) or Moderate Hepatic Impairment (Child Pugh B): Recommended starting dosage is 18.2 mg once daily. Dosage may be increased to 36.3 mg after Day 7.

❖ Contraindicated with Severe Hepatic Impairment

❖ Adjust gepirone dose by 50% with moderate CYP3A4 inHibitors

❖ Contraindicated with strong CYP3A4 inHibitors (gepirone levels would be too high)

❖ Contraindicated with strong CYP3A4 inDucers (gepirone levels would be too low)

Initial Impression of Gepirone

Gepirone does not sound like a winner due to questionable efficacy, risks of QT prolongation, requirements for ECG monitoring, high incidence of side effects, and cost. I would not recommend gepirone until after augmentation of another antidepressant with buspirone has failed. Yet, if buspirone augmentation fails, I doubt gepirone would work any better. If so many options have been exhausted that you are considering prescribing gepirone, reach for a monoamine oxidase inhibitor (MAOI) instead.

Azapirone class

Now that buspirone is no longer alone in the US, we should know about the azapirone class of drugs. The azapirone structure is relevant, considering 1-PP breaks off from buspirone and gepirone (actually CYP3A4 breaks it off) to form an active metabolite with antidepressant effects.

Mnemonics for azapirone class of medications, molecular / chemical structures of buspirone gepirone perospirone tandospirone compared

Two azapirones are available outside of the US.

  • Tandospirone is an anxiolytic and antidepressant available in China and Japan. Its mechanism is very similar to gepirone as a 5-HT1A partial agonist metabolized to an α2 receptor blocker–specifically 1-PP which is the same metabolite of buspirone and gepirone.

  • Perospirone is an azapirone antipsychotic approved in Japan for treatment of schizophrenia and mania. Perospirone is a 5-HT1A partial agonist (like buspirone and gepirone) but also a D2 antagonist and 5-HT2A antagonist like other atypical antipsychotics.

Buspirone (Buspar)

Pronunciation: BU spi rone / BU spar

Mascot: "Bus spear"

Interaction mnemonic: Fish (CYP3A4 substrate)

Available since: 1986

FDA-approved for: Generalized anxiety disorder

❖ Anxiolytic of the azapirone class

❖ 5-HT1A serotonin receptor partial agonist

❖ Alpha-2 antagonist (via active metabolite 1-PP)

 mnemonic for buspirone by Dr Jason Cafer MD
The 1-PP metabolite (Alpha-2 antagonist) appears to play a less prominent role in the action of buspirone, compared to gepirone.

Buspirone is used off-label for:

❖ Augmentation of SSRI for depression

❖ Antidepressant-associated sexual dysfunction

❖ SSRI-induced bruxism (tooth grinding)

❖ Movement disorders (high dose)

- Tardive dyskinesia

- Chorea

- Levodopa induced dyskinesias

❖ Hostility / irritability

“Buspar is benign.”

Buspirone is one of the safest psychotropic medications, with no need for laboratory monitoring. There are no absolute contraindications (other than allergy to buspirone). No deaths have been reported with single-drug overdose. Some have expressed possible concerns related to buspirone's binding of dopamine receptors (see below) which seems to be a nothingburger.

Speaking of burgers, absorption of buspirone is increased 2-fold when taken with food. The label advises to take it consistently, either always with or always without food. While an unintentional doubling of the available buspirone dose does not present significant safety concerns, it may bring side effects such as nausea, headache, or lightheadedness.

Buspirone is generally non-sedating at usual doses. Deliberate overdoses with 250 - 300 mg of buspirone resulted in drowsiness in about 50% of individuals.

Buspirone has a short half-life of 2–3 hours, so it requires BID or TID dosing (usually TID). Although inconvenient, some patients prefer multiple daily dosing for better perceived control of symptoms. However, it is not expected to be effective immediately. Benefit is achieved gradually over 2–4 weeks, but placebo effect can be a powerful thing.

mechanism of action and interactions of buspirone visualized by stephen stahl style ballicule
Ballicule representing the receptor binding affinities and other characteristics of buspirone, including the mechanism of its metabolite 1-PP

"Possible Concerns Related to Buspirone's Binding to Dopamine Receptors"

From the buspirone label: Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (eg, dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central noradrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (ie, represent akathisia). Voluntary reports since introduction have included rare occurrences of dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to BuSpar treatment has not been determined.

Pharmacodynamic interactions of buspirone:

❖ Serotonin modulator

❖ Sedative (minimal)

❖ Possible neurogenesis with cognitive benefits when combined with melatonin in depressed individuals

Pharmacokinetic interactions of buspirone:

CYP3A4 substrate (fish) - major

All of the following combinations warrant dose reductions of buspirone (to avoid side effects), but are not contraindicated (no safety concern):

​Medication combined with buspirone


Exposure to buspirone




​~4-fold increase



~4-fold increase



​​~5-fold increase

Grapefruit juice


​~5-fold increase

​ 200 mL double-strength grapefruit juice t.i.d.



​~8-fold increase

​The label recommends a very low dose of buspirone, 2.5 mg QD, if combined with itraconazole.


​>20-fold increase

This combination reduced the plasma concentration of buspirone's active metabolite 1-PP by about 50%. The label recommends a very low dose of buspirone, 2.5 mg QD



​~90% decrease

​ Rifampin 600 mg/day for 5 days. A longer course of rifampin may have decreased buspirone further because inDuction is "Down" and "Delayed"



​~30% increase

pharmacokinetic interaction buspirone cafer fish CYP3A4
Buspirone is a CYP3A4 substrate -- "fish" -- as is gepirone

Dosing of Buspirone

❖ Buspirone is typically started 7.5–10 mg BID or TID and titrated quickly to a target dose of 15 mg TID or 20 mg BID, with FDA maximum dose of 60 mg/day.

❖ It is recommended to take buspirone consistently with food or consistently without food, because it is absorbed twice as well when taken with meals.

❖ For off-label treatment of movement disorders, it may be necessary to titrate buspirone as high as 180 mg/day.

❖ A higher dose of buspirone will be needed if it is combined with a strong 3A4 inDucer such as carbamazepine (Tegretol).

❖ Unless the dose is very high, buspirone may be discontinued without tapering.

Impression of Buspirone

Total winner! I have prescribed buspirone hundreds of times. I consider it entirely benign and it is highly effective for some patients. I prescribe it for generalized anxiety, not usually for off-label uses. I consider it entirely benign. It is well tolerated other than an occasional complaint of dizziness. I recognize no contraindications to its use. Among commonly encountered medications, I combine buspirone with anything except vilazodone (Viibryd) and vortioxetine (Trintellix) because those two antidepressants have "buspirone built in" being 5-HT1A partial agonists themselves. It does pose a risk of dangerous serotonin toxicity. When antipsychotics or antidepressants share mechanisms of buspirone (5-HT1A partial agonism, 5-HT2A antagonism, D3 & D4 antagonism), it makes them better medications with fewer side effects. I do not consider buspirone's very weak binding to D2 receptors to pose any significant risk of tardive dyskinesia.

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