Gepirone is a serotonin (5-hydroxytryptamine, 5-HT) type1A receptor agonist and a pharmacologic analogue of buspirone. [1] On 28 September 2023, the FDA granted approval for Gepirone, designed for treating major depressive disorder (MDD) in adults. This approval positioned it as an innovative antidepressant, belonging to a distinctive class that exclusively targets 5HT1A receptors. [2]

This member of the azapirone group has demonstrated superior efficacy compared to selective serotonin reuptake inhibitors (SSRIs) in treating psychiatric disorders, without the limiting factor of causing sexual dysfunction linked with SSRIs. Gepirone exhibits heightened selectivity for the 5-HT1A receptor when compared to SSRIs. [3] 

Initial clinical trials displayed promising outcomes for it; however, its immediate-release (IR) tablet formulation required frequent administration due to short half-lives. It wasn't until the introduction of an extended-release (ER) variant that Gepirone emerged as a potential contender in the realm of antidepressants.

 

Pharmacological Class: Serotonin receptor agonist [2]

Gepirone is indicated for the management of MDD in adults.

Gepirone, an azapirone, functions as a pharmacologic analog to buspirone, exhibiting selective action on both pre- and post-synaptic 5HT1A receptors. [2,5] The mechanism of the antidepressant effect of Gepirone remains elusive. However, it is considered to be linked to its regulation of serotonergic action in the central nervous system via selective agonist effect at 5HT1A  receptors. [2]

• Amend any electrolyte imbalances and conduct an electrocardiogram (ECG) before commencing treatment with Gepirone. Refrain from starting Gepirone if the QTc exceeds 450 msec.
• Carry out ECGs during the dosage titration phase and at regular intervals throughout the treatment phase.
• Begin with a recommended initial dose of 18.2 mg orally once daily, preferably with food, at roughly the same time each day.
• On the basis of the patient's clinical response and tolerance, consider elevating the dosage to 36.3 mg once daily on Day 4. Further titration may lead to an increase to 54.5 mg once daily following Day 7 and 72.6 mg once daily following an additional week.
• For geriatrics, initiate treatment with a daily dose of 18.2 mg, with the option to increase to 36.3 mg after 7 days.
• In cases of renal impairment (creatinine clearance less than 50 mL/min), commence with a daily dosage of 18.2 mg, potentially escalating to 36.3 mg after 7 days.
• In cases of moderate liver dysfunction (Child Pugh B), consider escalating the dosage to 36.3 mg once daily post-seven days (2.6, 8.7).
• Adjust Gepirone's dose by 50% when administering a moderate CYP3A4 inhibitor. [4]

Absorption

Gepirone's pharmacokinetics exhibit linearity and dose proportionality in the range of 18.2 mg to 72.6 mg. Within two to four days of daily dosing, steady-state plasma concentrations are generally attained. The absolute bioavailability ranges from 14% to 17%. The maximum plasma concentration of Gepirone (Cmax) is achieved within 6 hours after dosing (Tmax).

Following a high-fat meal, the time to reach maximum plasma concentration (Tmax) for Gepirone is 3 hours. The influence of food on Gepirone's peak plasma concentration (Cmax) is significant, with a noticeable effect on total exposure (area under the curve [AUC]0-tlast, AUC0-∞), albeit to a lesser extent. The extent of the food effect is influenced by the meal fat content. Under fed conditions, the systemic exposure of Gepirone and its major metabolites consistently surpasses that in the fasted state.

Comparing different meal compositions, Gepirone Cmax is 27% higher after a low-fat (~ 200 calories) breakfast, 55% higher after a medium-fat (~ 500 calories) breakfast, and 62% higher after a high-fat (~850 calories) breakfast compared to the fasted state. The corresponding AUC values following a low-fat breakfast are approximately 14% more, following a medium-fat breakfast 22% more, and following a high-fat breakfast 32 to 37% more in comparison with the fasted state. The impact of fluctuating fat quantity on the Cmax and AUC of the major metabolites 3-OH-Gepirone and 1PP mirrors that observed for Gepirone.

 

Volume of distribution

Gepirone's apparent volume of distribution is about 94.5L.

 

Protein binding

Human in vitro plasma protein binding is 72%, and it doesn't vary with concentration. For the metabolite 3’- OH Gepirone, the in vitro plasma protein binding is 59%, while for 1-PP, it's 42%.

 

Metabolism

Gepirone undergoes extensive metabolism, and its fundamental metabolites, 1-PP and 3’-OH-Gepirone, are found in plasma at raised concentrations when compared to the parent compound. The key enzyme responsible for catalyzing gepirone's metabolism to its vital pharmacologically active metabolites is CYP3A4.

 

Route of elimination

After a single oral dosage of [14C]-labeled Gepirone, around 81% of the radioactivity was restored in the urine, and about 13% was found in the feces, both in the form of metabolites. Within the initial 24 hours, 60% of Gepirone was eliminated through urine. The apparent clearance of Gepirone was not significantly affected by the presence of liver or kidney impairment.
 

Half-life

Gepirone's mean terminal half-life is around 5 hours.

 

Clearance

Following the use of Gepirone (80 mg), the apparent clearance values for Gepirone and its two metabolites, 1-PP and 3’-OH-Gepirone, were found to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h, respectively. [2]

Gepirone is contraindicated in people with:

• Known hypersensitivity to Gepirone
• Severe hepatic impairment
• Congenital long QT syndrome
• Concomitant utilization of strong CYP3A4 inhibitors
• Extended QTc interval > 450 msec at baseline [4] 

Furthermore, Gepirone must not be coadministered with monoamine oxidase inhibitors (MAOIs); do not commence in those using MAOIs (like linezolid, intravenous methylene blue). If MAOI is necessary in a Gepirone-treated patient, discontinue Gepirone prior to commencing an MAOI. [6]

• Evade concomitant usage with strong CYP3A4 inducers as they reduce Gepirone exposure.
• Be cautious of serotonin syndrome, especially when Gepirone is given concurrently with other serotonergic agents. If symptoms of serotonin syndrome manifest, promptly cease the use of Gepirone and commence appropriate supportive measures. [4]

The most commonly reported adverse reactions are:

• Abdominal pain
• Dizziness
• Dyspepsia
• Insomnia
• Nausea  [4]

• Avoid Gepirone usage within 14 days of discontinuing an MAOI. 
• Watch out for QT interval prolongation with Gepirone, as it has the potential to lengthen the QTc. Address any electrolyte abnormalities and conduct ECGs before starting, during dosage titration, and periodically throughout Gepirone treatment.
• Keep a closer ECG monitoring when Gepirone is used alongside medications known to prolong the QT interval. Be particularly vigilant in those having a QTc ≥ 450 msec during therapy or those at higher risk of suffering from torsade de pointes. Do not increase the dosage if QTc exceeds 450 msec.
• Additionally, be mindful of the potential activation of mania/hypomania. Screen persons for bipolar disorder before initiating treatment with Gepirone.
• Avoid using Gepirone during the third trimester of pregnancy as it might elevate the chance of persistent pulmonary hypertension and result in symptoms of poor adaptation in the newborn, including irritability, hypotonia, respiratory discomfort, thermal fluctuations, and feeding challenges. [4] 

Efficacy of Gepirone-ER in MDD

A randomized, double-blind, 8-week study was performed to explore the efficacy and tolerability of Gepirone-ER vs placebo in MDD-affected adult outpatients. By the fourth week, a considerably higher decrease in the Hamilton Rating Scale for Depression [HAM-D (17)] total scores occurred in Gepirone-ER recipients compared with placebo recipients and persisted through weeks six and eight.

Secondary outcomes (like Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions scale, Bech Six-Item Scale, 28-item version of the HAM-D, and HAM-D depressed mood [item 1]) also improved profoundly at multiple timepoints. Hence, Gepirone-ER demonstrated a noteworthy decrease in depression symptoms and severity of illness among outpatients with MDD throughout the entire study duration, and it was generally well received in terms of tolerability.

[7]

In another study conducted by Feiger AD et al, Gepirone-ER was well-tolerated and illustrated effectiveness for the short-term treatment of MDD. The mean alteration from the base in HAM-D-17 score within the intent-to-treat group (Gepirone, N = 101; placebo, N = 103) was considerably larger with Gepirone-ER when compared to placebo at week 3 and week 8. Substantially more subjects receiving Gepirone-ER than placebo were HAM-D-17 remitters at weeks 6 (24.8% vs. 13.9%, respectively) and 8 (28.7% vs. 14.9%, respectively), and HAM-D-17 responders at weeks 3 (33.7% vs. 18.8%, respectively) and 4 (38.6% vs. 24.8%, respectively).

The mean alteration from baseline for HAM-D-25 total score was remarkably higher with Gepirone-ER at all assessments except week 6. The percentage of HAM-D-25 responders was considerably higher with Gepirone-ER at weeks 3 and 8. No serious adverse events were witnessed in Gepirone-treated participants. [8] 

 

Relapse prevention using Gepirone-ER in outpatients battling major depression

The findings of another randomized, placebo-controlled study demonstrated that Gepirone-ER at a dosage range of 40 to 80 mg/day was useful to prevent relapse in outpatients suffering from recurrent major depression. It showed a good tolerability profile during long-term therapy for up to about one year. [9]

 

Sustained efficacy of Gepirone-IR in MDD

A study conducted by Amsterdam JD et al  sought to assess the effectiveness of Gepirone-IR in preventing relapse in outpatients suffering from MDD who initially responded to Gepirone-IR therapy. The study involved treating MDD-affected people with Gepirone-IR for six weeks, followed by randomizing responders to either continue Gepirone-IR or receive a placebo for an additional six weeks.

Among 134 patients, 70 were responders. The study found that Gepirone-IR significantly reduced the relapse rate compared to placebo in four out of six definitions. Hence, Gepirone-IR was more effective than placebo in preventing relapse and was generally well-tolerated in outpatient MDD responders, although longer-term studies are needed for confirmation. [10]

 

Gepirone-ER treatment for anxious depression

A retrospective subgroup analysis by Alpert JE et al. aimed to assess the effectiveness and tolerability of Gepirone-ER tablets (20-80 mg daily) in patients dealing with MDD and high anxiety levels (anxious depression). This analysis was conducted as part of an 8-week, double-blind, placebo-controlled study on Gepirone-ER for MDD. Gepirone-ER showed a profound drop in HAM-D-17 total scores at weeks 3, 6, and 8 than placebo. From week 2 onward, favorable effects were also witnessed in mean changes from baseline in HAM-D-17 total scores and anxiety/somatization scores.

The improvement in anxiety (HAM-D-17 item 12) scores was consistently significant throughout the 8-week trial. In comparison with placebo recipients, Gepirone-ER treated patients had enhanced response and remission rates. Gepirone-ER was well-tolerated, with adverse events similar to placebo, and the most common were dizziness and nausea. The study concluded that Gepirone-ER is a valuable and well-tolerated therapeutic choice for those suffering from anxious depression. [11] 

Efficacy and tolerability of IR vs. ER formulations of Gepirone

Another study sought to review the pharmacology and clinical data for ER and IR formulations of Gepirone for MDD management. It was concluded that Gepirone-ER formulations exhibit better antidepressant effects and tolerability when compared to Gepirone-IR formulations to relieve MDD.  [12]

 

Double-blind study of Gepirone-ER, imipramine, and placebo in major depression

Another study by Feiger AD et al. compared the effectiveness of Gepirone-ER and imipramine, both with a placebo, in managing major depression. This double-blind, placebo-controlled study involved 123 subjects with major depression randomized to 8 weeks of treatment. Gepirone-ER (10-60 mg/day) and imipramine (50-300 mg/day) were found to be superior to placebo at weeks 6 and 8, as assessed by HAM-D-17 and HAM-D-28, Clinical Global Impressions Severity of illness scale, and the total Bech Six-Item Core Depression Cluster score. Gepirone-ER was better tolerated than imipramine, with lower dropout rates due to adverse events. [13]

 

Double-blind trial of low- and high-dose ranges of Gepirone-ER vs. placebo to treat depressed outpatients

A study by Wilcox CS et al. investigated the efficacy and safety of low-dose (10-50 mg) and high-dose (20-100 mg) ranges of Gepirone-ER compared to placebo in 145 outpatients battling MDD. The results of this double-blind study revealed that high-dose Gepirone-ER demonstrated a statistically significant drop in HAM-D scores when compared to placebo at multiple time points, including week 6.

Both the 17-item and 28-item HAM-D scores showed an early onset of antidepressant efficiency, with remarkable outcomes observed at weeks 1, 2, 4, and 6, particularly in the elevated-dose group. A rapid response was evident as early as week 1. Hence, Gepirone-ER was notably superior to placebo in terms of antidepressant effectiveness, and at elevated doses, it was deemed well-tolerated, effective, and safe in depressed outpatients. [14]

1. Jenkins SW, Robinson DS, Fabre LF Jr, Andary JJ, Messina ME, Reich LA. Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology. 1990 Jun;10(3 Suppl):77S-85S.
2. Gepirone. Drug Bank. Available from: https://go.drugbank.com/drugs/DB12184. Drug Bank Accession Number: DB12184.
3. Kaur Gill A, Bansal Y, Bhandari R, Kaur S, Kaur J, Singh R et al. Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties. Drugs Today (Barc). 2019 Jul;55(7):423-437.
4. Gepirone. FDA Label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021164s000lbl.pdf [Last Accessed on: 15 Nov 2023] 
5. Leslie RA. Gepirone. Organon. Current Opinion in Investigational Drugs. 2001 Aug;2(8):1120-7.
6. Gepirone (Rx). Medscape. Available from: https://reference.medscape.com/drug/exxua-gepirone-1000091#5 [Last Accessed on: 15 Nov 2023] 
7. Bielski RJ, Cunningham L, Horrigan JP, Londborg PD, Smith WT, Weiss K. Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study. Journal of Clinical Psychiatry. 2008 Apr;69(4):571-7.  
8. Feiger AD, Heiser JF, Shrivastava RK, Weiss KJ, Smith WT, Sitsen JM, Gibertini M. Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder. Journal of Clinical Psychiatry. 2003 Mar;64(3):243-9.
9. Keller MB, Ruwe FJ, Janssens CJ, Sitsen JM, Jokinen R, Janczewski J. Relapse prevention with gepirone ER in outpatients with major depression. Journal of Clinical Psychopharmacology. 2005 Feb;25(1):79-84.
10. Amsterdam JD, Brunswick DJ, Gibertini M. Sustained efficacy of gepirone-IR in major depressive disorder: a double-blind placebo substitution trial. Journal of Psychiatric Research. 2004 May-Jun;38(3):259-65.
11. Alpert JE, Franznick DA, Hollander SB, Fava M. Gepirone extended-release treatment of anxious depression: evidence from a retrospective subgroup analysis in patients with major depressive disorder. Journal of Clinical Psychiatry. 2004 Aug;65(8):1069-75.
12. Robinson DS, Sitsen JM, Gibertini M. A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clinical Therapeutics. 2003 Jun;25(6):1618-33.
13. Feiger AD. A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression. Psychopharmacology Bulletin. 1996;32(4):659-65.
14. Wilcox CS, Ferguson JM, Dale JL, Heiser JF. A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients. Psychopharmacology Bulletin. 1996;32(3):335-42.