Advancing Major Depressive Disorder Treatment: Exxua™ (gepirone extended release) Approval and Potential Impact
Major Depressive Disorder (MDD) is a significant health concern impacting millions of American adults each year, with over 8% affected annually. Diagnosis involves identifying specific symptoms, including persistent low mood, anhedonia, guilt, lack of energy, concentration problems, appetite and sleep changes, and thoughts of self-harm. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), diagnosing MDD requires at least five of these symptoms, with depressed mood or anhedonia causing social or occupational impairment being one of the symptoms. The disorder’s etiology is complex, involving biological, genetic, environmental, and psychosocial factors. Understanding the multifaceted nature of MDD is essential in addressing its prevalence and varied presentations.
Treatment options approved by the Food and Drug Administration (FDA) for MDD encompass medication, therapy, and specialized interventions. Combining medication with therapy tends to yield better results than using either approach alone. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are often the first line of treatment. Other medication classes include atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors, mood-stabilizers, and antipsychotics. Notably, electroconvulsive therapy is particularly effective for severe cases. In cases of treatment-resistant depression, the FDA has also approved alternative options like Transcranial Magnetic Stimulation (TMS), Vagus Nerve Stimulation (VNS), and esketamine2. These treatments are specifically indicated for cases where multiple medication trials have been unsuccessful.
While the current treatment landscape for MDD offers a variety of therapeutic options, significant limitations and challenges are still present. Despite these available treatments, many individuals with MDD face limited success with standard antidepressants or psychotherapies, leading to treatment-resistant depression. Additionally, common side effects associated with antidepressants, such as sexual dysfunction, weight gain, or nausea, can hinder medication adherence and impact the overall quality of life for those undergoing therapy. A lack of comprehensive understanding of depression’s underlying mechanisms also limits the development of highly targeted and effective therapies. Furthermore, access to specialized therapies like TMS or VMS may be restricted due to limited availability or cost, limiting their utilization among those who could benefit from them. Even after successful treatment, the risk of relapse persists, necessitating continuous monitoring and maintenance therapy.
Amidst the persistent challenges of managing MDD, a significant breakthrough emerged with the recent FDA approval of Exxua™ (gepirone) on September 28, 20234. Gepirone is the first oral selective 5HT1A receptor agonist indicated for MDD. Notably, gepirone’s distinction also lies in its FDA approval without warnings or adverse reactions related to sexual dysfunction or weight gain. Despite initial FDA rejection due to inconsistent trial results, a resubmission urged a reevaluation of its efficacy in treating MDD, which ultimately led to its approval. This advancement signals a new addition to antidepressant therapies and offers promising possibilities for individuals with MDD.
Gepirone’s efficacy in treating MDD in adults was examined in two separate eight-week, randomized, double-blind, placebo-controlled trials. The first trial assessed the efficacy and tolerability of gepirone versus placebo in the treatment of MDD. A total of 209 patients aged 18 to 70 with moderate-to-severe MDD, meeting DSM-5 criteria and exhibiting a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score ≥ 20, were enrolled. Patients were randomly assigned to receive gepirone at doses ranging from 20 to 80 mg/day (n= 101) or placebo (n= 103) for a duration of 56 days. Patients were initiated on gepirone ER 20 mg once daily or a matching placebo. On day 4, the dosage increased to 40 mg daily. If well-tolerated, further increases were allowed to 60 mg daily after day 7, and up to 80 mg daily after day 14. Dose reductions were permitted if needed; however, the minimum allowed dose was 40 mg/day. The primary outcome was the change in HAM-D-17 total score from baseline to the end of the trial.
The results revealed that gepirone demonstrated significant improvement in HAM-D-17 scores compared to placebo; the mean change from baseline in HAM-D-17 score was notably higher at weeks 3 (p = 0.013) and 8 (p = 0.018). Additionally, at week 8, a higher percentage of HAM-D-17 responders (≥ 50% reduction from baseline) in the gepirone group was observed, with 43.6% showing response compared to 30.7% in the placebo group (p= 0.059). Adverse events were reported in 81.4% of the gepirone group and 55.7% of the placebo group, with 9.8% discontinuing gepirone due to adverse events (dizziness and nausea) compared to 2.8% in the placebo group. No serious adverse events or deaths were reported with gepirone. Furthermore, very few reports of sexual problems were noted in both groups, with only one patient on gepirone and five on placebo reporting decreased libido/abnormal sexual function. Overall, these findings suggested that gepirone, administered at doses ranging from 20 to 80 mg/day, exhibits significant efficacy and manageable tolerability.
In the second trial, 248 adult participants (gepirone n = 124; placebo n = 124) aged 18 to 64 were enrolled to evaluate gepirone’s efficacy and safety in treating MDD. Patients met the DSM-5 criteria for MDD, exhibited a HAM-D17 score ≥ 20 at screening and baseline, and experienced significant dysphoria for ≥ 4 weeks before screening. The dosing regimen for gepirone in this trial mirrored that of the previous study, employing a similar titration strategy based on therapeutic response and tolerability, ranging from 20 to 80 mg/day over the 8-week treatment period. Similarly, the primary outcome of this trial was also the change in HAM-D17 total score6.
The analysis of the intent-to-treat population (gepirone n = 116; placebo n = 122) revealed significant reductions in HAM-D-17 scores with gepirone versus placebo at weeks 4, 6, and 8 (p= 0.004, p= 0.006, p= 0.032, respectively). By week 4, the gepirone group showed a significantly higher proportion of HAM-D-17 responders compared to the placebo group (34% vs. 18%, p= 0.008). This difference was sustained through weeks 6 and 8 (43% vs. 25%; p= 0.007 and 46% vs. 30%; p= 0.014, respectively). Additionally, gepirone was well tolerated among the patients, with low incidences of severe adverse events (8.9% in both groups) and serious adverse events (3.2% in both groups). Only one serious adverse event, suicidal ideation in a placebo-treated patient, was potentially linked to the study drug. Another gepirone patient experienced suicidal ideation/dissociative disorder, thought to be unrelated to the study drug by the investigator. Discontinuations due to adverse events were seen in 6.5% of the gepirone group and 2.4% of the placebo group, with all adverse events resolving without additional treatment. With these findings, it was concluded that gepirone significantly reduced depressive symptoms and illness severity in MDD outpatients, reaffirming the findings from the initial trial6.
Regarding administration, gepirone should be taken orally with food around the same time each day. Tablets should be swallowed whole and should not be split, crushed, or chewed. The recommended starting dosage is 18.2 mg once daily. Depending on the individual’s clinical response and tolerability, the dosage may be increased to 36.3 mg orally once daily on Day 4, further titrated to 54.5 mg orally once daily after Day 7, and potentially up to 72.6 mg orally once daily after an additional week. The maximum recommended daily dosage of gepirone is 72.6 mg. Dosage adjustments should be made based on clinical response and tolerability, following the prescribed titration schedule.
Although the approval of this agent marks a significant milestone in depression treatment, there are important safety considerations to note. Gepirone carries a boxed warning for suicidal thoughts and behaviors. Close monitoring for the worsening or emergence of suicidal thoughts and behaviors is crucial. Due to this heightened risk, gepirone is not approved for use in pediatric patients. Gepirone is also contraindicated in specific populations, including individuals with known hypersensitivity to gepirone or its components, those exhibiting a baseline QTc interval exceeding 450 msec or diagnosed with congenital long QT syndrome, and individuals with severe hepatic impairment. Additionally, concurrent use of strong CYP3A4 inhibitors or MAOIs, either simultaneously or within 14 days of discontinuing gepirone treatment is contraindicated.
Gepirone has the potential to prolong the QT interval; thus, correcting any electrolyte abnormalities is crucial. ECGs should be conducted before starting gepirone, during dose adjustments, and periodically during treatment. Monitoring ECGs becomes even more critical when using gepirone alongside medications known to extend the QT interval, in patients developing QTc ≥ 450 msec during treatment, or in those at significant risk of specific heart rhythm irregularities. Additionally, the risk of serotonin syndrome increases when co-administering gepirone with other serotonergic agents, necessitating discontinuation and the initiation of supportive measures if serotonin syndrome occurs. Moreover, screening for bipolar disorder is recommended due to the potential for gepirone to activate mania or hypomania in susceptible individuals.
Despite these safety considerations, gepirone provides a treatment option for individuals with MDD that addresses specific limitations and challenges posed by existing therapies. Conventional antidepressants, while beneficial for many, present drawbacks due to adverse effects such as sexual dysfunction, weight gain, and nausea. These issues significantly impact patients’ quality of life and may impact treatment adherence. Additionally, access to specialized treatments remains restricted, and potential of relapse even after successful therapy is. Overall, gepirone’s approval offers an alternative with the potential to address some of these challenges, underscoring its role as a promising addition to treatments available for MDD.
Written by Drug Information Fellow: Muna Said, PharmD
References:
1. National Institute of Mental Health. Major Depression. National Institute of Mental Health. Published July 2023. https://www.nimh.nih.gov/health/statistics/major-depression
2. Bains N, Abdijadid S. Major Depressive Disorder. In: StatPearls. Treasure Island (FL): StatPearls Publishing; April 10, 2023.
3. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–388. doi:10.2147/PPA.S29716
4. Fabre-Kramer Pharmaceuticals announces FDA approval of Exxua, the first and only oral selective 5HT1a receptor agonist for the treatment of major depressive disorder in adults. News release. PR Newswire. September 28, 2023. Accessed November 20, 2023. https://www.prnewswire.com/news-releases/fabre-kramer-pharmaceuticals-announces-fda-approval-of-exxua-the-first-and-only-oral-selective-5ht1a-receptor-agonist-for-the-treatment-of-major-depressive-disorder-in-adults-301941467.html#:~:text=Exxua%20has%20been%20shown%20to,in%20pharmacies%20in%20early%202024
5. Feiger AD, Heiser JF, Shrivastava RK, et al. Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder. J Clin Psychiatry. 2003;64(3):243–249.
6. 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. J Clin Psychiatry. 2008;69(4):571–577. doi:10.4088/jcp.v69n0408
7. Exxua™ (gepirone extended release). Prescribing information. Mission Pharmacal Company; 2023.
