Phase 3 clinical trials results of new antidepressant drugs published

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Phase 3 clinical trials results of new antidepressant drugs published

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Phase 3 clinical trials results of new antidepressant drugs published. AJP: One tablet a day, effective in three days!

Major depressive disorder (MDD) is the leading cause of disability worldwide [1], current main treatment drugs are limited by slow onset of action, taking weeks or even months to work [2], and some may Adverse events leading to discontinuation include weight gain, sexual dysfunction, and cognitive impairment [3-5].

To take the drug treatment of MDD one step further, researchers are exploring new mechanism-based drugs such as gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain that balances excitatory and inhibitory nerve signals Transmitting, neurological signaling network balance is impaired in patients with depression and GABA levels are reduced in plasma and CSF.

The GABA type A receptor modulating drug brexanolone has been approved by the FDA for the treatment of postpartum depression in 2019, and a significant improvement in depressive symptoms can be observed 60 hours after a single intravenous injection, which provides hope for regulating GABA signaling to treat MDD.

The American Journal of Psychiatry recently published the results of a randomized, double-blind, placebo-controlled phase 3 clinical trials of zuranolone, a positive allosteric modulator of the GABA type A receptor, evaluating the safety of once-daily oral zuranolone in the treatment of MDD and effectiveness.

The results show that zuranolone at a dose of 50mg/day can significantly improve depressive symptoms within 15 days, and the effect can be started on the third day. It is generally well tolerated, and compared with the low dose used in previous trials, no new adverse events were found.

The trial, conducted at 39 centers in the United States between May 2020 and April 2021, enrolled 534 participants aged 18-64 who were randomly assigned 1:1 to either zuranolone (n=266) or The placebo group (268 cases) received 14 days of treatment and 28 days of follow-up.

At baseline, the average time since the diagnosis of MDD in both groups was about 11 years, the average duration of the current depressive episode was >1 year, about 30% were receiving antidepressant medication, and the Hamilton Depression Scale (HAM- D) The severity of depressive symptoms assessed was similar (mean scores 26.8 and 26.9, respectively).

Test procedure

On day 15 after the start of the trial, depressive symptoms were significantly improved in the zuranolone group compared with the placebo group, with a least squares mean (LSM) change from baseline in the HAM-D score of -14.1 versus -12.3 in the placebo group (p=0.01 ).

The LSM change in the CGI-S score was also numerically greater in the zuranolone group at -1.8 compared to -1.6 in the placebo group, but was not statistically significant (p=0.12 ).

At different follow-up time nodes (days 3, 8, 12, 21, 28, 35, and 42), the LSM changes of HAM-D scores in the zuranolone group were also greater than those in the placebo group. The Montgomery-Asperger Depression Rating Scale (MADRS) assessment and subgroup analyzes according to different baseline characteristics also yielded consistent results.

Improvement in anxiety symptoms was also stronger in the zuranolone group than in the placebo group, with LSM changes from baseline in Hamilton Anxiety Scale (HAM-A) scores of -10.4 vs -9.1, respectively (p=0.02).

At Day 3, 30.0% of participants in the zuranolone group achieved a Clinical Global Assessment Inventory-Integrated Outcome (CGI-I) response (rated as “moderately improved” or “very much improved”), which was significantly higher than that in the placebo group 18.9% (OR=1.9, p=0.003), and the results were the same on day 15 and each follow-up time node.

In addition to the above indicators, the HAM-D response rate (HAM-D score reduction ≥50%) and HAM-D remission rate (HAM-D score ≤7) rate in the zuranolone group were also higher than those in the placebo group, regardless of whether they were concurrently Taking other antidepressants did not change the results.

Summary of effectiveness results for the zuranolone group

The incidence of post-treatment adverse events was 60.1% in the zuranolone group and 44.6% in the placebo group, of which 95.0% and 97.5% were mild or moderate, respectively.

The most common post-treatment adverse events (incidence >5% in either group) were somnolence, dizziness, headache, excessive sedation, and diarrhea.

There were 23 and 1 participants in the two groups who reduced the drug dose due to post-treatment adverse events, mainly dizziness and drowsiness in the zuranolone group, and fatigue in the placebo group, and 9 and 4 participants discontinued the drug due to post-treatment adverse events, It was mainly related to nervous system disturbance, manifested in dizziness and excessive sedation in the zuranolone group, and excessive sedation and drowsiness in the placebo group.

There were no significant differences in the incidence of adverse events after treatment, regardless of concurrent use of other antidepressant medications at baseline.

No participants reported adverse events of death, loss of consciousness, weight gain, sexual dysfunction, or euphoria, nor did laboratory results, electrocardiogram results, or changes in vital signs lead to treatment interruption or discontinuation.

There was no increase in suicidal ideation or behavior following baseline, and there was no increase in withdrawal symptoms after drug discontinuation.

The incidence of different adverse events

Therefore, the results of this trial suggest that zuranolone can act rapidly, improve symptoms of depression and anxiety in MDD patients, have a relatively high response and remission rate, and a favorable safety profile.

In February of this year, Biogen and Sage Therapeutics submitted a new drug application (NDA) for zuranolone to the FDA for the treatment of MDD and postpartum depression, and the FDA granted zuranolone a priority review qualification [7]. Patients bring new hope.

references:

[1] James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017[J]. The Lancet, 2018, 392(10159): 1789-1858.

[2] Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed patients requiring one or several treatment steps: a STAR* D report[J]. American Journal of Psychiatry, 2006, 163(11 ): 1905-1917.

[3] Ferguson J M. SSRI antidepressant medications: adverse effects and tolerance[J]. Primary care companion to the Journal of clinical psychiatry, 2001, 3(1): 22-27.

[4] Higgins A, Nash M, Lynch A M. Antidepressant-associated sexual dysfunction: impact, effects, and treatment[J]. Drug, healthcare and patient safety, 2010: 141-150.

[5] Sayyah M, Eslami K, AlaiShehni S, et al. Cognitive function before and during treatment with selective serotonin reuptake inhibitors in patients with depression or obsessive-compulsive disorder[J]. Psychiatry journal, 2016, 2016.

[6] Clayton AH, Lasser R, Parikh SV, et al. Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo‐Controlled Phase 3 Trial[J]. American Journal of Psychiatry, 2023: appi. ajp. 20220459.

[7] https://investors.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-announce-fda-accepts-filing-new

Phase 3 clinical trials results of new antidepressant drugs published

(source:internet, reference only)

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