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Zuranolone for Depression: Rapid Efficacy & Safety in Clinical Trials (2023 Review)

Zuranolone, a novel antidepressant, shows promise in treating depression, as evidenced by a recent meta-analysis.

A new study investigated zuranolone’s efficacy and safety, focusing on short-term rapid antidepressant effects.


  • Zuranolone Effectiveness: Demonstrated significant improvement in depression severity scores compared to placebo, with notable effects by day 15.
  • Treatment-Emergent Adverse Events (TEAEs): Increased incidence in the zuranolone group, yet most events were mild and temporary.
  • Dosage: The 30 mg dose of zuranolone showed more promising results compared to other dosages.
  • Research Needs: Additional studies with larger sample sizes and longer follow-up durations are necessary to fully understand zuranolone’s long-term efficacy and safety.

Source: Frontiers in Pharmacology (2023)

Zuranolone as an Antidepressant: Targeting GABA

Zuranolone, known for its potential in rapidly alleviating depressive symptoms, operates through a unique mechanism of action, primarily targeting the brain’s GABAergic system.

GABAergic System & Depression

  • Gamma-Aminobutyric Acid (GABA): GABA is the primary inhibitory neurotransmitter in the brain. It plays a crucial role in regulating neuronal excitability and maintaining the balance between neuronal inhibition and excitation.
  • Dysregulation in Depression: In depressive disorders, there is often a dysregulation of GABAergic signaling. This imbalance can lead to altered mood states, anxiety, and other symptoms associated with depression.

Zuranolone’s Mechanisms of Action

1. Modulation of GABAA Receptors

Allosteric Modulation: Zuranolone acts as a positive allosteric modulator of GABAA receptors. This means it binds to these receptors at a site distinct from the GABA binding site, enhancing the receptor’s response to GABA.

Increased Inhibition: By amplifying GABAergic inhibition, zuranolone helps to restore balance in neural circuits that are dysregulated in depression, leading to mood stabilization and symptom relief.

2. Neurosteroid Activity

Synthetic Analog of Allopregnanolone: Zuranolone is a synthetic analog of allopregnanolone, a naturally occurring neurosteroid that modulates GABAA receptors. Neurosteroids like allopregnanolone are known to have rapid effects on brain function.

Rapid Neurochemical Changes: The neurosteroid activity of zuranolone contributes to its ability to induce rapid neurochemical changes, which can lead to quick improvements in mood and anxiety symptoms.

3. Rapid Alleviation of Symptoms

Fast-Acting Nature: Traditional antidepressants often take weeks to exert their full effects. In contrast, zuranolone’s mechanism of action allows it to produce noticeable improvements in depressive symptoms much more quickly, often within days of initiation.

Direct Modulation of Neural Circuits: By directly modulating GABAergic neurotransmission and enhancing inhibitory signaling, zuranolone can rapidly influence mood-regulating neural circuits, leading to an expedited therapeutic effect.

4. Potential Neuroprotective Effects

Stress Response Regulation: There is evidence suggesting that neurosteroids like allopregnanolone, and by extension, zuranolone, may play a role in regulating the stress response, which is often dysregulated in depression.

Neuroplasticity: Zuranolone may also promote neuroplasticity – the brain’s ability to adapt and reorganize – which is crucial in recovering from the neural effects of chronic stress and depression.

Findings from Review of Zuranolone in Clinical Trials for Depression (2023)

The comprehensive review on zuranolone in depression provides a nuanced understanding of its potential as an antidepressant.

1. Rapid & Sustained Antidepressant Effect

  • Baseline to Day 15 Change: Zuranolone demonstrated a significant mean difference (MD) of 2.43 in the reduction of depression severity scores compared to placebo, indicating a notable improvement in depressive symptoms.
  • Time Points Beyond Day 15: The efficacy of zuranolone persisted beyond day 15. Significant improvements in depression severity scores were also observed on days 3, 8, 21, and 45. This suggests that zuranolone not only provides rapid relief from symptoms but also maintains its efficacy over a longer duration.
  • Heterogeneity in Results: The I2 values, indicating heterogeneity, varied across different time points. For instance, day 3 and 8 scores showed high heterogeneity (I2 = 57%), while day 21 and 45 scores exhibited lower heterogeneity (I2 = 9% and 11%, respectively). This variability might be due to differences in patient populations, zuranolone dosages, or study designs.

2. Significant Response & Remission Rates

  • Response Rates: The response rate, defined as a 50% reduction in the Hamilton Rating Scale for Depression (HAMD-17) score from baseline, showed a relative risk (RR) of 1.33 in the zuranolone group compared to placebo. This indicates a 33% higher likelihood of achieving a significant reduction in depressive symptoms with zuranolone.
  • Remission Rates: Remission, characterized by HAMD-17 scores ≤ 7, had an RR of 1.46 with zuranolone, suggesting a 46% greater chance of achieving remission compared to placebo.

3. Few Side Effects & Adverse Events

  • Overall Incidence: The zuranolone group showed a higher incidence of TEAEs, with an RR of 1.15. This finding highlights the need for careful monitoring of side effects during treatment.
  • Specific Adverse Events: Notable differences were observed in the incidence of dizziness (RR = 2.17) and somnolence (RR = 2.43), indicating that these side effects are more common with zuranolone treatment.
  • Severity and Duration: While the incidence of TEAEs was higher, the study noted that most adverse events were mild and temporary, suggesting manageable safety concerns.

4. Dosage-Specific Efficacy

  • Comparative Efficacy of Different Dosages: The study analyzed the efficacy of different dosages of zuranolone (20 mg, 30 mg, and 50 mg). The 30 mg dosage showed a statistically significant greater efficacy in reducing depression severity scores on day 15 compared to the 20 mg dosage.
  • Implications for Prescribing Practices: These findings indicate that the 30 mg dosage might be more optimal for treating depression, offering a balance between efficacy and safety.

5. Effect in Major Depression vs. Post-Partum Depression

  • MDD vs. PPD Outcomes: Zuranolone’s efficacy varied between patients with MDD and those with PPD. While significant improvements were observed in both groups, the drug showed a more positive response in PPD at almost every time point.
  • Possible Biological Underpinnings: This differential impact might be related to the pathophysiological differences between MDD and PPD, particularly concerning the GABAergic system and neurosteroid fluctuations.

Zuranolone for Depression: Efficacy & Dosage (2023 Review)

Youjia Qiu et al. evaluated the efficacy and safety of zuranolone in treating patients with depression.

Specifically, the research sought to understand how zuranolone, compared to a placebo, affected depression severity scores, response and remission rates, and the incidence of treatment-emergent adverse events (TEAEs).

The study also aimed to determine the optimal dosage of zuranolone and its differential impact on major depressive disorder (MDD) and postpartum depression (PPD).


  • Databases: The researchers conducted a comprehensive search across PubMed, Cochrane, and Embase databases, up to November 1, 2023.
  • Selection: Eligibility criteria were based on the PRISMA statement, focusing on patients over 18 years with a diagnosis of MDD or PPD. Only randomized controlled trials (RCTs) were considered.
  • Data: Key data extracted included study design, patient characteristics, dosage, and outcomes. The primary outcome was the change in depression severity scores by day 15. Secondary outcomes included response and remission rates, and safety outcomes focused on AEs.
  • Statistical Tools: Relative risk (RR) and mean differences (MD) were calculated using a random-effects model. Trial sequential analysis (TSA) was employed to evaluate the ideal sample size and the robustness of the findings.


  • Efficacy: Zuranolone demonstrated a significant reduction in depression severity scores by day 15 compared to the placebo. Improvements were also observed at other time points.
  • Response & Remission Rates: The zuranolone group showed statistically significant improvements in both response and remission rates compared to the placebo.
  • Safety: Zuranolone was associated with a higher incidence of TEAEs, but most were mild and temporary. Significant differences were noted in dizziness and somnolence.
  • Dosage Efficacy: The 30 mg dosage of zuranolone showed greater efficacy compared to the 20 mg dosage.
  • Differential Impact: The drug demonstrated varying degrees of effectiveness in MDD and PPD, with more positive responses observed in PPD.


  • Sample Size & Study Design: The cumulative sample size from the included RCTs was considered insufficient for conclusive long-term efficacy results, as indicated by TSA.
  • Comparison Limitation: The efficacy of zuranolone was only compared against a placebo, not other antidepressants, limiting a comprehensive understanding of its relative effectiveness.
  • Specific Depression Types: The study primarily focused on MDD and PPD, limiting the generalization of the findings to other types of depression.
  • Long-term Efficacy & Safety: The long-term effects of zuranolone, particularly beyond the study’s follow-up period, remain unclear and require further investigation.

(Related: Allopregnanolone Agonists for Depression: Brexanolone & Zuranolone in Focus)

Considerations for Using Zuranolone in Depression

  • Side Effects & Tolerability: Zuranolone has been associated with a higher incidence of TEAEs, such as dizziness and somnolence. This necessitates close monitoring of patients, especially during the initial phase of treatment.
  • Insufficient Long-Term Data: The long-term efficacy and safety profile of zuranolone is not yet fully established. This uncertainty is a significant consideration for clinicians contemplating its use, particularly for chronic management of depression.
  • Specific Patients: The study’s findings suggest that zuranolone may have varying degrees of effectiveness in different patient populations, such as between men and women or in those with MDD versus PPD. Zuranolone’s mechanism, closely related to neurosteroid modulation, might interact differently with the hormonal milieu in women, especially during postpartum periods, potentially making it more effective in treating PPD.
  • Cost & Accessibility: As a novel therapeutic agent, zuranolone might be more expensive and less accessible compared to traditional antidepressants, limiting its widespread use.

Why Zuranolone May Work Best in PPD and/or Women

Neurosteroid Fluctuations & Postpartum Depression (PPD)

  • Role of Allopregnanolone: In women, neurosteroid levels, particularly allopregnanolone, undergo significant fluctuations during and after pregnancy. Allopregnanolone, which modulates the GABAA receptors, tends to increase during pregnancy and sharply decline after childbirth, a change that has been implicated in the pathophysiology of PPD.
  • Zuranolone’s Neurosteroid Activity: As a synthetic analog of allopregnanolone, zuranolone can mimic its effects on the brain, potentially stabilizing the rapid neurochemical changes that contribute to PPD. By boosting GABAergic activity through allopregnanolone-like action, zuranolone could effectively address the mood dysregulation seen in PPD.

GABAergic System Sensitivity in Women

  • Hormonal Influences on GABAergic System: Women’s neurochemistry, particularly the GABAergic system, may be more sensitive to hormonal fluctuations. Estrogen and progesterone, which modulate GABA receptor sensitivity, fluctuate throughout the menstrual cycle and pregnancy, influencing mood and anxiety levels.
  • Increased Efficacy in Female Patients: These hormonal influences might make the GABAergic system in women more responsive to the modulatory effects of zuranolone. Therefore, women, especially those experiencing hormonal shifts like in PPD, might find more significant therapeutic benefits from zuranolone.
  • Addressing Postpartum Neurochemical Imbalance: The postpartum period involves drastic hormonal changes that can disrupt neurochemical balance. Zuranolone’s ability to act on the GABAA receptors and provide neurosteroid-like effects makes it potentially well-suited to counteracting the specific neurochemical changes associated with PPD.

Takeaway: Zuranolone for Depression

The study on zuranolone presents it as a promising new antidepressant, especially noteworthy for its rapid onset of action.

Its unique mechanism, targeting the GABAergic system through neurosteroid modulation, offers a novel approach to treating depression, potentially filling gaps left by traditional antidepressants.

While it shows particular promise in women with postpartum depression, its efficacy in other forms of depression, such as MDD in men, requires further research.

The higher incidence of treatment-emergent adverse events and the current lack of long-term data are significant considerations.

As such, while zuranolone represents an exciting development in psychiatric medication, its optimal use in clinical practice necessitates cautious application, further research, and a tailored approach considering individual patient profiles.


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