Overview
Major depressive disorders are associated with implications in γ-aminobutyric acid (GABA) transmission, whilst a reduction in the inhibitory neurotransmitter GABA has been reported to be a causative factor in depression. Current treatment strategies are thus aimed at GABA receptors. Sage 217 is a neurosteroid which acts as a positive allosteric modulator of the GABA receptors, which means that it binds onto a site other than the active site and increases their agonist affinity. This article focuses on understanding the safety and efficacy of Sage 217 in the treatment of major depressive disorders.
Major Depressive Disorders
Major depressive disorder (MDD) constitutes a debilitating neuropsychiatric syndrome which affects roughly 17% of the people globally. This complex disorder occurs in conjunction with other anxiety disorders and around 50-60% of the patients with depression have been reported to exhibit a history of anxiety disorders (Fava et al., 2000). It is characterized by a depressed mood and a lack of interest in the routine activities coupled with additional symptoms, encompassing fatigue, changes in appetite and sleep patterns, indecisiveness and suicidal thoughts (Kessler et al., 2003). Although current Antidepressant drug (AD) treatments for the disorder target monoaminergic neurotransmission and increase in release, turnover or function of monoamine transmitters, a more recent hypothesis suggested that GABAergic transmission as the major underlying cause of MDDs (Luscher et al., 2011).
GABA and its role in Major Depressive disorders
GABA is a naturally occurring inhibitory neurotransmitter which functions by inhibiting or blocking certain signals in the brain. GABA neurons constitute around 40% of all the neurons, playing a significant role in balancing the excitatory neurotransmission exerted by monoaminergic and cholinergic neurotransmitters. There are two different classes of GABA receptors through which it exerts its effects: GABAA receptors are ionotropic in nature and are found to be associated with major GABA functions, serving as the major targets for therapeutic strategies. In contrast, GABAB receptors are metabotropic G protein-coupled receptors, yet other ligands will bind to GDCRs and affect anxiety and depressive disorders, thus limiting GABAB’s potential in therapy (Luscher et al., 2011).
A disruption of GABAergic neurotransmission has been implicated in the pathophysiology of various neuropsychiatric disorders (Luscher et al., 2007). A strong evidence of GABA involvement in depressive disorders is a decrease in GABA levels in the plasma (Petty et al., 1984). Studies have also reported a reduction in the levels of GABA in the brains of patients with depression (Gerner at al., 1981; Mann et al., 2014; Sanacora et al., 2004). Additionally, a decrease in the expression levels of enzymes involved in the synthesis of GABA has also been observed in suicidal patients. (Guilloux et al., 2012) Therefore, it has been validated that a reduction in GABA, brought about by reduced expression of its synthesizing enzymes, GABAergic interneurons or GABA receptors, is associated with severe depression which induces suicidal tendencies.
Sage-217
Sage is a synthetic neurosteroid which relieves anxiety and induces sedation in rodent models of seizure. Studies reveal that Sage 217 potentiates both synaptic and extrasynaptic GABAA receptors, setting it apart from the other approved positive allosteric modulators of GABA receptor (Martinez Botella et al., 2017). In terms of molecular pharmacological profile, strikingly similar to allopregnanolone, an endogenous neuroactive steroid which potentiates neuronal excitability by acting as a positive allosteric modulator of both synaptic and extrasynaptic GABA receptors. Allopregnanolone is synthesized locally in the brain of rodents in response to stress, whilst is effective in clinical studies involving patients with postpartum depression and tremors (Kanes et al., 2017; Meltzer-Brody et al., 2018; Ellenbogen et al., 2016). While Sage-217 is administered orally, allopregnanolone requires systemic administration and has manifested anxiolytic, anticonvulsant, sedative and mood-improving effects in preclinical models (Lambert et al., 2001; Schule et al., 2014). Patient access to therapies involving systemic administration is limited, making Sage-217 a better alternative due to its oral bioavailability.
How Sage-217 can treat Major Depressive Disorders
Being a positive allosteric modulator of both synaptic and extrasynaptic GABA receptors, Sage 217 has demonstrated its antidepressant effects in rodent models. Studies conducted to ascertain its dose and bioavailability in healthy volunteers have suggested that it is orally bioavailable and has a plasma half-life of 16-23 hours. It is also well tolerated and displays a well-characterized pharmacokinetic profile with no adverse reactions (Hoffmann et al., 2020). Its rapid onset of action has also been reported in a pilot study conducted on patients with major depressive disorders for 14 days.
Methodology
This article outlines a randomized, double-blind, placebo-controlled trial of SAGE-217 in patients with major depressive disorder by Gunduz-Bruce et al. in 2017. Patients were recruited from outpatient clinics and admitted as in-patients for a duration of one week for daily follow-up. Interactive-response technology developed by 4G Clinical was used to perform randomization. Patients received 30 mg of Sage-217 or placebo in a 1:1 ratio. The dose was adjusted to 20 mg in patients experiencing adverse effects. The participants were made to follow the regime and were prohibited from initiating new antidepressants or undergoing psychotherapy during the 14-day treatment period. The patients were also allowed to discontinue the trial regimen in case they developed unexpected conditions or serious adverse effects.
The participants consisted of both genders between the ages of 18 to 65 who were diagnosed with major depressive disorder and exhibited a score of 22 or higher on the Hamilton Depression Rating Scale (HAM-D). HAM-D is a scale which assesses depression with scores ranging from 0 to 52 and higher scores are depictive of more severe depression. (Hamilton et al., 1960).
Change in the HAM-D score from baseline to day 15 served as the primary endpoint. The secondary endpoints included an assessment of depression and anxiety assessed using other rating scales like the Montgomery–Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale. A higher score in both of which denoted higher levels of depression and anxiety respectively. Furthermore, scales including Bech-6 and Clinical Global Impression of Improvement (CGI-I) were utilized. The former is a subscale of HAM-D that assesses depression on six major criteria including low mood, guilty feelings, disinterest in routine activities, anxiety and other psychomotor and somatic symptoms. A higher score on Bech-6 correlates with severe depression (Bech et al., 1981). On the other hand, a lower score on CGI-I is depictive of more improvements while higher scores denote worsening of symptoms (Busner et al., 2007)
Thorough physical assessment of the patient including vital signs and electrocardiography was done to identify the safety of Sage-217. In addition, the Stanford Sleepiness Scale was utilized to assess the sleep patterns and suicidal ideation and behavior was checked using the Columbia Suicide Severity Rating Scale. Clinical laboratory measurements were also conducted to understand the safety profile of Sage-217. Adverse events were carefully noted from the time of administration of the first dose until 7 days after the last dose.
Analysis was performed on all patients undergoing randomization. Standard deviations and means were used to report continuous variables while the categorical variables were reported as numbers and percentages. Meanwhile, mixed-effects models and generalized estimating equation models were employed, followed by statistical analysis conducted using SAS software, version 9.3 (SAS Institute). The results were also subjected to sensitivity analyses to determine the effect of missing data.
The study, however, was limited by the exclusion of a provision to correct the multiplicity of the analyses of secondary endpoints. Hence, treatment effects cannot be inferred by using point estimates and unadjusted 95% confidence intervals.
Results and discussion
The results of the study demonstrated a significant reduction in depression-associated symptoms in patients treated with SAGE-217 for 14 days. A total of 89 patients, among the 169 enrolled, underwent randomization. 45 patients received Sage 217, whilst 44 received placebo in a 1:1 ratio. Despite similar demographics in both groups, the mean age of patients in Sage-217 group was 49 years while that of the placebo group was 38 years. There were also fewer women and more black patients in the Sage 217 group comparatively.
More than 90% of all the patients reported depressive episodes, which was opposed to a diminutive percentage of the patients receiving antidepressants at baseline. Only two patients had to discontinue the Sage 217 regimen owing to adverse effects, 4 patients were lost during follow-up while 3 withdrew from the trial.
Sage 217 group attained a mean HAM-D score of 25.2 at baseline while the placebo group had a score of 25.7. The least-squares mean change from baseline in HAM-D score was −17.4±1.3 points in the SAGE-217 group and −10.3±1.3 points in the placebo group on day 15. The Bech-6 score was found to change on day 15 with least mean square changes from baseline of 40.7±3.3 points in the SAGE-217 group and −25.7±3.4 points in the placebo group. The MADRS score change observed was −22.5±1.9 in the SAGE-217 group and −15.0±1.9 in the placebo group. CGI-I also remained between 1 and 2 in a higher percentage of patients in Sage 217 group in comparison to the placebo.
Euphoria was reported as an adverse effect in one patient, suggesting the long-lasting effect of Sage-217 on depressive symptoms. No other serious events occurred during the study, thereby proposing the safety and efficacy of Sage-217. 53% of the patients in the SAGE-217 group and 45% in the placebo group reported at least one adverse effect during the regimen. Headache, nausea, dizziness and somnolence were the most common adverse events observed in at least 5% of patients in the SAGE-217 group. Subjective sleepiness was observed to be similar in both groups as assessed by the Stanford sleepiness scale. Interestingly, it was also discovered that among the patients receiving Sage-217, 67% experiencing adverse effects were also receiving concomitant antidepressants while 48% were receiving Sage-217 as monotherapy. The dose had to be reduced in 6 patients in the Sage-217 group due to adverse effects like dizziness, somnolence, sedation and GI disturbances.
Although the study demonstrated the significant efficacy and safety of Sage 217, it had certain limitations e.g. a limited sample size and ethnic diversity of participants. Another shortcoming was the inability to assess depression during the entire regime which was only detected on day 15. The study also did not involve a comparison with a standard or with other available antidepressants. As such, it calls for the need to conduct similar trials with a larger sample size and for longer durations to validate the safety and efficacy of Sage-217.
Conclusion
To conclude, this study revealed that Sage -217 exhibited a marked decrease in depressive symptoms in patients undergoing clinical trials in comparison to those receiving placebo. The trials demonstrated the safety and efficacy of Sage-217 as a novel positive allosteric modulator of GABA receptor, thereby proposing its promising therapeutic potential against major depressive disorders.
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