Faculty Bibliography

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X² =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X² =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Major depressive disorder (MDD) is characterized by behavioral and neural abnormalities in processing both rewarding and aversive stimuli, which may impact motivational and affective symptoms. Learning paradigms have been used to assess reinforcement encoding abnormalities in MDD and their association with dysfunctional incentive-based behavior, but how the valence and context of information modulate this learning is not well understood. To address these gaps, we examined responses to positive and negative reinforcement across multiple temporal phases of information processing. While undergoing functional magnetic resonance imaging (fMRI), 47 participants (23 unmedicated, predominantly medication-naïve participants with MDD and 24 demographically-matched HC participants) completed a probabilistic, feedback-based reinforcement learning task that allowed us to separate neural activation during motor response (choice) from reinforcement feedback and monetary outcome across two independent conditions: pursuing gains and avoiding losses. In the gain condition, MDD participants showed overall blunted learning responses (prediction error) in the dorsal striatum when receiving monetary outcome, and reduced responses in ventral striatum for positive, but not negative, prediction error. The MDD group showed enhanced sensitivity to negative information, and symptom severity was associated with better behavioral performance in the loss condition. These findings suggest that striatal responses during learning are abnormal in individuals with MDD but vary with the valence of information.

BACKGROUND: Major depressive disorder (MDD) is a debilitating, chronic, biologically based condition. Current oral antidepressants act mainly via monoamine mechanisms and are associated with high rates of inadequate response and suboptimal time to response (Rush AJ et al. Am J Psychiatry 2006). There is an urgent need for faster-acting, more effective, and mechanistically novel treatments. AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. AXS-05 utilizes a proprietary formulation and dose of dextromethorphan and bupropion, and metabolic inhibition technology, to modulate the delivery of the components. The dextromethorphan component of AXS-05 is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and the bupropion component serves to increase the bioavailability of dextromethorphan.
OBJECTIVE(S): To evaluate the efficacy and safety of AXS-05 versus placebo in MDD.
METHOD(S): GEMINI was a phase 3, randomized, double-blind, placebo-controlled, multicenter, U.S. trial that enrolled subjects with a confirmed diagnosis of moderate-severe MDD. Subjects (N=327) were randomized (1:1) to receive AXS-05 (dextromethorphan 45 mg-bupropion 105 mg) or placebo, twice daily for 6 weeks. The primary efficacy endpoint was the change in the MADRS total score from baseline to week 6.
RESULT(S): On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the MADRS total score of 16.6 points versus 11.9 for placebo (P = .002). AXS-05 demonstrated rapid, statistically significant improvement versus placebo on the key secondary endpoint of change from baseline in the MADRS total score at week 1, the earliest time point measured (P = .007), and all time points thereafter. Rates of response were statistically significantly greater for AXS-05 versus placebo at week 1 (P = .035) and at all time points thereafter, being achieved by 54% of AXS-05 patients versus 34% of placebo patients at week 6 (P < .001). Remission rates were statistically significantly greater for AXS-05 versus placebo at week 2 (P = .013) and at all time points thereafter, being achieved by 40% of AXS-05 patients versus 17% of placebo patients at week 6 (P < .001). Antidepressant effects translated into early and statistically significant improvements in daily functioning and quality of life. AXS-05 was safe and well tolerated, with the most common adverse events being dizziness, nausea, and headache. AXS-05 was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.
CONCLUSION(S): Treatment with AXS-05 resulted in rapid, substantial, durable, and statistically significant improvements in depressive symptoms across multiple efficacy endpoints versus placebo in patients with MDD. Symptomatic benefits translated into statistically significant improvements in daily functioning and quality of life. AXS-05 was safe and well tolerated

This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t-test p = 0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555.

(Appeared originally in Frontiers in Psychiatry 2020 Dec 23; 11:595584).

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

OBJECTIVE/UNASSIGNED:Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS/UNASSIGNED:Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Ã…sberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Background: AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is an investigational, oral, NMDA receptor antagonist with multimodal activity being developed for MDD.
Method(s): AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial was placebo-controlled and the ASCEND trial used bupropion as the control. The primary efficacy variable in both was change in the MADRS total score. Here we examine the efficacy in the first 2 weeks of treatment.
Result(s): AXS-05 met the primary endpoint in both studies. In GEMINI (N=327), starting at Week-1, AXS 05 was superior to placebo on: mean MADRS improvement (7.3 vs. 4.9; p=0.007), MADRS response (>=50% improvement; 15% vs. 7%; p=0.035), CGI-I (22% vs. 13%; p=0.035), CGI-S (0.7 vs. 0.4; p=0.013) and Q-LES-Q-SF (9.0% vs. 5.8%; p=0.031). At Week-2, AXS-05 was superior to placebo on MADRS remission (<=10; 17% vs. 8%; p=0.013) and SDS (6.8 vs. 4.5; p=0.003). In ASCEND (N=80), starting at Week-1, AXS-05 was superior to bupropion on: CGI-I (18% vs. 3%; p=0.045) and MADRS-6 response (>=50% improvement; 16% vs. 3%; p=0.044). From Week-2, AXS-05 was superior to bupropion on: mean MADRS improvement (12.5 vs. 7.8; p=0.024), MADRS remission (<=10; 26% vs. 3%; p=0.004), and CGI-S (1.41 vs. 0.9; p=0.049).
Conclusion(s): AXS-05 demonstrated rapid and statistically significant improvements in depression at Weeks 1 and 2 in placebo- and active- controlled trials. In both studies, rapid remission from depressive symptoms was achieved by Week-2 and maintained over the 6-week treatment period. The novel mechanisms of action of AXS-05 may contribute to these rapid antidepressant effects. Supported By: Axsome Therapeutics Keywords: Rapid Anti-Depressant Effect, Major Depressive Disorder (MDD), NMDA Antagonists, Novel Treatments, Glutamate Neurotransmission
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BACKGROUND:Depression affects many children and adolescents, leading to poor academic performance, impaired psychosocial functioning, and an increased frequency of suicidal behavior. Depression has also been notably associated with trauma and distress tolerance. Our study sought to understand the relationships of these variables across age and sex categories in youth and adolescents. METHODS:The current study examined data from a total of 324 participants between the ages of 7 and 17 years-old who were a part of a larger study. Data related to age, sex, depression, trauma, and distress tolerance were examined. RESULTS:A multiple regression revealed a significant interaction between age and sex on depression severity. Further, trauma and age by sex categories significantly predicted depression score, as well as distress tolerance predicting depression score. Lastly, a regression analysis, including trauma, distress tolerance, and age by sex categories were significant predictors of depression. LIMITATIONS/CONCLUSIONS:The results are limited by the cross-sectional design. CONCLUSION/CONCLUSIONS:Clinicians should consider age by sex effects when treating childhood depression. Future research should further the understanding of depression across age and sex groups, as well as among children with extensive trauma experiences. Future research should also seek to further understand the implications of distress tolerance therapy on childhood depression.