Faculty Bibliography

BACKGROUND/UNASSIGNED:Previous studies have demonstrated elevated levels of the S100B protein (located in glial cells) in major depressive disorder (MDD) as compared to healthy controls. However, studies reporting correlation between S100B levels and depression severity have been conflicting. METHODS/UNASSIGNED:We investigated, through systematic review and meta-analysis, whether the correlation between S100B levels and depression severity is significant in patients with MDD. Pearson correlation coefficients reported in the individual studies were converted to Fisher's Z scores, then pooled using the random effects model. Meta-regression was used to test modifiers of the effect size. RESULTS/UNASSIGNED:16 studies including 658 patients with MDD met eligibility criteria. No publication bias was observed. There was a significant and positive correlation between serum S100B level and depression severity (r = 0.204, z = 2.297, p = 0.022). A meta-regression determined that onset age of MDD and percentage of female participants are significant modifiers of this correlation. A moderate, but non-significant heterogeneity was observed in serum studies (44%). CONCLUSION/UNASSIGNED:As many studies have reported significantly increased levels of S100B in MDD compared to controls, this meta-analysis supports the assumption that the increase in S100B correlates with the severity of MDD. Additional studies investigating the precise biological connection between S100B and MDD are indicated.

BACKGROUND:False suffocation alarm hypothesis has been widely used to explain carbon dioxide hypersensitivity in panic disorder (PD). However, hypersensitivity to carbon dioxide has been observed in other psychiatric disorders. We explored the specificity of carbon dioxide inhalation as a panic provocation test among psychiatric disorders via network meta-analysis. METHODS:A systematic literature search on PubMed, EMBASE, and PsycNET was performed to acquire the studies using the carbon dioxide provocation test in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists. Odds ratios (OR) for a panic attack (PA) induced by the carbon dioxide inhalation tests were extracted from each of the original studies and were pooled using the random-effects model. RESULTS:Network meta-analysis on a pool of 2181 participants from 41 studies was used to compare the efficacy of carbon dioxide provocation tests among psychiatric disorders. The network meta-analysis showed that the odds for PA in response to carbon dioxide inhalation are higher in patients with PD, premenstrual dysphoric syndrome (PMDD), and social anxiety disorder (SAD) than healthy controls (HC). The odds for PA were not significantly different among patients with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and healthy controls (HC). CONCLUSIONS:The vulnerability to the carbon dioxide provocation test is not limited to PD. The specificity of the test for PD is questionable, as individuals suffering from PMDD and SAD are also significantly more responsive to carbon dioxide inhalation compared to HC, OCD, MDD, and GAD. There may be shared underpinning biological mechanisms between PD, PMDD, and SAD.

Reports an error in "Selective kappa-opioid antagonism ameliorates anhedonic behavior: Evidence from the fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)" by Diego A. Pizzagalli, Moria Smoski, Yuen-Siang Ang, Alexis E. Whitton, Gerard Sanacora, Sanjay J. Mathew, John Nurnberger Jr., Sarah H. Lisanby, Dan V. Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Wayne Goodman, William Z. Potter and Andrew D. Krystal (Neuropsychopharmacology, 2020[Sep], Vol 45[10], 1656-1663). In the original article, conflict of interest was missing. The co-author Sanjay J. Mathew served as a consultant to Alkermes. The original article has been corrected. (The following abstract of the original article appeared in record 2020-45589-001). Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

BACKGROUND:We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response. METHODS:We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10). RESULTS:We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks. CONCLUSIONS:Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression.

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).