Faculty Bibliography

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

BACKGROUND:The heterogenous nature of depression continues to stymie efforts to identify biomarkers or predict treatment response. Efforts leveraging large datasets to define more uniform subtypes of depression or subgroups of depressed patients have considered only small subsets of symptoms. We aimed to understand how inclusion of more diverse complaints would impact data-emergent symptom and patient clusters. METHODS:We applied principal components analysis to baseline IDS data from 1491 STAR-D patients with major depressive disorder to derive naturally co-occurring symptom subsets before utilizing k-means clustering to divide patients into groups based on standardized residuals of each symptom subset score. We evaluated the clinical utility of our approach by comparing how cluster membership impacted response to citalopram. RESULTS:PCA identified nine naturally co-occurring symptom clusters: core affective symptoms, appetite/weight loss, anxiety, somatic symptoms, insomnia, negative intrusive thoughts, leaden paralysis/mood quality, diurnal mood variation, and irritability. Cluster analysis identified two patient groups, differing significantly in 7 of 9 clusters. Patients distinguished by the prominence of somatic vs. core affective symptoms exhibited greater reduction in depression severity with citalopram treatment. LIMITATIONS/CONCLUSIONS:Results depend not only on raw data, but also parameter selection, and interpretation. Replication is indicated. CONCLUSIONS:Findings are consistent with previous reports linking somatic symptoms and treatment resistance and demonstrating that SSRIs are most effective in treating affective symptoms. A novel distinction between physical somatic symptoms and psychic anxiety highlights the utility of assessing a broad spectrum of symptoms when exploring heterogeneity in depression and the need for treatments targeting physical somatic symptoms specifically.

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: Transcranial photobiomodulation (t-PBM) with nearinfrared (NIR) light penetrates into the cerebral cortex and is absorbed by the mitochondrial enzyme cytochrome c oxidase (CCO), stimulating the mitochondrial respiratory chain. t-PBM also significantly increases cerebral blood flow (CBF) and oxygenation. Small studies have reported that t-PBM may be an effective treatment in major depressive disorder (MDD). However, relationships between t-PBM dose (irradiance and/or total energy) and clinical or biological effects are unclear. In this experimental medicine study, we evaluated the dose-dependent effects of t-PBM in MDD subjects.
Method(s): We enrolled subjects meeting DSM-5 criteria for MDD, not treatment-resistant (0-2 failed antidepressants in the current episode), either unmedicated or on stable doses of antidepressants, with no other significant medical or psychiatric comorbidities. All subjects underwent 4 t-PBM sessions in the MRI scanner, 1 week apart, administered in random order, with 1) sham (no energy emitted); 2) High dose: Pulse wave (PW), average irradiance 300mW/cm2, peak irradiance 900 mW/cm2, 42Hz, 33% duty cycle, 4.3 KJ total energy; 3) Medium dose: Continuous Wave (CW), 300 mW/cm2 irradiance, 2.4 KJ total energy; 4) Low dose: CW, 50mW/cm2 irradiance; 1.4 kJ total energy. Other t-PBM parameters were kept unchanged (808 nm; 12.0 cm2 x 2 treatment area; delivered to the anterior prefrontal cortex, bilaterally). Resting state multi-echo (3), multi-band (2) fMRI was recorded on a 3T Siemens Trio using a 12ch head coil (TR = 2500ms, TE1 = 12.8ms, TE2 = 32.33 ms, TE3 = 51.86 ms, 60 slices, slice thickness 2.5mm) before, during and after t-PBM, using measures of the change in blood-oxygenation-level dependent (BOLD) signal on fMRI as marker of target engagement (t-PBM effect on cerebral blood flow). The BOLD signal was preprocessed using standardized automated tools [AFNI]. In order to test whether t-PBM modulated the BOLD signal during and after tPBM, we performed a region-of-interest (ROI) analysis taking into account the illuminated region of the brain. We extracted the signal from the transverse frontopolar giry, bilateral (ROIs 6 and 81 from the Desikan atlas) and separated the resulting time series into the pre-, peri-, and post-stimulation segments. We then performed spectral analysis in order to measure the BOLD power during each segment, employing the Thomson multitaper technique to increase the signal-to-noise ratio of the ensuing power estimates. This produced three spectra for each echo and dose (before, during, and after stimulation). We then tested for significant differences in BOLD power spectrum both during and after stimulation in each t-PBM dose, compared to sham (Wilcoxon rank sum test, corrected for multiple comparisons by controlling the false discovery rate at 0.05).
Result(s): We analyzed data from the first 7 MDD subjects (age = 32.1 +/- 13.1; 57% female) undergoing all 4 experimental sessions. We found a dose-dependent effect of t-PBM on the BOLD. Namely, low-intensity t-PBM produced a marked decrease in BOLD that was observed in all three echos (p < 0.05, n = 7). The reduction in BOLD was most pronounced near 0.03 Hz at echos 2 and 3. In contrast, CW 300 mW/cm2 t-PBM increased BOLD power, with a significant increase resolved near 0.1 Hz at all 3 echos (p < 0.05, n = 7). This suggests that higher irradiance CW t-PBM increased the power of the "fast" component of the BOLD signal during stimulation. However, no significant differences from sham were observed during PW 300 mW/cm2 stimulation. We were also not able to detect any significant BOLD changes after tPBM (at any echo or t-PBM dose).
Conclusion(s): We found a U-shaped, dose-dependent effect of t-PBM on the BOLD, with the medium dose leading to an increase in the hemodynamic effect. These findings suggest that specific parameters of t-PBM (total energy, irradiance, CW versus PW) modulate the effect of near-infrared light on cerebral blood flow. This is important, as t-PBM doses optimized for their hemodynamic effect might also offer superior clinical efficacy

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

BACKGROUND:Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response. METHODS:Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. RESULTS:Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. CONCLUSIONS:In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.

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.