Faculty Bibliography

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

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: 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

Background: Major depressive disorder (MDD) is a debilitating and prevalent condition. Nearly two-thirds of treated patients with MDD do not experience an adequate response to first-line therapy, and most of these inadequate responders also fail second-line treatment. Time to clinically meaningful response with currently available antidepressants (up to 6-8 weeks) is also suboptimal. There is an urgent need for new, more effective, mechanistically novel, and faster-acting MDD treatments. AXS-05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity, including sigma-1 receptor agonism. AXS-05 is being developed for the treatment of MDD.
Objective(s): To evaluate the efficacy and safety of AXS-05 versus placebo in MDD.
Method(s): The GEMINI study is a Phase 3, randomized, double-blind, placebo-controlled, multi-center, which enrolled subjects with a confirmed diagnosis of moderate to severe MDD. Three hundred twenty-seven (327) subjects were randomised (1:1) to receive AXS-05 (45 mg DM/105 mg bupropion) or placebo, twice daily for 6 weeks. The primary efficacy endpoint was the change in the Montgomery-Asberg Depression Rating Scale (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=0.002) after 6 weeks of treatment. AXS-05 rapidly, substantially and durably reduced depressive symptoms, demonstrating a statistically significant improvement compared to placebo on the key secondary endpoint of change from baseline in the MADRS total score at Week 1, the earliest time point measured (p=0.007), and at all timepoints thereafter. Rates of response (>= 50% MADRS improvement) were statistically significantly greater for AXS-05 compared to placebo at Week 1 (p=0.035) and at every time point thereafter, being achieved by 54% of AXS-05 patients versus 34% of placebo patients at Week 6 (p<0.001). Rates of remission (MADRS <=10) were statistically significantly greater for AXS-05 compared to placebo at Week 2 (p=0.013) and at every time point thereafter, being achieved by 40% of AXS-05 patients versus 17% of placebo patients at Week 6 (p<0.001). The observed rapid and durable antidepressant effects translated into early and statistically significant improvements in daily functioning as measured by the Sheehan Disability Scale, and in quality of life as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire. AXS-05 was safe and well tolerated with the most commonly reported adverse events being dizziness, nausea, headache, diarrhea, somnolence and dry mouth. Treatment with AXS-05 was not associated with psychotomimetic effects. Rates of discontinuation due to adverse events in the trial were low (6.2% for AXS-05 and 0.6% for placebo).
Conclusion(s): Treatment with AXS-05 resulted in rapid, substantial, durable and statistically significant improvements in depressive symptomatology across multiple efficacy endpoints as compared to placebo in patients with MDD. Symptomatic benefits translated into statistically significant improvements on validated measures of daily functioning and quality of life. AXS-05 was safe and well tolerated in this trial and was not associated with psychotomimetic effects. Disclosure statement: Employee and shareholder of Axsome Therapeutics Inc.
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Interoceptive sensibility (IS) refers to the subjective experience of perceiving and being aware of one's internal body sensations, and is typically evaluated using self-report questionnaires or confidence ratings. Here we evaluated IS in 81 patients with OCD and 76 controls using the Multidimensional Scale of Interoceptive Awareness (MAIA), which contains 8 subscales assessing adaptive and maladaptive responses to sensation. Compared to controls, OCD patients showed hyperawareness of body sensations. Patients also demonstrated a more maladaptive profile of IS characterized by greater distraction from and worry about unpleasant sensations, and reduced tendency to experience the body as safe and trustworthy. These findings were independent of medication status and comorbidities in the patient group. Correlational analyses showed that subscales of the MAIA were differentially associated with OCD symptom dimensions. These findings indicate that patients with OCD show abnormality of IS that is independent of confounding factors related to medication and comorbidities and associated with different OCD symptom dimensions. Future work would benefit from examining neural correlates of these effects and evaluating whether dimensions of IS are impacted by treatments for the disorder.

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.