Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

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This Report involves work collected under protocols 01-M-0254 (NCT00024635); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), 19-M-0107 (NCT03973268), and 000101-M (NCT04821271). Results this past year: 1. Brain correlates of suicide attempt in 18,925 participants across 18 international cohorts. Here, we pooled data from 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (non-attempters with depression), and healthy control subjects. We identified 25 regions of interest with statistically significant differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. 2. A participant-level integrative data analysis of differential placebo response for suicidal ideation and nonsuicidal depressive symptoms in clinical trials of intravenous racemic ketamine. Clinical trials of intravenous (IV) racemic (R,S)-ketamine have consistently reported rapid and substantial reductions in overall depressive symptoms compared with saline (inactive placebo) or midazolam (active placebo). The evidence for IV ketamine's specific effects on suicidal ideation is less clear, however. Data for this participant-level integrative data analysis were drawn from 151 participants across 10 studies, and linear regression was used to examine the relationship between placebo response for suicidal ideation vs other depressive symptoms indexed from standard rating scales-specifically, depressed mood, anhedonia, anxiety, and guilt-over time. For participants receiving saline placebo, greater placebo response was observed for suicidal ideation compared with other symptoms indexed from standard depression rating scales, except for anxiety. For those receiving midazolam placebo, greater placebo response was observed for suicidal ideation compared with depressed mood or anhedonia. Taken together, the results provide preliminary evidence of a differential placebo response for suicidal ideation vs other depressive symptoms, while anxiety and suicidal ideation appear to produce similar placebo response profiles. These findings may help explain the more modest findings in clinical IV ketamine trials for suicidal ideation than overall depression. 3. Concurrent validity and reliability of suicide risk assessment instruments. A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. We observed moderate-to-high correlations between measures, consistent with the wide range ( range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. 4. Predictors of suicidal ideation trajectories in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A better understanding of suicidal ideation (SI), including patterns of SI, may help elucidate links between depression, SI, and suicidal behavior. This study sought to identify trajectories of SI in a large, community-based clinical trial of participants with major depressive disorder (MDD) and to investigate the relationships between these trajectories and predictors of interest, including anxiety and anhedonia. A longitudinal latent class analysis was conducted in 3923 participants enrolled in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of citalopram for the treatment of MDD. An unconditional latent class analysis was conducted using SI at study weeks 0, 2, 4, 6, and 9 as the indicators. A multinomial regression was then conducted with SI trajectory as the outcome and anhedonia, severity of depressive symptoms, atypical depression, anxiety, history of suicide attempt, history of substance abuse, history of trauma, and other covariates as the predictors. Four SI trajectories were identified: 1) variable SI; 2) little-to-no SI; 3) persistent SI; and 4) improving SI. Compared to the little-to-no SI trajectory, those with more severe anhedonia were more likely to experience persistent SI, while those with more severe anxiety were more likely to experience improving SI. Factors that distinguish SI trajectories, such as anxiety and anhedonia, may be critical targets for intervention or profiles for prognosis. 5. The association between variability, intensity, and persistence of suicidal ideation and prospective suicidal behavior in the systematic treatment enhancement program for bipolar disorder (STEP-BD) study. This study sought to examine the association between prospective suicidal behavior and variability, intensity, and persistence of suicidal ideation (SI) in bipolar disorder (BD). Data were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a naturalistic study of 4360 outpatients 15 years or older with BD. After adjusting for possible confounders, the odds of prospective suicidal behavior were 1.2 times greater per 10% increase in SI variability. SI persistence was not associated with suicidal behavior. For SI intensity, a median SI score of 'rare/fleeting' or 'several days' of SI was not associated with suicidal behavior, but the odds of prospective suicidal behavior were nearly five times greater for participants with the highest observed median SI intensity score of 'nearly every day'. The findings suggest that, in BD participants, monitoring SI variability may be clinically useful for assessing suicide risk.