Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Asberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n=18) or matching placebo (n=16) at the primary outcome showed no difference in depression severity between groups (t32=0.11, p=0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.
View details for DOI 10.1038/s41386-019-0365-0
View details for PubMedID 30858518
Resting-state functional connectivity and inflexibility of daily emotions in major depression.
Journal of affective disorders
2019; 249: 26–34
BACKGROUND: Major Depressive Disorder (MDD) is characterized by aberrant resting-state functional connectivity (FC) in anterior cingulate regions (e.g., subgenual anterior cingulate [sgACC]) and by negative emotional functioning that is inflexible or resistant to change.METHODS: MDD (N = 33) and control (CTL; N = 31) adults completed a resting-state scan, followed by a smartphone-based Experience Sampling Methodology (ESM) protocol surveying 10 positive and negative emotions 5 times per day for 21 days. We used multilevel modeling to assess moment-to-moment emotional inflexibility (i.e., strong temporal connections between emotions). We examined group differences in whole-brain FC analysis of bilateral sgACC, and then examined associations between emotional experiences and the extracted FC values within each group.RESULTS: As predicted, MDDs had inflexibility in sadness and avoidance (p<.001, FDR-corrected p<.05), indicating that these emotional experiences persist in depression. MDDs showed weaker FC between the right sgACC and pregenual/dorsal anterior cingulate (pg/dACC) than did CTLs (FWE-corrected, voxelwise p=.01). Importantly, sgACC-pg/dACC FC predicted sadness inflexibility in both MDDs (p = .046) and CTLs (p = .033), suggesting that sgACC FC is associated with day-to-day negative emotions.LIMITATIONS: Other maladaptive behaviors likely also affect the flexibility of negative emotions. We cannot generalize our finding of a positive relation between sgACC FC and inflexibility of sadness to individuals with more chronic depression or who have recovered from depression.CONCLUSIONS: Our preliminary findings suggest that connections between portions of the ACC contribute to the persistence of negative emotions and are important in identifying a brain mechanism that may underlie the maintenance of sadness in daily life.
View details for DOI 10.1016/j.jad.2019.01.040
View details for PubMedID 30743019
Longitudinal decreases in suicidal ideation are associated with increases in salience network coherence in depressed adolescents.
Journal of affective disorders
2018; 245: 545–52
BACKGROUND: Suicidal ideation (SI) is an important predictor of suicide attempt, yet SI is difficult to predict. Given that SI begins in adolescence when brain networks are maturing, it is important to understand associations between network functioning and changes in severity of SI.METHODS: Thirty-three depressed adolescents were administered the Columbia-Suicide Severity Rating Scale to assess SI and completed resting-state fMRI at baseline (T1) and 6 months later (T2). We computed coherence in the executive control (ECN), default mode (DMN), salience (SN), and non-relevant noise networks and then examined the association between changes in brain network coherence and changes in SI severity from T1 to T2.RESULTS: A greater reduction in severity of SI was associated with a stronger increase in SN coherence from T1 to T2. There were no associations between the other networks and SI.LIMITATIONS: We cannot generalize our findings to more psychiatrically diverse samples. More time-points are necessary to understand the trajectory of SI and SN coherence change.CONCLUSIONS: Our finding that reductions in SI are associated with increases in SN coherence extends previous cross-sectional results documenting a negative association between SI severity and SN coherence. The SN is involved in coordinating activation of ECN and DMN in response to salient information. Given this regulatory role of the SN, the association between SN coherence and SI suggests that adolescents with reduced SN coherence might more easily engage in harmful thoughts. Thus, the SN may be particularly relevant as a target for treatment applications in depressed adolescents.
View details for DOI 10.1016/j.jad.2018.11.009
View details for PubMedID 30439679
Differing Windows of Sensitivity to Stress in Amygdala-Ventromedial Prefrontal Cortex Structural and Functional Connectivity: Implications for the Neurobiology of Depression in Youth
ELSEVIER SCIENCE INC. 2018: S81
View details for Web of Science ID 000432466300201