Early life stress and glutamate neurotransmission in major depressive disorder.

Early life stress (ELS) and glutamate neurotransmission have been implicated in the pathophysiology of major depressive disorder (MDD). In non-human primates, ELS was positively correlated with cortical Glx (i.e., glutamate + glutamine). However, the relationship between ELS and cortical glutamate in adult patients with MDD is not fully known. Using 1H Magnetic Resonance Spectroscopy (MRS), we conducted exploratory analyses measuring occipital cortical glutamate and glutamine levels in 36 medication-free patients with MDD. In a subsample (n=11), we measured dynamic glutamate/glutamine cycling (Vcycle) using advanced 13C MRS methods. ELS history was assessed using Early-life Trauma Inventory (ETI). Exploratory analyses suggest a relationship between ETI and glutamine as reflected by a significant positive correlation between ETI scores and occipital glutamine (rs=0.39, p=0.017) but not glutamate. Post-hoc analyses showed that the association with glutamine was driven by the ETI emotional abuse (ETI-EA) subscale (rs=0.39, p=0.02). Vcycle correlation with ETI was at trend level (rs=0.55, p=0.087) and significantly correlated with ETI-EA (rs=0.67, p=0.03). In this small sample of patients with MDD, those with childhood emotional abuse appear to have increased occipital glutamate neurotransmission as reflected by increased glutamate/glutamine cycling and glutamine level. Future studies would be needed to confirm this pilot evidence and to examine whether ELS effects on glutamate neurotransmission underlie the relationship between ELS and psychopathology.

Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression.

INTRODUCTION: Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine's antidepressant effects. METHODS: Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol. RESULTS: Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT. CONCLUSIONS: CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine's antidepressant effects.

A history of early life parental loss or separation is associated with successful cognitive-behavioral therapy in major depressive disorder.

BACKGROUND: There is a clinical need for evidence-based psychotherapy response biomarkers in major depressive disorder (MDD). Based on previous studies, we hypothesized that lower 24-h urinary cortisol levels and a history of early life stress/trauma would predict an improved antidepressant response to cognitive-behavioral therapy (CBT). METHODS: 50 currently depressed MDD subjects were enrolled. 24-h urine was collected and measured for cortisol levels by radioimmunoassay (RIA). Subjects were also administered early life stress/trauma measures at baseline: Global Perceived Early-Life Stress (GPELS), The Early Life Trauma Inventory (ELTI) and Klein Loss Scale (KLS). The efficacy of a twelve-week course of once-weekly CBT was evaluated by the primary outcome measure, the 24-item Hamilton Depression Rating Scale (HDRS24), at baseline and every four weeks, and the Beck Depression Inventory at baseline and weekly thereafter. 42 subjects had at least one complete follow-up visit (≥4 weeks of CBT), and 30 subjects completed the full 12-week course. RESULTS: Baseline 24-h urinary cortisol levels did not correlate with CBT's antidepressant response. Higher KLS scores, a measure of early life parental loss or separation, correlated with delta HDRS24 (rs=-0.39, padjusted=0.05). Complementary general linear model analysis revealed enhanced CBT efficacy in patients with a history of early life parental loss or separation [F(1,35)=6.65, p=0.01]. LIMITATIONS: Small sample size, Treatment-naïve population. CONCLUSIONS: Early life parental separation or loss positively correlated with CBT's antidepressant efficacy in our sample and may warrant further study in larger clinical samples.

Decreased occipital cortical glutamate levels in response to successful cognitive-behavioral therapy and pharmacotherapy for major depressive disorder.

BACKGROUND: Previous studies have demonstrated that antidepressant medication and electroconvulsive therapy increase occipital cortical γ-aminobutyric acid (GABA) in major depressive disorder (MDD), but a small pilot study failed to show a similar effect of cognitive-behavioral therapy (CBT) on occipital GABA. In light of these findings we sought to determine if baseline GABA levels predict treatment response and to broaden the analysis to other metabolites and neurotransmitters in this larger study. METHODS: A total of 40 MDD outpatients received baseline proton magnetic resonance spectroscopy (1H-MRS), and 30 subjects completed both pre- and post-CBT 1H-MRS; 9 CBT nonresponders completed an open-label medication phase followed by an additional/3rd 1H-MRS. The magnitude of treatment response was correlated with occipital amino acid neurotransmitter levels. RESULTS: Baseline GABA did not predict treatment outcome. Furthermore, there was no significant effect of CBT on GABA levels. However, we found a significant group × time interaction (F1, 28 = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders. CONCLUSIONS: These findings corroborate the lack of effect of successful CBT on occipital cortical GABA levels in a larger sample. A reduction in glutamate levels following treatment, on the other hand, correlated with successful CBT and antidepressant medication response. Based on this finding and other reports, decreased occipital glutamate may be an antidepressant response biomarker. Healthy control comparator and nonintervention groups may shed light on the sensitivity and specificity of these results.

Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy.

BACKGROUND: Reduced gamma-aminobutyric acid (GABA) concentrations have been reported in plasma, cerebrospinal fluid, and cortex of depressed subjects. Treatment with both electroconvulsive therapy (ECT) and selective serotonin reuptake inhibitors (SSRI) increased occipital cortex GABA concentrations in prior studies. The purpose of this study was to determine whether treatment of major depression with cognitive behavioral therapy (CBT) produces similar changes in cortical GABA concentrations. METHODS: Occipital cortex GABA concentrations were measured in eight subjects with Major Depressive Disorder prior to and after a course of CBT using proton magnetic resonance spectroscopy. RESULTS: The effect of CBT on occipital cortex GABA content was different than that seen for ECT and SSRI medication treatment of depressed patients. CONCLUSIONS: This preliminary finding suggests CBT has a less robust effect on cortical GABA content than ECT and SSRI treatments and might indicate a difference between the mechanisms of antidepressant action.

Monoamine depletion in unmedicated depressed subjects.

BACKGROUND: Although significant evidence suggests that diminished monoamine function is associated with clinical depression, catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects or never-depressed control subjects. This study assesses the integrated role of these monoamine systems in depressed patients. METHODS: Unmedicated depressed subjects underwent a 2-week, double-blind, random-ordered crossover study consisting of the following active and control conditions respectively: indoleamine (via tryptophan depletion) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) catecholamine depletion. Ten subjects completed both conditions; two subjects were withdrawn after active testing and one after control testing. RESULTS: Mean Hamilton Depression Rating Scale (HDRS) scores decreased progressively throughout the study days (baseline 26.7 points +/- 1.7 SEM and termination 20.0 +/- 2.4, active depletion; baseline 26.1 points +/- 2.3 SEM and termination 23.2 +/- 2.6, control testing) but did not differ between groups. Only three patients demonstrated 20% or greater increases from baseline HDRS at any point during the observation days. CONCLUSIONS: Overall, results show that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects, thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms.