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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 (1)H 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 (V(cycle)) using advanced (13)C 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 (r(s) = 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 (r(s) = 0.39, p = 0.02). V(cycle) correlation with ETI was at trend level (r(s) = 0.55, p = 0.087) and significantly correlated with ETI-EA (r(s) = 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.

Introduction: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. Objective: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). Methods: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. Results: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI –0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI –0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] p ns). Conclusions: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.

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).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.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].Small sample size, Treatment-naïve population.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.

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.

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.

OBJECTIVE Veterans with posttraumatic stress disorder (PTSD) presenting for care with Veterans Affairs Health Care System (VA) tend not to engage in evidence-based psychotherapies (EBPs) despite widespread availability of these treatments. Though there is little evidence that "readiness for treatment" affects treatment choice, many VA providers believe that interventions to increase readiness would be helpful. This naturalistic study examined the effects of a 4-session education/treatment-planning group on treatment choice among veterans in a VA outpatient PTSD treatment program. METHOD Treatment choices and completion rates of 114 veterans who received at least 1 session of the group (EG) were compared with those of 68 veterans who did not receive the group and received PTSD program treatment as usual (TAU). TAU and EG cases were matched on gender and service era. RESULTS Of 114 EG cases, 52 (45.6%) chose to receive EBPs, compared with 10 of 68 TAU cases (14.7%). These rates were significantly different, χ2(1) = 18.1, p < .0001. Among cases choosing EBPs, 52.2% of EG cases completed the EBPs as planned, compared with 60% of TAU cases. These percentages were not significantly different. Among EG cases choosing EBPs, lower likelihood of treatment completion was related to psychiatric medication prescription, presence of PTSD service connection, and higher overall service-connection level. CONCLUSION The education/treatment-planning group was associated with higher likelihood of selecting but not completing EBPs for PTSD. The decision to engage in trauma-focused treatment may be a different process from the decision to complete such treatment. (PsycINFO Database Record

Background Excessive glutamatergic neurotransmission may contribute to the pathophysiology of major depressive disorder (MDD). Recent evidence suggests that riluzole and other agents that target glutamate neurotransmission may show antidepressant activity. Methods Ten patients with treatment-resistant depression had riluzole added to their ongoing medication regimen for 6 weeks, followed by an optional 6-week continuation phase. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Linear mixed models were used to test for a linear trend in HDRS and HARS scores across time with treatment. Results Subjects' HDRS and HARS scores declined significantly following the initiation of riluzole augmentation therapy. The effect of riluzole was significant at the end of the first week of treatment and persisted for the 12-week duration of the study. Conclusions These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression.

The prediction of the World Health Organization that, by 2020, major depression will be second only to ischemic heart disease as a cause of disability highlights the importance of pursuing novel treatment approaches to this intractable psychiatric problem. In their article in Biological Psychiatry, Brakemeier et al. (1) illustrate the implementation of one novel approach by using talk therapy to prolong the robust but shortlived antidepressant effects of a somatic therapy for severe depression. Although research efforts regarding pharmacologic and psychotherapeutic approaches have recently been attracting growing attention, far less attention has been paid to combining treatment modalities to achieve a synergistic effect. Electroconvulsive therapy (ECT) is an effective and rapidly acting treatment of severe major depressive disorder with initial success rates commonly reported in the range of 60%–90% (2). However, relapse rates are notoriously high, and the field continues to strive for evidenced-based guidelines to sustain the antidepressant effect of ECT. To date, recommendations for immediate follow-up care have focused exclusively on continued medication, timing and combination of medications, and various schedules of continuation and maintenance ECT. Thinking outside the proverbial “somatic” box, Brakemeier et al. note that cognitive-behavioral therapy (CBT) has an evidenced-based reputation for sustaining antidepressant response. In the treatment of acute depression, CBT is as effective as antidepressant medication, and evidence exists for its prophylactic effects in reducing relapse in chronic depression (3). Studies have shown that CBT and related talk therapies can be beneficial to depressed patients who show only a partial response to medication (4) and when

Objective: The goal of this study was to explore the potential of providing cognitive behavioral therapy (CBT) after an index course of electroconvulsive therapy (ECT) for depression to improve long-term outcome. Method: The Beck Depression Inventory (BDI) and Clinical Global Impression (CGI) scale were used to assess depression and treatment outcome for 6 patients who received 12 weeks of CBT after an index course and concurrent with a continuation course of ECT. Results: Patients either maintained their response or showed decreased depressive symptoms at the 6-month post-index ECT evaluation. At the 9-month follow-up, 5 of 6 patients had BDI scores below their post-index ECT scores. The CGIs were rated "much improved" or "very much improved" by 5 patients at the termination of CBT. All 6 patients maintained or improved their CGIs at the 6-month follow-up. Conclusions: These results provide preliminary evidence that CBT after ECT is feasible and may extend the antidepressant effects ofECT.

Background Reduced γ-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.

The Yale Adherence and Competence Scale (YACS) is a general system for rating therapist adherence and competence in delivering behavioral treatments for substance use disorders. The system includes three scales measuring 'general' aspects of drug abuse treatment (assessment, general support, goals of treatment), as well as three scales measuring critical elements of three treatments that are frequently implemented as control or comparison treatments in clinical research in the addictions (clinical management (CM), twelve step facilitation (TSF), and cognitive behavioral therapy (CBT)). Validation of the YACS using data from a randomized clinical trial indicated that the scales have excellent reliability, factor structure, concurrent and discriminant validity. Correlations between adherence and competence scores within scales were in the moderate range, indicating independence (and thus nonredundancy) of these dimensions. Strategies for using the YACS in both psychotherapy and pharmacotherapy research in the addictions are described.

Disulfiram has emerged as a promising treatment for cocaine dependence, but it has not yet been evaluated in general populations of cocaine users.To compare the effectiveness of disulfiram therapy with that of a placebo condition in reducing cocaine use and to compare the effectiveness of 2 active behavioral therapies-cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT)-in reducing cocaine use.Randomized, placebo-controlled, double-masked (for medication condition), factorial (2 x 2) trial with 4 treatment conditions: disulfiram plus CBT, disulfiram plus IPT, placebo plus CBT, and placebo plus IPT.A community-based outpatient substance abuse treatment program.A total of 121 individuals meeting the criteria for current cocaine dependence.Patients received either disulfiram (250 mg/d) or placebo in identical capsules. Medication compliance was monitored using a riboflavin marker procedure. Both behavioral therapies (CBT and IPT) were manual guided and were delivered in individual sessions for 12 weeks.Random regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens.Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo, and those assigned to CBT reduced their cocaine use significantly more than those assigned to IPT (P.01 for both). Findings were consistent across all study samples (eg, intention to treat, treatment initiators, and treatment completers). Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment. Adverse effects experienced by participants who received disulfiram were mild and were not considerably different from those experienced by participants who received placebo.Disulfiram and CBT are effective therapies for general populations of cocaine-dependent individuals. Disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use.

A major problem encountered with autistic children is their characteristic self-stimulatory behavior, which frequently interferes with on-task responding and other appropriate behaviors. However, the experimental literature suggests that with many populations, increased physical activity might positively influence subsequent responding. Therefore, the purpose of this study was to investigate the use of increased physical activity (in this experiment, jogging) as a possible method of decreasing subsequent self-stimulatory behaviors as well as increasing subsequent appropriate responding. Seven autistic children with exceptionally high levels of self-stimulatory behavior participated in the investigation. Self-stimulatory and appropriate behaviors were measured both before and after jogging in a repeated-reversal design. The results demonstrated the following: (1) Brief jogging sessions produced decreases in subsequent levels of self-stimulatory behaviors and also produced increases in appropriate play and academic responding; (2) These changes after jogging were evident in three different experimental settings: during academic responding on preschool level tasks' in a clinic; during ball-playing in an outside play area; and in a quiet room, while no other activity was occurring; (3) Supplementary measures obtained in an applied classroom setting showed a similar relationship with both increases in on-task activity and general interest ratings for school tasks following the jogging sessions.

In spite of the burgeoning demand for treatment of cocaine abuse and the explosive growth of treatment centres, there is as yet no concensus on optimal treatment strategies for cocaine abuse. The reason for this lack of concensus is twofold: First, while a variety of promising treatments for cocaine abuse have recently been proposed (Anker and Crowley, 1982; Rounsaville, Gawin and Kleber, 1985; Gawin and Kleber, 1984; Gold, Washton, and Dackis, 1985; Tennant and Rawson, 1982; Siegel, 1982; Khantzian, 1983), none has as yet been systematically evaluated. Second, treatment-seeking cocaine abusers appear to be heterogeneous on a variety of dimensions, par ticularly the level of the severity of use and the psychiatric diagnoses (Helfrich, Crowley, Atkinson and Post, 1983; Schnoll, Karrigan, Kitchen, Daghestani, and Hansen, 1985; Kleber and Gawin, 1986; Weiss, Mirin, Michel and Sollugub, 1983). Given such heterogeneity, it follows that no single treatment will be identified as superior for all cocaine abusers.