Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression.

BACKGROUND: A substantial number of patients with major depressive disorder (MDD) do not sufficiently remit after the first lines of antidepressant treatments, making them vulnerable to poor clinical outcomes. Patients who have not had adequate resolution of their depressive symptoms after four antidepressant treatments and/or have been experiencing their current episode of MDD for two years or more (with insufficient responses to adequate antidepressant treatments) should be evaluated for antidepressant vagus nerve stimulation (VNS Therapy). Adjunctive VNS Therapy is a promising long-term treatment option for patients with difficult-to-treat depression (DTD), offering significantly improved remission rates in comparison with usual treatments. However, VNS Therapy requires specialized treatment centers to support patients. MATERIALS AND METHODS: In this narrative review, we aim to outline the necessary steps for setting up an antidepressant VNS Therapy service in an efficient manner. RESULTS: Establishing a VNS Therapy service requires several high-level considerations: initiation of a collaborative multidisciplinary team of health care professionals; developing a surgical pathway for implantation; consideration of reimbursement and health care coverage; setting up a specialist clinic to identify optimal candidates for VNS Therapy; educating patients and their families about VNS Therapy; and training health care providers on patient-specific VNS Therapy treatment and long-term treatment management. CONCLUSIONS: Antidepressant VNS Therapy is a promising treatment option for the long-term treatment of patients with DTD. We have successfully initiated four VNS Therapy service centers for DTD in the United States, Austria, and Germany. Based on our experiences and lessons learned, herein, we have provided advice to psychiatric centers planning to set up a VNS Therapy service for their patients with DTD.

Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression.

BACKGROUND: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. METHODS: In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days. RESULTS: The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo. CONCLUSIONS: Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial.

Importance: Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear. Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD. Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018. Interventions: Maintenance of or withdrawal from treatment with ADM. Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases. Results: A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88). Conclusions and Relevance: Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear. Trial Registration: ClinicalTrial.gov identifier: NCT00057577.

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. Conclusions and Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02493868.

Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3).

BACKGROUND: The endogenous opioid system is a fundamental regulator of mood in humans. Previously reported clinical trials have demonstrated the efficacy of the investigational agent buprenorphine/samidorphan (BUP/SAM) combination, an opioid-system modulator, for the adjunctive treatment of major depressive disorder. We present here a third phase III study of different design. METHODS: Adult patients with major depressive disorder and inadequate response to antidepressant therapy were enrolled in this double-blind, placebo-controlled, placebo run-in study to evaluate the efficacy, safety, and tolerability of adjunctive BUP/SAM 2 mg/2 mg. Patients with baseline Hamilton Depression Rating Scale score $20 received double-blind placebo in addition to background antidepressant therapy for 4 weeks. Nonresponders were randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period. RESULTS: Least-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], P=0.782). There were no differences in MADRS-based response or remission rates. Overall, 42.9% of the BUP/SAM 2 mg/2 mg group and 34.5% of the placebo group experienced at least one treatment-emergent adverse event during the 6-week treatment period, most of which were mild or moderate in severity. There were no clinically important changes in laboratory parameters, weight, or vital signs and no evidence of abuse potential during treatment or opiate-withdrawal symptoms post treatment. CONCLUSION: Efficacy results in FORWARD-3 measured by change in MADRS-10 score did not meet the primary end point, but postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was consistent with that seen in previously reported trials. BUP/SAM 2 mg/2 mg was well tolerated.

A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality.

OBJECTIVE: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. METHOD: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. RESULTS: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). CONCLUSIONS: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study.

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study.

OBJECTIVE: To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg. METHOD: Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks. Subjects were enrolled between September 2006 and February 2010. Efficacy outcomes included predefined criteria for response, remission, recovery, relapse, and recurrence. Subjects treated with adjunctive L-methylfolate 15 mg were included in the efficacy analysis. RESULTS: Of 68 subjects who met criteria for the 12-month open-label phase, 38% (n = 26) achieved full recovery, and none experienced a recurrence of MDD. For subjects entering the open-label phase in remission (n = 11), 91% (n = 10) achieved full recovery with L-methylfolate 15 mg, and none experienced a relapse or recurrence. Among 57 subjects who entered the open-label phase as nonremitted, 61% (n = 35) achieved remission. Of subjects who entered the open-label phase with a response without remission (n = 4), 50% (n = 2) had full recovery, and of subjects entering the open-label phase with no response (n = 53), 26% (n = 14) met recovery criteria. CONCLUSIONS: Adjunctive L-methylfolate 15 mg/d may be an early option in patients who fail to adequately respond to antidepressant monotherapy, with preliminary evidence demonstrating sustained remission and sustained recovery. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00321152.

Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs.

OBJECTIVE: Adjunctive treatment with L-methylfolate calcium significantly improved treatment outcomes in patients with major depressive disorder (MDD) and an inadequate response to antidepressants. This post hoc exploratory analysis evaluated baseline concentrations of cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, and IL-17; tumor necrosis factor α [TNF-α]; and interferon γ [IFN-γ]), high-sensitivity C-reactive protein (hsCRP), insulin, adiponectin and leptin and body mass index (BMI [kg/m2]) on L-methylfolate calcium treatment response. METHOD: Adults with DSM-IV MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) were eligible. Patients were randomized 3:3:2 according to the sequential parallel comparison design to placebo versus placebo, placebo versus L-methylfolate calcium (15 mg/d), or L-methylfolate calcium versus L-methylfolate calcium (15 mg/d) during two 30-day phases. The primary outcome was change on the 17-item Hamilton Depression Rating Scale (HDRS-17). Treatment effect with 95% CIs was estimated from baseline concentrations of individual biomarkers and combinations. Cytokines were measured by immunoassay; adiponectin, insulin, and leptin by radioimmunoassay; and hsCRP by a standard turbidimetric assay. The effects of baseline biomarker levels (above and below the median) on outcome were analyzed. The first participant was enrolled July 14, 2009, and the last participant completed April 28, 2011. RESULTS: Mean change on HDRS-17 from baseline was significantly improved with L-methylfolate calcium versus placebo (pooled treatment effect, -2.74; 95% CI, -4.99 to -0.48; P = .017) overall and for those with baseline BMI ≥ 30 (pooled treatment effect, -4.66; 95% CI, -7.22 to -1.98; P = .001) but not BMI < 30. Pooled mean changes in depression across treatment for baseline levels of individual markers above median were significant (L-methylfolate calcium vs placebo) for TNF-α, IL-8, hsCRP, and leptin (pooled treatment effects, -4.33 to -3.94 [P ≤ .02]) and for combinations of BMI ≥ 30 with elevated levels of TNF-α, IL-6, IL-8, hsCRP, and leptin (pooled treatment effects, -6.31 to -3.98 [P ≤ .05]). CONCLUSIONS: In this exploratory analysis, inflammatory and obesity-related factors were associated with greater symptom improvement with L-methylfolate calcium. Combinations of BMI ≥ 30 with elevated IL-6, IL-8, hsCRP, TNF-α, and leptin predicted improved response to L-methylfolate calcium in MDD patients with an inadequate antidepressant response. Further studies are necessary to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955.

The pro-inflammatory profile of depressed patients is (partly) related to obesity.

Many people with major depressive disorder (MDD) show evidence of systemic inflammation, including elevations in inflammatory factors, but the cause is unclear. The purpose of this analysis was to determine if obesity might contribute to the pro-inflammatory state in MDD patients. Blood was obtained from 135 MDD patients and 50 controls. Serum was extracted and assayed for interleukin (IL) -1ß, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), C-reactive protein (CRP), leptin, and adiponectin using single- or multi-plex human immunoassay kits. The primary analysis contrasted IL-6, TNFα, and CRP between MDD and control groups with body mass index (BMI) as a covariate. The other analytes were compared in an exploratory fashion. IL-6 (but not TNFα or CRP) showed significant differences between MDD and controls even after covarying for BMI. Obese controls and obese MDD groups were significantly higher in IL-6 than both lean groups, but the two obese groups did not differ from each other. In the exploratory analyses, the IL-2 level showed robust and significant differences between MDD and controls even after covarying for BMI. Both lean and obese MDD were higher than lean and obese controls. Adiponectin levels were also lower in the MDD sample than controls. Prior findings of higher IL-6, and CRP in MDD patients may be explained, at least in part, based on obesity. High IL-2, however, was associated with depression and not obesity. The results have significant implications for the understanding of pathophysiology and, potentially treatment of MDD.

A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder.

This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ⩾ 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.

Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial.

IMPORTANCE: Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone. OBJECTIVE: To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS: A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved. INTERVENTIONS: Antidepressant medication with or without CT. MAIN OUTCOMES AND MEASURES: Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation. RESULTS: Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6% vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95% CI, 1.06-1.68; number needed to treat [NNT], 10; 95% CI, 5-72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3% vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95% CI, 1.54-3.57; NNT, 3; 95% CI, 2-5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9% vs 26.8%; t451 = -2.04; P = .04; HR, 0.66; 95% CI, 0.45-0.98). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode. CONCLUSIONS AND RELEVANCE: Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057577.

Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.

OBJECTIVE: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). METHOD: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011. RESULTS: Seventy-five patients were enrolled. Patients with specific biological (body mass index ≥ 30 kg/m², elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo. CONCLUSIONS: Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955.

Residual symptoms and relapse: mood, cognitive symptoms, and sleep disturbances.

Remission is the standard of care in major depressive disorder (MDD). However, even in patients who respond to treatment and achieve remission, residual symptoms significantly inhibit functionality and increase the risk of relapse and recurrence. The most common residual symptoms are fatigue, sleep problems, and cognitive dysfunction. Clinicians should be cognizant of these potential residual symptoms and the unique ways in which they present in patients with MDD. Treating these symptoms as target symptoms from baseline increases the patient's chances of an asymptomatic remission. Making use of clinically practical screening instruments and monitoring these target symptoms throughout the course of treatment can improve patients' functional recovery.