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In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

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Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD., Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who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.

Background: Depression can adversely affect employment status., Aims: To examine whether there is a relative advantage of cognitive therapy or antidepressant medication in improving employment status following treatment, using data from a previously reported trial., Method: Random assignment to cognitive therapy (n = 48) or the selective serotonin reuptake inhibitor paroxetine (n = 93) for 4 months; treatment responders were followed for up to 24 months. Differential effects of treatment on employment status were examined., Results: At the end of 28 months, cognitive therapy led to higher rates of full-time employment (88.9%) than did antidepressant medication among treatment responders (70.8%), χ(2) 1 = 5.78, P = 0.02, odds ratio (OR) = 5.66, 95% CI 1.16-27.69. In the shorter-term, the main effect of treatment on employment status was not significant following acute treatment (χ(2) 1 = 1.74, P = 0.19, OR = 1.77, 95% CI 0.75-4.17); however, we observed a site×treatment interaction (χ(2) 1 = 6.87, P = 0.009) whereby cognitive therapy led to a higher rate of full-time employment at one site but not at the other., Conclusions: Cognitive therapy may produce greater improvements in employment v. medication, particularly over the longer term., (Royal College of Psychiatrists.)

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.

Objective: Research indicates that cognitive therapy (CT) can be differentiated from other treatment modalities based on in-session therapist behavior. However, to our knowledge, consistency in the implementation of individual CT across clinical trials has not been tested. We compared therapist adherence to CT, as well as the therapeutic alliance, in two randomized clinical trials (RCTs) of depression treatment., Method: Data were drawn from two highly cited RCTs of CT for major depression, representing a total of three sites. Trained raters coded sessions for therapist adherence to CT and the therapeutic alliance., Results: Significant differences were obtained between sites in overall level of adherence to CT, therapist emphasis on cognitive vs behavioral strategies, and therapist focus on homework. In contrast, no significant differences emerged in the collaborative structure of CT and in the therapeutic alliance., Conclusions: Despite efforts to maximize the consistency of CT implementation (e.g., via the use of the same treatment manuals, delivered by carefully-selected and experienced therapists), differences in the implementation of CT can result. Although preliminary, these findings raise questions regarding the uniformity of CT delivery across published clinical trials, and underline the importance of assessing treatment integrity, both across clinical trials and in dissemination research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Cognitive therapy and antidepressant medications are effective treatments for depression, but little is known about their relative efficacy in reducing individual depressive symptoms. Using data from a recent clinical trial comparing cognitive therapy, antidepressant medication, and placebo in the treatment of moderate-to-severe depression, we examined whether there was a relative advantage of any treatment in reducing the severity of specific depressive symptom clusters. The sample consisted of 231 depressed outpatients randomly assigned to: cognitive therapy for 16 weeks (n = 58); paroxetine treatment for 16 weeks (n = 116); or pill placebo for 8 weeks (n = 57). Differential change in five subsets of depressive symptoms was examined: mood, cognitive/suicide, anxiety, typical-vegetative, and atypical-vegetative symptoms. Medication led to a greater reduction in cognitive/suicide symptoms relative to placebo by 4 weeks, and both active treatments reduced these symptoms more than did placebo by 8 weeks. Cognitive therapy reduced the atypical-vegetative symptoms more than placebo by 8 weeks and more than medications throughout the trial. These findings suggest that medications and cognitive therapy led to different patterns of response to specific symptoms of depression and that the general efficacy of these two well-validated treatments may be driven in large part by changes in cognitive or atypical-vegetative symptoms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Previous research has found that therapist adherence to concrete, problem-focused cognitive therapy (CT) techniques predicts depressive symptom change (e.g., Feeley, DeRubeis, & Gelfand, 1999). More recently, Strunk, DeRubeis, Chui, and Alvarez (2007) demonstrated that in-session evidence of patients' use of CT skills was related to a lower rate of relapse in the year following CT for depression. The current investigation attempts to integrate and extend these findings within 2 separate samples of patients and therapists., Method: Drawing from the CT samples (N = 105, mean age = 40 years, female = 62%, White = 82%) of 2 published randomized clinical trials of depression treatment, we conducted analyses to examine whether therapist adherence to concrete CT techniques (Collaborative Study Psychotherapy Rating Scale) and the quality of the therapeutic alliance (Working Alliance Inventory) predict patients' use of CT skills (Performance of Cognitive Therapy Strategies) and subsequent Beck Depression Inventory symptom change., Results: Results indicated a differential pattern of prediction in the 2 samples. In one, CT techniques exhibited a stronger association with patient CT skills and symptom change than did the alliance, whereas the reverse pattern emerged in the second sample. A baseline symptom severity × CT techniques interaction indicated that between-study differences in intake depression severity might in part explain the process-outcome differences., Conclusions: The present findings suggest that the nature of the therapy sample examined may moderate process-outcome findings in psychotherapy research. The implications of these results and directions for future research are discussed.

Objective: The therapeutic alliance has been linked to symptom change in numerous investigations. Although the alliance is commonly conceptualized as a multidimensional construct, few studies have examined its components separately. The current study explored which components of the alliance are most highly associated with depressive symptom change in cognitive therapy (CT)., Method: Data were drawn from 2 published randomized, controlled clinical trials of CT for major depressive disorder (n = 105, mean age = 40 years, female = 62%, White = 82%). We examined the relations of 2 factor-analytically derived components of the Working Alliance Inventory (WAI; Horvath & Greenberg, 1986, 1989) with symptom change on the Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) that occurred either prior to or subsequent to the examined sessions. WAI ratings were obtained at an early and a late session for each therapist-patient dyad., Results: Variation in symptom change subsequent to the early session was significantly related to the WAI factor that assesses therapist-patient agreement on the goals and tasks of therapy but not to a factor assessing the affective bond between therapist and patient. In contrast, both factors, when assessed in a late session, were significantly predicted by prior symptom change., Conclusions: These findings may reflect the importance, in CT, of therapist-patient agreement on the goals and tasks of therapy. In contrast, the bond between therapist and patient may be more of a consequence than a cause of symptom change in CT. The implications of these results and directions for future research are discussed., ((PsycINFO Database Record (c) 2011 APA, all rights reserved).)

A recent randomized controlled trial found nearly equivalent response rates for antidepressant medications and cognitive therapy in a sample of moderate to severely depressed outpatients. In this article, the authors seek to identify the variables that were associated with response across both treatments as well as variables that predicted superior response in one treatment over the other. The sample consisted of 180 depressed outpatients: 60 of whom were randomly assigned to cognitive therapy; 120 were assigned to antidepressant medications. Treatment was provided for 16 weeks. Chronic depression, older age, and lower intelligence each predicted relatively poor response across both treatments. Three prescriptive variables-marriage, unemployment, and having experienced a greater number of recent life events-were identified, and each predicted superior response to cognitive therapy relative to antidepressant medications. Thus, 6 markers of treatment outcome were identified, each of which might be expected to carry considerable clinical utility. The 3 prognostic variables identify subgroups that might benefit from alternative treatment strategies; the 3 prescriptive variables identify groups who appear to respond particularly well to cognitive therapy.

Background: The authors examined the patterns of improvement in cognitive and vegetative symptoms of major depression in individuals treated with cognitive therapy (CT) or pharmacotherapy (PT)., Method: Outpatients diagnosed with major depressive disorder (n=180) were randomized to receive either CT or PT. Cognitive and vegetative symptoms of major depression were measured by the Beck Depression Inventory-II at baseline and regularly throughout 16 weeks of treatment., Results: Multivariate hierarchical linear modeling demonstrated the same patterns of change over time for cognitive and vegetative symptoms within CT and within PT., Limitations: Self-report measures may not be sufficiently specific to capture subtle differences in improvements between vegetative and cognitive symptoms., Conclusions: These results are consistent with Beck's [Beck, A.T., 1984, November. Cognition and theory [Letter to the editor]. Arch. Gen. Psychiatry 41, 1112-1114.] hypothesis that CT and PT have a similar site of action, which when targeted, results in changes in both cognitive and vegetative features.

Background: There is conflicting evidence about comorbid personality pathology in depression treatments., Aims: To test the effects of antidepressant drugs and cognitive therapy in people with depression distinguished by the presence or absence of personality disorder., Method: Random assignment of 180 out-patients with depression to 16 weeks of antidepressant medication or cognitive therapy. Random assignment of medication responders to continued medication or placebo, and comparison with cognitive therapy responders over a 12-month period., Results: Personality disorder status led to differential response at 16 weeks; 66% v. 44% (antidepressants v. cognitive therapy respectively) for people with personality disorder, and 49% v. 70% (antidepressants v. cognitive therapy respectively) for people without personality disorder. For people with personality disorder, sustained response rates over the 12-month follow-up were nearly identical (38%) in the prior cognitive therapy and continuation-medication treatment arms. People with personality disorder withdrawn from medication evidenced the lowest sustained response rate (6%). Despite the poor response of people with personality disorder to cognitive therapy, nearly all those who did respond sustained their response., Conclusions: Comorbid personality disorder was associated with differential initial response rates and sustained response rates for two well-validated treatments for depression.

Randomization procedures are performed in order to maximize the internal validity of treatment outcome studies. Objections have been made that this practice undermines the external validity of these studies because it ignores patients' treatment preferences, thereby precluding the self-selection of treatment that can occur in the community. This study used data from a multisite, double-blind, randomized, placebo-controlled trial comparing antidepressant medication to cognitive therapy for moderately to severely depressed outpatients. It compared the treatment outcomes of patients who, via randomization, received their preferred treatment versus those who did not. Although the majority of patients stated a preference for one treatment over the other, there was no significant difference in the magnitude of reduction in symptoms of depression between those who received their treatment of choice versus those who did not. These results do not provide support for the claim that the external validity of randomized controlled trials suffers from this aspect of the randomization procedure.

Recent research suggests that there may be a reduction in therapeutic response after multiple administrations of antidepressant drug (AD) therapy in patients with major depressive disorder. This study assessed the response to AD therapy and cognitive therapy (CT) of patients with a history of prior AD exposures. A sample of 240 patients with moderate-to-severe major depressive disorder entered a randomized controlled trial comparing pharmacotherapy with paroxetine to CT. Treatment was administered for 16 weeks. History of prior AD exposure was assessed with structured interviews, self-report, and medical records. Analyses were conducted using hierarchical linear models on the intent-to-treat sample. After controlling for various demographic and clinical factors, more prior AD exposures predicted poor response to paroxetine therapy but not to CT, as measured by the Hamilton Rating Scale for Depression (Hamilton, 1960; Williams, 1988). Whereas CT outcome was not significantly related to the number of prior AD exposures, a higher number of prior AD exposures was significantly associated with a lower response to paroxetine. If these findings are replicated in methodologically rigorous studies of paroxetine and other antidepressants, CT should be recommended, in preference to AD, for patients with multiple prior AD exposures., (Copyright 2007 APA, all rights reserved.)

Background: Antidepressant medication prevents the return of depressive symptoms, but only as long as treatment is continued., Objectives: To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication., Design: Patients who responded to CT in a randomized controlled trial were withdrawn from treatment and compared during a 12-month period with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal. Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a subsequent 12-month naturalistic follow-up., Setting: Outpatient clinics at the University of Pennsylvania and Vanderbilt University., Patients: A total of 104 patients responded to treatment (57.8% of those initially assigned) and were enrolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to severe depression., Interventions: Patients withdrawn from CT were allowed no more than 3 booster sessions during continuation; patients assigned to continuation medication were kept at full dosage levels., Main Outcome Measures: Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression or Hamilton Depression Rating Scale scores of 14 or higher during the continuation phase. Recurrence was defined in a comparable fashion during the subsequent naturalistic follow-up., Results: Patients withdrawn from CT were significantly less likely to relapse during continuation than patients withdrawn from medications (30.8% vs 76.2%; P = .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%; P = .20). There were also indications that the effect of CT extends to the prevention of recurrence., Conclusions: Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication.

Background: There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy's effects in this population., Objective: To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial., Design: Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60)., Setting: Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn., Patients: Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder., Interventions: Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy., Main Outcome Measure: The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission., Results: At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site x treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction., Conclusion: Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.

Cognitive therapy has emerged as 1 of the most promising psychosocial interventions for the treatment of depression. It appears to be at least the equal of alternative interventions (including pharmacotherapy) with respect to acute treatment. In addition, there are indications that it may reduce risk of symptom return after treatment termination. Nonetheless, design limitations reduce the certainty with which such conclusions can be drawn. Furthermore, tests of its efficacy have largely been limited to nonbipolar outpatient (or subclinical) samples. At this time, cognitive therapy is best considered a promising, but as yet not adequately tested, intervention for the treatment of depression.

Cognitive therapy (CT) for depression has generated considerable interest in recent years. Comparisons with tricyclic pharmacotherapy in nonbipolar outpatients have suggested that (a) CT may be roughly comparable in the treatment of the acute episode: (b) combined CT-pharmacotherapy does not appear to be clearly superior to either modality (although indications of potential enhancement do exist to justify additional studies with larger samples), and (c) treatment with CT during the acute episode (either alone or with medications) may reduce the risk of subsequent relapse following termination. Nonetheless, for a variety of reasons (e.g., limitations in study design and execution, inadequate design power, and possible differential retention), these conclusions can be considered only suggestive at this time. More than a decade after the publication of the first controlled study involving CT, the approach remains a promising, but not adequately tested, alternative to pharmacotherapy in the treatment of depression.