Anatomical and fMRI-network comparison of multiple DLPFC targeting strategies for repetitive transcranial magnetic stimulation treatment of depression.

BACKGROUND: The efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance. OBJECTIVE: In rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks. METHODS: Forty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed. RESULTS: Scalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response. CONCLUSION: EEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems.

Targeting location relates to treatment response in active but not sham rTMS stimulation.

BACKGROUND: Precise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression. OBJECTIVE: To use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations. METHODS: An imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks. RESULTS: The average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome. CONCLUSION: These results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans.

Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

Improved cognitive content endures for 2 years among unstable responders to acute-phase cognitive therapy for recurrent major depressive disorder.

BACKGROUND: The cognitive model of depression suggests that cognitive therapy (CT) improves major depressive disorder (MDD) in part by changing depressive cognitive content (e.g. dysfunctional attitudes, hopelessness). The current analyses clarified: (1) the durability of improvements in cognitive content made by acute-phase CT responders; (2) whether continuation-phase CT (C-CT) or fluoxetine (FLX) further improves cognitive content; and (3) the extent to which cognitive content mediates continuation treatments' effects on depressive symptoms and major depressive relapse/recurrence. METHOD: Out-patients with recurrent MDD who responded to acute-phase CT (n = 241) were randomized to 8 months of C-CT, FLX or pill placebo (PBO) and followed for an 24 additional months. Cognitive content was assessed approximately every 4 months using five standard patient-report measures. RESULTS: Large improvements in cognitive content made during acute-phase CT were maintained for 32 months, with 78-90% of patients scoring in normal ranges, on average. Cognitive content varied little between C-CT, FLX and PBO arms, overall. Small, transient improvements in cognitive content in C-CT or FLX compared with PBO patients did not clearly mediate the treatments' effects on depressive symptoms or on major depressive relapse/recurrence. CONCLUSIONS: Outpatients with recurrent MDD who respond to acute-phase CT show durable improvements in cognitive content. C-CT or FLX may not continue to improve patient-reported cognitive content substantively, and thus may treat recurrent MDD by other paths.

Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS).

This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1 month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.

General medical burden in bipolar disorder: findings from the LiTMUS comparative effectiveness trial.

OBJECTIVE: This study examined general medical illnesses and their association with clinical features of bipolar disorder. METHOD: Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively. RESULTS: The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14). CONCLUSION: The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials.

BACKGROUND: Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. METHOD: To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥ 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. RESULTS: As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. CONCLUSIONS: LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. LIMITATIONS: Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

Composite International Diagnostic Interview screening scales for DSM-IV anxiety and mood disorders.

BACKGROUND: Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem. METHOD: Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives. RESULTS: Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9-38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0-2.9, p = 0.09-0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81-0.86, sensitivity 68.0-80.2%, specificity 90.1-98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR- is 0.1 or less at informative thresholds for all diagnoses. CONCLUSIONS: CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Change in psychosocial functioning and depressive symptoms during acute-phase cognitive therapy for depression.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent, is recurrent, and impairs people's work, relationships and leisure. Acute-phase treatments improve psychosocial impairment associated with MDD, but how these improvements occur is unclear. In this study, we tested the hypotheses that reductions in depressive symptoms exceed, precede and predict improvements in psychosocial functioning. METHOD: Patients with recurrent MDD (n=523; 68% women, 81% Caucasian, mean age 42 years) received acute-phase cognitive therapy (CT). We measured functioning and symptom severity with the Social Adjustment Scale - Self-Report (SAS-SR), Range of Impaired Functioning Tool (RIFT), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAMD) and Inventory for Depressive Symptomatology - Self-Report (IDS-SR). We tested cross-lagged correlations between functioning and symptoms measured at baseline and the beginning, middle and end of acute-phase CT. RESULTS: Pre- to post-treatment improvement in psychosocial functioning and depressive symptoms was large and intercorrelated. Depressive symptoms improved more and sooner than did psychosocial functioning. However, among four assessments across the course of treatment, improvements in functioning more strongly predicted later improvement in symptoms than vice versa. CONCLUSIONS: Improvements in psychosocial functioning and depressive symptoms correlate substantially during acute-phase CT, and improvements in functioning may play a role in subsequent symptom reduction during acute-phase CT.

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD).

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

Clinical outcomes following switch from venlafaxine ER to desvenlafaxine in nonresponders and responders.

OBJECTIVE: This post hoc analysis examined efficacy and tolerability of open-label desvenlafaxine in patients with major depressive disorder switched from blinded placebo, venlafaxine extended release (ER), or desvenlafaxine. RESEARCH DESIGN AND METHODS: Patients who completed 8 weeks of double-blind therapy with placebo (n = 176), venlafaxine ER (n = 175), or desvenlafaxine (n = 143) enrolled in a 10-month, open-label extension study and received desvenlafaxine 200 to 400 mg/d. Efficacy (17-item Hamilton Depression Rating Scale [HDRS(17)]) was assessed separately for nonresponders and responders to double-blind treatment. Tolerability during the first month of open-label desvenlafaxine was assessed. RESULTS: Among nonresponders (n = 134) to double-blind placebo, venlafaxine ER, and desvenlafaxine, mean decreases in HDRS(17) scores were -10.9, -7.3, and -7.7, respectively; HDRS(17) response rates were 67%, 53%, and 48%, respectively. Although responders (n = 360) to double-blind placebo, venlafaxine ER, and desvenlafaxine had more modest decreases on the HDRS(17), response rates were higher (84%, 87%, and 83%, respectively). Rates of adverse events were highest during week 1, and decreased afterward for the remainder of the first month of treatment. CONCLUSIONS: Among nonresponders to 8 weeks of double-blind venlafaxine ER, desvenlafaxine, or placebo, 48% to 67% subsequently responded to open-label desvenlafaxine. Over 80% of responders to double-blind therapy maintained response on open-label desvenlafaxine. The switch from venlafaxine ER to desvenlafaxine was well tolerated.

Dyadic discord at baseline is associated with lack of remission in the acute treatment of chronic depression.

BACKGROUND: Dyadic discord, while common in depression, has not been specifically evaluated as an outcome predictor in chronic major depressive disorder. This study investigated pretreatment dyadic discord as a predictor of non-remission and its relationship to depressive symptom change during acute treatment for chronic depression. METHOD: Out-patients with chronic depression were randomized to 12 weeks of treatment with nefazodone, the Cognitive Behavioral Analysis System of Psychotherapy or their combination. Measures included the Marital Adjustment Scale (MAS) and the Inventory of Depressive Symptomatology - Self Report (IDS-SR30). Of 681 original patients, 316 were partnered and 171 of these completed a baseline and exit MAS, and at least one post-baseline IDS-SR30. MAS scores were analysed as continuous and categorical variables ('dyadic discord' v. 'no dyadic discord' defined as an MAS score >2.36. Remission was defined as an IDS-SR30 of 14 at exit (equivalent to a 17-item Hamilton Rating Scale for Depression of 7). RESULTS: Patients with dyadic discord at baseline had lower remission rates (34.1%) than those without dyadic discord (61.2%) (all three treatment groups) (chi2=12.6, df=1, p=0.0004). MAS scores improved significantly with each of the treatments, although the change was reduced by controlling for improvement in depression. Depression remission at exit was associated with less dyadic discord at exit than non-remission for all three groups [for total sample, 1.8 v. 2.4, t(169)=7.3, p<0.0001]. CONCLUSIONS: Dyadic discord in chronically depressed patients is predictive of a lower likelihood of remission of depression. Couple therapy for those with dyadic discord may increase remission rates.

A history of childhood attention-deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD.

OBJECTIVE: The occurrence of comorbid attention-deficit hyperactivity disorder (ADHD) might have an impact of the course of the bipolar disorder. METHOD: Patients with bipolar disorder (n = 159) underwent a comprehensive evaluation with respect to affective symptoms. Independent psychiatrists assessed childhood and current ADHD, and an interview with a parent was undertaken. RESULTS: The prevalence of adult ADHD was 16%. An additional 12% met the criteria for childhood ADHD without meeting criteria for adult ADHD. Both these groups had significantly earlier onset of their first affective episode, more frequent affective episodes (except manic episodes), and more interpersonal violence than the bipolar patients without a history of ADHD. CONCLUSION: The fact that bipolar patients with a history of childhood ADHD have a different clinical outcome than the pure bipolar group, regardless of whether the ADHD symptoms remained in adulthood or not, suggests that it represent a distinct early-onset phenotype of bipolar disorder.

Whole-genome association study of bipolar disorder.

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Remission is the optimal goal of acute phase antidepressant therapy

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Urinary free cortisol levels among depressed men and women: differential relationships to age and symptom severity?

BACKGROUND: Preclinical and clinical models of depression suggest sex differences may be mediated at least in part, by differences in hormonal modulation of hypothalamic-pituitary-adrenal (HPA) axis activity. Unraveling the consequences of moderating influences from the effect of sexual dimorphism will be vital to elaborating models of pathophysiology. METHODS: The current study investigated urinary free cortisol (UFC) among younger adults with mild to moderate major depressive disorder to clarify the relationship with potential demographic and clinical moderators. RESULTS: Male patients had higher mean UFC levels than female patients. Moreover, significant interactions between age and severity were found among men, but not women. In contrast to prior findings, neither age nor severity effects on UFC levels were found among female patients. LIMITATIONS: Conclusions from the current study are limited by the absence of cortisol data from matched controls. Thus it was not possible to disentangle sex differences in baseline physiology from that of pathophysiological differences tied specifically to depression. CONCLUSIONS: Despite several methodological limitations, the interactions between sex and both age and severity in this large sample of depressed patients are suggestive of differential pathophysiology for regulation of UFC excretion, and could reflect a neuroprotective effect for estrogen among younger depressed women.

Identifying "paradigm failures" contributing to treatment-resistant depression.

BACKGROUND: "Treatment resistant depression" is likely to emerge from a number of factors, including application of the wrong diagnostic and treatment models. METHOD: Current paradigms for managing both depression and treatment resistant depression are considered. We then examine the prevalence of a set of paradigm failures that appeared to contribute to treatment resistant depression in outpatients of a tertiary referral Mood Disorders Unit. RESULTS: Six illustrative paradigm failures are described and their frequencies within the clinical sample reported. Identified paradigm failures were diagnosing and/or managing a non-melancholic condition as if it were melancholic depression, failure to diagnose and manage bipolar disorder, psychotic depression or melancholic depression, misdiagnosing secondary depression and failure to identify organic determinants. CONCLUSION: We suggest that the identification of such "paradigm failures"--and of others that can be assumed to operate--has the potential to enrich the assessment and management of depressed patients, and reduce the prevalence of treatment resistance.

Patient's therapeutic skill acquisition and response to psychotherapy, alone or in combination with medication.

BACKGROUND: We tested the hypotheses that the addition of medication to psychotherapy enhances participation in the latter by: (1) speeding the acquisition of the psychotherapy's targeted skill; and (2) facilitating higher skill level acquisition. METHOD: Participants were 431 chronically depressed patients who received Cognitive Behavioral Analysis System of Psychotherapy (CBASP), alone (N=214) or in combination with nefazodone (N=217), as part of a randomized chronic depression study (Keller et al. 2000). CBASP, developed specifically to treat chronic depression, uses a specific procedure, 'situational analysis' to help patients engage in more effective goal-oriented interpersonal behaviours. At the end of each session, therapists rated patients on their performance of situational analysis. Outcome on depressive symptoms was assessed with the 24-item Hamilton Rating Scale for Depression. RESULTS: Although reductions in depression were significantly greater in combined treatment compared to CBASP alone, there were no between-group differences in either the rate of skill acquisition or overall skill level at the end of treatment. Proficiency in the use of the main skill taught in psychotherapy at treatment midpoint predicted outcome independently of medication status and of baseline depressive severity. CONCLUSIONS: Effective participation in CBASP, as reflected by proficiency in the compensatory skill taught in psychotherapy, is not enhanced by the addition of medication and does not mediate the between-group difference in depression outcome.

Does early intervention increase latency to relapse in major depressive disorder? Re-evaluation with cognitive behavior therapy.

BACKGROUND: Major depressive disorder (MDD) has been studied in relation to its propensity for remission and likelihood of relapse. While the general clinical lore suggests that early intervention benefits treatment outcome, the empirical validation of this assumption is inconclusive. Specifically, no studies have been conducted concerning Time to Treatment Entry and long-term clinical course for MDD. METHODS: For the current study, 53 participants received 16-weeks of cognitive behavioral therapy (CBT). Participants who remitted (n=41) from their depression were then inducted into a longitudinal follow-up protocol. RESULTS: Longer Time to Treatment Entry was predictive of longer time to relapse. A greater number of previous depressive episodes was associated with decreased Time to Treatment Entry. LIMITATIONS: A more elaborate protocol could be designed in order to explore the nature of treatment effects and Time to Treatment Entry within one study. CONCLUSIONS: CBT may be the most effective for patients who have delayed seeking treatment. Although the present study adds to the developmental neurobiological assumptions of Post [Severe depressive disorders (1994) 23-65] concerning affective 'kindling,' it also challenges the kindling theory's assumptions concerning early intervention.