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Objectives: To identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode., Methods: Youth with BP (N = 30) were compared with youth with unipolar depression (N = 59) during an acute depressive episode using the depression and mania items derived from the Schedule for Affective Disorders and Schizophrenia for Children (K-SADS)-Present Version. The results were adjusted for multiple comparisons, and any significant between-group differences in demographic, nonmood comorbid disorders, and psychiatric family history., Results: In comparison with unipolar depressed youth, BP depressed youth had significantly higher scores in several depressive symptoms and all subsyndromal manic symptoms, with the exception of increased goal-directed activity. Among the depressive symptoms, higher ratings of nonsuicidal physical self-injurious acts and mood reactivity, and lower ratings of aches/pains, were the symptoms that best discriminated BP from unipolar depressed youth. Subsyndromal manic symptoms, particularly motor hyperactivity, distractibility, and pressured speech, were higher in BP depressed youth and discriminated BP depressed from unipolar depressed youth., Conclusions: The results of this study suggest that it is possible to differentiate BP depression from unipolar depression based on depressive symptoms, and in particular subsyndromal manic symptoms. If replicated, these results have important clinical and research implications.

Objective: Side effects to antidepressant medication can affect the efficacy of treatment, but few predictors foretell who experiences side effects and which side effects they experience. This secondary data analysis examined whether depressed patients with comorbid panic disorder were more likely to experience side effects than those without panic disorder. The study also examined whether greater burden of side effects predicted a poorer treatment course for patients with panic disorder than those without panic disorder. To examine the specificity of these effects, analyses also examined 2 other anxiety disorders-social phobia and generalized anxiety disorder (GAD)., Methods: Between 2002 and 2006, a large sample (N = 808) of chronically depressed individuals (assessed using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders [SCID-IV]) received antidepressants according to a predetermined algorithm for 12 weeks. Every 2 weeks, depressive symptoms (per the Hamilton Depression Rating Scale) and side effects (specific side effects as well as several indicators of side effect burden) were assessed., Results: Lifetime diagnosis of panic disorder (assessed using the SCID-IV) at baseline was associated with higher likelihood of gastrointestinal (OR = 1.6 [95% CI, 1.0-2.6]), cardiac (OR = 1.8 [95% CI, 1.1-3.1]), neurologic (OR = 2.6 [95% CI, 1.6-4.2]), and genitourinary side effects (OR = 3.0 [95% CI, 1.7-5.3]) during treatment. Increases in side effect frequency, intensity, and impairment over time were more strongly associated with increases in depressive symptoms for patients with panic disorder compared to those without panic disorder. Neither social phobia nor GAD was associated with these effects., Conclusions: Potentially due to heighte​ned interoceptive awareness of changes in their body, chronically depressed individuals with panic disorder may be at greater risk than those without panic disorder for antidepressant side effects and to experience a worsening of depressive symptoms as a result of these side effects over time., Trial Registration: ClinicalTrials.gov identifier: NCT00057551​., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Objective: To examine the risk of suicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar II, and unipolar major depressive disorders., Design: A 27-year longitudinal (1981-2008) observational study of mood disorders (Research Diagnostic Criteria diagnoses based on Schedule for Affective Disorders and Schizophrenia and review of medical records) was used to evaluate antidepressants and risk for suicidal behavior. Mixed-effects logistic regression models examined propensity for antidepressant exposure. Mixed-effects survival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior., Setting: Five US academic medical centers., Results: Analyses of 206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2,745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confirmed that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-effects survival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P < .001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = -2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder., Conclusions: Based on observational data adjusted for propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Objective: To evaluate the effects of sex and menopausal status on acute-, continuation-, and maintenance-phase treatment outcomes in patients with recurrent major depressive disorder (MDD)., Method: This was a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) trial, a multiphase, multicenter, double-blind study in which adult outpatients with recurrent MDD (by DSM-IV criteria) were randomly assigned to 10 weeks of acute-phase venlafaxine extended release (ER) (75-300 mg/d) or fluoxetine (20-60 mg/d). Patients achieving response or remission had 6 months of continuation-phase treatment. Responding or remitting patients in the venlafaxine ER group were randomly assigned to venlafaxine ER or placebo for 2 consecutive 12-month maintenance phases; fluoxetine-treated patients continued receiving fluoxetine. The outcome measures for this analysis were acute- and continuation-phase response and remission rates (as measured by the 17-item Hamilton Depression Rating Scale) and time to depression recurrence in the maintenance phases according to sex and menopausal status at baseline., Results: The intent-to-treat population comprised 781 patients in the venlafaxine ER group (65% women) and 266 patients in the fluoxetine group (61% women); 64% of all women were premenopausal, and 25% were postmenopausal (5% perimenopausal; not analyzed). At acute-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 44% vs 47% in men, 51% vs 52% in women, 50% vs 52% in premenopausal women, and 52% vs 55% in postmenopausal women. At continuation-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 71% vs 74% in men, 72% vs 67% in women, 72% vs 69% in premenopausal women and 71% vs 63% in postmenopausal women. Response rates were consistent with these findings. Based on a Cox proportional hazards model, sex was not a significant predictor of recurrence during the first or second maintenance phase (hazard ratio [HR] = 1.233; P = .3712 and HR = 1.103; P = .8075, respectively), and neither was menopausal status at acute-phase baseline (HR = 0.941; P = .8234 and HR = 0.531; P = .2065, respectively)., Conclusions: In this study of patients with recurrent MDD, treatment outcomes with venlafaxine ER and fluoxetine did not differ on the basis of sex or menopausal status. Our confidence in these findings is limited by the lack of a placebo arm during the acute and continuation phases and by the small sample sizes for subgroup analyses in the maintenance phases., Trial Registration: ClinicalTrials.gov identifier: NCT00046020., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

In contrast to "remission" from an episode of major depressive disorder (MDD), for which there is general agreement in the literature, the optimal definition of "recovery" from MDD is uncertain. Previous definitions of recovery have used inconsistent thresholds for symptom severity and duration of wellness. To address the effects of duration and degree of recovery from an episode of MDD on recurrence risk, and the impact of maintenance antidepressant treatment on recurrence, we analyzed 258 patients from a randomized, double-blind study of outpatients with recurrent MDD. All patients had responded to 8½ months of venlafaxine extended release and were subsequently randomized to receive venlafaxine ER or placebo during 2 consecutive 12-month maintenance phases. Four definitions of recovery were used to evaluate recovery rates and time to recurrence: (1) 17-item Hamilton Depression Rating Scale (HAM-D(17)) total score ≤3 with duration ≥120 days; (2) HAM-D(17) ≤3 with duration ≥56 days; (3) HAM-D(17) ≤7 with duration ≥120 days; and (4) HAM-D(17) ≤7 with duration ≥56 days. Recovery definitions using lower symptom severity and longer duration thresholds produced lower rates of recurrence. Patients on placebo were more likely to have a recurrence than patients on venlafaxine ER, with hazard ratio (HR) ranging from 2.5 among patients who recovered by the most relaxed criteria (definition 4), to 5.3 among patients who recovered by the most stringent criteria (definition 1). We conclude that protection against recurrence derives from the degree and duration of recovery, particularly for patients maintained on antidepressant medication., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: It is well established that the presence of prominent anxiety within depressive episodes portends poorer outcomes. Important questions remain as to which anxiety features are important to outcome and how sustained their prognostic effects are over time., Aims: To examine the relative prognostic importance of specific anxiety features and to determine whether their effects persist over decades and apply to both unipolar and bipolar conditions., Method: Participants with unipolar (n = 476) or bipolar (n = 335) depressive disorders were intensively followed for a mean of 16.7 years (s.d. = 8.5)., Results: The number and severity of anxiety symptoms, but not the presence of pre-existing anxiety disorders, showed a robust and continuous relationship to the subsequent time spent in depressive episodes in both unipolar and bipolar depressive disorder. The strength of this relationship changed little over five successive 5-year periods., Conclusions: The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.

Objective: In the Treatment of Resistant Depression in Adolescents, study participants who received medication for sleep had a lower response rate. This report sought to clarify this finding., Method: Depressed adolescents who had not responded to a previous adequate serotonin-selective reuptake inhibitor (SSRI) trial were randomly assigned to another SSRI, venlafaxine, another SSRI+cognitive behavior therapy (CBT), or venlafaxine+CBT. Augmentation with sleep medication was permitted as clinically indicated., Results: Youth who received trazodone were six times less likely to respond than those with no sleep medication (adjusted odds ratio [OR]=0.16, 95% confidence interval [CI]: 0.05-0.50, p=0.001) and were three times more likely to experience self-harm (OR=3.0, 95% CI: 1.1-7.9, p=0.03), even after adjusting for baseline differences associated with trazodone use. None (0/13) of those cotreated with trazodone and either paroxetine or fluoxetine responded. In contrast, those treated with other sleep medications had similar rates of response (60.0% vs. 50.4%, χ(2)=0.85, p=0.36) and of self-harm events (OR=0.5, 95% CI: 0.1-2.6, p=0.53) as those who received no sleep medication., Conclusions: These findings should be interpreted cautiously because these sleep agents were not assigned randomly, but at clinician discretion. Nevertheless, they suggest that the use of trazodone for the management of sleep difficulties in adolescent depression should be re-evaluated and that future research on the management of sleep disturbance in adolescent depression is needed. The very low response rate of participants cotreated with trazodone and either fluoxetine or paroxetine could be due to inhibition of CYP 2D6 by these antidepressants.

Objective: Nonadherence to antidepressant treatment may contribute to poor outcome and to suicidal adverse events in adolescent depression. We examine the relationship between adherence and both clinical response and suicidal events in participants in the Treatment of Resistant Depression in Adolescents (TORDIA) study., Method: The relationship between adherence to medication and clinical outcome was assessed in 190 treatment-resistant depressed adolescents who were randomized to one of four cells: switch to another selective serotonin reuptake inhibitor (SSRI), switch to venlafaxine, or either of these two medication switches plus cognitive behavioral therapy. Plasma levels of antidepressant drug and metabolites were determined after 6 and 12 weeks of treatment. A twofold or greater variation in the dose-adjusted concentration of drug plus metabolites (level/dose ratio [LDR]) was defined as nonadherence. Nonadherence was also determined by clinician pill counts (CPC) of the proportion of prescribed pills that were unused and was defined as having greater than 30% of the prescribed pills remaining., Results: LDR and CPC showed low concordance. LDR was unrelated to clinical response. CPC adherence was related to a higher response rate overall (adherent, 63.0% versus nonadherent, 47.2%, p = .03). Approximately half (50.8%) of the sample surveyed showed evidence of nonadherence by CPC. Neither measure of adherence was related to the occurrence of suicidal events or to the pace of decline in suicidal ideation., Conclusions: Clinician pill counts may be a relevant measure of adherence that is related to outcome under formal clinical trial conditions in depressed adolescents. Nonadherence appears to be a common and significant source of treatment nonresponse. Clinical Trial Registration Information-Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://www.clinicaltrials.gov; NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective., Objective: To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI., Design: Randomized controlled trial., Setting: Six US academic and community clinics., Patients: Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression., Intervention: Participants were randomly assigned to (1) switch to a different medication only or (2) switch to a different medication plus cognitive behavior therapy., Main Outcome Measures: Clinical outcomes were depression-free days (DFDs), depression-improvement days (DIDs), and quality-adjusted life-years based on DFDs (DFD-QALYs). Costs of intervention, nonprotocol services, and families were included., Results: Combined treatment achieved 8.3 additional DFDs (P = .03), 0.020 more DFD-QALYs (P = .03), and 11.0 more DIDs (P = .04). Combined therapy cost $1633 more (P = .01). Cost per DFD was $188 (incremental cost-effectiveness ratio [ICER] = $188; 95% confidence interval [CI], -$22 to $1613), $142 per DID (ICER = $142; 95% CI, -$14 to $2529), and $78,948 per DFD-QALY (ICER = $78,948; 95% CI, -$9261 to $677,448). Cost-effectiveness acceptability curve analyses suggest a 61% probability that combined treatment is more cost-effective at a willingness to pay $100,000 per QALY. Combined treatment had a higher net benefit for subgroups of youth without a history of abuse, with lower levels of hopelessness, and with comorbid conditions., Conclusions: For youth with SSRI-resistant depression, combined treatment decreases the number of days with depression and is more costly. Depending on a decision maker's willingness to pay, combined therapy may be cost-effective, particularly for some subgroups., Trial Registration: clinicaltrials.gov Identifier: NCT00018902.

Background: We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized trial of 334 adolescents (aged 12-18 years) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor (SSRI) treatment who were subsequently treated for 12 weeks with another SSRI, venlafaxine, another SSRI + cognitive-behavioral therapy (CBT), or venlafaxine + CBT. Responders then continued with the same treatment through week 24, while nonresponders were given open treatment., Method: For the current study, patients were reassessed 48 (n = 116) and 72 (n = 130) weeks from intake. Data were gathered from February 2001 to February 2007. Standardized diagnostic interviews and measures of depression, suicidal ideation, related psychopathology, and level of functioning were periodically administered. Remission was defined as ≥ 3 weeks with ≤ 1 clinically significant symptom and no associated functional impairment (score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [A-LIFE]), and relapse, as ≥ 2 weeks with probable or definite depressive disorder (score of 3 or 4 on the A-LIFE). Mixed-effects regression models were applied to estimate remission, relapse, and functional recovery., Results: By 72 weeks, an estimated 61.1% of the randomized youths had reached remission. Randomly assigned treatment (first 12 weeks) did not influence remission rate or time to remission, but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine (P < .03). Participants with more severe depression, greater dysfunction, and alcohol or drug use at baseline were less likely to remit. The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment (P < .001). Of the 130 participants in remission at week 24, 25.4% relapsed in the subsequent year., Conclusions: While most adolescents achieved remission, more than one-third did not, and one-fourth of remitted patients experienced a relapse. More effective interventions are needed for patients who do not show robust improvement early in treatment., Trial Registration: clinicaltrials.gov Identifier: NCT00018902., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: We previously reported that a history of abuse was associated with a poorer response to combination treatment in the Treatment of Resistant Depression in Adolescents study (TORDIA). We now report on the nature and correlates of abuse that might explain these findings., Method: Youth who did not benefit from an adequate selective serotonin re-uptake inhibitor (SSRI) trial (N = 334) were randomized to one of the following: an alternative SSRI; an alternative SSRI plus cognitive behavior therapy (CBT); venlafaxine; or venlafaxine plus CBT. Analyses examined the effect of history of abuse on response to the pharmacotherapy and combination therapy., Results: Those without a history of physical abuse (PA) or sexual abuse (SA) had a higher 12-week response rate to combination therapy compared with medication mono-therapy (62.8% versus 37.6%; odds ratio [OR] = 2.8, 95% confidence interval [CI] = 1.6-4.7, p < .001). Those with a history of SA had similar response rates to combination versus medication monotherapy (48.3% versus 42.3%; OR = 1.3, 95% CI = 0.4-3.7; p = .66), whereas those with history of PA had a much lower rate of response to combination therapy (18.4% versus 52.4%, OR = 0.1; 95% CI = 0.02-0.43). Even after adjusting for other clinical predictors, a history of PA moderated treatment outcome., Conclusion: These results should be considered within the limitations of a post hoc analysis, lack of detailed assessment of abuse and other forms of trauma, and neuropsychological status. Depressed patients with history of abuse, especially PA may require specialized clinical approaches. Further work is needed to understand by what mechanisms a history of abuse affects treatment response., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.

Objective: The authors assessed whether subthreshold hypomanic symptoms in patients with major depression predicted new-onset mania or hypomania., Method: The authors identified 550 individuals followed for at least 1 year in the National Institute of Mental Health Collaborative Depression Study with a diagnosis of major depression at intake. All participants were screened at baseline for five manic symptoms: elevated mood, decreased need for sleep, unusually high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 years and up to 31 years. The Longitudinal Interval Follow-up Examination was used to monitor course of illness and to identify any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox proportional hazards regression., Results: With a cumulative probability of one in four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II disorder and 7.5% to bipolar I disorder. Number of subthreshold hypomanic symptoms, presence of psychosis, and age at illness onset predicted progression to bipolar disorder. Decreased need for sleep, unusually high energy, and increased goal-directed activity were specifically implicated., Conclusions: Symptoms of hypomania, even when of low intensity, were frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. These results suggest that continued monitoring for the possibility of progression to bipolar disorder is necessary over the long-term course of major depressive disorder.

Background: Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated., Methods: Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q), Life Enjoyment Scale-Short Version (LES-S), Social Adjustment Scale-Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE)., Results: At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40) on SF-36 vitality and role function-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05)., Limitations: Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind., Conclusions: For patients with recurrent MDD, 2 years' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

In this report, we conducted a secondary analysis of the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study to explore the impact of specific cognitive-behavioral therapy (CBT) treatment components on outcome. In TORDIA, 334 youths (ages 12 to 18 years) with major depressive disorder who had failed to respond to an adequate course of selective serotonin reuptake inhibitor (SSRI) medication were randomized to a medication switch (either to an alternative SSRI or venlafaxine) with or without 12 weeks of adjunctive CBT. Participants who had more than 9 CBT sessions were 2.5 times more likely to have adequate treatment response than those who had 9 or fewer sessions. CBT participants who received problem-solving and social skills treatment components, controlling for number of sessions and other confounding variables, were 2.3 and 2.6 times, respectively, more likely to have a positive response. These preliminary findings underscore the importance of receiving an adequate number of sessions to attain an adequate clinical response. Finally, social skills and problem solving may be active elements in CBT for adolescent depression and should be considered in treatment by those working with seriously depressed youths.

Context: Previous studies have found that few chronically depressed patients remit with antidepressant medications alone., Objective: To determine the role of adjunctive psychotherapy in the treatment of chronically depressed patients with less than complete response to an initial medication trial., Design: This trial compared 12 weeks of (1) continued pharmacotherapy and augmentation with cognitive behavioral analysis system of psychotherapy (CBASP), (2) continued pharmacotherapy and augmentation with brief supportive psychotherapy (BSP), and (3) continued optimized pharmacotherapy (MEDS) alone. We hypothesized that adding CBASP would produce higher rates of response and remission than adding BSP or continuing MEDS alone., Setting: Eight academic sites., Participants: Chronically depressed patients with a current DSM-IV-defined major depressive episode and persistent depressive symptoms for more than 2 years., Interventions: Phase 1 consisted of open-label, algorithm-guided treatment for 12 weeks based on a history of antidepressant response. Patients not achieving remission received next-step pharmacotherapy options with or without adjunctive psychotherapy (phase 2). Individuals undergoing psychotherapy were randomized to receive either CBASP or BSP stratified by phase 1 response, ie, as nonresponders (NRs) or partial responders (PRs)., Main Outcome Measures: Proportions of remitters, PRs, and NRs and change on Hamilton Scale for Depression (HAM-D) scores., Results: In all, 808 participants entered phase 1, of which 491 were classified as NRs or PRs and entered phase 2 (200 received CBASP and MEDS, 195 received BSP and MEDS, and 96 received MEDS only). Mean HAM-D scores dropped from 25.9 to 17.7 in NRs and from 15.2 to 9.9 in PRs. No statistically significant differences emerged among the 3 treatment groups in the proportions of phase 2 remission (15.0%), partial response (22.5%), and nonresponse (62.5%) or in changes on HAM-D scores., Conclusions: Although 37.5% of the participants experienced partial response or remitted in phase 2, neither form of adjunctive psychotherapy significantly improved outcomes over that of a flexible, individualized pharmacotherapy regimen alone. A longitudinal assessment of later-emerging benefits is ongoing.

Background: Suicide is a leading cause of death and has been strongly associated with affective disorders. The influence of affective disorder polarity on subsequent suicide attempts or completions and any differential effect of suicide risk factors by polarity were assessed in a prospective cohort., Method: Participants with major affective disorders in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) were followed prospectively for up to 25 years. A total of 909 participants meeting prospective diagnostic criteria for major depressive and bipolar disorders were followed through 4204 mood cycles. Suicidal behavior was defined as suicide attempts or completions. Mixed-effects, grouped-time survival analysis assessed risk of suicidal behavior and differential effects of risk factors for suicidal behavior by polarity. In addition to polarity, the main effects of age, gender, hopelessness, married status, prior suicide attempts and active substance abuse were modeled, with mood cycle as the unit of analysis., Results: After controlling for age of onset, there were no differences in prior suicide attempts by polarity although bipolar participants had more prior severe attempts. During follow-up, 40 cycles ended in suicide and 384 cycles contained at least one suicide attempt. Age, hopelessness and active substance abuse but not polarity predicted suicidal behavior. The effects of risk factors did not differ by polarity., Conclusions: Bipolarity does not independently influence risk of suicidal behavior or alter the influence of well-established suicide risk factors within affective disorders. Suicide risk assessment strategies may continue to appraise these common risk factors without regard to mood polarity.

Objective: The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment., Method: Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants., Results: Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events., Conclusions: Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to self-harm events requires further study and clinical caution.

Objective: Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication., Method: Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire., Results: Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone., Conclusion: Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.

Background: Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment., Methods: Data were collected from a multiphase, doubleblind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) score

During a multisite, NIMH-sponsored clinical trial entitled, "Research Evaluating the Value of Augmentation of Medication by Psychotherapy" (REVAMP), we assessed the adequacy of prior antidepressant treatment in patients with chronic forms of major depressive disorder using the Antidepressant Treatment History Form (ATHF). We hypothesized that when compared to earlier studies treatment adequacy would not have increased over the past decade. We found that only 33% of the 801 subjects enrolled had ever had a prior adequate trial of antidepressant medication. Patients significantly more likely to have received prior adequate antidepressant trials were older, married, white, had a longer duration of illness, had more melancholic features or met criteria for the melancholic subtype or met lifetime criteria for panic disorder. The hypothesis that rates of treatment adequacy have not significantly increased over the past decade was supported. These results and the consistency of similar results over time point to the dire need for patient and provider education regarding the signs and symptoms of depression and its treatment.

Background: This study examined psychosocial functioning as a predictor of recovery from episodes of unipolar major depression., Methods: 231 subjects diagnosed with major depressive disorder according to Research Diagnostic Criteria were prospectively followed for up to 20 years as part of the NIMH Collaborative Depression Study. The association between psychosocial functioning and recovery from episodes of unipolar major depression was analyzed with a mixed-effects logistic regression model which controlled for cumulative morbidity, defined as the amount of time ill with major depression during prospective follow-up. Recovery was defined as at least eight consecutive weeks with either no symptoms of major depression, or only one or two symptoms at a mild level of severity., Results: In the mixed-effects model, a one standard deviation increase in psychosocial impairment was significantly associated with a 22% decrease in the likelihood of subsequent recovery from an episode of major depression (OR=0.78, 95% CI: 0.74-0.82, Z=-3.17, p<0.002). Also, a one standard deviation increase in cumulative morbidity was significantly associated with a 61% decrease in the probability of recovery (OR=0.3899, 95% CI: 0.3894-0.3903, Z=-7.21, p<0.001)., Limitations: The generalizability of the study is limited in so far as subjects were recruited as they sought treatment at academic medical centers. The analyses examined the relationship between psychosocial functioning and recovery from major depression, and did not include episodes of minor depression. Furthermore, this was an observational study and the investigators did not control treatment., Conclusions: Assessment of psychosocial impairment may help identify patients less likely to recover from an episode of major depression.

Unlabelled: This report presents the rationale, design, and baseline sample characteristics for the REVAMP study. This project is a multisite clinical trial designed to evaluate the efficacy of augmenting state-of-the-art pharmacotherapy with psychotherapy in chronically depressed patients who fail to respond or respond incompletely to an initial trial of antidepressant medication., Background: Chronic forms of major depression disorder (cMDD) are longitudinally continuous forms of major depressive disorder (MDD), and may account for a significant portion of the societal burden of disease associated with M D D. Antidepressant medications and depression-focused psychotherapies have been shown to be effective for cMDD, though the majority fail to achieve remission following an acute course of treatment. There is a pressing need to evaluate whether the outcomes obtained from a well implemented medication algorithm combined with depression-focused psychotherapy can significantly enhance outcomes for cMDD., Rationale: Although there is evidence for the effectiveness of depression-focused psychotherapy for the treatment of cMDD, this is the first prospective, randomized, controlled trial investigating psychotherapy as an augmentation strategy for patients with cMDD incompletely responsive to a trial of antidepressant medication., Specific Aims: The REVAMP study has three specific aims: first, to compare the efficacy of adding psychotherapy to a medication change versus changing medication alone in chronic depressives with partial response or nonresponse to an initial trial of antidepressant medication; second, to test efficacy of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) as an augmentation strategy by comparing it to Supportive Psychotherapy (SP); and third, to test a hypothesized mechanism of therapeutic action of CBASP by examining whether patients receiving CBASP exhibit significantly greater improvements in social problem solving than patients receiving adjunctive SP or continued medication alone. As a subsidiary aim, the study also compares the effects of the three randomized treatments on psychosocial outcomes., Design: The study involves two 12-week phases. During Phase 1, patients with cMDD receive antidepressant monotherapy selected according to an algorithm that takes into account their prior treatment history. Their pattern of response is evaluated, those with no response at 8 weeks or less than a full response at 12 weeks advance to Phase 2. At the beginning of Phase 2, patients who did not respond to the initial antidepressant monotherapy during Phase 1 are switched to the next medication in the pharmacotherapy algorithm and randomly assigned in a 2:2:1 ratio to one of three treatment cells: 16 sessions of either CBASP (40% of randomizations) or SP (40%) added to pharmacotherapy, or medication alone (20%) with no added psychotherapy. Similarly, patients achieving a partial response during Phase 1 have their initial medication augmented with a second antidepressant agent during Phase 2 and are randomly assigned to either CBASP, SP, or medication alone. Patients who achieve remission during Phase 1 are not randomized to Phase 2, but rather are monitored monthly for an additional 12 weeks., Comment: Recent sequential treatment studies have provided state-of-the-art knowledge about the need for multiple steps in order to achieve remission. The current study, therefore, provides an important next step in understanding the role of depression-focused psychotherapy in a treatment algorithm so essential in the management of difficult-to-treat depression such as chronic forms of major depression.

Objectives: To test the long-term efficacy and safety of venlafaxine extended-release (ER) in preventing recurrence in patients with major depression., Method: This multiple-phase study, entitled "Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years" (PREVENT), was conducted from December 2000 through July 2005 in patients with recurrent unipolar depression (DSM-IV) who were initially randomly assigned to double-blind treatment with venlafaxine ER (75 mg/day to 300 mg/day) or fluoxetine (20 mg/day to 60 mg/day) for 10 weeks of acute treatment. Responders then received 6 months of continuation treatment. Those who remained responders were then enrolled into a 12-month maintenance period. Venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo. Fluoxetine responders were not randomly assigned but continued taking fluoxetine in order to maintain the blind during the maintenance study. Time to recurrence of depression (17-item Hamilton Rating Scale for Depression total score > 12 and < 50% reduction from acute phase baseline) with venlafaxine ER versus that of placebo were compared., Results: The efficacy evaluable sample consisted of 129 patients in each group. The mean daily dose of venlafaxine ER was 224.7 mg (SD = 66.7). The cumulative probability of recurrence through 12 months, based on the primary definition, was 23.1% (95% CI = 15.3 to 30.9) for venlafaxine ER and 42.0% (95% CI = 31.8 to 52.2) for placebo (p = .005, log-rank test)., Conclusion: Patients who had been successfully treated with venlafaxine ER during acute and continuation therapy were significantly less likely to experience recurrence with venlafaxine ER than with placebo over a 12-month maintenance treatment period., Clinical Trials Registration: ClinicalTrials.gov identifier NCT00046020.

In contrast to continuation therapy, a treatment aimed at suppressing symptoms during a current depressive episode, maintenance therapy is designed to prevent the development of a new episode. Candidates for maintenance therapy include patients who have achieved remission and have had 2 or more lifetime episodes, especially if they have comorbid disorders, ongoing psychosocial stressors, poor symptom control, or severe depressive episodes. Maintenance pharmacotherapy data strongly support the use of antidepressants at the dosage that helped the patient achieve remission. Other maintenance treatment interventions include psychotherapy, especially cognitive-behavioral therapy, and in some extreme cases, electroconvulsive therapy. Maintenance therapy considerations for clinicians include assessing treatment guidelines, addressing nonadherent patients, and measuring medication treatment response.

The goal of the study was to describe the naturalistic course of unipolar major depression in subjects not receiving somatic therapy for their depressive illness. Affectively ill individuals were recruited into the Collaborative Depression Study and followed prospectively for up to 15 years. One hundred thirty subjects who recovered from their intake episode of major depression subsequently experienced a recurrence that went untreated for at least 4 weeks following onset of the recurrence. The duration of the recurrent episode was examined using survival analytic techniques. Of the 130 subjects, 46 obtained somatic therapy at some time during the course of their depressive illness, while 84 subjects received no somatic therapy throughout their entire depressive episode. Survival analysis, which accounts for these 46 individuals by censoring their episodes at the time treatment was obtained, yielded a median time to recovery of 23 weeks. In the subsample of 84 subjects whose depressive illness went untreated from its inception through its resolution, the median time to recovery was 13 weeks. These results suggest that there is a high rate of recovery in individuals not receiving somatic treatment of their depressive illness, particularly in the first 3 months of an episode. Because treatment-seeking behavior is known to be associated with a worse prognosis, 23 weeks probably represents a lower-limit approximation of the median duration of an untreated depressive episode.

Background: Patients with bipolar I or II major depression are often misdiagnosed with unipolar major depression. The goal of this study was to develop and validate a brief instrument to screen for bipolar disorder in patients actively ill with major depression., Method: The sample consisted of subjects who enrolled in the National Institute of Mental Health-Collaborative Program on the Psychobiology of Depression-Clinical Studies from 1978 to 1981 during an episode of major depression and included 91 subjects with bipolar I major depression, 52 with bipolar II major depression, and 338 with unipolar major depression diagnosed according to Research Diagnostic Criteria. Most of the subjects were inpatients at the time of enrollment, and subjects were prospectively followed for up to 20 years. In order to create, test, and cross-validate the screening instrument, a split-sample data analytic procedure was performed. This procedure yielded 3 groups of subjects: the bipolar I index sample, the bipolar I cross-validation sample, and the bipolar II cross-validation sample. Each group included subjects with bipolar major depression and subjects with unipolar major depression. Within the bipolar I index sample, subjects with bipolar I major depression at study intake were compared with subjects with unipolar major depression at study intake on a pool of 59 sociodemographic and clinical candidate variables. The 3 variables showing the greatest disparity between bipolar I subjects and unipolar subjects were selected for the screen, the Screening Assessment of Depression-Polarity (SAD-P). The operating characteristics of the SAD-P were then examined within the bipolar I index sample, bipolar I cross-validation sample, and bipolar II cross-validation sample., Results: The items selected for the screening instrument were (1) presence of delusions during the current episode of major depression, (2) number of prior episodes of major depression, and (3) family history of major depression or mania. The screen identified bipolar major depression with a sensitivity of 0.82 in the bipolar I index sample, 0.72 in the bipolar I cross-validation sample, and 0.58 in the bipolar II cross-validation sample. With regard to misclassifying subjects with unipolar major depression, the screen provided a positive predictive value of 0.36 in the bipolar I index sample, 0.29 in the bipolar I cross-validation sample, and 0.27 in the bipolar II cross-validation sample., Conclusion: We suggest using the 3-item SAD-P as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression.

Context: Although various strategies are available to manage nonresponders to an initial treatment for depression, no controlled trials address the utility of switching from an antidepressant medication to psychotherapy or vice versa., Objective: To compare the responses of chronically depressed nonresponders to 12 weeks of treatment with either nefazodone or cognitive behavioral analysis system of psychotherapy (CBASP) who were crossed over to the alternate treatment (nefazodone, n = 79; CBASP, n = 61)., Design: Crossover trial., Setting: Twelve academic outpatient psychiatric centers., Patients: There were 140 outpatients with chronic major depressive disorder; 92 (65.7%) were female, 126 (90.0%) were white, and the mean age was 43.1 years. Thirty participants dropped out of the study prematurely, 22 in the nefazodone group and 8 in the CBASP group., Interventions: Treatment lasted 12 weeks. The dosage of nefazodone was 100 to 600 mg/d; CBASP was provided twice weekly during weeks 1 through 4 and weekly thereafter., Main Outcome Measures: The 24-item Hamilton Rating Scale for Depression, administered by raters blinded to treatment, the Clinician Global Impressions-Severity scale, and the 30-item Inventory for Depressive Symptomatology-Self-Report., Results: Analysis of the intent-to-treat sample revealed that both the switch from nefazodone to CBASP and the switch from from CBASP to nefazodone resulted in clinically and statistically significant improvements in symptoms. Neither the rates of response nor the rates of remission were significantly different when the groups of completers were compared. However, the switch to CBASP following nefazodone therapy was associated with significantly less attrition due to adverse events, which may explain the higher intent-to-treat response rate among those crossed over to CBASP (57% vs 42%)., Conclusions: Among chronically depressed individuals, CBASP appears to be efficacious for nonresponders to nefazodone, and nefazodone appears to be effective for CBASP nonresponders. A switch from an antidepressant medication to psychotherapy or vice versa appears to be useful for nonresponders to the initial treatment.

Background: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis., Method: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis., Results: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval., Conclusions: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

To evaluate long-term efficacy and tolerability of the serotonin 5-HT1A receptor agonist, gepirone extended release (ER), a multicenter, randomized, placebo-controlled relapse prevention study was performed in patients with recurrent major depression (DSM-IV criteria). Patients 18 to 70 years, with a primary diagnosis of recurrent major depression (DSM-IV; 296.3) and a screening and baseline HAMD-17 total score >/=20 were eligible. After a 3- to 14-day (dependent on pretrial medication) single-blind placebo washout period, eligible patients entered an 8- or 12-week (depending on time to remission) open-label gepirone ER treatment period. They initially received a dose of 20 mg/d gepirone ER and were titrated to a dose of 40 to 80 mg/d. Patients who achieved remission (HAMD-17 total score /=16 or discontinuation for lack of efficacy. A total of 420 patients were treated in the open-label phase. Of these, 303 (72.1%) completed the open-label phase and 250 (59.5%) fulfilled the criteria for remission and were randomized into the double-blind continuation phase (gepirone ER: n = 126; placebo: n = 124). The mean (+/-SD) final titrated dose of gepirone ER was 61.9 (+/-17.0) mg/d in the double-blind continuation phase. The relapse rate in the gepirone ER group was statistically significantly lower than that in the placebo group, 23.0% versus 34.7%, respectively (P = 0.024). During the open-label phase, adverse events that occurred in more than 5% of patients were nausea (15.7%), dizziness (13.1%), headache (12.9%), insomnia (6.2%), and vertigo (6.0%). During the continuation phase, the incidence of newly or re-emerging adverse events was similar with gepirone ER (43.7%) and placebo (42.7%). Adverse events different from those occurring during the open-label phase were not apparent. All adverse events occurred in less than 5% of patients with the exception of flu syndrome and headache. In conclusion, gepirone ER at a dose range of 40 to 80 mg/d is effective for relapse prevention in patients with recurrent major depression. It is well tolerated during long-term treatment for up to approximately one year.

The present study examined the relationships among impaired psychosocial functioning, comorbidity, and the cumulative probability of future recurrence of anxiety disorders and major depression in recovered patients. Participants were part of the Harvard/Brown Anxiety Disorders Research Program (HARP), a naturalistic, prospective, longitudinal study of anxiety disorders in psychiatric outpatients. Using proportional hazards regressions, worsening psychosocial impairment in general and in specific areas was significantly associated with an increased risk of panic disorder, generalized anxiety disorder, and major depression recurring, even after controlling for diagnostic comorbidity. These results are consistent with and extend similar findings for patients with major depression [Leon, A., Solomon, D. A., Mueller, T. I., Endicott, J., Posternak, M., Judd, L. L., et al. (1999). The range of Impaired Functioning Tool (LIFE-RIFT): a brief measure of functional impairment. Psychological Medicine, 29, 869-878; Leon, A., Solomon, D. A., Mueller, T. I., Endicott, J., Posternak, M., Judd, L. L., et al. (2000). A brief assessment of psychosocial functioning of subjects with bipolar I disorder: The LIFE-RIFT. The Journal of Nervous and Mental Disease, 188, 805-812], and suggest that increased psychosocial impairment may be a risk factor for relapse.

Major depressive disorder is a debilitating disease that imposes significant social and economic burdens not only on patients but also on society. Although various treatment options are available, treatment-resistant depression is common. Determining the exact prevalence of treatment-resistant depression is difficult because definitions vary, as do definitions of antidepressant response. Operational definitions of antidepressant response, nonresponse, partial response, and remission will be discussed in this article. Pharmacotherapy options for patients with treatment-resistant depression include augmentation, combination, and switching therapies; however, data from controlled clinical trials supporting these therapies are limited. Electroconvulsive therapy and psychotherapy offer additional treatment strategies. New nonpharmacologic therapies are under investigation. Remission is the goal of treatment.

Major depressive disorder is often marked by multiple recurrences. Unfortunately, it is difficult to predict specifically which patients will suffer a recurrence. This study examined whether psychosocial impairment is a risk factor for recurrence. A total of 290 subjects with unipolar major depressive disorder according to Research Diagnostic Criteria (RDC) were prospectively followed for up to 15 years as part of the Collaborative Depression Study (CDS), a multicenter longitudinal observational study of the mood disorders. Follow-up data on course of illness and psychosocial functioning were collected with the Longitudinal Interval Follow-up Evaluation (LIFE). The association of psychosocial impairment with recurrence of major depression was examined with mixed-effects logistic regression. The mean (SD) score for psychosocial functioning during recovery from an episode of major depression was 9.0 (2.7), with a possible range of 4 (no impairment) to 20 (severe impairment). For euthymic subjects who recovered from an episode of major depression, elevated psychosocial impairment was significantly associated with subsequent recurrence of major depression, with an odds ratio of 1.12 (95% confidence interval [CI], 1.06 to 1.19). The odds ratio of 1.12 indicates that for each 1-point increase in the functional impairment score, the risk of recurrence increases by about 12%. In patients who have recovered from an episode of major depression, the presence of psychosocial impairment may help identify who is at increased risk of recurrence.

Although the efficacy of maintenance pharmacotherapy for the prevention of recurrence in major depressive disorder (MDD) is well documented, few studies have tested the efficacy of psychotherapy as a maintenance treatment. The authors examined the efficacy of the cognitive-behavioral analysis system of psychotherapy (CBASP) as a maintenance treatment for chronic forms of MDD. Eighty-two patients who had responded to acute and continuation phase CBASP were randomized to monthly CBASP or assessment only for 1 year. Significantly fewer patients in the CBASP than assessment only condition experienced a recurrence. The 2 conditions also differed significantly on change in depressive symptoms over time. These findings support the use of CBASP as a maintenance treatment for chronic forms of MDD.

Objective: Studies on the course of major depressive disorder (MDD) among elderly persons are limited to short periods of follow-up, seldom provide comparisons with younger cohorts, and raise other methodological concerns., Methods: Utilizing 15 years of prospective data from the NIMH Collaborative Depression Study, the authors examined the index episode of MDD and the time until first observed recurrence in those who recovered for subjects in four age-groups defined by age at intake: 17-30, 31-50, 51-64, and 65-79 years. Assessments were conducted every 6 months for 5 years and annually thereafter. Survival analysis examined time until recovery and time to first recurrence., Results: Median time-to-recovery was similar for the four groups. Median time-to-first recurrence was significantly shorter for oldest versus the 51-64-year-old group but not the two other groups. The oldest age-group was distinguished from the younger groups by being more likely to be divorced/widowed/separated, to have primary depression, and to have a history of medical illness, particularly cardiovascular disease or cancer. There was no difference in the generally low levels of pharmacotherapy prescribed during the index episode or the subsequent well interval., Conclusions: Elderly patients with MDD may have a greater risk of recurrence than younger individuals. Low levels of treatment characterize the somatic treatment in all the study subjects, regardless of age-group.

Although many studies report that the therapeutic alliance predicts psychotherapy outcome, few exclude the possibility that this association is accounted for by 3rd variables, such as prior improvement and prognostically relevant patient characteristics. The authors treated 367 chronically depressed patients with the cognitive-behavioral analysis system of psychotherapy (CBASP), alone or with medication. Using mixed effects growth-curve analyses, they found the early alliance significantly predicted subsequent improvement in depressive symptoms after controlling for prior improvement and 8 prognostically relevant patient characteristics. In contrast, neither early level nor change in symptoms predicted the subsequent level or course of the alliance. Patients receiving combination treatment reported stronger alliances with their psychotherapists than patients receiving CBASP alone. However, the impact of the alliance on outcome was similar for both treatment conditions., ((c) 2003 APA)

This study examined whether reactance would negatively influence treatment outcome in 347 patients diagnosed with chronic forms of depression and treated at 9 sites with either Nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), or combination therapy. Contrary to our hypotheses, reactance positively predicted treatment outcome in CBASP on 2 of 4 scales. These effects were independent of the therapeutic alliance, which also positively predicted outcome. Reactance did not predict outcome in the groups receiving medication alone or in combination with CBASP. The findings suggest that reactance may be an asset in psychotherapy among chronically depressed individuals and that reactant patients can benefit from directive psychotherapy when therapists flexibly respond to perturbations in the therapeutic relationship. Results support the importance of Aptitude * Treatment interactions in psychotherapy outcome. The direction and significance of such interactions may vary with different forms of psychopathology., ((c) 2003 APA)

Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma.

The nosology of chronic depression in Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV, American Psychiatric Association, 1994) is highly complex and requires clinicians to differentiate among several chronic course subtypes. This study replicates an earlier investigation (J. McCullough et al., 2000; see record 2000-05424-007) that found few differences among Diagnostic and Statistical Manual of Mental Disorders (3rd ed. rev.; DSM-III-R; American Psychiatric Association, 1987) categories of chronic depression. In the present study, 681 outpatients with chronic major depression, double depression, recurrent major depression without full interepisode recovery, and chronic major depression superimposed on antecedent dysthymia were compared. Few differences were observed on a broad range of demographic, clinical, psychosocial, family history, and treatment response variables. The authors suggest that chronic depression should be viewed as a single, broad condition that can assume a variety of clinical course configurations., (((c) 2003 APA, all rights reserved))

A major challenge facing primary care physicians is to prescribe the most appropriate antidepressant medication for patients with major depression. The relatively recent discoveries of several classes of pharmaceutical agents that alleviate depression has led to a helpful but unwieldy arsenal of antidepressants. Only since the 1990s has there been more rational drug development and focused research of the biologic mechanisms of major depression. The field is currently in transition in the understanding of major depression and the drugs used to treat it. Thus, it is critical to stay up to date with the best therapeutic approach, while remaining flexible as new therapies are developed.

Background: Maintenance treatment to prevent recurrences is recommended for chronic forms of major depressive disorder (MDD), but few studies have examined maintenance efficacy of antidepressants with chronic MDD. This randomized, placebo-controlled study of the efficacy and safety of nefazodone in preventing recurrence was conducted for patients with chronic MDD., Methods: A total of 165 outpatients with chronic, nonpsychotic MDD, MDD plus dysthymic disorder ("double-depression"), or recurrent MDD with incomplete inter-episode recovery, who achieved and maintained a clinical response during acute and continuation treatment with either nefazodone alone or nefazodone combined with psychotherapy, were randomized to 52 weeks of double-blind nefazodone (maximum dose 600 mg/day) or placebo. The occurrence of major depressive episodes during maintenance treatment was assessed with the 24-item Hamilton Rating Scale for Depression, a DSM-IV MDD checklist, and a blinded review of symptom exacerbations by a consensus committee of research clinicians., Results: Application of a competing-risk model that estimated the conditional probability of recurrence among those patients remaining on active therapy revealed a significant (p =.043) difference between nefazodone (n = 76) and placebo (n = 74) when the latter part of the 1-year maintenance period was emphasized. At the end of 1 year, the conditional probability of recurrence was 30.3% for nefazodone-treated patients, compared with 47.5% for placebo-treated patients. Prior concomitant psychotherapy during acute/continuation treatment, although enhancing the initial response, was not associated with lower recurrence rates. Discontinuations due to adverse events were relatively low for both nefazodone (5.3%) and placebo (4.8%). Somnolence was significantly greater among the patients taking active medication (15.4%), compared with placebo (4.6%)., Conclusions: Nefazodone is well-tolerated and is an effective maintenance therapy for chronic forms of MDD.

The 16-item Quick Inventory of Depressive Symptomatology (QIDS), a new measure of depressive symptom severity derived from the 30-item Inventory of Depressive Symptomatology (IDS), is available in both self-report (QIDS-SR(16)) and clinician-rated (QIDS-C(16)) formats. This report evaluates and compares the psychometric properties of the QIDS-SR(16) in relation to the IDS-SR(30) and the 24-item Hamilton Rating Scale for Depression (HAM-D(24)) in 596 adult outpatients treated for chronic nonpsychotic, major depressive disorder. Internal consistency was high for the QIDS-SR(16) (Cronbach's alpha =.86), the IDS-SR(30) (Cronbach's alpha =.92), and the HAM-D(24) (Cronbach's alpha =.88). QIDS-SR(16) total scores were highly correlated with IDS-SR(30) (.96) and HAM-D(24) (.86) total scores. Item-total correlations revealed that several similar items were highly correlated with both QIDS-SR(16) and IDS-SR(30) total scores. Roughly 1.3 times the QIDS-SR(16) total score is predictive of the HAM-D(17) (17-item version of the HAM-D) total score. The QIDS-SR(16) was as sensitive to symptom change as the IDS-SR(30) and HAM-D(24), indicating high concurrent validity for all three scales. The QIDS-SR(16) has highly acceptable psychometric properties, which supports the usefulness of this brief rating of depressive symptom severity in both clinical and research settings.

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.

Major depression is recognized as a common, often chronic and recurrent illness that is associated with significant disability and comorbidity. The treatment of patients with major depressive disorder has advanced tremendously in the past decade as a result of the availability of effective and well-tolerated antidepressants. Paroxetine is a widely studied selective serotonin reuptake inhibitor (SSRI) with evidence for efficacy and safety that is supported by a large body of published literature. Evidence for the efficacy and tolerability of anew controlled-release formulation of paroxetine also has been published. Findings from paroxetine clinical studies have added considerably to our knowledge and understanding of the treatment of major depressive disorder, particularly with regard to duration of treatment, the need for treating to full remission and with full doses, and treatment of patients with concurrent symptoms of anxiety.

Little is known about the relative benefits of psychotherapy, medication, and combined treatment as continuation therapies for chronic forms of major depressive disorder (MDD) after a positive response to acute treatment. We hypothesize that combined treatment would demonstrate superior continuation phase outcomes compared to either monotherapy, as evidenced by lower relapse rates and greater rates of improvement from partial to full remission. We report 16-week continuation phase outcomes for 324 patients who had participated in either the acute phase of a randomized multicenter trial of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combination therapy (COMB) for chronic forms of MDD. Patients entering the continuation phase had either fully or partially remitted after 12 weeks of acute phase treatment. The primary efficacy measure was the 24-item Hamilton Rating Scale for Depression. For patients in remission at acute phase exit, 73.3% (107/146) maintained their remitted status at endpoint of the continuation phase. Of those having a partial remission at acute phase exit, 52.9% (92/174) achieved full remission by end of continuation. A greater proportion of patients maintained a partial or full remission status on COMB (90%) compared to nefazodone (80%, p=0.011) or to CBASP (82%, p=0.042). These differences reflected greater symptom re-emergence in the partial remission groups on CBASP and nefazodone monotherapy compared to COMB. Continuation treatment assignment was not randomized or blinded. There was no placebo group. Most patients with chronic forms of MDD sustained their acute phase response and more than 50% of partial remitters achieved full remission while continuing treatment with nefazodone, CBASP, or COMB. COMB was associated with less symptom re-emergence during the continuation phase than either monotherapy, particularly for partial remitters.

Unipolar major depression is a disorder with a high incidence of relapse and recurrence. Some patients with major depression fail to recover from an episode and develop chronic depression. Both episodic and chronic depression are associated with considerable morbidity and mortality. An improved long-term outcome for patients may be achieved by the use of longer courses of treatment in the management of depression, which may ultimately enable recovery from depressive symptoms. The data reviewed in this article indicate that both selective serotonin reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine are effective in reducing the incidence of relapse during 6 months of continuation therapy for major depression. In addition, longer-term treatment using imipramine or venlafaxine has shown maintenance therapy to be effective in reducing the risk of recurrence of major depression. Pharmacotherapy using sertraline or imipramine for extended periods of time has also been shown to be effective in attaining remission from, and preventing, recurrence of symptoms in patients with chronic depression. The data reviewed suggest that long-term therapy is beneficial in achieving a sustained return to complete functioning for patients with depression. The significantly higher remission rates attained with venlafaxine treatment as compared with some SSRIs warrant further studies of SNRIs for the long-term treatment of depression.

Background: Although various strategies have been proposed to treat antidepressant nonresponders, little controlled research has been published that examines prospectively the use of switching to an alternate antidepressant., Methods: This was a multisite study in which outpatients with chronic major depression (with or without concurrent dysthymia), who failed to respond to 12 weeks of double-blind treatment with either sertraline hydrochloride (n = 117) or imipramine hydrochloride (n = 51), were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication. Outcome measures included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions--Severity and Improvement scales., Results: The switch from sertraline to imipramine (mean dosage, 221 mg/d) and from imipramine to sertraline (mean dosage, 163 mg/d) resulted in clinically and statistically significant improvements. The switch to sertraline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to adverse effects. Although sertraline treatment also resulted in significantly higher response rates in the intent-to-treat samples (60% in the sertraline group and 44% in the imipramine group), neither the intent-to-treat remission rates nor the response and remission rates among study completers differed significantly. Moreover, after considering the effect of attrition, there were no significant treatment effects on the more comprehensive generalized estimating equation analyses of the continuous dependent measures., Conclusions: More than 50% of chronically depressed antidepressant nonresponders benefited from a switch from imipramine to sertraline, or vice versa, despite a high degree of chronicity. As in the initial trial, sertraline was generally better tolerated than imipramine. Switching to a standard antidepressant of a different class is a useful treatment strategy for antidepressant nonresponders and could be considered a standard of comparison for future studies of novel alternate strategies.

Background: Although it is known that antidepressant treatment improves psychosocial functioning, whether such changes occur independent of depressive symptoms is not known. This study compared efficacy of nefazodone, psychotherapy, and their combination in improving psychosocial functioning in chronically depressed outpatients., Methods: Patients with chronic forms of major depressive disorder were randomized to 12 weeks of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combined nefazodone/CBASP. Psychosocial assessments measured overall psychosocial functioning, work functioning, interpersonal functioning, and general health., Results: Relative to community norms, patients with chronic major depression evidenced substantially impaired psychosocial functioning at baseline. Combined treatment produced significantly greater psychosocial improvement than either CBASP alone or nefazodone alone on all primary measures. Combined treatment remained superior to nefazodone on primary measures of work, social, and overall functioning, and superior to CBASP on social functioning when depressive symptoms were controlled. Unlike the two groups receiving nefazodone, CBASP alone's effect on psychosocial function was relatively independent of symptom change. Psychosocial functioning improved more slowly than depressive symptoms, and moderate psychosocial impairments remained at end point., Conclusions: Combined treatment had greater effect than either monotherapy. Change in depressive symptoms did not fully explain psychosocial improvement. Moderate residual psychosocial impairment remained, suggesting the need for continuation/maintenance treatment.