Recovery and Recurrence Following Treatment for Adolescent Major Depression FREE

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders among adolescents, with rates of approximately 5.9% among females and 4.6% among males.¹ It is associated with functional impairment, risk of suicide, and risk of adult depression.^2- 4 Thus, it is important to investigate not only the efficacy of adolescent MDD treatments but also whether they reduce risk of subsequent negative outcomes, especially depression recurrence.

The episodic nature of adolescent MDD is evident across community and clinical samples. In community samples, approximately 75% of MDD episodes end within 6 to 15 months.^5- 7However, recurrence rates reach 45% in 6 years.⁴ In clinical samples, recovery rates 1 year after treatment onset range from 81% to 98%,^8- 9 but recurrence rates range from 54% in 3 years among outpatients⁸ to more than 60% in 1 year for inpatients.⁹

Treatment studies usually report outcomes of response (clinically significant improvement) and remission (no or very few remaining symptoms).^10- 11 Three clinical trials have also reported rates of recovery (maintenance of remission for an extended period) and recurrence (a new episode following recovery). Emslie et al¹² assessed 87 child and adolescent outpatients with MDD 1 year after treatment with fluoxetine hydrochloride or placebo. Eighty-five percent had recovered, but 39% of recovered patients experienced a recurrence. Rates were not reported by initial randomized treatment. Clarke et al¹³ followed up 64 depressed adolescents treated with cognitive behavioral therapy (CBT). Over 2 years, almost all recovered; however, 22% of recovered adolescents experienced a recurrence. Birmaher et al¹⁴ followed up 107 depressed adolescents 2 years after treatment with 1 of 3 psychotherapies. Eighty percent recovered, with no differences among treatments. However, 30% of recovered adolescents had 1 recurrence and 8% had 2 recurrences. Thus, even effective treatments can be followed by recurrence rates of 30% to 40% within 1 to 2 years, with no treatment yet surpassing others in preventing recurrence.

In this study, we investigated recovery from and recurrence of MDD during an extended naturalistic follow-up of participants in the Treatment for Adolescents With Depression Study (TADS). We first described recovery rates over 5 years from TADS baseline, and to facilitate comparison with previous research,¹⁴ we tested predictors of recovery by 2 years. Second, we described recurrence rates over the 5-year period and tested predictors of recurrence. Third, we investigated long-term effects of initial treatment and short-term response on recovery or recurrence. Finally, because about 8% to 20% of depressed adolescents are at risk for developing bipolar disorder,⁸ we described the rate of this outcome in our sample.

The Treatment for Adolescents With Depression Study compared fluoxetine, CBT, and their combination and included a placebo condition. The combination of fluoxetine and CBT was the most efficacious short-term treatment.¹⁵ Active treatment groups did not differ in rates of sustained response (75%-88%) or remission (55%-60%) at 9 months following maintenance treatment^16- 17 or in rates of remission (68%) 1 year later.¹⁸ Among adolescents randomized to placebo followed by open treatment, 48% were in remission at 9 months.¹⁹

To investigate longer-term recovery and recurrence, we first identified baseline or post–short-term treatment predictors found in 3 studies of recovery following a fluoxetine trial,¹² recurrence following inpatient treatment,⁹ or recovery and recurrence following a psychotherapy trial.¹⁴ We included all predictors from these studies except psychotic features,⁹ an exclusion criterion in TADS. Second, we included variables that had predicted or moderated short-term TADS outcome.²⁰ Third, we included residual symptoms following short-term TADS treatment, which had predicted nonremission after maintenance treatment.¹⁷ Finally, because of sex differences in MDD prevalence, we included sex. Potential predictors are shown in Table 1.

Although it is not ethically possible to test long-term treatment effects by withholding treatment from a control group, it is possible to compare groups who responded more or less successfully to short-term treatment.²¹ We hypothesized that favorable response to short-term treatment would predict higher rates of recovery and lower rates of recurrence. Following the study by Birmaher et al,¹⁴ we also tested the hypotheses that treatment with the most efficacious short-term intervention would predict higher rates of recovery and lower rates of recurrence than treatment with other interventions.

The Treatment for Adolescents With Depression Study compared fluoxetine, CBT, and their combination with one another across short-term (12 weeks), continuation (6 weeks), and maintenance (18 weeks) treatment and with short-term placebo. Participants (N = 439) were randomized to fluoxetine, CBT, their combination, or placebo. Following short-term treatment, placebo partial responders, nonresponders, or responders who relapsed were offered their TADS treatment of choice. Following maintenance treatment, adolescents were followed up openly for 1 year.¹⁸ The present study, Survey of Outcomes Following Treatment for Adolescent Depression (SOFTAD), was an open follow-up extending an additional 3.5 years after the TADS follow-up year. The TADS-SOFTAD period spanned 63 months (21 months of TADS and 42 months of SOFTAD), with diagnostic interviews administered according to the schedule shown in Table 2.

The design, sample characteristics, and outcomes of TADS have been described previously.^15,22- 23 Treatment response was defined as an independent evaluator rating of 1 (very much improved) or 2 (much improved), partial response was defined as a rating of 3 (minimally improved), and nonresponse was defined as a rating of 4 or higher on the 7-point Clinical Global Impressions–Improvement scale.²⁴ During TADS, remission was defined as a normalized score (<29) on the Children's Depression Rating Scale–Revised (CDRS-R).²⁵

Participants in SOFTAD were recruited from among all 439 adolescents who had been randomized in TADS. The TADS participants were recruited between spring 2000 and summer 2003. The SOFTAD recruitment occurred from March 8, 2004, to December 20, 2006, with the final assessment completed on December 4, 2008. Recruitment involved recontacting TADS early completers and dropouts and, after March 8, 2004, asking TADS completers to participate. For minors, written parental consent and adolescent assent were obtained. For adults, written consent was obtained from them and from their parents, since parents completed some measures. The Duke University Medical Center and site institutional review boards approved this study.

Initial SOFTAD assessment optimally occurred 27 months after TADS baseline, but participants began assessments at whatever assessment point corresponded most closely to the time of their recruitment. At most, participants could complete 7 SOFTAD assessments at 6-month intervals, of which 5 assessments included diagnostic interviews.

The SOFTAD participants included 196 adolescents (44.6% of youths randomized in TADS), representing 12 of 13 TADS sites. One site was unable to recruit participants. The sample included 110 females (56.1%). The mean (SD) age at SOFTAD entry was 18 (1.8) years (range, 14-22 years). The sample was 78.6% white, 9.2% Latino, 8.2% African American, and 4.1% other ethnicity. Points of entry into SOFTAD by months since TADS baseline were as follows: month 27 (33.7%), month 33 (21.9%), month 39 (13.8%), month 45 (10.7%), month 51 (9.7%), month 57 (8.2%), and month 63 (2.0%). The modal number of completed SOFTAD assessments was 5, with a mean (SD) of 3.5 (1.5) completed SOFTAD assessments.

The Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL)²⁶ was administered at 5 SOFTAD assessment points (Table 2). The Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used in TADS and by Birmaher et al¹⁴ and assessed mood, anxiety, behavior, eating, substance use, psychotic disorders, and tic disorders using DSM-IV criteria²⁷ for the time since the last TADS or SOFTAD assessment and current MDD episode.

When the K-SADS-PL indicated MDD at any point since the last interview, the interviewer inquired about episode onset (time when the participant met full diagnostic criteria) and, if relevant, offset (time when the participant had no remaining clinically significant MDD symptoms for ≥2 weeks). We used the absence of MDD symptoms on the K-SADS-PL rather than a normalized CDRS-R score to define remission in SOFTAD to facilitate comparison with previous research¹⁴ and because participants exceeded CDRS-R age limits.

Consistent with adult criteria and prior adolescent research,^14,28 we defined recovery as remission lasting at least 8 weeks, with the exception noted later for recovery during the TADS period. Following recovery, time of MDD recurrence was estimated as the month when 5 or more symptoms again became present.

Although SOFTAD interviews inquired about the time since the preceding TADS or SOFTAD interview, TADS interviews had only inquired about current symptoms. To deal with this limitation, we assumed that an index episode of MDD during the TADS period was in remission if no symptoms were reported on a K-SADS-PL assessment and in recovery if no symptoms were reported at 2 consecutive TADS assessments.

The SOFTAD evaluators met the same educational and experience criteria as the TADS evaluators. Certification following didactic training required the following: (1) rating a videotaped standard patient interview, with agreement on presence or absence of MDD, 80.0% agreement on the full MDD criterion set, and agreement on other classes of disorders (eg, anxiety disorder); and (2) rating a site-based interview, subsequently rated at the coordinating center with acceptable reliability, using these same criteria.

Evaluators had monthly conference calls and annually rated a standard patient interview. On these, there was complete agreement between evaluators and coordinating center ratings for diagnosis of MDD since the last interview and 95.6% agreement on current MDD; 91.3% of evaluator ratings exceeded 80.0% agreement on diagnostic criteria.

The following predictors of recovery and recurrence were measured at TADS baseline. Age, ethnicity, sex, family income, and referral source were reported by participants or parents. Income was dichotomized at $75 000 and ethnicity as white or nonwhite for comparison with previous findings.^9,20 For duration of index episode and depression severity, an independent evaluator estimated the duration of the index major depressive episode (MDE) and completed the CDRS-R²⁵ for severity. Adolescents completed the Reynolds Adolescent Depression Scale (RADS).²⁹ For global functioning, the evaluator assigned a rating on the Children's Global Assessment Scale.³⁰ To measure suicidal ideation, adolescents completed the Suicide Ideation Questionnaire–Junior High Version.³¹ The index for melancholic features included 5 CDRS-R items: anhedonia, insomnia, appetite disturbance, guilt, and psychomotor retardation. Comorbid diagnoses were yielded by the K-SADS-PL. To measure hopelessness, cognitive distortions, and treatment expectancy, adolescents completed the Beck Hopelessness Scale,³² completed the Children's Negative Cognitive Errors Questionnaire,³³ and rated their expectations for improvement with fluoxetine, CBT, or their combination. To determine parent-adolescent conflict, adolescents and parents completed the Conflict Behavior Questionnaire.³⁴

The following predictors of recovery were assessed at the end of TADS short-term treatment: CDRS-R scores, RADS scores, Children's Negative Cognitive Errors Questionnaire scores, Beck Hopelessness Scale scores, Children's Global Assessment Scale scores, residual K-SADS MDD symptoms, and Conflict Behavior Questionnaire scores. The latter two were also investigated as predictors of recurrence.

At each SOFTAD assessment, participants were asked what services they had received (if any) for emotional, behavioral, or substance abuse problems. As part of this review of services, they reported whether they had received psychotherapy or antidepressant medication.

Baseline characteristics of TADS participants who enrolled in SOFTAD (n = 196) were compared with those who did not (n = 243) using general linear models for continuous measures and χ² test for binary outcomes. Fisher exact test and nonparametric median test were alternatively performed as needed.

Because recovery during the TADS period was estimated on the basis of 2 consecutive symptom-free interviews separated by 3 or 6 months and not, as in SOFTAD, on the basis of a specific month of recovery, we reported the cumulative percentages of recovered subjects in 6-month intervals from TADS baseline. Participants were subdivided into 3 groups: (1) those with persistent depression (baseline MDE never resolved); (2) those with recovery from baseline MDE without recurrence; and (3) those with recovery with recurrence. For comparison with previous research,¹⁴ we examined recovery by 2-year follow-up, testing its predictors with logistic regression. Among those who recovered at any point, we examined predictors of recurrence over the 63-month period using logistic regression and reported mean and median time from recovery to recurrence.

All analyses were conducted with SAS version 9.2 statistical software (SAS Institute, Inc, Cary, North Carolina). Non directional hypotheses were tested, with the significance level set at .05 for each test. The α was not adjusted for multiple outcomes or tests owing to the exploratory nature of the investigation.

To determine whether SOFTAD participants represented the full TADS sample, we compared them with TADS participants not in SOFTAD on the variables related to hypothesis testing. Participants and nonparticipants did not differ on percentage of short-term treatment responders (53.6% vs 51.0%, respectively; χ²₁ = 0.28; P = .60) or initial treatment condition (χ²₃ = 1.54; P = .67). Figure 1 depicts the number of SOFTAD participants from each condition.

Demographic and clinical comparisons are shown in Table 3. There were few differences. The SOFTAD participants were younger (P = .006), included fewer minority adolescents (P = .04), were more likely to be experiencing their initial episode (P = .02), had fewer total comorbid disorders (P = .04), and had fewer anxiety disorders (P = .04).

The vast majority of SOFTAD participants recovered from their index MDE during the 63 months (Figure 2). Specifically, 189 (96.4%) recovered and 7 (3.6%) did not. Cumulative recovery rates were as follows: 29.6% at 6 months, 66.3% at 12 months, 84.7% at 18 months, 88.3% at 24 months, 92.3% at 30 months, 94.8% at 36 months, and 96.4% at 42 months. Among the 189 adolescents who recovered, 68.8% had recovered by 1 year after baseline and 91.5% had recovered within 2 years.

As hypothesized, recovery by 2 years was significantly more likely for those who were short-term treatment responders (96.2%) than for others (79.1%) (χ²₁ = 11.02; P < .001). However, it was not associated with the combination of fluoxetine and CBT, any particular treatment, or any baseline variables. Among post–short-term treatment variables, recovery was significantly predicted by less severe evaluator-rated depression (CDRS-R score; χ²₁ = 12.54; P < .001) and higher global functioning (Children's Global Assessment Scale score; χ²₁ = 5.48; P = .02). There were trends for lower parent-reported conflict (Conflict Behavior Questionnaire score; χ²₁ = 3.70; P = .05) and more cognitive distortions (Children's Negative Cognitive Errors Questionnaire score; χ²₁ = 3.00; P = .08) to predict recovery by year 2. Self-reported depression (RADS score), hopelessness (Beck Hopelessness Scale score), and adolescent-reported conflict (Conflict Behavior Questionnaire score) with the mother or father were not significant predictors (all P > .15).

For 186 participants with complete K-SADS symptom ratings after short-term treatment, any of 7 MDD symptoms (excluding psychomotor or concentration disturbance) was associated with lower probability of recovery in 2 years. With all 7 MDD symptoms in a multivariable logistic regression, the significant predictors were appetite or weight disturbance (χ²₁ = 1.13; P = .03) and sleep disturbance (χ²₁ = 1.11; P = .03).

Of 189 participants who recovered, 101 (53.4%) remained well throughout the SOFTAD period and 88 (46.6%) had MDD recurrence. Most had 1 recurrence (n = 74), but 12 had 2 recurrences and 2 had 3 recurrences. Figure 2 shows the rate of first recurrence across time. Among all recovered participants, cumulative recurrence rates for years 1 through 4 were 1.6%, 12.2%, 29.6%, and 38.1%, respectively. One year after TADS baseline, only 3.4% of the 88 recurrences had occurred. Corresponding rates for years 2, 3, and 4 were 26.1%, 63.6%, and 81.8%, respectively.

For those with recurrence, the mean (SD) time from recovery to the first recurrence was 22.3 (13.9) months (median, 20.3 months). Time from recovery to recurrence ranged from 2 to 55 months, with cumulative rates as follows: 12.5% at 6 months, 26.1% at 12 months, 40.9% at 18 months, 61.3% at 24 months, 77.3% at 30 months, and 84.9% at 36 months.

Within the SOFTAD sample of 196 participants, 105 (53.6%) had been full responders to short-term treatment, whereas 91 (46.4%) had not been (54 partial responders and 37 nonresponders). For the 189 participants who recovered, the full response rate was 55.6% and the partial response or nonresponse rate was 44.4%.

Contrary to our hypothesis, the recurrence rate for full responders (45.7%) was not significantly lower than for others (47.6%) (χ²₁ = 0.07; P = .79). We explored whether the combined group of full and partial responders had a lower recurrence rate than nonresponders. Recurrence rates were 42.9% for full or partial responders and 67.6% for nonresponders, which was a significant difference (χ²₁ = 4.68; P = .03).

Also contrary to our hypothesis, the recurrence rate for participants receiving the combination of fluoxetine and CBT (49.0%) did not differ from that of others (45.7%) (χ²₁ = 0.16; P = .69). There were no treatment condition differences in recurrence rates (χ²₃ = 1.91; P = .59).

In individual regression models, 4 baseline variables predicted recurrence: sex (χ²₁ = 10.58; P = .001), self-reported depression (RADS score; χ²₁ = 6.16; P = .01), suicidal ideation (Suicide Ideation Questionnaire–Junior High Version score; χ²₁ = 6.88; P = .009), and comorbid anxiety disorder (χ²₁ = 4.98; P = .03). Among females, 57.0% experienced recurrence, compared with 32.9% of males. Among those with anxiety disorder, 61.9% experienced recurrence compared with 42.2% of others. Participants with recurrence compared with those without recurrence had higher mean (SD) RADS and Suicide Ideation Questionnaire–Junior High Version scores (RADS: 81.5 [14.6] vs 75.7 [15.8], respectively; Suicide Ideation Questionnaire–Junior High Version: 25.4 [21.1] vs 17.4 [18.4], respectively).

In a multivariable regression including these 4 predictors, only female sex remained significant (χ²₁ = 5.04; P = .02). Anxiety disorder approached significance (χ²₁ = 3.35; P = .07).

The emergence of bipolar disorder was relatively rare. Twelve participants (6.1%; 3 males, 9 females) were diagnosed with bipolar I disorder (n = 5), bipolar II disorder (n = 4), or, if the duration was 1 day shorter than the criterion, bipolar disorder not otherwise specified (n = 3). Bipolar outcome was unrelated to treatment condition, but most of these participants (n = 9) had not responded to short-term treatment. One never recovered from the index MDE; the other 11 recovered but had recurrence. In each case, bipolar disorder emerged after the end of the TADS period, at a mean (SD) age of 18.0 (1.4) years. Given the small number, we did not conduct further statistical comparisons.

During SOFTAD, 83 participants (42.3%) received psychotherapy and 88 (44.9%) received antidepressant medication, each unrelated to TADS treatment condition (P > .05). Each treatment was more likely among participants who had not recovered by 2 years (psychotherapy: χ²₁ = 5.23; P = .02; medication: χ²₁ = 4.13; P = .04) and among those with recurrence (psychotherapy: χ²₁ = 13.77; P < .001; medication: χ²₁ = 16.00; P < .001) than among those with recovery and no recurrence.

We followed up 196 adolescent participants in TADS, the largest treatment follow-up sample of depressed adolescents to date. Rate of recovery from the index MDE over 5 years from TADS baseline was very high (96.4%), and 88.3% of participants recovered within 2 years. As hypothesized, full short-term treatment response was associated with recovery by 2 years, as were other post–short-term treatment variables: less severe depression, absence of sleep or appetite disturbance, and better functioning. Contrary to our hypothesis, treatment with a combination of fluoxetine and CBT did not predict recovery in 2 years.

Slightly fewer than half of recovered adolescents (46.6%) experienced a recurrence by 5 years after baseline. Contrary to our hypotheses, neither full response to short-term treatment nor treatment with a combination of fluoxetine and CBT reduced the risk of recurrence. However, short-term treatment nonresponders were more likely to experience recurrence than full and partial responders. Females were significantly more likely to have a recurrence than males.

The SOFTAD 2-year recovery rate of 88.3% is comparable to the previously reported rate of 80%.¹⁴ Comparisons with previous TADS findings^17- 18 indicate that remission rates increase and that progress toward recovery continues after treatment ends, consistent with other studies.^12,14 This is the second study to indicate that longer-term recovery rates are not superior for adolescents receiving the most efficacious short-term treatment.¹⁴ Such findings may be attributed to the episodic nature of depressive disorder and limited variance in 2-year recovery as a comparative index.

The SOFTAD recurrence rate reached 29.6% 3 years after baseline, whereas it had reached this rate 2 years after a previous psychotherapy trial.¹⁴ Although sample differences cannot be ruled out, it is possible that incorporating continuation and maintenance treatment within TADS slowed the pace of recurrence. The lower rate of recurrence in TADS is consistent with the previous finding that TADS treatment gains were generally maintained during the first year of follow-up.¹⁸ Unfortunately, no treatment has yet been identified that reduces adolescent recurrence rates.

The most robust predictor of recurrence was female sex. Females are more likely than males to experience MDD after approximately age 14 years,³⁵ but to our knowledge this is the first study documenting higher recurrence rates among treated adolescent females. Adult studies do not show a sex difference in recurrence.³⁶ One adolescent community study did show such a difference³⁷ from ages 19 to 23 years. This age range overlaps ours, suggesting that female vulnerability to recurrence may be age related. Factors implicated as potential causes of higher depression rates among postpubertal women include sex steroids,³⁸ long-term environmental stressors, low perceived mastery, and ruminative response style.³⁹ Further research should investigate whether more frequent MDD recurrence among young women is confirmed and, if so, what variables are associated with it.

Anxiety disorder was an individual predictor of recurrence. Anxiety disorders were more frequent among females (28.2%) than among males (15.1%) (χ²₁ = 4.73; P = .03), likely accounting for the elimination of anxiety disorder as a predictor when considering sex simultaneously. Anxiety disorders also predicted poorer short-term outcome in TADS.²⁰ In depressed adults, anxiety mitigates the effectiveness of antidepressant treatment⁴⁰ and slows response time to CBT.⁴¹ These findings suggest that adolescent MDD with anxiety requires further treatment development.

The rate of bipolar outcome in our sample was lower than in adolescent inpatient samples but similar to rates found among outpatients.⁸ Our rate likely reflects TADS exclusion of participants for whom a placebo-controlled outpatient study was inappropriate (eg, those with psychotic depression or short-term suicidal risk).

Our results reinforce the importance of modifying a short-term treatment that leads to partial response or nonresponse because these were associated with less likelihood of recovery in 2 years. A study of adolescent selective serotonin reuptake inhibitor nonresponders showed that augmentation with CBT improved response rates.⁴² To our knowledge, no parallel study has been completed investigating medication augmentation for incomplete CBT response, but treatment algorithms recommend such augmentation.⁴³ The finding that recurrence rates increased significantly from 2 to 3 years after baseline suggests that recurrence prevention efforts, such as symptom or medication monitoring or CBT booster sessions, may be of value beyond the maintenance period included in TADS.

The most significant limitation of this study is that slightly fewer than half of the TADS participants took part. This likely reflects the difficulty maintaining a sample of adolescents during a period when many are moving away from home. Indeed, SOFTAD participants were somewhat younger than nonparticipants. Nevertheless, they did not differ on most measures, including depression characteristics, initial treatment, short-term treatment response rates, or sex. Participants had fewer anxiety disorders, suggesting that recurrence rates may have been higher if all TADS adolescents had participated.

Two other limitations should be noted. First, there was not a no-treatment condition in TADS. Second, most participants receiving placebo eventually received a TADS treatment,¹⁹ and access to treatment was not controlled during SOFTAD. Thus, findings do not reflect the naturalistic course of untreated depression. In a separate report, we will describe participants' treatment utilization in more detail.

In summary, all predictors of recovery by 2 years were associated with clinical status after short-term treatment. Female sex was the most robust predictor of recurrence, indicating the importance of understanding and reducing the vulnerabilities of female adolescents to recurrent episodes.

Correspondence: John Curry, PhD, Duke Child and Family Study Center, Duke University Medical Center, 718 Rutherford St, Durham, NC 27705 (curry005@mc.duke.edu).

Submitted for Publication: February 8, 2010; final revision received July 12, 2010; accepted August 20, 2010.

Published Online: November 1, 2010. doi:10.1001/archgenpsychiatry.2010.150

Author Contributions: Dr Curry had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Drs Curry and Wells provide training through the REACH Institute. Dr Kratochvil receives grant support from Lilly, Abbott, and Somerset and is a consultant for Lilly, Abbott, Neuroscience Education, AstraZeneca, and Pfizer. Dr Emslie is a consultant for BioBehavioral Diagnostics, Lilly, GlaxoSmithKline, Pfizer, and Wyeth, is a speaker for Forest, and receives research funding from Somerset. Dr Walkup receives research support from Pfizer, Lilly, and Abbott and receives royalties from Oxford University Press and Guilford Press. Dr March owns equity in MedAvante, is a consultant for Pfizer, Wyeth, Bristol-Myers Squibb, and Johnson & Johnson, is an advisor for Pfizer, Lilly, Scion, and Psymetrix, receives research support from Pfizer and Lilly, and receives royalties from MultiHealth Systems, Guilford Press, and Oxford University Press.

Funding/Support: This study was funded by grant R01 MH070494 from the National Institute of Mental Health (Dr Curry).

Role of the Sponsor: The National Institute of Mental Health had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: Benedetto Vitiello, MD, coordinated administration of SOFTAD at the National Institute of Mental Health. We thank participants and the site staff who recruited them, including Margaret Price, Stephenie Frank, MS, and Sue Baab, MSN. We acknowledge the many contributions of the late Dr Elizabeth Weller, a dedicated clinical scientist.