For the week’s topics of Mood Disorders, analyze the primary arguments presented in either one of additional articles posted on Canvas OR? a relevant emp

Effects of Family-Focused Therapy vs Enhanced Usual Care for Symptomatic Youths at High Risk for Bipolar Disorder A Randomized Clinical Trial David J. Miklowitz, PhD; Christopher D. Schneck, MD; Patricia D. Walshaw, PhD; Manpreet K. Singh, MD, MS; Aimee E. Sullivan, PhD; Robert L. Suddath, MD; Marcy Forgey Borlik, MD; Catherine A. Sugar, MS, PhD; Kiki D. Chang, MD

IMPORTANCE Behavioral high-risk phenotypes predict the onset of bipolar disorder among youths who have parents with bipolar disorder. Few studies have examined whether early intervention delays new mood episodes in high-risk youths.

OBJECTIVE To determine whether family-focused therapy (FFT) for high-risk youths is more effective than standard psychoeducation in hastening recovery and delaying emergence of mood episodes during the 1 to 4 years after an active period of mood symptoms.

DESIGN, SETTINGS, AND PARTICIPANTS This multisite randomized clinical trial included referred youths (aged 9-17 years) with major depressive disorder or unspecified (subthreshold) bipolar disorder, active mood symptoms, and at least 1 first- or second-degree relative with bipolar disorder I or II. Recruitment started from October 6, 2011, and ended on September 15, 2016. Independent evaluators interviewed participants every 4 to 6 months to measure symptoms for up to 4 years. Data analysis was performed from March 13 to November 3, 2019.

INTERVENTIONS High-risk youths and parents were randomly allocated to FFT (12 sessions in 4 months of psychoeducation, communication training, and problem-solving skills training; n = 61) or enhanced care (6 sessions in 4 months of family and individual psychoeducation; n = 66). Youths could receive medication management in either condition.

MAIN OUTCOMES AND MEASURES The coprimary outcomes, derived using weekly psychiatric status ratings, were time to recovery from prerandomization symptoms and time to a prospectively observed mood (depressive, manic, or hypomanic) episode after recovery. Secondary outcomes were time to conversion to bipolar disorder I or II and longitudinal symptom trajectories.

RESULTS All 127 participants (82 [64.6%] female; mean [SD] age, 13.2 [2.6] years) were followed up for a median of 98 weeks (range, 0-255 weeks). No differences were detected between treatments in time to recovery from pretreatment symptoms. High-risk youths in the FFT group had longer intervals from recovery to the emergence of the next mood episode (χ2 = 5.44; P = .02; hazard ratio, 0.55; 95% CI, 0.48-0.92;), and from randomization to the next mood episode (χ2 = 4.44; P = .03; hazard ratio, 0.59; 95% CI, 0.35-0.97) than youths in enhanced care. Specifically, FFT was associated with longer intervals to depressive episodes (log-rank χ2 = 6.24; P = .01; hazard ratio, 0.53; 95% CI, 0.31-0.88) but did not differ from enhanced care in time to manic or hypomanic episodes, conversions to bipolar disorder, or symptom trajectories.

CONCLUSIONS AND RELEVANCE Family skills-training for youths at high risk for bipolar disorder is associated with longer times between mood episodes. Clarifying the relationship between changes in family functioning and changes in the course of high-risk syndromes merits future investigation.

TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01483391.

JAMA Psychiatry. 2020;77(5):455-463. doi:10.1001/jamapsychiatry.2019.4520 Published online January 15, 2020.

Supplemental content

CME Quiz at jamacmelookup.com and CME Questions page 548

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles (Miklowitz, Walshaw, Suddath, Forgey Borlik, Sugar); Department of Psychiatry, University of Colorado Anschutz Medical Campus, Denver (Schneck, Sullivan); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (Singh); Department of Biostatistics, Fielding School of Public Health, UCLA, Los Angeles (Sugar); Private practice, Menlo Park, California (Chang).

Corresponding Author: David J. Miklowitz, PhD, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Room A8-256, Los Angeles, CA 90024-1759 (dmiklowitz@mednet. ucla.edu).

Research

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Y ouths who develop bipolar I disorder (BD-I) or bipolar II disorder (BD-II) during late adolescence or early adult- hood often experience subthreshold mood symptoms

in childhood.1 In the Pittsburgh Bipolar Offspring Study, youths with depression, anxiety, mood instability, and subthreshold manic symptoms who had a parent with childhood-onset BD had a 49% chance of converting to BD-I or BD-II in 8 years com- pared with 6.8% of youth without these symptom features whose parents had childhood-onset BD.2 Onset of BD in child- hood and delays to first treatment are associated with more time being depressed, less time being euthymic, and poorer functioning in adulthood.3,4 However, there is little agree- ment on what treatments are most effective in preventing symptom progression among high-risk children.4-9

Psychosocial interventions may facilitate the high-risk youths’ acquisition of skills for coping with stress, develop- ing social supports, and achieving autonomy.10 In a 2-site pilot randomized clinical trial11 of 40 youths with active symp- toms of major depressive disorder (MDD) or unspecified (sub- threshold) BD and a family history of BD-I or BD-II, Miklowitz et al11 found that family-focused therapy (FFT) for high-risk youths, consisting of 12 sessions of family psychoeducation, communication skills training, and problem-solving skills train- ing was associated with more rapid recovery from mood symp- toms, more time in remission, and a more favorable trajec- tory of hypomania symptoms during 1 year compared with brief family education. These findings are consistent with trials showing that FFT and pharmacotherapy are more effective than comparison treatments and pharmacotherapy in enhanc- ing mood stabilization and delaying mood recurrences among adults with BD.12-15

We conducted a randomized clinical trial of the effects of FFT compared with standard psychoeducation (enhanced care [EC]) on time to recovery and time to prospectively observed mood episodes among symptomatic high-risk youths. This study expanded on the pilot randomized clinical trial11 by including 3 sites with a larger number of participants (N = 127) followed up for 1 to 4 years. The duration of the EC treatment was standardized at 4 months to match the duration of FFT. Participants received pharmacotherapy from study psychia- trists (C.D.S., M.K.S., R.L.S., M.F-B., and K.D.C.) using algo- rithms designed for this population.16 We hypothesized that high-risk youths receiving FFT would have (1) shorter times to recovery from pretreatment symptoms and longer inter- vals until their next prospectively observed mood episode (coprimary outcomes), and (2) lower rates of conversion to syn- dromal BD-I or BD-II and greater improvements in symptom severity over time (secondary outcomes) compared with youths receiving EC.

Methods This randomized clinical trial was approved by medical insti- tutional review boards of the University of California, Los An- geles (UCLA), the University of Colorado, Boulder, the Univer- sity of Colorado Anschultz Medical Center, Aurora, and Stanford University, Stanford, California. After receiving an ex-

planation of the procedures, participants and parents gave writ- ten informed assent and consent to participate. The trial pro- tocol is available in Supplement 1.

Participants Recruitment of participants occurred from October 6, 2011, to September 15, 2016. Data were analyzed from March 13, to November 3, 2019. Participants were clinically referred or learned of the study through online, radio, or print advertise- ments or public presentations. Eligibility criteria included (1) age between 9 years 0 months and 17 years 11 months; (2) meeting lifetime DSM-IV and, later, DSM-5 criteria17,18 for unspecified BD or major depressive disorder (MDD) (eMethods in Supplement 2); (3) having at least 1 first- or second-degree relative with a lifetime history of BD-I or BD-II; and (4) a prior week Young Mania Rating Scale (YMRS)19 score more than 11 or a 2-week Children’s Depression Rating Scale, Revised (CDRS-R)20 score more than 29, indicating at least moderate current mood symptoms. Unspecified BD (formerly BD, not otherwise specified) was defined as distinct periods of abnor- mally elevated, expansive, or irritable mood and 2 (3, if irri- table mood only) symptoms of mania that caused a change in functioning, lasted 1 to 3 days, and occurred for at least 10 days in the child’s lifetime.21,22

Baseline Assessments Study diagnosticians administered the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version (KSADS-PL)23,24 with the youth and at least 1 parent, with final item ratings based on consensus judgments. Inter- rater reliability for KSADS Depression and Mania Rating scales23,25 had means of 0.74 and 0.84 (intraclass correla- tions) across sites. A trained research assistant interviewed each parent about their own psychiatric history using the MINI International Neuropsychiatric Interview26 and about psychi- atric illnesses in the youth’s other first- and second-degree rela- tives using the Family History Screening instrument.27

Study Design and Procedures Before the study, the independent data core at UCLA created a dynamic random allocation procedure28 that assigned par- ticipants to FFT (n = 61) or EC (n = 66). Assignments were made

Key Points Question Is family-focused therapy for youths at high risk for bipolar disorder effective in delaying mood disorder episodes?

Findings This randomized clinical trial included 127 youths (aged 9-17 years) with symptomatic mood disorder and a family history of bipolar disorder. For a mean of 2 years, youths at high risk for bipolar disorder who received 12 sessions of family-focused therapy (psychoeducation, communication, and problem-solving skills training) with their families had longer well intervals between mood episodes compared with youths who received less intensive family and individual psychoeducation.

Meaning The findings suggest that family-focused therapy is associated with longer times between mood episodes among youths at high risk for bipolar disorder.

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separately by site. After a participant was determined to be eli- gible, the site’s principal investigator entered a diagnosis (un- specified BD or MDD), age (<13 years or ≥13 years), and initial medications (mood stabilizers or antipsychotics vs neither) into the algorithm, which then randomly allocated a treatment as- signment to minimize imbalances between study arms across these variables.

Pharmacotherapy At baseline, a study psychiatrist conducted a separate medi- cal evaluation of the youth. Participants were offered main- tenance pharmacologic care (biweekly and then monthly meet- ings) when clinically indicated or requested by the youth or parents. Physicians who were unaware of psychosocial assign- ments followed a pharmacotherapy algorithm for high-risk youths that described medication choices, starting doses, dose ranges, and clinical adjustments to manage mood or comor- bid conditions and control adverse effects (trial protocol in Supplement 1 and eResults in Supplement 2).16,22

Psychosocial Treatments All therapists administered both psychosocial treatments. Fam- ily-focused therapy involved the high-risk child, parents or stepparents, and when possible, siblings. The protocol con- sisted of 12 sixty-minute sessions (8 weekly, 4 biweekly) in 4 months of psychoeducation, communication enhancement training (eg, practicing active listening or expressing positive or negative feelings), and problem-solving skills training. The 4-month EC treatment consisted of 3 weekly 60-minute fam- ily psychoeducation sessions followed by 3-monthly youth- only sessions that focused on implementing a mood manage- ment plan (eMethods and eTable in Supplement 2). Family clinicians were trained in the FFT and EC protocols during a study launch meeting and supervised in monthly teleconfer- ences throughout the study. Clinician fidelity ratings on the Therapist Competence and Adherence Scales29 indicated high levels of adherence and skill (mean [SD], 5.04 [0.96] on a 7-point scale) in administering both treatments (eMethods in Supplement 2).

Outcome Assessments Independent evaluators blinded to treatment condition inter- viewed the youth and at least 1 parent (regarding the youth) at baseline (covering the previous 4 months), every 4 months af- ter randomization in year 1, and every 6 months for up to 4 years. At each assessment, the evaluators administered the Adoles- cent Longitudinal Interval Follow-up Evaluation (A-LIFE) and associated Psychiatric Status Ratings (PSRs),30 defined as 1 (asymptomatic) to 6 (fully syndromal, severe) point scales of depression, mania, and hypomania rated for every week of the interval. Interrater reliabilities for 6-point depression PSR was 0.79 (intraclass r) and for 6-point mania PSR was 0.76 (intra- class r) calculated across evaluators at each study site.

Statistical Analysis All participants had at least subthreshold mood symptoms (PSR scales ≥3) in the 2 weeks before randomization. The primary analysis was a 2-stage survival model of the coprimary out-

comes. Using conventions for the A-LIFE PSRs, we first com- pared the FFT and EC groups on the number of weeks from treatment assignment to the beginning of a recovery period (all PSR mood scales rated 1 [asymptomatic] or 2 [mildly sympto- matic] for ≥8 consecutive weeks).21,30 For those who recov- ered from prerandomization symptoms, we next compared treatment arms on time to a new mood episode, defined as either at least 2 weeks with PSR depression ratings of 4 (syn- dromal with moderately severe), 5 (severe), or 6 (extremely se- vere symptoms or impairment) or at least 1 week with PSR hy- pomania or mania ratings of 5 (syndromal with full intensity) or 6 (severe intensity). Reliability between raters for estimat- ing time to recovery was 0.93 and for time to mood episodes was 0.89. Secondarily, we fit individual survival models for time to depressive episodes, time to manic or hypomanic epi- sodes, and time to diagnostic conversion, defined as onset of mood symptoms that changed the diagnosis from MDD or un- specified BD to BD-I or BD-II (eMethods in Supplement 2).

For the time-to-event analyses, we obtained Kaplan- Meier estimates of the survival curves for each study arm and used the log-rank procedure (PROC LIFETEST in SAS, version 9.4 [SAS Institute Inc]31) to test for overall treatment effects. In follow-up analyses, we used Cox proportional hazards re- gression models (PROC PHREG in SAS31) to quantify the treat- ment effects (via hazard ratio estimates) and to explore the in- dependent effects of specific baseline covariates (site, age, sex, primary and comorbid diagnoses, family history [first- vs sec- ond-degree affected relatives], YMRS and CDRS-R scores, and medication regimens) beyond treatment effects.

In secondary analyses examining the differential effects of FFT vs enhanced care on the trajectory of mood symptoms over time, we computed a maximum PSR mood (depression, mania, or hypomania) severity score for each week of fol- low-up and then averaged these weekly maximum scores (range, 1-6) in each 4- to 6-month study interval for up to 48 months. We fit a mixed effect regression model (in PROC MIXED in SAS31) with mean maximum PSR scores as the out- come, treatment as the between-persons effect, time as the within-persons effect, and treatment-by-time interaction terms. We used a piecewise linear segmentation of time, allowing for a change in slope at 8 months because we ex- pected faster improvements during and immediately after the acute treatment period followed by a leveling after treat- ment as the corresponding skills learned in treatment were consolidated.

For all analyses, we initially included site and its interac- tions with group and time to ensure that differential imple- mentations of the interventions were not affecting observed results. Because there was no evidence of any site effects, we present the final results for models with site terms removed. Statistical significance was set at 2-sided P < .05.

Results Participants Participants were 127 youths (82 female [64.6%]; mean [SD] age, 13.2 [2.6] years; range, 9.0-17.9 years.), including 75 youths

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with MDD (59.1%) and 52 youths with unspecified BD (40.9%). The FFT participants did not differ from the EC participants on any baseline characteristic overall or by site (Table). The fi- nal sample of 127 participants did not differ in sex, age, or race/

ethnicity from 154 candidates who were screened and found ineligible or who refused to participate in the study (Figure 1).

Participants were in the study for a median of 98 weeks (range, 0-255 weeks); 14 (11.0%) were lost to follow-up (10 in

Table. Demographic and Illness History Features of High-risk Youths Receiving Family-Focused Therapy or Enhanced Carea

Variable

Family-Focused Therapy (n = 61)

Enhanced Care (n = 66)

Total (N = 127)

Age, mean (SD), y 13.2 (2.7) 13.3 (2.5) 13.2 (2.6)

Socioeconomic status, mean (SD)b 3.7 (0.8) 4.1 (0.8) 3.9 (0.8)

Young Mania Rating Scale at baseline, mean (SD) 12.8 (6.8) 12.5 (7.7) 12.6 (7.3)

Children's Depression Rating Scale–Revised at baseline, mean (SD)

46.3 (13.5) 48.3 (15.5) 47.3 (14.5)

Children’s Global Assessment Scale in the last 2 wk at baseline, mean (SD)

52.7 (9.8) 52.2 (22.5) 52.5 (10.6)

Children’s Global Assessment Scale, most severe past episode, mean (SD)

44.5 (7.6) 42.8 (8.5) 43.6 (8.1)

Female 37 (60.7) 45 (68.2) 82 (64.6)

Nonwhite race 12 (19.7) 10 (15.2) 22 (17.3)

Hispanic ethnicity 15 (24.6) 8 (12.1) 23 (18.1)

Primary diagnosis

Major depressive disorder 37 (60.7) 38 (57.6) 75 (59.1)

Bipolar disorder, not otherwise specified 24 (39.3) 28 (42.4) 52 (40.9)

Mood polarity at study entry

Depression, no mania or hypomania 27 (44.3) 31 (47.0) 58 (45.7)

Hypomania, no depression 0 1 (1.5) 1 (0.8)

Depression, subthreshold mania or hypomania 24 (39.3) 26 (39.4) 50 (39.4)

Hypomania, subthreshold depression 3 (4.9) 3 (4.5) 6 (4.7)

Subthreshold depression and mania or hypomania

7 (11.5) 5 (7.6) 12 (9.4)

Comorbid disordersc

None 6 (9.8) 11 (16.7) 17 (13.4)

Internalizing disorders only 21 (34.4) 26 (39.4) 47 (37.0)

Externalizing disorders 13 (21.3) 14 (21.2) 27 (21.3)

Internalizing and externalizing disorders 21 (34.4) 15 (22.7) 36 (28.4)

Baseline medications

None 23 (37.7) 33 (50.0) 56 (44.1)

Lithium 1 (1.6) 0 1 (0.8)

Antipsychotic 13 (21.3) 17 (25.8) 30 (23.6)

Anticonvulsant 10 (16.4) 8 (12.1) 18 (14.2)

Antidepressant 27 (44.3) 20 (30.3) 47 (37.0)

Anxiolytic 2 (3.3) 2 (3.0) 4 (3.1)

Psychostimulant or other ADHD agent 12 (19.7) 14 (21.2) 26 (20.5)

Family composition

Both biological parents, intact family 32 (52.5) 30 (45.5) 62 (48.8)

Both biological parents, joint custody 6 (9.8) 5 (7.6) 11 (8.7)

1 Biological parent without stepparent 7 (11.5) 14 (21.2) 21 (16.5)

1 Biological parent plus stepparent 9 (14.8) 11 (16.7) 20 (15.7)

Grandparent 2 (3.3) 1 (1.6) 3 (2.4)

Other relative 5 (8.2) 5 (7.6) 10 (7.9)

Family history of bipolar disorder

Youths with first-degree relatives only 35 (57.4) 47 (71.2) 82 (64.6)

Youths with second-degree relatives 10 (16.4) 9 (13.6) 19 (15.0)

Youths with first- and second-degree relatives 16 (26.2) 10 (15.2) 26 (20.5)

Abbreviation: ADHD, attention-deficit/hyperactivity disorder. a Data are presented as number

(percentage) of participants unless otherwise indicated.

b Higher values for socioeconomic status indicate higher educational level and occupation.

c Internalizing disorders include all anxiety disorders and eating disorders. Externalizing disorders include ADHD, conduct disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder.

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EC and 4 in FFT) shortly after randomization (Figure 1). Duration of follow-up did not differ significantly across psy- chosocial treatments (FFT: median, 114 weeks; range, 0-255 weeks; EC: median, 92.5 weeks, range, 0-221 weeks; survival analysis log-rank χ2 = 2.78; P = .10) nor as a function of base- line depression (CDRS-R) or mania or hypomania (YMRS) scores, study site, sex, age, family history, or primary or comorbid diagnoses. Patients in the FFT and EC groups attended the same proportion (91.7%) of protocol therapy sessions (FFT: mean [SD], 11.0 [3.4] of 12.0; EC: mean [SD], 5.5 [2.4] of 6.0), and the proportion of participants who dropped out during the 4-month treatment period did not differ significantly across groups (8.2% vs 16.7%; χ2 = 2.07; P = .15). Additional checks of the potential impact of follow-up duration on the primary outcome results are pre- sented in the eResults in Supplement 2.

Effects of Treatment on Time to Recovery Of the 127 participants, 90 (70.9%) met the 8-week mood re- covery criteria at some point during follow-up, 23 (18.1%) did not, and 14 (11.0%) withdrew at baseli

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