Early psychosocial intervention for youth at risk for bipolar I or II disorder: A one-year treatment development trial

Division of Child and Adolescent Psychiatry, University of California Los Angeles School of Medicine, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
Bipolar Disorders (Impact Factor: 4.97). 02/2011; 13(1):67-75. DOI: 10.1111/j.1399-5618.2011.00890.x
Source: PubMed
ABSTRACT
Previous studies have identified behavioral phenotypes that predispose genetically vulnerable youth to a later onset of bipolar I or II disorder, but few studies have examined whether early psychosocial intervention can reduce risk of syndromal conversion. In a one-year open trial, we tested a version of family-focused treatment adapted for youth at high risk for bipolar disorder (FFT-HR).
A referred sample of 13 children (mean 13.4±2.69 years; 4 boys, 9 girls) who had a parent with bipolar I or II disorder participated at one of two outpatient specialty clinics. Youth met DSM-IV criteria for major depressive disorder (n=8), cyclothymic disorder (n=1), or bipolar disorder not otherwise specified (n=4), with active mood symptoms in the past month. Participants were offered FFT-HR (12 sessions in four months) with their parents, plus psychotropic medications as needed. Independent evaluators assessed depressive symptoms, hypomanic symptoms, and global functioning at baseline and then every four months for one year, with retrospective severity and impairment ratings made for each week of the follow-up interval.
Families were mostly adherent to the treatment protocol (85% retention), and therapists administered the FFT-HR manual with high levels of fidelity. Youth showed significant improvements in depression, hypomania, and psychosocial functioning scores on the Adolescent Longitudinal Interval Follow-up Evaluation. They also showed significant improvements in Young Mania Rating Scale and Children's Depression Rating Scale scores.
FFT-HR is a promising intervention for youth at high risk for BD. Larger-scale randomized trials that follow youth into young adulthood will be necessary to determine whether early psychosocial intervention can reduce the probability of developing bipolar I or II disorder among genetically vulnerable youth.

Full-text

Available from: Judy Garber
Original Article
Early psychosocial intervention for youth at
risk for bipolar I or II disorder: a one-year
treatment development trial
Miklowitz DJ, Chang KD, Taylor DO, George EL, Singh MK, Schneck
CD, Dickinson LM, Howe ME, Garber J. Early psychosocial
intervention for youth at risk for bipolar I or II disorder: a one-year
treatment development trial.
Bipolar Disord 2011: 13: 67–75. ª 2011 The Authors.
Journal compilation ª 2011 John Wiley & Sons A S.
Objectives: Previous studies have id ent ified behav ioral phenotypes that
predis pose genetically vulnerable youth to a later onset of bipolar I or II
disorder, but few studies have examined whether early psychosocial
intervention can reduce risk of syndromal conv ersion. In a one-year open
trial, we tested a version of family-focused treatment adapted fo r youth
at high risk for bipolar di sorder (FFT-HR).
Methods: A referred sample of 13 children (mean 13.4 ± 2.69 years; 4
boys, 9 girls) who had a parent with bipolar I or II disorder participated
at one of tw o outpat ient specialty clinics. Youth met DSM-IV criteria for
major depressive disorder (n = 8), cyclothymic disorder (n = 1), or
bipolar disorder n ot otherwise specified (n = 4), with active m ood
sympto ms in the past month. Participants were oered FFT-HR
(12 sessions in four months) w ith their parents, plu s psychotropic
medica tions as needed . Independe nt evaluators assessed depres sive
symptoms, hypomanic symptoms, and global functioning at baseline and
then every four months for one year, with retrospective severity and
impairment ra tings m ade for each week of t he follow-up interval.
Result s: Families were mostly adherent to the treatment protocol (85%
retention), and therapists administered th e FFT-HR ma nual with high
levels of fidelity. Youth showed significant im provements in depression,
hypomania, and ps ychosocial functioni ng scores on the Adoles cent
Longitudinal Interval F ollow-up Evaluation. They also showed
significant improvements in Young Mania Rating Scale and
Childr en!s Depression Ra ting Scale scores.
Conclusions: FFT-HR is a pr omising intervention for youth at high
risk for BD. Larger-scale randomized trials that follow you th into young
adulthood will be necessary to determine whether early psychosoci al
intervention can red uce the probability of developing bipolar I or II
disorder among genetically v ulnerable youth.
David J Miklowitz
a,b
, Kiki D Chang
c
,
Dawn O Taylor
b
, Elizabeth L
George
b
, Manpreet K Singh
c
,
Christopher D Schneck
d
, L Miriam
Dickinson
d
, Meghan E Howe
c
and
Judy Garber
e
a
Division of Child and Adolescent Psychiatry,
University of California Los Angeles School of
Medicine, Los Angeles, CA,
b
Department of
Psychology, University of Colorado, Boulder, CO,
c
Department of Psychiatry, Stanford University
School of Medicine, Stanford, CA,
d
Department of
Psychiatry, University of Colorado Denver School of
Medicine, Denver, CO,
e
Department of Psychology,
Vanderbilt University, Nashville, TN, USA
doi: 10.1111/j.1399-5618.2011.00890.x
Key words: early intervention family therapy
high risk pediatric prevention psychoeducation
Received 15 August 2010, revised and accepted
for publication 30 November 2010
Corresponding author:
David J. Miklowitz, Ph.D.
Division of Child and Adolescent Psychiatry
UCLA Semel Institute for Neuroscience and
Human Behavior
David Geffen School of Medicine at UCLA
760 Westwood Plaza, Room 58-217
Los Angeles, CA 90024-1759, USA
Fax: +1-310-206-4446
E-mail: dmiklowitz@mednet.ucla.edu
Http://www.clinicaltrials.gov identifier:
NCT00943085.
DJM has received funding from the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Danny Alberts Foundation,
the National Institu te of Mental Health (NIMH), and the Robert L. Sutherland Foundation; and royalties from Guilford Press and John Wiley &
Sons. KDC has received research funding from NARSAD, NIMH, and GlaxoSmithKline; and has received honoraria from GlaxoSmithKline, Eli
Lilly & Co., Bristol-Myers Squibb, and Merck. D OT, ELG, MKS, CDS, LMD, MEH, and JG do not have any conflicts of interest to report.
Bipolar Disorders 2011: 13: 67–75
ª 2011 John Wiley and Sons A/S
BIPOLAR DISORDERS
67
Page 1
Between 50–66% of adult patients with bipolar
disorder (BD) report onset of their disease prior to
18 years, and 15–28% report onset before age 13
(1). BD in childhood or adolescence exhibits a
more severe, protracted, and continuously cycling
course compared to adult-onset BD, often with
mixed episodes, longer episode durations, psycho-
sis, and multiple comorbidities (2). Many of these
features also characterize prodromal forms of the
illness, which can be identified in childhood or
early adolescence (3, 4).
Several research groups have identified the
phenotypes that may be most likely to predispose
youth to the later development of bipolar illness.
Birmaher et al. (3) found that youth (mean age
7–17 years) who met research criteria for BD not
otherwise specified (NOS)—operationalized by
multiple short periods of mania that do not meet
the DSM-IV episode duration thresholds or symp-
tom count criteria—are at substantially elevated
risk for "converting! to bipolar I disorder (BD-I) or
bipolar II disorder (BD-II). When stratifying by
family history of BD-I or BD-II, the risk of
conversion in youth presenting with the BD-NOS
phenotype was 51% over four years, compared to
30% among BD-NOS patients with no family
history of BD.
Major depressive disorder (MDD) and cyclo-
thymic disorder also occur disproportionately in
children who later develop BD. Geller et al. (5)
found that 33% of children (mean age = 10.3
years) with prepubertal-onset MDD developed
BD-I by a 10-year follow-up, compared to none
of a group of matched healthy controls. Strober
and Carlson (6) found that 20% of adolescents
with MDD developed BD-I over 3–4 years, espe-
cially if they had a positive family history of BD,
rapid symptom onset, and psychosis. A two-year
prospective study in France found that among 80
youth (age 7–17 years) with MDD, 35 (43%)
converted to BD-I or BD-II (7). In that same
study, children with cyclothymic presentations
were highly likely (64%) to experience at least
one full-blown hypomanic or manic episode within
two years, as compared to only 15% without
cyclothymic presentations (7).
Given the observed trajectories of early-onset
forms of bipolar spectrum disorder, it is reasonable
to assert that without early intervention, the social
and emotional development of high-risk youth
may be seriously compromised. Accordingly, inter-
ventions designed to reduce aective morbidity and
functional impairment in the high-risk period may
prevent the progression to full BD-I or BD-II and
have a dramatic, favorable impact on individual
suering.
Pharmacological treatments for the prodrome
of BD are few and have not produced conclusive
results (8–10). Psychosocial interventions, partic-
ularly those involving psychoeducation and skill
training, may provide a treatment alternative for
children at risk for BD, especially in cases where
the youth decline medications or experience
significant side eects. Several studies indicate
that family-focused therapy (FFT) and multifam-
ily psychoeducation groups are eective in alle-
viating mood symptoms, preventing recurrences,
and enhancing psychosocial functioning among
adult (11, 12), adolescent (13), and child BD
patients (14, 15). Recent studies also suggest that
youth at high risk for bipolar spectrum disor-
ders—including those with depressive spectrum
disorders with transient manic symptoms or
severe emotional dysregulation—benefit from tar-
geted psychoeducational therapy or behavior
modification approaches (14, 16, 17). Notably,
Nadkarni and Fristad (17) found that multifam-
ily psychoeducation groups exert a protective
eect on conversion to bipolar spectrum disor-
ders among children with depressive spectrum
disorders.
Using an open-trial design, the current study
tested whether a brief (four-month), modified
version of FFT (i) was acceptable to youth and
families, (ii) was associated with high treatment
adherence and competence by clinicians at two
study sites, and (iii) promoted symptom stabiliza-
tion and enhanced functioning over one year
among high-risk youth. The FFT was designed to
reduce stress, conflict, and aective arousal among
youth and family members through enhancing
knowledge about emotional regulation strategies,
eective communication skills, and strategies for
solving and implementing solutions to family or
peer problems.
Materials and methods
Participants
Children between the ages of 9 years, 0 months,
and 17 years, 11 months were recruited at Stanford
University and the University of Colorado to
participate in a one-year open trial of FFT adapted
for youth at high risk for BD (FFT-HR), con-
ducted between 1 September 2007 and 31 August
2008. Referrals originated from community prac-
titioners, parent support groups, primary care
doctors, and inpatient settings. After receiving a
description of the study procedures, all participat-
ing children and parents read and signed Univer-
sity IRB-approved assent and consent forms.
Miklowitz et al.
68
Page 2
Eligibility criteria for the youth were as follows:
(i) English speaking; (ii) at least one biological
parent with BD-I or BD-II according to the DSM-
IV-TR (18); (iii) meeting DSM-IV criteria for a
lifetime diagnosis of BD-NOS, MDD, or cyclothy-
mic disorder. Diagnosis of the biological parent
was confirmed by direct interview using the Mini-
International Neuropsychiatric Interview (MINI)
(19). The parent!s diagnosis did not have to be
active or treated. BD-NOS required a distinct
period of abnormally elevated, expansive, or irri-
table mood plus two (three, if irritable only) DSM-
IV symptoms of mania that caused a change in
functioning, lasted for at least four hours in a day,
and were present for a total of at least four days
in the child!s lifetime, even if the days were not
consecutive (3). Cyclothymia required at least one
year with numerous periods of both hypomanic
symptoms and depressive symptoms that did not
meet full MDD or mania criteria. If the main
diagnosis was MDD, the youth must have had a
full DSM-IV depressive episode within the previ-
ous two years (20). Lastly (iv), the youth had to
have significant aective symptoms as determined
by a current Young Mania Rating Scale (YMRS)
(21) score > 11 or a current Children!s Depression
Rating Scale, Revised (CDRS-R) (22) score >29.
Controversy surrounds the use of the BD-NOS
category and its relation to BD-I and BD-II (2–4).
Youth who meet the operational criteria for BD-
NOS show levels of functional impairment com-
parable to youth with BD-I and BD-II (4). When
they also have a parent with BD, they are at
substantially heightened risk for developing BD-I
or BD-II (3). Thus, youth with BD-NOS are an
appropriate population with whom to investigate
an early intervention program focused on the
prevention of syndromal conversion.
Diagnostic evaluation
Children!s diagnoses were evaluated using the
Washington University version of the Schedule
for Aective Disorders and Schizophrenia for
Children (WASH-U-KSADS) (23) and the
KSADS-Present and Lifetime Version (KSADS-
PL) non-mood supplements (24, 25). The time
frame of the WASH-U-KSADS and KSADS-PL
was lifetime, with current episode ratings based on
the worst 1–2 weeks in the prior four months. Both
sites had master!s-level social workers, clinical
psychologists, or child psychiatrists who were
trained and reliable in administering the KSADS,
MINI, YMRS, CDRS-R, and the Adolescent
Longitudinal Interval Follow-up Evaluation
[A-LIFE (26); see below]. At each site, board-certified
psychiatrists conducted separate diagnostic evalu-
ations with the youth and parents; final diagnoses
were based on a consensus among all sources of
information. Inter-rater reliability on the WASH-
U-KSADS at Stanford was consistently j > 0.90
at the item level. Reliability among 11 Colorado
raters for KSADS depression items was 0.89 and
for mania items 0.97. Cross-site reliability between
diagnosticians at Colorado and Stanford for
symptom presence absence was 94% for KSADS
depression items and 91% for mania hypomania
items.
Longitudinal assessment protocol
All follow-up interviews were conducted by an
independent evaluator (IE) who was not involved
in the patient!s treatment. The A-LIFE, the
primary outcome instrument, is a semistructured
interview that yields psychiatric status ratings
(PSRs) on 1–6 scales for each week of a follow-
up period and covers the severity of mania,
hypomania, MDD, patterns of cycling, and evi-
dence of significant departures from baseline mood
states. The IE started by rating retrospectively each
of the 16 weeks prior to the initial evaluation, and
then rating prospectively each week of follow-up,
based on separate interviews of the youth and
parents every four months postbaseline. A weekly
1–7 rating of global functioning was also obtained
from the A-LIFE Psychosocial Schedule at base-
line (covering the prior 16 weeks) and every four
months thereafter.
Secondary outcome instruments administered at
baseline and every four months during the study
year included the YMRS, an 11-item parent and
child interview. Severity of YMRS items range
from 0–4 or 0–8, and the maximum attainable
score is 60. The clinician-rated CDRS-R, which
assesses the presence and severity of 17 depressive
symptoms, consists of a brief interview adminis-
tered to parents and children separately, with
consensus ratings based on both sources of infor-
mation. The YMRS covered symptoms over the
previous week and the CDRS-R the previous two
weeks. Finally, at each research follow-up visit,
parents filled out the Beck Depression Inventory-II
(27) regarding their own mood states over the past
two weeks.
Structure of FFT-HR
The modified FFT-HR consisted of 12 sessions
over four months (8 weekly, 4 biweekly). During
the remainder of the study year, the clinician could
oer monthly booster sessions to help the family
Youth at risk for bipolar disorder
69
Page 3
solidify new coping skills. The objectives of FFT-
HR are to assist high-risk youth and their family
members (i.e., parents, siblings) in: (i) recognizing
the prodromal symptoms of depressive or
manic hypomanic episodes; (ii) distinguishing sig-
nificant mood dysregulation from developmentally
appropriate emotional reactivity; (iii) identifying
stress-related triggers of mood swings; (iv) enhanc-
ing family communication and problem solving;
and (v) developing prevention plans to avert mood
escalations or deteriorations. In each FFT-HR
module there are opportunities for youth and
family members to learn behavioral strategies to
modulate aective intensity and duration, espe-
cially when feeling provoked by other family
members. In this manner, the treatment attempts
to address the negative interactional patterns often
associated with home environments with high
expressed emotion (EE)—i.e., highly critical, hos-
tile, or overprotective (28).
Psychoeducation (Sessions 1–4). The first two
sessions of psychoeduction acquaint the proband
and family with the goals of FFT-HR and the signs
and symptoms of mood disorders. The treatment
objectives are described as: improving the child!s
ability to regulate emotions, enhancing day-to-day
functioning, and improving the emotional climate
of the family. The youth is asked to describe his or
her experiences with depression or, if relevant,
hypomanic symptoms or comorbid disorders,
whereas parents or siblings share their perceptions
of how the youth!s mood or behavioral changes
have aected the family. The parent with BD is
asked to explain to the child, to the extent that
he or she is comfortable, the nature of BD and how
the parent has come to terms with his or her own
diagnosis.
In session 3, the participants identify stressors
currently aecting the youth, such as negative
family interactions and peer or romantic relational
conflicts. Youth are encouraged to monitor their
daily moods and sleep wake rhythms using a daily
mood chart. Clinicians explain the nature of risk
factors (e.g., alcohol or drug usage, provocative
interpersonal interactions) and protective factors
(e.g., regular sleep rhythms, eective family com-
munication).
In session 4, the family develops a "mood
management plan! to list medical and behavioral
strategies to implement if the child!s mood, sleep,
or thinking patterns start to change. The plan
typically involves reducing interpersonal stress at
home, stabilizing sleep rhythms, and, where appro-
priate, adjusting medications. Emotion regulation
skills, to be initiated when participants identify the
first signs of negative emotional arousal in them-
selves or others, may include relaxation or mind-
fulness exercises, distraction, or adaptive self-talk.
Communication enhancement training (Sessions 5–
8). Communication enhancement training is
guided by the assumption that aversive communi-
cation and high EE reflect distress within the
family in its attempts to cope with mood disorder
in one or more family members (29). During this
module, families become acquainted with four
skills: expressing positive feelings, active listening,
making positive requests for change, and express-
ing negative feelings. Through role-play skills
training exercises and between-session homework,
participants learn to (i) "down-regulate! impulsive
expressions of negative emotions through pausing
and putting dicult feelings into words; (ii) com-
municate in a manner that does not trigger or
exacerbate emotional dysregulation in others; and
(iii) shift attention from negative or destructive
emotions to more conciliatory emotional states.
Problem-solving skills training (Sessions 9–
12). Problem-solving skills training is used to
encourage families to identify dicult problems,
break down large problems (e.g., ‘‘we don!t get
along’’) into smaller ones (‘‘we need to lower our
tones of voice’’), generate lists of solutions and
evaluate the pros and cons of each, and choose one
or more solutions to implement (e.g., ‘‘alert each
other when voice tones are becoming aggressive’’).
Topics often addressed in problem solving include
the youth!s diculties getting along with siblings,
chaotic sleeping or eating habits, school perfor-
mance, and irritable outbursts.
Youth with or at risk for early-onset BD often
have mood or behavior problems that interfere
with their ability to solve interpersonal problems
(30). Problem solving allows the child and family
members to express emotionally charged informa-
tion within a structured context and to manage
familial conflicts with adaptive self-talk, distrac-
tion, or negotiation techniques in place of shout-
ing, hurling insults, or becoming assaultive.
Modification of the FFT-HR manual for younger children
We modified the FFT treatment for children
between 9 and 12 years, including using simplified
handouts that emphasized visual stimuli (e.g.,
mood charts with facial images portraying emo-
tional states), flipcharts to explain key concepts,
and flexible session structures. Parents played more
active roles in directing younger children during
in-session role-playing tasks or weekly homework
Miklowitz et al.
70
Page 4
assignments, whereas adolescents were given more
autonomy in these tasks.
Data analyses
Statistical analyses tested a specific hypothesis:
high-risk youth undergoing the 12-session course
of FFT-HR would show reductions in mood
symptom severity over one year. We used mixed-
eects regression modeling with random slope
random intercept assumptions (31) to assess with-
in-group changes in the primary outcome variables
(A-LIFE weekly PSR ratings for depression and
hypomania) and secondary outcome variables
(CDRS-R and YMRS ratings made every four
months, A-LIFE weekly functioning ratings) as a
function of time. All longitudinal analyses were
conducted by intent-to-treat. Assuming a one-year
follow-up, the sample size of 13 had power of 0.76
to detect a large eect (i.e., R
2
= 0.40) for changes
in symptom scores (a = 0.05).
Results
Sample composition
The 13 patients recruited for this study were drawn
from 72 referrals to the Stanford (n = 47) and
Colorado (n = 25) sites (see Fig. 1). The Stanford
site was simultaneously recruiting for another
study of children of BD parents with or without
active symptoms, and thus obtained more referrals
than the Colorado site. The most frequent reason
for ineligibility at both sites was that neither of the
youth!s parents, upon evaluation with the MINI,
met DSM-IV criteria for BD-I or BD-II (n = 28).
The 13 youth (8 Colorado, 5 Stanford) ranged in
age from 9 to 16 years (mean 13.4 ± 2.69); 4
(30.8%) were boys and 9 (69.2%) were girls.
Eleven youth were Caucasian and 2 were of
Hispanic ethnicity; one was of mixed race. Of the
13, 7 (5 with MDD, 2 with BD-NOS) had a major
depressive episode lasting at least two weeks within
the four months prior to study entry (Table 1). All
participants were actively symptomatic at study
entry; the mean YMRS score for the sample was
13.88 ± 7.65 and the mean CDRS-R score was
39.36 ± 8.58. Of the 13, 9 scored 12 on the
YMRS and 12 scored 29 on the CDRS-R,
indicating clinically significant symptoms of
(hypo)mania and depression, respectively. None
met the DSM-IV-TR criteria for a manic or mixed
episode at study entry.
The parent with BD and any other parent who
lived with the child were invited to participate in
FFT-HR sessions, and all but two parents agreed.
In all but one of the families, a healthy co-parent
also participated; in a single case, the child
participated only with his mother with BD-I. Beck
Depression Inventory-II scores among parents at
entry into the four-month FFT-HR protocol
averaged 11.8 ± 9.7, indicating low levels of
depression but with considerable range (from 2
to 37).
Therapy adherence
Families attended a mean of 11.85 ± 5.18 (range
0–19) FFT-HR sessions. One family never
appeared for the first session, and one had only 3
sessions; the remainder (n = 11) attended 9 or
more sessions. Two cases—both with fathers with
BD (one with BD-I, one with BD-II)—were
classified as study withdrawals (15%) and 11 were
classified as completers (85% retention). All 13
Phone screens (n = 72)
Stanford 47
Colorado 25
13 included:
Stanford 5
Colorado 8
Refusal/did not call back (n = 8)
Excluded on basis of diagnosis (n = 11)
No first-degree relative with BD (n = 28)
Did not meet other inclusion criteria
(n = 12)
11 completed treatment
Fig. 1. CONSORT diagram. BD = bipolar disorder.
Table 1. Child and family characteristics
Child diagnoses
Major depressive disorder 8 (61.5)
Cyclothymic disorder 1 (7.7)
Bipolar disorder NOS 4 (30.8)
Parent diagnoses
Biological mother with BD-I 6 (46.2)
Biological mother with BD-II 1 (7.7)
Biological father with BD-I 2 (15.4)
Biological father with BD-II 4 (30.8)
Youth lives with
Both biological parents 8 (61.5)
Both biological parents in separate households 2 (15.4)
Biological mother only 1 (7.7)
Biological father only 1 (7.7)
Biological mother and partner 1 (7.7)
Values are presented as n (%).
NOS = not otherwise specified; BD-I = bipolar I disorder;
BD-II = bipolar II disorder.
Youth at risk for bipolar disorder
71
Page 5
families were oered monthly "booster! sessions
after the 12-session protocol, and 8 attended. Two
families attended one extra session, 5 attended 2–4
booster sessions, and one attended 7 booster
sessions. The mean duration of research follow-
up from study entry to study exit was 53.7 ±
30.5 weeks.
Participants were permitted to continue with
their individual therapy if they were enrolled in
such treatment prior to the study. Of the 13 cases,
3 (23.1%) opted to continue in individual therapy
during the four-month FFT protocol.
Youth attended a mean of 3.69 ± 4.29 (range
0–15) pharmacological management sessions dur-
ing the year. They entered the study on a variety of
medication regimens, and in most cases the study
psychiatrists did not significantly alter these regi-
mens during the course of the study. Of 8 partic-
ipants with MDD: 1 was treated with an
antidepressant only, 2 with atypical antipsychotics,
1 with lamotrigine, and 1 with the combination of
lithium, an antidepressant, and a typical antipsy-
chotic; 3 were not taking any medications. Of the 4
youth with BD-NOS: 2 were treated with stimu-
lants alone, 1 with an antidepressant alone, and 1
with the combination of lithium, valproate, que-
tiapine, and an antidepressant. The single youth
with cyclothymic disorder was treated with a
psychostimulant and an antidepressant.
Therapist training and fidelity
Two expert trainers (DJM, ELG) conducted an
eight-hour seminar at a study launch meeting to
familiarize new clinicians with the FFT-HR man-
ual and provided monthly group supervision ses-
sions for the remainder of the trial. Independent
raters assessed fidelity to the FFT-HR manual
using the Treatment Competence and Adherence
Scale, Revised (TCAS-R) (11, 32), which includes
13 adherence skill items rated from 1 (poor) to 7
(excellent), followed by 27 items rated from 0–3,
measuring specific treatment strategies, therapeutic
style, nonspecific factors, and proscribed tech-
niques. The clinicians from Stanford and Colorado
did not dier in overall adherence competence
ratings (range 1–7) measured throughout the study
(Colorado, mean = 6.2 ± 1.2; Stanford, mean =
5.6 ± 1.5; p > 0.10; 39 ratings). In cases where
overall adherence ratings fell below threshold (i.e.,
£ 4 on the 7-point scale), extra supervision was
given to help ensure skillful application of the
manual.
Clinical outcomes
Youth showed substantial improvements in depres-
sion PSR scores [time eect, F(1,799) = 315.62,
p < 0.0001; Cohen!s d = 1.77, SE = 0.46] and
modest improvements in hypomania PSR scores
[time eect, F(1,795) = 21.10, p < 0.0001;
d = 0.51, SE = 0.40; Table 2]. When the eects
of medications (no mood stabilizers or antidepres-
sants, n = 5; taking one or more of these, n = 8)
were covaried, there was still significant improve-
ment in depression scores [F(1,798) = 315.54,
p < 0.0001] and hypomania scores [F(1,795) =
21.26, p < 0.0001] over the study year. There were
no independent eects of medication status on
depression or mania PSR scores or any eects of
age in these models (all p > 0.10).
Of the 11 cases with one-year follow-up data,
9 changed from A-LIFE PSR depression scores of
5(severe; n = 7) or 6 (extremely severe; n = 2) to
scores of 3 (moderate; n = 4), 2 (mild; n = 1) or
1(asymptomatic; n = 4) by the year!s end. Two
participants began with moderately severe depres-
sion (ratings of 4) and were moderately or mildly
depressed by year!s end.
Participants showed moderate improvement
on the CDRS-R from baseline to 12 months
[F(1,40) = 6.73, p = 0.013; d = 0.63, SE =
0.40] and more significant improvement on the
YMRS [F(1,33) = 12.98, p < 0.001; d = 1.15,
SE = 0.42; Table 2]. At baseline, 9 of 13 partici-
pants (69.2%) scored 12 on the YMRS, whereas
Table 2. Symptom scores at baseline and 4, 8, and 12 months post-baseline
Measure Baseline 4 months 8 months 12 months Cohen!s d (SE) 95% CI p-value
Depression PSR score (A-LIFE) 3.95 (1.16) 2.87 (1.17) 1.87 (1.15) 2.04 (0.99) 1.76 (0.46) 0.82–2.61 0.0001
Hypomania score (A-LIFE) 1.62 (0.88) 1.38 (0.82) 1.40 (0.84) 1.26 (0.49) 0.51 (0.40) )0.29–1.27 0.0001
CDRS-R 39.36 (8.58) 36.80 (5.45) 28.22 (4.49) 32.89 (11.63) 0.63 (0.40) )0.17–1.40 0.013
Young Mania Rating Scale 13.88 (7.65) 13.30 (10.05) 9.67 (7.47) 6.22 (5.52) 1.15 (0.42) 0.29–1.94 0.001
Global functioning (A-LIFE) 3.60 (1.17) 2.92 (0.89) 2.45 (1.33) 2.02 (1.05) 1.42 (0.44) 0.52–2.23 0.0001
Scores are presented as mean (SD).
CI = confidence interval; PSR = psychiatric status rating; A-LIFE = Adolescent Longitudinal Interval Follow-up Evaluation; CDRS-
R = Children!s Depression Rating Scale–Revised.
Miklowitz et al.
72
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only 1 of 11 (9.1%) was above this clinical
threshold at one year. Finally, youth showed
significant improvements in weekly global func-
tioning ratings on the A-LIFE [F(1,141) = 28.05,
p < 0.0001; d = 1.42, SE = 0.44]. There were no
eects of age on CDRS-R, YMRS, or global
functioning scores (all p > 0.10).
Of the 13 youth, only 1 with a diagnosis of BD-
NOS developed a manic episode during the one-
year interval. This child, who entered the study
during a major depressive episode, became ill at
week 22 of the follow-up and remained ill for
11 weeks. This rate of conversion to BD-I or BD-
II (25%) among BD-NOS youth with a parent
with BD is comparable to the one-year conversion
rate of 26.6% among BD-NOS positive family
history youth in the Course and Outcome of
Bipolar Illness in Youth study (3). Additionally, 2
participants (15.4%) had recurrences of major
depression after recovering from the major depres-
sive episode that had brought them into the study.
One had an eight-week episode starting at
28 weeks and the other a two-week episode start-
ing at 50 weeks.
Discussion
This article described a one-year treatment devel-
opment trial of an adapted version of FFT for
youth who were at high risk of developing BD-I or
BD-II. The results suggest that FFT-HR is feasible
to administer in this population and associated
with a high rate of treatment retention (85%).
Clinicians at both study sites showed high levels of
fidelity to the treatment manual. Moreover, youth
who participated in FFT-HR showed significant
reductions in depression and hypomania symptoms
and improvements in global functioning over one
year.
Family psychoeducation may augment individ-
ual and family coping skills and protect high-risk
youth from family stress or other life stressors that
would otherwise contribute to their overall vulner-
ability to disease onset. Youth with adverse parent-
child relationships are vulnerable to more severe
depressions when under chronic stress than are
youth with healthier parent-child relationships
(33). The skill-training modules of FFT attempt
to ameliorate the impact of high-EE attitudes and
behaviors in families, including aversive commu-
nication between parent and ospring, hostility,
low family cohesion and adaptability, and dicul-
ties with conflict resolution (28). Family psycho-
education has been shown to improve similar
dimensions of family behavior among adults with
mood disorders (29).
Because the primary goals of this study were to
determine the feasibility and acceptability of FFT-
HR, it was designed as an open trial with no
randomized control. Thus, it was not designed to
address whether family treatment is necessary to
bring about symptom reductions in high-risk youth
or whether the passage of time would have
accomplished the same result. Relatedly, this study
could not determine whether any form of psycho-
social intervention, whether or not it involved the
family, would have been associated with significant
reductions in mood symptoms. Longer-term fol-
low-up (i.e., four years or more) would be neces-
sary to determine whether the addition of FFT-HR
to usual care reduces the likelihood of syndromal
manic onset, and, in turn, whether improvements
in family aect, communication, or problem solv-
ing mediate the likelihood or timing of this
endpoint.
We also cannot rule out the explanatory eects
of medications on the observed symptom out-
comes. Although medication regimens were largely
stable during the period of study, they were also
quite variable, and the sample size precluded
examining each medication in relation to symptom
severity. For example, a larger sample would have
enabled an examination of whether psychostimu-
lants (3 13, or 23% of cases) were associated with
the emergence of manic or mixed symptoms among
high-risk youth.
Only three studies have examined whether early
intervention with mood stabilizers has preventative
eects on children at risk for BD. In an open trial,
Chang et al. (8) showed that children with sub-
threshold mood symptoms and a positive family
history of BD improved with divalproex over
12 weeks. DelBello et al. (9) reached a similar
conclusion in an open trial of quetiapine. The
single randomized, controlled trial (RCT) compar-
ing divalproex and placebo found that children
with BD-NOS or cyclothymia and at least one
biological parent with BD-I did not dier on time
to medication discontinuation due to a mood event
(10). Thus, evidence for the eectiveness of specific
forms of pharmacotherapy in high-risk youth is
quite limited. Nonetheless, in future RCTs involv-
ing psychosocial interventions, the impact of
pharmacotherapy should be examined through
implementing medication algorithms administered
by psychiatrists who are blind to psychosocial
treatment conditions.
We were unable to examine whether FFT-HR
was equally eective with youth with dierent risk
subtypes (e.g., MDD versus BD-NOS) or with
comorbid disorders that might have aected
responses to the skill-building strategies (for
Youth at risk for bipolar disorder
73
Page 7
example, attention-deficit hyperactivity disorder). We
also were unable to determine whether attributes
of the parent (e.g., whether it was the mother or
father who had BD, or whether he or she had BD-I
or BD-II) were associated with the degree of
clinical response or attrition rates.
Fortunately, randomized trials of psychother-
apy in BD and MDD youth are beginning to
unravel the role of moderators of response. For
example, we found in an earlier RCT that
adolescents with BD-I or BD-II who were in
high-EE families showed a greater magnitude of
response to FFT than adolescents in low-EE
families (28). In contrast, in the Treatment for
Adolescent Depression Study, adolescents who
described their family environments as more
negative showed a poorer response to cognitive-
behavioral therapy and a better response to
fluoxetine (34). Identifying moderators of response
in high-risk populations will be increasingly
important as the number of evidence-based treat-
ment options grows (35).
Finally, examining the impact of psychosocial
interventions on the social and academic function-
ing and quality of life of high-risk youth—dimen-
sions which are compromised substantially in this
population (4, 36)—should be a key objective of
future trials. Preventing or minimizing the toxic
and impairing eects of early episodes before they
become recurrent may help prevent the long-term
functional disability caused by bipolar illness.
Acknowledgements
Financial support for this study was provided by National
Institute of Mental Health (NIMH) grants MH077856 and
MH073871 to DJM and an Independent Investigator Award to
KDC from the National Alliance for Research on Schizophre-
nia and Depression (NARSAD). The authors thank David
Axelson, M.D., Victoria Cosgrove, Ph.D., Julia Maximon,
M.D., Kathleen Kline, M.D., Marianne Wamboldt, M.D.,
Christopher Hawkey, Tenah Acquaye, Aimee Sullivan, Erica
Weitz, Dana Elkun, Jedediah Bopp, and Jessica Lunsford for
their assistance. Copies of the treatment manual may be
obtained from DJM. LMD was the statistical consultant.
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  • Source
    • "A partir dos resultados da presente revisão, observouse que há uma diversidade das variáveis investigadas, métodos e instrumentos de avaliação utilizados, o que contribui para a impossibilidade de propor uma generalização dos resultados. Apesar disso, os estudos demonstraram eficácia em alguns aspectos, tais como, a redução dos sintomas do TB (e.g., Miklowitz et al., 2008; Fristad, 2006; Fristad et al., 2002; Miklowitz et al., 2004; Miklowitz et al., 2011), comportamentos mais adequados dos pais frente ao TB de seus filhos (e.g., Fristad et al., 2003; Fristad, 2006); melhora do relacionamento familiar (e.g., Fristad, 2006; Fristad et al., 2002); ganho de experiência, aumento do conhecimento dos pais em relação à doença e aumento do apoio familiar e social (e.g., Fristad et al., 2003; Fristad et al., 2002). Estes resultados se mantiveram após o follow-up. "
    Full-text · Article · Jan 2016
  • Source
    • "The psychotherapy treatment was either family focused therapy or a comparison treatment-as-usual administered for up to 16 weekly sessions as described in the previous publication (Miklowitz et al., 2011). Both of these treatments included psychoeducation and mood stabilization plus medication management as needed. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms. Methods: Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms. Results: At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms. Discussion: Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.
    Full-text · Article · Oct 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • Source
    • "These structured measures are applied in the present study. Regarding treatment in these at-risk states, in a recent systematic review [21] we identified three studies: an exploratory, controlled study of multi-family psychoeducational psychotherapy from the group of Fristad and colleagues [22], an open, uncontrolled easibility study of family-focussed therapy by Miklowitz et al. [23] and the subsequent randomised controlled study of the same group [24] . Treatment with the studied interventions (in addition to treatment as usual, including psychopharmacology) showed a potential for symptom reduction and prevention of conversion to BD and a significantly faster recovery from initial mood symptoms and more time in remission during follow-up compared to control conditions. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Bipolar disorders (BD) are among the most severe mental disorders with first clinical signs and symptoms frequently appearing in adolescence and early adulthood. The long latency in clinical diagnosis (and subsequent adequate treatment) adversely affects the course of disease, effectiveness of interventions and health-related quality of life, and increases the economic burden of BD. Despite uncertainties about risk constellations and symptomatology in the early stages of potentially developing BD, many adolescents and young adults seek help, and most of them suffer substantially from symptoms already leading to impairments in psychosocial functioning in school, training, at work and in their social relationships. We aimed to identify subjects at risk of developing BD and investigate the efficacy and safety of early specific cognitive-behavioural psychotherapy (CBT) in this subpopulation. Methods/Design EarlyCBT is a randomised controlled multi-centre clinical trial to evaluate the efficacy and safety of early specific CBT, including stress management and problem solving strategies, with elements of mindfulness-based therapy (MBT) versus unstructured group meetings for 14 weeks each and follow-up until week 78. Participants are recruited at seven university hospitals throughout Germany, which provide in- and outpatient care (including early recognition centres) for psychiatric patients. Subjects at high risk must be 15 to 30 years old and meet the combination of specified affective symptomatology, reduction of psychosocial functioning, and family history for (schizo)affective disorders. Primary efficacy endpoints are differences in psychosocial functioning and defined affective symptomatology at 14 weeks between groups. Secondary endpoints include the above mentioned endpoints at 7, 24, 52 and 78 weeks and the change within groups compared to baseline; perception of, reaction to and coping with stress; and conversion to full BD. Discussion To our knowledge, this is the first study to evaluate early specific CBT in subjects at high risk for BD. Structured diagnostic interviews are used to map the risk status and development of disease. With our study, the level of evidence for the treatment of those young patients will be significantly raised. Trial registration WHO International Clinical Trials Platform (ICTRP), identifier: DRKS00000444, date of registration: 16 June 2010.
    Full-text · Article · May 2014 · Trials
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