Elsevier

Journal of Affective Disorders

Volume 235, 1 August 2018, Pages 348-356
Journal of Affective Disorders

Research paper
Early intervention for adolescents at-risk for bipolar disorder: A pilot randomized trial of Interpersonal and Social Rhythm Therapy (IPSRT)

https://doi.org/10.1016/j.jad.2018.04.049Get rights and content

Highlights

  • Interpersonal and Social Rhythm Therapy (IPSRT) is feasible and acceptable to deliver to youth at high risk for bipolar disorder by virtue of a first-degree family history of the illness.

  • Few youth referred for community mental health services at intake initiated services over 6 month follow-up, highlighting the need for engagement efforts with this population.

  • No youth developed new-onset mood disorder over follow-up. Self- and parent-reported mood and non-mood psychiatric symptoms did not distinguish youth receiving IPSRT + Data-Informed Referral (DIR) for any psychiatric disorders present at baseline versus DIR-alone.

  • Per clinician ratings, 1 youth receiving IPSRT + DIR displayed subthreshold hypo/manic symptoms, versus 2 receiving DIR-alone over 6-months, possibly signaling less subthreshold hypo/manic symptoms, and for fewer weeks.

  • Although no self-reported measure of sleep distinguished the groups, we found a small effect for youth in the IPSRT + DIR group to evidence more wake after sleep onset (WASO; an index of sleep continuity) via actigraphy over follow-up.

Abstract

Objective

To conduct a pilot randomized trial of Interpersonal and Social Rhythm Therapy plus Data-Informed Referral (IPSRT + DIR) versus DIR-alone for adolescents at-risk for bipolar disorder (BP).

Method

Eligible participants included youth (12–18) with a BP parent; youth with BP were excluded. Participants (n = 42) were randomized to receive IPSRT + DIR to treat any psychiatric disorders present at baseline, or DIR-alone. A blind evaluator assessed outcomes at baseline, 3- and 6-months. Participants wore an actigraph to measure sleep/wake patterns for 7 days at baseline and 6-months. Primary outcomes included mood and non-mood symptoms and sleep disturbance.

Results

Youth randomized to IPSRT + DIR attended approximately half of scheduled IPSRT sessions. Although 33% of DIR-alone youth were referred for mental health services at intake (another 33% were already engaged in services), none initiated new services over follow-up. No youth developed new-onset mood disorder over follow-up. Self- and parent-reported mood and non-mood psychiatric symptoms did not distinguish the groups, although youth in DIR-alone tended to have higher baseline scores on most measures. Per clinician ratings, 1 youth receiving IPSRT + DIR displayed subthreshold hypo/manic symptoms, versus 2 receiving DIR-alone (OR = 14.7, p = 0.03), possibly signaling less subthreshold hypo/manic symptoms, and for fewer weeks (χ2= 11.06, p = 0.0009), over 6-months with IPSRT + DIR. We found a small effect for youth in the IPSRT + DIR group to evidence more WASO at pre-treatment, but less at follow-up (cohen's d = 0.28).

Limitations

Small sample size limits statistical power, and we are unable to definitively attribute group differences to IPSRT versus greater clinical contact. Ability to examine distal/rare (i.e., BP onset) outcomes was limited.

Conclusions

Adolescents at-risk for BP present challenges to psychosocial treatment engagement and retention. IPSRT merits further study as an acceptable intervention for at-risk youth, though necessary frequency and intensity to affect outcomes should be examined. The potential to delay or prevent subthreshold hypo/manic symptoms via enhanced sleep continuity is an area for further examination. Future studies with larger samples and extended follow-up can help determine whether IPSRT may delay or prevent syndromal hypo/mania in youth at-risk.

Introduction

Bipolar disorder (BP) is an episodic mood disorder that affects 3–5% of individuals. The illness is of substantial public health import given its elevated risk for negative outcomes including substance misuse, disability, and suicide (Goodwin & Jamison, 2007).

A positive family history of BP is the most potent risk factor for developing BP (Mortensen et al., 2003), with first-degree relatives at greatest risk. While not all individuals who develop BP have a family history, those with a family history demonstrate earlier illness onset (Singh et al., 2007). Furthermore, those with early illness onset exhibit the most severe illness course (Post et al., 2015). Studies indicate between 5 and 19% of offspring of parents with BP (OPB) develop BP themselves by young adulthood (Axelson et al., 2015, DelBello and Geller, 2001). OPB are also at greater risk for other psychiatric conditions including depression, anxiety, and behavioral disorders. Although estimates vary between studies, likely due to differing methodology (Duffy et al., 2011), up to 75% exhibit at least one axis I disorder during childhood (DelBello & Geller, 2001). In 20% of cases, other psychiatric disorders precede development of BP in OPB by young adulthood, whereas 55% display other psychiatric conditions but do not develop BP by young adulthood (Axelson et al., 2015). Thus, OPB represent a readily identifiable population at ultra-high risk for early onset of psychiatric disorder, and specifically BP.

Intervention for OPB has the potential to alleviate early psychiatric symptoms, delay illness onset, minimize illness severity, and possibly even prevent illness onset altogether, yet little is known about effective interventions for this population. “Clinical staging models” of chronic medical disease management are increasingly being applied in the field of psychiatry, whereby interventions are matched with individuals based on the individual's status along an illness continuum (i.e., high-risk, asymptomatic = 0; family history and non-specific symptoms/subthreshold manic symptoms = 1; full hypo/manic episode = 2; recurrent/chronic illness with functional impairment = 3–4). This approach asserts treatments with lower risk-benefit ratio and higher acceptability are warranted during earlier stages of illness, at which time short-term symptoms and prevention of disease progression are targeted (McGorry et al., 2006, Scott et al., 2013).

With regard to early intervention (i.e., stages 0–1), results from psychopharmacological studies are mixed (DelBello et al., 2007) and concerns regarding use of medications with potentially concerning side effects in minimally symptomatic youth exist. Psychosocial treatment may mitigate the effects of biopsychosocial factors that contribute to risk (e.g., sleep, stress), and may be more acceptable to youth and families in early illness stages (McHugh et al., 2013, Scott et al., 2012, Vallarino et al., 2015). Yet, the only psychosocial intervention specifically evaluated for adolescent OPB to date is Family Focused Therapy for High-Risk Children (FFT-HR). FFT-HR targets OPB age 9–17 with active mood symptoms, and a diagnosis of BP Not Otherwise Specified (NOS), cyclothymia, or depressive disorder. A small randomized trial showed more rapid recovery from mood symptoms, more weeks in remission, and less mania symptoms over follow-up among OPB who received FFT-HR versus an educational control (Miklowitz et al., 2013). Nadkarni and Fristad (2010) also reported lower rates of conversion to BP among depressed youth who received their multi-family psychoeducational intervention, although this sample was not expressly selected for biological risk. These studies included youth who had already developed mood disorders. Ongoing trials of other treatment approaches for youth at-risk for BP, including group CBT, individual CBT, and Mindfulness-based CBT, are pending (Vallarino et al., 2015). Thus, there are currently no other available data on psychosocial intervention for high-risk youth who do not already meet criteria for a BP spectrum or mood disorder (i.e., stage 0 or 1). Experts identify this as a high priority area, particularly amidst interest in clinical staging models for classifying and treating BP (Benarous et al., 2016, Vallarino et al., 2015).

In the experimental therapeutics approach to treating and preventing mental disorders (Report of the National Advisory Mental Health Council's Workgroup, 2010), a measurable target, or “mechanism of action” hypothesized to underlie the cause of a disorder and/or a treatment's efficacy is identified and engaged. In BP, neurobiological risk markers (i.e., endophenotypes) for course and outcome among OPB are being explored (e.g., genes, brain function) (Chang et al., 2006), yet no evidence to date supports their ability to predict illness trajectories. Another promising endophenotype for BP involves abnormalities of the sleep and circadian systems. The instability model of BP (Goodwin & Jamison, 2007) posits that aberrant circadian genes and their modulation underlie the pathophysiology of the illness. Indeed, dysregulated sleep is a core symptom of manic and depressive episodes in BP, and sleep frequently remains disrupted between episodes (Geoffrey et al., 2014). Sleep disturbance is also a pathway to recurrence in biologically vulnerable individuals (Kasper & Wehr, 1992).

Sleep studies in OPB indicate that sleep and circadian dysregulation are risk markers for BP. As compared with controls, adolescent OPB report more variable sleep duration and timing (Stoleru et al., 1997), more severe and persistent sleep problems (Giles et al., 2007), later bedtimes (Levenson et al., 2015), greater sleep fragmentation and efficiency via actigraphy (Ankers & Jones, 2009), and more REM sleep disturbances via EEG (Friess et al., 2008). In one sample of OPB, the most common non-affective disorder preceding a mood disorder was a sleep disorder (Duffy et al., 2007); in another, baseline sleep variables, including frequent nighttime awakenings and inadequate sleep, predicted development of BP over follow-up (Levenson et al., 2015). Critically, sleep and circadian disturbances are modifiable risk factors, rendering them promising targets for early intervention among OPB.

Furthermore, recent studies document epic rates of sleep deprivation and circadian dysregulation among adolescents generally, attributable to an interaction between biological and psychosocial factors unique to this developmental stage (Keyes et al., 2015). Such sleep disturbances during adolescence are linked to risk for a host of negative outcomes including substance use, automobile accidents, and obesity (Carskadon et al., 2004). Perhaps most alarming is the association between sleep disturbance and suicide in adolescents (Goldstein et al., 2008). Sleep is therefore a critical domain for intervention that may underlie multiple negative health-related outcomes.

Sleep and social rhythms may become disrupted via stressful life events. Among OPB, the family environment, characterized by high levels of conflict, can serve as a stressor (Miklowitz & Chang, 2008); family conflict positively correlates with severity of offspring psychopathology (Grgoroiu-Serbanescu et al., 1989). Households with a parent with BP also exhibit less cohesion and organization than normative households (Grgoroiu-Serbanescu et al., 1989), possibly contributing further to offsprings’ irregular social rhythms. In the face of such environmental stress, social support serves a protective function (Heponiemi et al., 2006). Yet, OPB report less social support (Pellegrini et al., 1986). Therefore, additional social support, particularly around the stressful circumstance of having a parent with BP, may be protective for OPB.

Interpersonal and Social Rhythm Therapy (IPSRT)(Frank, 2005) is an intervention developed for adults with BP. IPSRT is based on the Social Zeitgeber theory (Ehlers et al., 1993), and builds on interpersonal psychotherapy for depression (IPT) (Klerman et al., 1984), emphasizing the connection between mood symptoms and stress from interpersonal relationships. The central IPSRT treatment goal is to regularize daily rhythms and facilitate good sleep hygiene to promote mood stability. In adults, IPSRT is associated with more regular social rhythms (Frank, 2005) and depressive remission (Miklowitz et al., 2007). Hlastala and Frank adapted IPSRT for adolescents with BP. An open study indicates mood and functional improvement with treatment (Hlastala et al., 2010). Based on these encouraging results, we modified the adolescent IPSRT model for adolescent OPB who are at-risk for BP (but have not yet developed BP themselves) targeting sleep, social rhythm disturbance, psychoeducation and support around parental BP. Results from our open trial (n = 13) (Goldstein et al., 2013) indicate challenges to initial engagement, but high satisfaction with the model, and change in select sleep/circadian patterns (i.e., less weekend oversleeping) with treatment.

As a next step, we conducted a pilot randomized trial of IPSRT plus referral for community treatment for any psychiatric conditions identified through intake psychiatric assessment (i.e., Data-Informed Referral, DIR) versus DIR-alone for adolescent OPB. In keeping with our prior work, we included OPB who have not yet developed BP but may be exhibiting symptoms of other psychiatric disorders. We hypothesized that at-risk youth receiving IPSRT + DIR would demonstrate: (1) less severe mood and non-mood psychiatric symptoms; and (2) more regular sleep and social rhythms (via objective and subjective measures).

Section snippets

Study design overview

All participants received a thorough assessment of psychiatric and sleep disturbance at intake, followed by a feedback session (Fig. 1). All youth were offered DIR as clinically indicated for any psychiatric symptoms/disorders identified at intake. Youth were then randomly allocated (see Stratified Randomization) to also receive either IPSRT or no IPSRT. We carefully considered the selection of a control condition in the trial. Data support great heterogeneity in both type and severity of

Study sample

Sample demographic and clinical characteristics can be seen in Table 1. The sample included 42 OPB with a mean age of 14 (50% male). Thirty-two (76%) participants met criteria for at least one lifetime psychiatric disorder, and 27 (64%) had at least one current psychiatric disorder. Although there were no statistically significant between-group differences on any of the intake demographic or clinical variables examined (p > 0.1 for all), in general, the DIR-alone group tended to have higher

Discussion

The ability to delay or prevent onset of BP in individuals at high risk represents a critical area for further study. This is the first randomized trial to investigate a psychosocial intervention for youth at genetic risk of BP who are not already symptomatic of the illness. We found that recruitment and engagement of OPB for psychosocial treatment research presented unique challenges. OPB engaged in IPSRT at high rates, rendering the treatment generally acceptable. However, attendance was

Conclusions

IPSRT merits further study as an acceptable intervention for at-risk youth; critical questions regarding necessary frequency and intensity of early intervention for this population should be further explored. Furthermore, efforts to understand and target specific barriers to engagement and retention in mental health treatment in this high-risk population are warranted. These initial steps toward “preemption” of BP by employing early detection and intervention as informed by targeting biomarkers

Disclosures

Dr. Goldstein has received grant funding from NIMH, The Brain and Behavior Foundation, the American Foundation for Suicide Prevention, and receives royalties from Guilford Press. Dr. Franzen has received grant funding from NIMH, NIDA and The Brain and Behavior Foundation. Dr. Levenson has received grant funding from NHLBI, the American Sleep Medicine Foundation, and royalties from the American Psychological Association Books. Dr. Axelson has received research support from NIMH, royalties from

Acknowledgments

The authors thank study therapists Nina Hotkowski LCSW, Amy Schlonski LCSW, and Timothy Winbush LCSW; study staff Kelly Monk RN, Reality Price MA, Rachael Fersch-Podrat LCSW, Dawn Rone MA, Sarah Gratzmiller BA, Annette Wood; Joel Sherrill from NIMH; Jamie Feldman; and the staff of the Child and Adolescent Bipolar Spectrum Services (CABS) clinic. Funding: R34 (MH 091177).

Statistical Expert: John Merranko MS.

Funding Source

This work was supported by the National Institute of Mental Health (R34 MH091177; Goldstein).

References (63)

  • D. Axelson et al.

    Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study

    Am. J. Psychiatry

    (2015)
  • D.A. Axelson et al.

    A preliminary study of the kiddie schedule for affective disorders and schizophrenia for school-age children mania rating scale for children and adolescents

    J. Child Adolesc. Psychopharmacol.

    (2003)
  • X. Benarous et al.

    Early interventions for youths at high risk for bipolar disorder: a developmental apporach

    Eur. Child Adolesc. Psychiatry

    (2016)
  • B. Birmaher et al.

    Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh bipolar offspring study

    Arch. Gen. Psychiatry

    (2009)
  • M.A. Carskadon

    Adolescent Sleep Patterns: Biological, Social and Psychological Influences

    (2002)
  • M.A. Carskadon et al.

    Regulation of adolescent sleep: implications for behavior

    Ann. N.Y. Acad. Sci.

    (2004)
  • ChangK. et al.

    Prevention of pediatric bipolar disorder: Integration of neurobiological and psychosocial processes

    Ann. N.Y. Acad. Sci.

    (2006)
  • W.B. Daviss et al.

    Criterion validity of the mood and feelings questionnaire for depressive episodes in clinic and non-clinic subjects

    J. Child Psychol. Psychiatry

    (2006)
  • M.P. DelBello et al.

    A 12-week single-blind trial of quetiapine for the treatment of mood symptoms in adolescents at high risk for developing bipolar I disorder

    J. Clin. Psychiatry

    (2007)
  • M.P. DelBello et al.

    Review of studies of child and adolescent offspring of bipolar parents

    Bipolar Disord.

    (2001)
  • A. Duffy et al.

    The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents

    Bipolar Disord.

    (2007)
  • A. Duffy et al.

    Findings from bipolar offspring studies: methodology matters

    Early Interv. Psychiatry

    (2011)
  • A. Duffy et al.

    The developmental trajectory of bipolar disorder

    Br. J. Psychiatry

    (2014)
  • B. Efron

    Forcing a sequential experiment to be balanced

    Biometrika

    (1971)
  • C.L. Ehlers et al.

    Biological rhythms and depression: the role of zeitgeibers and zeitstorers

    Depression

    (1993)
  • Y. Fatima et al.

    Parent and adolescent reports in assessing adolescent sleep problems: results from a large population study

    Acta Paediatr.

    (2016)
  • First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1996. Structured Clinical Interview for DSM-IV Axis I...
  • E. Frank

    Treating Bipolar disorder: A Clinician's Guide to Interpersonal and Social Rhythm Therapy

    (2005)
  • E. Frank et al.

    Two year outcomes for Interpersonal and Social Rhythm Therapy in individuals with bipolar I disorder

    Arch. Gen. Psychiatry

    (2005)
  • E. Friess et al.

    The Munich vulnerability study on affective disorders: microstructure of sleep in high-risk subjects

    Eur. Arch. Psychiatry Clin. Neurosci.

    (2008)
  • P. Geoffrey et al.

    Sleep in remitted bipolar disorder: a naturalistic case-control study using actigraphy

    J. Affect. Disord.

    (2014)
  • Cited by (33)

    • Sleep disturbances in children and adolescents with mood disorders

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • Affective Disorders

      2022, Comprehensive Clinical Psychology, Second Edition
    View all citing articles on Scopus
    View full text