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