Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

Early recognition and prevention in bipolar disorder (BD), particularly in youth, has gained considerable interest (1–16). The significant impairment and severity associated with BD underscores the importance of early identification and intervention (17–19). However, the concept of an identifiable clinical precursor state consisting of subsyndromal (i.e., prodromal) symptoms is still controversial for BD (20, 21). Numerous approaches have been proposed to identify those at highest risk for developing BD (3). These include studying offspring of patients with BD, focusing on youth with disorders frequently comorbid with BD [e.g., attention-deficit hyperactivity disorder (ADHD), disruptive behavior disorders] or preceding BD (i.e., major depressive disorder), assessing temperamental traits in patients with full BD, or, more recently, following patients with mania-like symptoms that are subthreshold to BD (3). Since family history arguably is the most replicated risk factor for BD, many studies focused on bipolar offspring and described their psychiatric disorders and symptom constellations (17–19, 22–33). However, these studies are limited by their cross-sectional nature, often small samples, lack of systematic assessment of symptoms or consideration of severity or change in symptoms over time. Moreover, longitudinal studies of youth at familial high-risk for BD have generally reported low rates of conversion to BD (26–29, 30, 31, 33) and largely excluded patients without a first-degree relative with the disorder. Furthermore, a significant proportion of patients with BD report no clear family history of BD, thus limiting the generalizability of family high-risk studies. Studies investigating inter-episode symptoms prior to relapse (34, 35) may also have questionable generalizability, as it is unclear whether the time course and type of prodromal symptoms are identical with early signs of initial illness manifestation. While childhood depression and ADHD have been identified as risk factors or comorbid precursor states for BD, conversion usually occurs after many years, and most of these youth do not develop BD (36–39). Studies that assessed premorbid temperament and character traits in youth and adults with BD or their offspring (40–43) reported prevalent clusters of behavioral disinhibition, mood lability, and oppositionality (10, 33, 44–46,), but these observations may not necessarily be specific to BD. To date, relatively few studies have characterized the prodrome to BD in detail (for review, see 10, 11, 15). These have included studies of adults with BD or of caregivers of children with BD (47–49), or case series of patients enrolled into a program for people at risk for psychosis who developed BD (8, 9, 50). Across these studies, the following characteristics have been identified most frequently prior to a first or relapsing manic episode: depressed mood, changes in energy level, disturbance in sleep, anger dyscontrol, argumentativeness, irritability, mood swings/lability, reckless/dangerous behavior, emotional hypersensitivity, diminished concentration, psychomotor change, social isolation, deterioration in role functioning, increased anxiety, suicidal ideation or attempts, cyclothymic-hypersensitive temperament traits and psychotic symptoms. However, some studies were limited by the lack of a systematic assessment to confirm the BD diagnosis and all employed non-standardized approaches to obtaining information about the putative prodromal phase. These assessments of the BD prodrome included the use of unstructured interviews, chart reviews or mailed surveys, resulting in the reporting of symptom frequencies without knowledge of individual symptom duration, severity or impact. The absence of reliable illness markers and information about the presence and timing of specific signs and symptoms that precede a first mania has limited the development of early interventions for high-risk samples of BD offspring who have familial risk and significant mood symptoms (51–55). Moreover, there is a paucity of data about which person (e.g., patient, parent, teacher, peer) is most likely to first notice the prodromal symptoms, which could inform the most effective psychoeducation strategies. Therefore, as a first step, and to guide future prospective studies of the bipolar prodrome, this study aimed to retrospectively, but comprehensively characterize subsyndromal symptoms preceding a first mania in youth with BD, utilizing the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R) (56). We hypothesized that a substantial number of youth would have experienced a prodrome of sufficient duration and severity with a relevant number of recognizable symptoms that emerged prior to their first syndromal manic episode allowing sufficient time for early identification and prevention efforts. We further hypothesized that some prodromal symptoms would be specific to BD, resembling subthreshold mania.