The Clinical Phenotypes of Juvenile Bipolar Disorder: Toward a Validation of the Episodic-Chronic- Distinction Gabriele Masi, Giulio Perugi, Cristina Toni, Stefania Millepiedi, Maria Mucci, Nicoletta Bertini, and Hagop S. Akiskal Background: Recent research has addressed the issue of subtyping juvenile bipolar disorder (JBD). Accordingly, we set out to find out, in a naturalistic sample of bipolar children and adolescents with mania and mixed mania, whether the most useful subtyping should be based on clinical features (elated vs. irritable) or course (episodic vs. chronic). Methods: We studied 136 patients, 81 male patients (59.6%) and 55 female patients (40.4%), mean age 13.5  2.9 years, meeting the DSM-IV diagnosis of bipolar disorder, assessed by a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version [K-SADS-PL]). Results: Regarding course, 77 patients (56.6%) had an episodic course and 59 patients (43.4%) had a chronic course. Patients with chronic course were significantly younger, had an earlier onset of JBD, and presented a more frequent comorbidity with disruptive behavior disorders. According to the prevalent mood disturbance, 75 patients (55.1%) showed an elated and 61 patients (44.9%) showed an irritable mood. Elated mood was more frequent in patients with episodic course, whereas irritable mood was more frequent in the patients with chronic course. Conclusions: These findings suggest that chronic versus episodic course may be a putative differential feature. Further validation of such a distinction would require prospective studies, temperament evaluation, gender and neurobiologic approaches, and differential psychopharmacologic assignment and response. Key Words: Bipolar disorder, mania, children, adolescents, sub- grouping, course, phenotype E ven if bipolar disorder (BD) has a well-established clinical picture in adults, formal systematic studies of juvenile bipolar disorder (JBD) are of relatively more recent vin- tage (e.g., Akiskal et al 1985; Weller et al 1986; Geller et al 1995; Lewinshon et al 1995; Biederman 1998). Reasons for such understudy include the developmentally different presentation of the early-onset form from the adult disorder (Ballenger et al 1982; Carlson 1983; Wozniak et al 1995a), as well as the high rate of comorbidity, namely with attention-deficit/hyperactivity dis- order (ADHD) (Biederman et al 1996; Carlson 1998), conduct disorder (Kovacs and Pollock 1995; Biederman et al 1999; Masi et al 2003), and multiple anxiety disorders (Masi et al 2001, 2004b; Wozniak et al 2002). Recent research suggests that JBD can be considered a specific subtype, not only in terms of genetic load and clinical picture but also in terms of treatment response (Biederman et al 2000; Schuroff et al 2000). “Atypical” presentation of early-onset mania, compared with adult “standards,” consists principally in two issues: 1) the mood presentation, with severe irritability and dysphoria rather than with euphoria, grandiosity, and elated mood; and 2) the lack of distinct cyclic course, with a subcontinuous or chronic rather than clearly episodic course (Biederman 1998; Klein et al 1998), and/or shorter episodes, and/or rapid-cycling course than in adults (Geller et al 1995; Wozniak et al 1995b; Findling et al 2001). Considering these putative discrepancies in clinical character- ization of adult and early-onset mania, recent studies have addressed the subtyping of juvenile mania according to distin- guishing clinical features. The identification of such features, which may reflect meaningful differences among groups of bipolar children and adolescents, can help to define more homogeneous groups in terms of family history, clinical presen- tation, comorbidity, course, and response to treatments. Such homogeneity may help further studies on pathophysiology and genetics of the early-onset mania. The first clinical differentiation among manic children and adolescents was between a “narrow” and a “broad” phenotype, according to the degree of fit to the full DSM-IV diagnostic criteria for adult mania (National Institute of Mental Health 2001). The narrow phenotype should be characterized by an episodic course with prominent features of elated mood, euphoria, and grandiosity, as well as other typical manic symptoms, meeting the DSM-IV duration criteria. However, atypical features are frequently reported also in concomitance with the “typical” manic picture, such as shorter episodes and partial remissions with few euthymic periods (Geller et al 1995) or short and acute worsening superim- posed on an impaired baseline (Wozniak et al 1995a). The broad phenotype is characterized by a subcontinuous rather than episodic course, irritability and dysphoria being the most prominent features, along with unstable and/or mixed mood, chronic hyperarousal (hyperactivity, distractibility, increased en- ergy, etc.), hostility and temper outbursts, often reactive to negative stimuli (Wozniak et al 1995a). This subgroup is probably not homogeneous and poses the greatest nosographic challenges (Biederman 1998; Klein et al 1998). Further research is needed for a reliable and valid diagnosis in these patients. Recently, Leibenluft et al (2003) have proposed a refinement of this categorization, including two intermediate phenotypes from the narrow to the broad. The first phenotype, called From the IRCCS Stella Maris (GM, SM, MM, NB), Scientific Institute of Child Neurology and Psychiatry, Calambrone (Pisa), Italy; Institute of Behavioral Sciences “G. De Lisio” (GP, CT), Carrara-Pisa, Italy; Department of Psychi- atry, Neurobiology, Pharmacology and Biotechnologies (GP), Psychiatry Section, University of Pisa, Pisa, Italy; and International Mood Center (HSA), Department of Psychiatry, University of California at San Diego, and Veterans Administration Medical Center, La Jolla, California. Address reprint requests to Gabriele Masi, M.D., IRCCS Stella Maris, Via dei Giacinti 2, 56018 Calambrone (Pisa) Italy; E-mail: gabriele.masi@ inpe.unipi.it. Received April 11, 2005; revised July 5, 2005; accepted August 10, 2005. BIOL PSYCHIATRY 2006;59:603– 610 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.08.034 © 2006 Society of Biological Psychiatry