An admixture analysis of the age at index episodes in bipolar disorder

Abstract

The interaction between polarity at onset (PAO) and age at onset (AAO) appears to be important for interpreting results of previous analyses of AAO in bipolar disorder (BD). Using an admixture analysis, we examined independently the distributions of age at first depressive and hypomanic/manic episodes in 379 BD I and II patients. Subsequently, we examined the association of PAO and AAO with specific clinical variables, using parametric and nonparametric analyses. Both depressive and manic onsets showed bimodal distributions. For depressive episodes, the means were: 18.5 ± 4.1 (early onset) and 33.6 ± 10.4 (late onset) years; and for manic episodes 18.9 ± 3.3 (early onset) and 34.8 ± 10.9 (late onset) years. For the overall AAO the best fit was for a mixture of three lognormal distributions (mean ± S.D.): 15.5 ± 2.0, 22.8 ± 4.6, and 36.1 ± 10.1 years. Overall, an early onset was significantly associated with a chronic course of the disorder, a stronger family history of affective disorder, higher rates of rapid cycling, suicidal behavior, psychotic symptoms, and co-morbid anxiety disorders. Early onset depressive episodes were associated with higher rates of suicidal behavior and anxiety disorders, whereas early onset manic episodes were associated with psychotic symptoms and rapid cycling. Our results suggest the presence of a bimodal distribution of age at onset in BD according to the polarity of the index episode, and denote that an early onset BD, irrespective of polarity, may be a more serious subtype of the disorder.

Introduction

Bipolar disorder (BD) is a major, recurrent, mood disorder characterized by alternating episodes of mania and depression. It has an overall prevalence of 1% in the general population, and typically manifests in late adolescence or early adulthood (McElroy et al., 2001, Weissman et al., 1988). Age at onset (AAO) has been proposed as a variable that may distinguish more homogeneous subgroups in BD. An early onset BD has been associated with a chronic course of the illness, co-morbid substance abuse, higher rapid cycling rates, higher number of mixed episodes, higher co-morbidity with anxiety disorders, poorer lithium prophylactic response, higher rates of suicidal behavior, and poor overall outcome (Ernst and Goldberg, 2004, Lin et al., 2006, Schurhoff et al., 2000). More recently, an early age at onset has also been associated with higher affective lability (Henry et al., 2008). In contrast, late-onset BD has been linked to more significant thought disorder and a history of concurrent vascular disease (Hays et al., 1998, Patel et al., 2006). An important limitation of these studies, however, is the use of cutoff points, with arbitrary definitions of early and late-onset (Carter et al., 2003, Ernst and Goldberg, 2004, Goldstein and Levitt, 2006, Hays et al., 1998, Leboyer et al., 2005, Lin et al., 2006, Sax et al., 1997), making it difficult to draw unequivocal conclusions.

Age at onset appears to correlate negatively with the genetic risk: early onset BD has been associated with an increased morbid risk for affective disorders among first-degree relatives, suggesting that early and late-onset BD may have differential familial loading (Leboyer et al., 2005, Schurhoff et al., 2000). These findings have led to speculation that age at onset could define subgroups of BD with distinct etiologies and genetic liability. The efforts to define subgroups in BD according to age at onset have typically found three subgroups—early, intermediate, and late onset (Bellivier et al., 2001, Bellivier et al., 2003, Benazzi, 2004, Hamshere et al., 2009, Manchia et al., 2008), although a two-component distribution has been described for the age at onset of mania exclusively (Kennedy et al., 2005).

Studies have shown that polarity of the index episode may be associated with future course of illness and particular clinical features. Percentage estimates of the proportion of BD patients whose illness starts with a depressive index episode range between 21% and 66% (Goodwin and Jamison, 2007, Roy-Byrne et al., 1985), even when controlling for misidentified hypomanic/manic symptoms. Several studies have reported that depressive polarity at onset is more frequent in women (Angst, 1978, Forty et al., 2009, Perlis et al., 2005), and has been associated with higher number of depressive episodes (Forty et al., 2009, Perlis et al., 2005, Perugi et al., 2000), higher risk of suicide attempts (Azorin et al., 2009, Forty et al., 2009, Perlis et al., 2005, Perugi et al., 2000), rapid cycling (Perugi et al., 2000), family history of major depression (Perugi et al., 2000), co-morbid anxiety disorders (Chaudhury et al., 2007, Colom et al., 2006, Kleindienst et al., 2007, Perlis et al., 2004, Perugi et al., 2000, Rosa et al., 2008), and earlier age at onset (Forty et al., 2009, Perlis et al., 2004, Perlis et al., 2005); whereas the presence of drug abuse and psychotic symptoms has been associated with manic index episodes (Calabrese et al., 2004b, Rosa et al., 2008). Consequently, it has been suggested that polarity at onset may reflect the predominant episode polarity for individual patients and may be a predictor of polarity for subsequent episodes (Calabrese et al., 2004a, Perlis et al., 2005).

Analyzing the interaction between polarity at onset and age at onset can be useful for re-interpreting previous data on age at onset in BD. In this paper, we investigated the overall age at onset of bipolar disorder, age at first depressive episode and age at first manic/hypomanic episode, in a large population of bipolar patients and studied the clinical characteristics associated with age at onset and polarity of onset.