آسیب شناسی روانی در فرزندان جوان والدین مبتلا به اختلال دوقطبی: یک مطالعه مقدماتی کنترل شده

Studies have suggested that the offspring of parents with bipolar disorder are at risk for a spectrum of psychopathology, but few have focused on children in the youngest age ranges or examined the impact of comorbid parental disorders. We utilized a pre-existing sample of young (mean age: 6.8 years) offspring of parents with bipolar disorder (n = 34), of parents with panic or major depression (n = 179), and of parents with neither mood or anxiety disorder (n = 95). Children were assessed blindly to parental diagnoses using the Schedule for Affective Disorders and Schizophrenia-Epidemiologic version (K-SADS-E). Offspring of bipolar parents had significantly higher rates of disruptive behavior and anxiety disorders than offspring from both of the comparison groups, accounted for by elevated rates of ADHD and overanxious disorder. These comparisons were significant even when lifetime histories of the corresponding categories of comorbid disorders in the parents (disruptive behavior disorders and anxiety disorders) were covaried. In addition, offspring of bipolar parents had increased rates of bipolar I disorder, compared with psychiatric controls. Results support the hypotheses of elevated behavior, anxiety, and mood disorders among offspring at risk for bipolar disorder, and suggest that this psychopathology is already evident in early childhood.

1.1. Background Bipolar disorder is one of the most virulent, costly, and debilitating of psychiatric disorders (Keller et al., 1993, Prien and Potter, 1990, Solomon et al., 1995, Gitlin et al., 1995, Woods, 2000, Begley et al., 2001, Bryant-Comstock et al., 2002, Goetzel et al., 2003, Stender et al., 2002 and Judd and Akiskal, 2003), with high rates of disability (Coryell et al., 1993, Solomon et al., 1995, Tse and Walsh, 2001, Zwerling et al., 2002 and Judd and Akiskal, 2003), comorbid substance abuse (McElroy et al., 2001, Pini et al., 1999, Regier et al., 1990, Kessler et al., 1996, Brady and Lydiard, 1992 and Salloum and Thase, 2000), dysfunction (Carlson et al., 1974, Keller et al., 1992, Solomon et al., 1995 and Calabrese et al., 2003), and attempted suicide (Goodwin and Jamison, 1990, Nierenberg et al., 2001, Osby et al., 2001, Lopez et al., 2001, Dalton et al., 2003 and Tondo et al., 2003). Although bipolar disorder and its spectrum disorders are estimated to afflict approximately 1–6% of individuals (Weissman et al., 1988 and Judd and Akiskal, 2003), the disorder often goes undetected, with over a third of patients reporting at least ten years elapsing between onset of symptoms and accurate diagnoses (NDMDA-Survey, 1993). A handful of retrospective studies of bipolar adults suggest an early course marked by childhood psychopathology (Manzano and Salvador, 1993 and Winokur et al., 1993), including behavior and mood disorders. For example, Winokur et al. (1993) reported that compared to adults with unipolar depression, those with bipolar disorder were more likely to have shown traits of hyperactivity as children. Among bipolar adults, a history of childhood psychopathology has also been related to poorer functional and clinical outcomes (Carlson et al., 2002). Although these retrospective accounts are important for hypothesis-generating, prospective studies of individuals at high risk for bipolar disorder are needed to properly examine early prodromes of this disorder. Because bipolar disorder is highly familial (Gershon et al., 1982 and Rice et al., 1987), with heritability estimated at 59–87% (Bertelsen et al., 1977, Cardno et al., 1999, Kendler et al., 1993, Kendler et al., 1995 and Smoller and Finn, 2003), a rational approach to the study of early risk factors is to examine offspring of parents affected with bipolar disorder. Indeed, several studies have suggested that the offspring of parents with bipolar disorder are at increased risk in childhood for a broad range of behavioral and mood disorders, (DelBello and Geller, 2001, Cytryn et al., 1982, Decina et al., 1983, Gershon et al., 1985, Pellegrini et al., 1986, Zahn-Waxler et al., 1988, Grigoroiu-Serbanescu et al., 1989, Hammen et al., 1990, Radke-Yarrow et al., 1992, Carlson and Weintraub, 1993 and Chang et al., 2000). In a meta-analysis of 17 studies, offspring of bipolar patients were it found to show elevated rates of affective and all other psychiatric illnesses (4.0 and 2.7 times higher than controls, respectively) during childhood and adolescence (LaPalme et al., 1997). To date, nine controlled studies have focused on rates of disorder in children and adolescents at risk for bipolar disorder (Cytryn et al., 1982, Decina et al., 1983, Gershon et al., 1985, Klein et al., 1985, Zahn-Waxler et al., 1988, Grigoroiu-Serbanescu et al., 1989, Hammen et al., 1990, Radke-Yarrow et al., 1992 and Carlson and Weintraub, 1993) (see DelBello and Geller, 2001 for a review). Of these, 7 / 8 who examined the question found significantly higher rates of any psychopathology among bipolar offspring than among offspring of healthy or non-affected parents (Decina et al., 1983, Gershon et al., 1985, Klein et al., 1985, Zahn-Waxler et al., 1988, Grigoroiu-Serbanescu et al., 1989, Hammen et al., 1990 and Carlson and Weintraub, 1993); 5 / 8 found significantly higher rates of mood disorders (Cytryn et al., 1982, Klein et al., 1985, Grigoroiu-Serbanescu et al., 1989, Radke-Yarrow et al., 1992 and Carlson and Weintraub, 1993); 2 / 6 found significantly higher rates of disruptive behavior disorders (Radke-Yarrow et al., 1992) or ADHD (Grigoroiu-Serbanescu et al., 1989); and 1 / 7 found significantly higher rates of anxiety disorders (Grigoroiu-Serbanescu et al., 1989). However, these published studies have been limited in several ways (DelBello and Geller, 2001). Many had small sample sizes and were insufficiently powered to detect meaningful differences in the rates of distinct subcategories of disorders. Some did not directly assess psychopathology in both parents, did not conduct all diagnostic interviews of children blindly to parental psychopathology, or were limited in the range of disorders they assessed, e.g., focusing predominantly on mood disorders. Also, with few exceptions (Zahn-Waxler et al., 1988 and Radke-Yarrow et al., 1992), the studies of offspring at risk focused mainly upon children in late childhood and adolescence. However, to identify prodromal symptoms in a group well below the age of risk for bipolar disorder, it is necessary to study younger children. In addition, most studies compared offspring of bipolar parents only with offspring of healthy control parents and not with psychiatric comparison offspring (Cytryn et al., 1982, Gershon et al., 1985, Zahn-Waxler et al., 1988 and Grigoroiu-Serbanescu et al., 1989). Contrasts with other psychiatric control groups are necessary to control for the possibility that disorders in offspring are generally related to parents' clinical status and not specifically to bipolar disorder. Finally, although bipolar disorder is associated with a range of comorbid psychopathology (McElroy et al., 2001), prior studies did not covary parental comorbid disorders in examining predictions of child psychopathology. For example, since bipolar disorder in adults has been shown to have high comorbidity with disorders including substance use disorders (Regier et al., 1990 and Kessler et al., 1996), panic disorder (Chen and Dilsaver, 1995 and Calabrese et al., 2003), and history of ADHD and other disruptive behavior disorders (Nierenberg et al., 2005 and Carlson et al., 1998), it is unclear whether elevated rates of disruptive behavior and anxiety disorders found in some offspring studies are related to parental bipolar disorder or to other comorbid disorders in the parents. An improved ability to identify early in life those individuals at highest risk for bipolar disorder is of high scientific and public health importance. From a scientific standpoint, it would enable the elucidation of etiologic mechanisms of risk and protective factors. From a public health perspective, it would enable the development and delivery of early intervention programs to those individuals at highest risk. Moreover, the ability to identify prodromal symptoms of bipolar disorder might also help inform accurate diagnosis of early mood disturbance (Akiskal and Weller, 1989 and Akiskal, 1995). In particular, if a child showing such symptoms had high suspected risk for bipolar disorder, therapeutic agents with manic-inducing potential could be avoided in favor of other first-line medications (e.g., anti-manic agents). The purpose of this study was to assess young offspring at risk for bipolar disorder attending to the methodological shortcomings of the available literature. To this end we analyzed data from a large pre-existing sample of young children of parents with and without panic disorder or major depression (Biederman et al., 2001a), some of whom had bipolar disorder. Based upon the literature, we hypothesized that the offspring of bipolar parents would have higher rates of anxiety, disruptive behavior and mood disorders compared with offspring of parents with other psychiatric disorders, and offspring of parents without anxiety or mood disorders, and that these would not be accounted for solely by comorbid disorders in the parents.