Awareness of bipolar spectrum disorders in children is rapidly increasing, and a more precise definition of clinical subtypes and early signs is being accomplished. One indication of this greater awareness is the research to detect prodromal features of early-onset disorders in high-risk populations, such as the offspring of bipolar probands [1]. Retrospective findings from adult bipolar patients show that 59% report the onset of their symptoms before the age of 14, with an average time lapse of 5 years between symptom onset and correct diagnosis and treatment [2]. Offspring studies on children and adolescents of people with mental disorders are useful to improve our knowledge about the factors that may influence the development and the natural history of these diseases, including predictors of psychopathology, factors of resilience or early signs of the disorders [1,3]. Furthermore, these studies can improve our capacities of prevention, early diagnosis and timely interventions. They are of great importance to families where one or both parents are bipolar, because they facilitate the detection of bipolar prodromes. The relevant data can be used by patient and advocacy organizations serving bipolar families [4].

Children and adolescents of parents with bipolar disorder are a cohort of intensively studied patients, and many studies are available in the literature on their psychopathological characteristics [5-24]. It is more than of

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historical interest that the first study of the clinical characteristics of the offspring of manic-depressive parents was conducted by one of the authors of this chapter, an adult psychiatrist working in a mood clinic [25]. He did so because bipolar mothers bitterly complained that child psychologists, child psychiatrists and paediatricians neglected the affective symptoms of their children as transitory problems, despite insistence by these mothers that they themselves had experienced the same symptoms; they simply wanted their children to receive the earliest possible care. Most child professionals [9-23] ventured into this arena much later. Overall, these studies demonstrate an elevated prevalence of affective disorders, disruptive behaviour disorders and anxiety disorders in the child and adolescent offspring of affected parents. However, prevalence rates reported in the existing studies vary greatly. A number of methodological issues hamper the comparability across studies, and the interpretation of findings [22]. First of all, there is a large variation in the sample composition: most studies used selected clinical samples of adults with bipolar disorder, including inpatients, outpatients or a mix, with different types of bipolar disorder (type I, type II or both), and different degrees of severity. Furthermore, the comparison samples (usually small and unrepresentative) vary greatly among studies. Several studies did not include comparison groups; in several others only healthy volunteers were considered as a control group. The majority of studies included children of normal parents and/or children of psychiatrically ill, nonbipolar parents, and/or medically ill patients. Diagnostic procedures also varied greatly, as well as the diagnostic system of reference, the number of diagnoses and the informants.

All the studies which compared bipolar offspring to healthy volunteers' offspring show that bipolar offspring present an increased risk for a wide range of mental disorders, including mood disorders (major depressive disorder and bipolar disorder), behavioural disorders (mainly attention-deficit/hyperactivity disorder, ADHD), and anxiety disorders [8-10,14, 16-19], suggesting a lack of phenotypic specificity. Rates of mood disorders in bipolar offspring range from 5 to 67% versus 0-38% in children of healthy volunteers, and rates of other mental disorders range from 5 to 52% versus 0-25% in children of healthy volunteers [3]. Subsyndromal and temperamental characteristics are also described in children without concurrent affective episodes in studies of the offspring of bipolar parents [25,26], as well as atypical cognitive functioning [8,27].

Overall, current results emphasize the clinical importance of the routine and systematic assessment of family histories for judging the likelihood of the development of affective disorders, namely a bipolar disorder, in the child and adolescent offspring and siblings of bipolar patients [28]. Why can early signs of bipolar disorder be expected in children of bipolar patients? Because family, twin and adoption studies strongly support the role of genetic factors in the aetiology of bipolar disorder, even though the complex inheritance pattern is not yet clearly understood [29]. This complex inheritance includes, among others, unstable DNA trinucleotide repeat sequences, which appear to expand in length over successive generations, offering, hypothetically, an explanation for the many deviations from Mendelian inheritance in bipolar disorder. These mutations are considered the basis of a clinical phenomenon, called anticipation, characterized by earlier onset and increasingly severe phenotype in younger generations for certain diseases, including bipolar disorder [30-33]. Genetic anticipation may thus lead to increased detection of bipolar disorder in children and adolescents. This is consistent with studies confirming a secular trend in the age of onset of bipolar disorder, with the average age of onset decreasing in more recently born individuals [34].

Besides genetic factors, environmental stressors are related to having a parent with bipolar disorder, who is unstable due to mood swings, possible hospitalizations, substance abuse and other less severe but more persistent behavioural excesses. Families with a bipolar parent report differences in their environment, in terms of cohesion and organization, conflictuality and dyscontrol [35]. This is not surprising, considering the psychosocial disruptions in bipolar patients. During development, the child born into a family with a bipolar parent is exposed to extremes of moods and related social instabilities, validating his or her own inherited proclivity to mood instability [36].

Finally, it is likely that increased use of antidepressants and/or stimulants in bipolar offspring with depression, anxiety or ADHD may elicit an earlier onset of bipolar disorder [37]. However, not all studies support an increased risk for manic switch in young bipolar patients treated with psychostimulants, at least in the short term [38].

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