Studies on the risk for early-onset bipolar disorder in the offspring of bipolar patients are made more difficult by the relative uncertainty of the phenomenology of bipolar disorder in childhood, given the developmental differences of the disorder in prepubertal patients, including atypicality of phenomenology , and the high frequency of comorbidity, mainly with ADHD . More recently a new effort was made to develop diagnostic criteria for different phenotypes of juvenile mania [41,42], and to produce methodological guidelines, including inclusion and exclusion criteria, for clinical studies in child and adolescent patients with bipolar disorder .
An early study found that the risk of developing an affective disorder for first-degree relatives of bipolar probands was 27% if one parent, and 74% if both parents had a bipolar disorder . A meta-analysis of studies conducted before 1997 showed that bipolar offspring (both children and adults) are at 2.7 times higher risk for developing any psychiatric disorder, and 4 times higher risk for developing a mood disorder, compared to children of parents without psychiatric illness . Cyclothymia has been repeatedly found to be more common in bipolar offspring than in controls [12,28,46]. Subsequent studies confirm that about 50% of children of bipolar parents have at least one psychiatric disorder, and bipolar spectrum disorders (bipolar I, bipolar II and cyclothymia) are reported in 14-50% of these children [20,21,25]. It is debatable whether clinical features of bipolar offspring are different from those of bipolar samples which are mixed for the presence or absence of family history .
Depressive disorders are frequently reported in the offspring of bipolar parents and, according to several studies [15,17,25], they are the most frequently reported disorder. For Kashani et al. , depression is more frequent in bipolar offspring (22%) than in offspring of depressed parents, while Hammen et al.  and Radke-Yarrow et al.  found higher rates in children of depressed parents than in children of bipolar parents. Longitudinal studies may be needed to explore the eventual bipolar outcome in this population of depressed offspring, in view of the high rates of subsequent manic episodes in early-onset depression . This risk is reported to be even higher in depressed children with a positive family history of bipolar disorder .
Duffy et al.  explored psychopathological features in the offspring of two groups of bipolar parents, divided on the basis of their response to long-term lithium prophylaxis. The leading hypothesis was that the response to lithium prophylaxis was a clinical marker of a more homogeneous, genetically based subgroup of bipolar disorder. Of the 36 children, 19 (52.8%) met DSM-IV criteria for at least one psychiatric disorder (9/21 in the lithium responders' offspring, 10/15 in the lithium nonresponders' offspring). The children of lithium responder parents tended to manifest psychiatric illnesses clustering in the affective domain, with episodic course and fewer comorbid conditions. On the contrary, children of lithium nonresponders tended to present a wider range of psychopathology, a chronic course and a higher comorbidity. These data were confirmed in an expansion of this study with a larger sample and a prospective, longitudinal design . Parents with classical episodic bipolar disorder characterized by complete remissions and an excellent response to lithium tended to have children with typical, episodic affective disorders, with abrupt onset superimposed on a normal premorbid development, and a good quality of remissions. On the contrary, parents with bipolar disorder characterized by incomplete remissions tended to have children with early problems in social and academic functioning, which continued alongside the mood disorder, which itself followed a chronic course with poor quality of remission. Differences in the course of the disorders between the offspring groups did not appear to be attributable to psychosocial stress. These different bipolar phenotypes have been more recently described in greater detail . Whether these phenotypes have different rates of response to lithium treatment is a matter for further research.
Chang et al.  described cross-sectional psychopathological features in 60 subjects (mean age 11.1 years) from 37 families with at least one bipolar parent. Of these 60 subjects, 33 (55%) had a DSM-IV axis I disorder: 17 subjects (28%) met lifetime (but mostly also current) diagnostic criteria for ADHD, 9 (15%) for major depressive disorder or dysthymia, 9 (15%) for bipolar disorder or cyclothymia, 6 (10%) for oppositional defiant disorder, 3 (5%) for an anxiety disorder, 2 (3%) for obsessive-compulsive disorder and 2 (3%) for tic disorder. Of the children with a diagnosis of bipolar disorder, 88% had a co-occurring ADHD; 81% of offspring with ADHD and 88% of offspring with bipolar disorder were males. Bipolar parents of offspring with bipolar disorder were more likely to have had an ADHD themselves, and there was a tendency to an earlier onset of their psychiatric symptoms, compared to parents of offspring without axis I disorders.
The finding of an association of parental ADHD+bipolar disorder with bipolar offspring suggests the possibility of a genetic transmission of a distinct, more virulent subtype of bipolar disorder with earlier onset and ADHD features . This may be confirmed by the observation that bipolar parents with childhood ADHD tended to have an earlier age of onset of their bipolar symptoms, compared to those without ADHD. Severity of mood symptoms was separately considered in the unilineal or bilineal risk groups (one or two ill parents). Depressed mood, irritability, lack of mood reactivity, rejection sensitivity, social withdrawal and crying were significantly more severe in the bilineal group, while manic symptoms (grandiosity, euphoric mood, decreased need for sleep) did not significantly differ between the groups. These data suggest that an innate difficulty in mood regulation in the highest risk subjects may represent a prodromal state of bipolar disorder, whereas manic symptoms may represent later signs of a more advanced and crystallized presentation of bipolar disorder. Given the cross-sectional design of the study, it was not possible to define longitudinal risk during subsequent development, as well as the rate of remission of the current disorders (the mean age of this cohort was 11.1 years).
More recently a prospective study of prodromal features for bipolarity has been conducted in psychiatrically well Amish children . The risk for bipolar disorder was 38% among children with a bipolar parent, compared with 17% in the control sample. The risk in the control sample was mostly (15 out of 18 children) accounted for by children of psychiatrically well parents who were siblings of a bipolar patient. Children with negative family history rarely received even a low risk rating. The clinical features which were most frequent in children with a bipolar parent were mood lability, low energy, anxiety/worry, hyperalertness, sensitivity and somatic complaints. Increased and decreased energy, decreased sleep and anger/ temper were noted to occur periodically in more than 50% of the children, and these miniclusters (episodic affective storms) were considered the more typical prodromal manifestation in children at risk for bipolarity. Disruptive behaviours and conduct problems were very rare in the Amish children with a bipolar parent, presumably due to psychosocial and environmental influence.
Todd et al. [28,49] explored mental disorders in children and adolescent members of extended families identified through adult bipolar probands. In the first study  there was a significant relationship between the risk of an early-onset affective disorder in children and adolescents, and the degree of genetic relatedness to affected adults in the family, while there was no significant correlation between affective disorders and any of the psychosocial measures. Furthermore, there was not an increased risk of developing disruptive behaviour disorders or anxiety disorders. In the subsequent, extended pilot study , 12 of the 50 interviewed offspring (24%) received a lifetime diagnosis of an affective disorder, 6 of bipolar disorder, 5 of depressive disorder and 1 of dysthymia. The offspring of a parent with an affective disorder showed a five-fold higher risk of having an affective disorder diagnosis than the offspring with healthy parents, supporting a major role of genetic factors, compared to presumably shared cultural and environmental factors. An increased risk of anxiety disorders, but not of disruptive behaviour disorders, was found in the bipolar offspring.
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