Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies
by Stephen V. Faraone, Ph.D.; Joseph Biederman, M.D.; Janet Wozniak, M.D.
American Journal of Psychiatry. 2012 169:1256-1266.
Objective The existence of comorbidity between attention deficit hyperactivity disorder [ADHD] and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder.Method The authors applied random-effects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands.Results These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies.Conclusions The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies.
[the studies in red had bipolar children as probands (left) or targets (right)]
Evidence of familial association between attention deficit disorder and major affective disorders
by Biederman J, Faraone SV, Keenan K, and Tsuang MT
Archives of General Psychiatry. 1991 48(7):633-42.
With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following:
- the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls;
- the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%);
- the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%);
- ADD and AFFs did not cosegregate within families;
- there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.
Comorbidity: It became a buzz-word like evidence-based-medicine, a sign you were on-board. literally, it means two [plus] Disorders at the same time, but is often used to imply that Disorders ‘run together" as in are related to each other in some way. It can be used as an excuse like when the poor DSM-5 reliability for MDD and GAD are explained as "too many comorbidities" as if that’s a meaningful explanation.
Soft Genetics: This is a study of the rate of ADHD in first-degree relatives of Bipolar I patients and vice versa. In psychiatry, we don’t have much in the way core Mendelian genetics. We have statistical family associations or risk factors like the ones reviewed in this study. ADD "runs with" Bipolar Disorder. It’s just the way it is – and it makes for endless speculations. Are ADD and Bipolar Disorders separate entities? comorbid? genetically carried cousins? different manifestations of the same thing? separate from each other and yet a third syndrome with symptoms of both? These are questions often discussed but rarely resolved.
"Bipolar": After the DSM-III, the diagnosis of Bipolar Disorder took off. With the DSM-IV it became Bipolar I and Bipolar II. With the COBY and other studies, there was Bipolar NOS. So things have gotten increasingly confusing. So Bipolar Disorder overflowed the boundaries of its humble Manic-Depressive origins before it metastasized to childhood under Dr. Biederman who redefined the syndrome in kids with neither periodicity nor "poles."
Diagnosis by "Symptom List": The descriptive diagnoses of the DSM-III may have moved psychologizing out of the system, but they weren’t without some confusion of their own. In the past, we spoke of Manic Depressive Illness as a disease entity with reasonably defined borders. Since then, those borders have become fuzzier and that is nowhere more apparent than in Dr. Biederman’s extension into childhood. But it’s also clear in the rural clinic where I volunteer and frequently hear patients say something like, "I’ve been told I’m Bipolar" – and have the pill bottles to prove it. As I said above, Manic Depressive Illness, the disease, has grown geometrically as the Bipolar Disorders. The clinic patients are people with unhappy lives, difficult circumstances, all sorts of other chronic problems. A handful actually have Manic Depressive Illness. But they have chronic symptoms, and that seems to be what lead to the label [and the meds]. I personally think it’s like "chemical imbalance," it gives their dysphoria a concrete explanation and the medication is validating [just the musings of an old shrink]. But diagnostic blurring of this type is common in modern times [symptoms = disorder = disease].
in Results: Most studies of bipolar I probands (Table 1) ascertained parents with bipolar I disorder and reported the prevalence of ADHD in their offspring. The only exceptions were the Geller et al. and Massachusetts General Hospital child studies, which ascertained pediatric bipolar I probands and assessed the prevalence of ADHD in parents and siblings. Most studies of ADHD probands (Table 2) ascertained child probands and reported the prevalence of bipolar I disorder in siblings or parents. The only exception was the Massachusetts General Hospital adult ADHD study, which ascertained adults with ADHD and evaluated bipolar I disorder in offspring, siblings, and parents…
in Discussion: Regarding misdiagnosis, the samples diagnosed by the Massachusetts General Hospital group (data collected by the authors of this article) have been described as deviating from “classic” presentations of bipolar I disorder by allowing “severe, nonepisodic irritability” to qualify for the mood criterion… However, despite these concerns, if we exclude the Massachusetts General Hospital studies (or any other research group) from our meta-analyses, the estimated relative risks do not change and remain significant. Moreover, as Figures 2 and 3 show, the estimates of relative risk and confidence intervals from the Massachusetts General Hospital child proband studies are clearly consistent with the work of Geller et al., which is considered a more conservative approach to the diagnosis of pediatric bipolar I disorder.
Despite these limitations, our meta-analyses provide substantial evidence for a greater prevalence of ADHD among relatives of bipolar I probands and a significantly greater prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. Our results suggest that ADHD and bipolar I comorbidity cannot be accounted for by misdiagnoses, but further work is needed to rule out artifactual sources of comorbidity.