The emotional side of adult ADHD

In their scholarly paper on the knowns and unknowns of adult attention-deficit/hyperactivity disorder (ADHD), Cortese et al1 address the multifaceted aspects of this prevalent, early-onset, and often life-spanning disorder, including the role of emotional dysregulation and psychiatric comorbidities. Large scale meta-analyses, investigating a six- to seven-digit number of patients, clearly demonstrate that comorbidities include major depressive disorder (MDD)2 and bipolar disorder (BD)3, with an odds ratio of 4.5 and 8.7, respectively2. These epidemiological data are corroborated by family-based studies on relatives of patients with ADHD, but also of patients with either MDD or BD. However, there is comparably little research on how mood disorders are linked to ADHD – and even lesser data on how this comorbidity should be treated. There is significant shared heritability between ADHD, MDD and BD4. However – even though there are multiple common genetic risk variants, especially between ADHD and MDD, and Mendelian randomization studies further argue that the genetic liability for ADHD is causally related to MDD – effect sizes are too small to account for the considerable comorbidity. So, what else might play a role here? First, almost every environmental risk factor for MDD is over-represented in ADHD. Childhood adversity has been present in many cases. This includes disturbed parental bonding (which may be due to the child's disruptive behaviors as well as to possible ADHD in a parent), repeated social rejection, being subjected to bullying and educational failure, as well as physical and emotional trauma. Also later in life, people with ADHD are more prone to traumatic life events. Furthermore, lower socioeconomic status, unstable relationships, and a plethora of other negative life events all add up to increase the risk for later depression. Comorbidities such as obesity and substance use further contribute to MDD risk. Adult ADHD-MDD comorbidity is thus a prime example for the bio-psycho-social model of the pathogenesis of mental disorders, with genetic as well as environmental risk factors adding up to finally increase the risk above threshold. There are only few studies on the phenotype of depression in the context of adult ADHD. ADHD-MDD seems to be associated with an earlier onset of depression, a higher disease burden (e.g., more hospitalizations and a higher number of episodes), increased suicidality, higher functional impairment, lower quality of life, and a higher risk for treatment-resistant depression (TRD). Notably, ADHD polygenic risk scores are associated with TRD. According to the BRIDGE-II-MIX study5, ADHD-MDD goes along with a higher number of (hypo)manic symptoms in MDD, a higher prevalence of mixed and atypical depression, a positive family history for (hypo)mania, and a history of manic switch upon antidepressant treatment. Thus, the ADHD-MDD phenotype may look like bipolar depression. Therefore, when it comes to clinical assessment, this requires diagnostic rigor and knowledge about the connections between these disorders. An up to 30-year follow-up study of MDD patients6 found the conversion risk of MDD to bipolar disorder to be 26%. However, when three or more subthreshold hypomanic symptoms were present at baseline, this proportion increased to more than 45%. As indicated above, ADHD-MDD with (hypo)manic symptoms is precisely the phenotype going along with a higher risk to conversion into BD. Bringing these data together, a clinical trajectory from ADHD to ADHD-MDD with bipolar features, then converting into ADHD-BD, seems conceivable. This course of disease could actually be described in longitudinal studies on offspring of patients with BD, especially those who were lithium non-responders7. This adds to the concept of a more episodic, lithium-responsive subtype of BD, as opposed to a more chronic, lithium-non-responsive subtype, where chronicity might be due to underlying ADHD. As pointed out by Cortese et al, emotional dysregulation – usually defined as the inability to adequately control emotions, resulting in frequent, prolonged and abnormally intense emotional states – goes along with childhood as well as adulthood ADHD. Whether, and how, emotional dysregulation is linked to full-blown mood episodes is, however, unknown. The currently ongoing DynAMoND study8, based on dense ecological momentary assessment sampling of affect and arousal in ADHD and BD, will hopefully shed light on this issue. The therapeutic implications of ADHD-MDD and ADHD-BD remain largely unknown, and somewhat rely on which disorder has been diagnosed first. Most clinical guidance suggests that, if MDD is diagnosed together with ADHD, it should be treated first and according to pertinent guidelines. Upon remission or at least response, the impairment of comorbid ADHD should be evaluated and, if still relevant, ADHD should be treated using first-line medication, i.e. stimulants. However, this sequence is not empirically grounded. It might well be that simultaneous treatment with antidepressant medication and stimulants increases remission rates, given that ADHD is a risk factor for TRD. Further, the summary of product characteristics of stimulants usually conveys a warning, or contraindication, regarding stimulant use when MDD is, or has been, present. This warning is mostly theoretical in nature, and clinical experience suggests that stimulant use is safe in ADHD-MDD. However, randomized clinical trials are urgently needed to address this issue, given that about 1-2% of the overall adult population at least once in their lifetime suffer from ADHD-MDD. Recommendations to preferentially use antidepressants with a dopaminergic or noradrenergic mechanism of action in ADHD-MDD rely on valid pharmaco-theoretic reasoning, yet they have no empirical underpinning. Again, such advice should be tested in controlled trials. When it comes to ADHD-BD, there is the frequent concern that stimulant use in BD might trigger manic episodes. While this might indeed be the case in the absence of mood-stabilizing agents, it has been shown9 that a combination of mood stabilizers (e.g., lithium) and stimulants is safe with respect to switch risk. Thus, if ADHD causes impairment outside of mood episodes in ADHD-BD, it should be treated accordingly, which might also improve adherence to mood-stabilizing therapy. The role of psychotherapy and neurostimulation has not yet systematically assessed in either ADHD-MDD or ADHD-BD. Certainly, psychoeducation is of high relevance in both conditions. In conclusion, the connections between ADHD, emotional dysregulation, and mood disorders are manifold, and many important questions are still unanswered. More studies on these highly prevalent comorbidities are clearly needed to improve patients' life. This requires clinicians and researchers to leave their "diagnostic silos" to fully appreciate the complexities of mental disorders.