Introduction

Starting from the broad symptom overlap between attention-deficit/hyperactivity disorder (ADHD) and mania and the high comorbidity between ADHD and bipolar disorder, this review provides arguments that these facts result not only from a superficial similarity at the symptom level, but possibly also from common underlying neurobiological pathomechanisms. Pathophysiological commonalities may be found between ADHD and the manic state in bipolar disorder, explaining the symptom overlap, and may also be found between ADHD and bipolar disorder independent of the present manic, depressed or euthymic state, explaining the high comorbidity.

Common symptomatology and comorbidity

The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnostic criteria for the manic episode and ADHD directly overlap for symptoms of talkativeness, distractibility and psychomotor agitation. Other criteria, although not directly overlapping, can be difficult to discern. For example, consider ‘flight of ideas’ in mania versus ‘difficulty sustaining attention’ in ADHD, and ‘excessive involvement in pleasurable activities that have a high potential for painful consequences’ in mania versus ‘impulsivity’ in ADHD. Other features of the disorders that overlap are mood instability [1,2•], impairments in social and family relationships and school performance [3••]. The occurrence of both clear-cut depressive and manic episodes is helpful for differential diagnosis. At the symptom level, there are, however, only a few aspects useful for separating ADHD from mania: elevated mood and decreased sleep could discriminate juvenile-onset bipolar disorder from ADHD [4], although it might be difficult to discern decreased need for sleep in bipolar disorder from sleep difficulties common in ADHD. Other differences between ADHD and bipolar disorder exist regarding the course of the respective disorders. Whereas the symptomatology of ADHD is more or less stable over many years, mania typically occurs in episodes [3••]. In adults, a chronic course of unipolar mania over more than 2 years has been described but has to be considered as a rare exception [5]. For pediatric bipolar disorder, a chronic course is reported more frequently (40%; [6]), making the separation of the two disorders more difficult.

ADHD and bipolar disorder show comorbidity which decreases with growing age of the population under examination [7]. In pediatric bipolar disorder, comorbidity with ADHD is especially high; it is estimated that 85% of children with bipolar disorder also have ADHD and up to 22% of children with ADHD have bipolar disorder [8].

Common pathophysiology during manic state and in attention-deficit/hyperactivity disorder

The following section summarizes possible neurobiological bases ADHD might share with mania.

Androgens: a common pathophysiological factor?

Androgens, including testosterone, androstenedione and dehydroepiandrosterone (DHEA), are reported to be involved in the pathogenesis of both ADHD and mania. Therefore, we briefly discuss arguments for the pathogenetic role of androgens in both disorders.

ADHD is more prevalent in males, with a sex ratio in childhood of 3: 1. Additionally, an increased prenatal testosterone exposure appears to be related to an increased risk for ADHD [9••]. After birth, males may be at increased risk for hyperactivity because testosterone slows normal structural development in the left hemisphere of the brain [10]. And during puberty, sensation seeking – a core symptom of ADHD and mania – has been shown to be correlated with free testosterone and DHEA plasma levels [11].

Regarding mania, both experimental studies and naturalistic field studies suggest that androgenic steroid abuse can directly cause hypomanic or manic states sometimes associated with aggression and violence [12]. For example, Malone et al.[13] retrospectively studied 164 weightlifters and bodybuilders who used anabolic–androgenic steroids and found that about 10% had hypomania. Depression occurred when steroids were stopped in about 10%. In mice, androgen application leads to behavioral disinhibition similar to the behavior observed in anabolic–androgenic steroid abusers [14].

As behavioral disinhibition and sensation seeking can be induced by androgens and as both are core symptoms of ADHD and mania, one could speculate that androgens may contribute to both disorders as a common pathophysiological factor. This androgenic influence might explain why unipolar depression is more frequent in women, whereas bipolar disorder is equally distributed among men and women.

Much remains unknown about the pathophysiological contribution of androgens to ADHD and mania, but the basis of the reported studies seems to advise taking androgens into account while investigating these disorders.

Vigilance regulation in attention-deficit/hyperactivity disorder and mania

Our brain exhibits several different functional states (vigilance stages) not only during sleep [nonrapid eye movement (REM)-sleep stages and REM-sleep] but also during wakefulness. These different vigilance stages can best be discerned using EEG-based algorithms [15–17]. At the behavioral level, they go along with different levels of wakefulness such as high alertness, relaxed wakefulness, drowsiness and the transition to sleep onset. It is obvious that the precise regulation of vigilance is of highest importance for all higher organisms and that state or trait-dependent dysregulations of vigilance have profound consequences on behavior.

Arguments have been presented that dysregulation of vigilance is a central pathogenetic factor in both ADHD and mania. It has been proposed that the behavioral pattern of both ADHD and mania represents an autoregulatory attempt to stabilize wakefulness (vigilance) by creating an intense and stimulating environment. A nonpathological analogy of such a vigilance autostabilization behavior can be observed in daily life: when children go to bed too late and become overtired, some of them become hyperactive and show strong sensation-seeking behavior, possibly in order to stabilize vigilance by increasing external stimulation. This theory of vigilance autoregulation expands earlier concepts of brain function [18,19] and is related to personality theories about extraversion [20] and sensation seeking [21], which similarly explain these traits as an attempt to compensate for low central nervous system arousal.

Figures 1 and 2 summarize the suggested pathogenetic role of an unstable vigilance in mania and ADHD. As shown in Fig. 1, sleep deficits or other factors inducing an unstable vigilance trigger an autoregulatory behavioral syndrome with hyperactivity, sensation seeking and distractibility. This behavioral syndrome has the function to stabilize vigilance by creating a highly stimulating environment. In vulnerable individuals, the autoregulatory mechanism overrides the physiological tendency to seek sleep, aggravates the sleep deficits, worsens the vigilance instability and thereby starts a vicious circle, finally resulting in full-blown mania. The cognitive deficits associated with mania result directly from the unstable vigilance.

Figure 1: Model of a pathogenetic circle of vigilance stabilization syndrome leading to full-blown mania Figure 2: Attention-deficit/hyperactivity disorder subtypes explained by an unstable vigilance trait with or without vigilance stabilization syndrome (combined type versus inattentive type, respectively)

An unstable vigilance is also supposed to be of relevance in ADHD, though not as a state-dependent factor as in mania, but as an acquired or genetic trait (see Fig. 2). The attention deficits directly result from this vigilance dysregulation. Those patients who do not show a strong autoregulatory behavior with hyperactivity and sensation seeking would constitute the attention deficit subgroup (without hyperactivity). If, however, an autoregulatory behavioral syndrome develops, then the combined subgroup with hyperactivity would result. The concept explains why a pure hyperactive subtype of ADHD is rare, because without an unstable vigilance with the corresponding attention deficits, no autoregulatory hyperactivity will develop.

The pathogenetic concepts presented in Figs 1 and 2 are supported by several lines of evidence and provide an explanation for some seemingly paradoxical aspects:

Patients with both mania and ADHD are indeed characterized by an unstable vigilance. This may be surprising for some clinicians, especially when keeping in mind the highly energetic behavior of manic patients. However, it is a robust finding that manic patients, when studied in a quiet environment with low external stimulation and eyes closed, show rapid declines to low vigilance stages within the first minutes of EEG recording (overview in [15,22••]). Often micro sleeps (defined as an abrupt intrusion of sleep spindles) are found within the first minute [23]. In patients with ADHD, the vigilance also appears to be unstable. In EEG studies, an increase of slow theta and delta activity and a decrease of alpha activity have been found, which is in line with the EEG pattern found during low vigilance stages. Furthermore, ADHD has been associated with sleepiness, shortened sleep latency and several sleep disorders [24,25]. This unstable vigilance is not only a consequence of sleep deficits or low sleep quality, which are associated with mania and ADHD, but appears to play a causal role. This is suggested by the fact that sleep deprivation can trigger or worsen manic behavior [26,27] and that life events that affect the sleep–wake cycle often precede the onset of mania [28,29]. In line with this, stabilization of sleep–wake rhythm is used in behavior therapies for mania [30,31]. Concerning ADHD, it is a consistent finding that disturbed sleep is common in affected children as well as adults and that all disorders impairing sleep quality worsen ADHD. Additionally, it was shown that improving sleep quality improves ADHD and that treatment with psychostimulants can improve sleep quality [32,33]. Some aspects of ADHD-like behavior can be induced in children by sleep restriction [34,35]. In accordance, it has also been proposed by other authors that restlessness and hyperactivity in ADHD may be a functional response to chronic underarousal (see [24,36]). Withdrawal of vigilance-stabilizing drugs, such as nicotine, can trigger mania , and a high smoking prevalence has been reported for both ADHD and bipolar disorder [37–39]. This high prevalence may indicate that these patients benefit more than other individuals from the vigilance-stabilizing properties of nicotine. In line with this, smoking and coffee drinking have not been associated with higher occurrence of mania in bipolar disorder , when confounding factors are controlled for [40]. Furthermore, several case studies, outlined below, suggest a possible antimanic effect of vigilance-stabilizing medications.

Common pathophysiology in bipolar disorder and attention-deficit/hyperactivity disorder

In this section, commonalities between ADHD and bipolar disorder will be presented, which are largely independent of the present disease state. Among these are genetic and structural brain imaging findings.

Common genetic bases

ADHD and bipolar disorder are both among the most heritable psychiatric diseases [41,42••]. Several recent studies suggest that common genetic factors may be involved in these disorders:

The prevalence of bipolar disorder is approximately twice as high in the relatives of patients with ADHD as in the relatives of control children. Also, the diagnostic frequency of ADHD is about three times as high in children of parents with bipolar disorder compared with those of controls [3••]. Patients with comorbid ADHD/ bipolar disorder have significantly elevated risk of having relatives with comorbid ADHD/ bipolar disorder [43]. Considering genome-wide association studies (GWASs) in ADHD and in bipolar disorder , there are no common genetic polymorphisms which reached formally genome-wide significance level. However, given the complexity of both diseases and the low odds ratios of most single polymorphisms, the former GWASs are underpowered for a strict genome-wide significance level (P < 5 × 10−8 is often used). Nonetheless, when considering the strongest, though not genome-wide significant, associations, one has to take note of the fact that GWAS findings in ADHD overlap with GWAS findings for bipolar disorder . Those common polymorphisms are located in or close to genes encoding for the dipeptyl peptidase 10 (which alters potassium channel function), a voltage-gated potassium channel-interacting protein, the zinc finger protein 385D, the cAMP-response element-binding protein 5, the Forkhead box protein P1, the citrate lyase beta-like protein, a kainate 1 glutamate receptor, members of the protein tyrosine phosphatase family, glypican 6, a netrin-1 receptor, an adhesion glycoprotein called cadherin-like 23 and catenin alpha 2 [42••]. These findings indicate that genetic overlapping of ADHD and bipolar disorder is more strongly localized in genes apart from the classical neurotransmitter focused models. Based on these data, processes of the cell physiology, such as cell growth and differentiation, cell–cell communication and electrolyte channel expression and regulation should come into greater focus of ADHD and bipolar disorder research. Concerning the candidate gene approach, associations have been found for both diseases for genes related to the serotonergic system (TPH2 [44,45]; 5-HTTLPR, [45,46••]) and the dopaminergic system (DAT1, DRD4, [45,46••]). These monoaminergic neurotransmitter systems are also involved in vigilance regulation [47], which might be a common etiological factor in ADHD and bipolar disorder , as discussed above. Recently, another interesting polymorphic region at the neurokinin coding gene has been associated with both ADHD and bipolar disorder [48]. The relevance of this association is that neurokinin-knockout mice show dopaminergic dysfunctions and hyperactivity, which is prevented by psychostimulants [48]. Finally, polymorphisms of circadian genes have been associated with both ADHD and bipolar disorder [49], which is notable because of the proposed pathogenetic role of vigilance regulation and because abnormalities in circadian rhythm are discussed as a pathogenetic factor for both disorders [49,50]. Of special interest is a polymorphism in the CLOCK gene, which has been associated with bipolar disorder [41], but also recently with ADHD [50]. Additionally, mice harboring a mutation of the CLOCK gene have been introduced as an animal model of mania [51]. The manic-like phenotype of these mice is normalized by the mood stabilizer lithium [51]. Most interestingly, the CLOCK polymorphism has also been related to eveningness preference [52], with eveningness in turn being associated with bipolar disorder [53], ADHD [54,55] and novelty seeking [56], a suggested psychometric endophenotype of bipolar disorder and ADHD [57].

Common neuropsychological findings

Impaired sustained attention has been found in bipolar disorder across all phases, including euthymic, and also in unaffected relatives of bipolar disorder patients [58–61]. In ADHD, sustained attention has also been shown to be impaired and to be partly ameliorated by stimulant treatment [62]. Interestingly, sustained attention has been associated with candidate genes for ADHD/bipolar disorder described above, namely with DAT1 and DRD4 [63,64].

Given the fact that sustained attention is also impaired in euthymic phases and in unaffected relatives, one can hypothesize that bipolar disorder patients might not only be characterized by an extremely unstable vigilance state while being in an escalated manic phase, but also by a trait-like unstable vigilance. The assumption of a chronic unstable vigilance in bipolar disorder would also be in line with findings of higher sensation or novelty-seeking scores in euthymic bipolar disorder patients or unaffected relatives [57], with these traits presumably reflecting compensatory personality styles due to underarousal.

Overlap in neuroimaging studies

Neuroimaging studies in bipolar disorder have mainly reported abnormalities of the prefrontal cortex, the striatum and the amygdala [65]. In ADHD children, however, the most frequently replicated structural findings include smaller total brain volumes and abnormalities of the prefrontal cortex, the striatum, pallidum, corpus callosum and the cerebellum [66]. But in addition to these partly diverse findings in ADHD and bipolar disorder, there are also common brain structural findings, possibly resulting from similar abnormalities during the early brain development, beginning with the formation of the neural tube and ending with myelination.

Among these findings is an impaired fiber density or reduced myelination in the prefrontal tract found in both bipolar disorder and ADHD using diffusion tensor imaging [67]. Also, structural as well as functional magnetic resonance imaging suggests common abnormalities in frontal–subcortical control loops involved in affect regulation [67,68].

Common treatments?

The model presented in Figs 1 and 2 provides an explanation of why stabilizing vigilance with stimulants is an effective treatment in ADHD. Even more important, it raises the intriguing question of whether psychostimulants may also be beneficial in mania. This question has not been systematically addressed up to now, because of the prevailing idea that manic patients are overaroused and should be treated with neuroleptics and benzodiazepines. However, the efficacy of sedating drugs for treatment of mania is moderate [69,70], and it seems that neuroleptics and benzodiazepines, in many cases, do not rapidly interrupt the manic illness process, but merely cause a forced sedation.

The fear of many clinicians that psychostimulants have a high probability of triggering or aggravating manic syndromes is not based on empirical evidence. A systematic analysis by the Food and Drug Administration (FDA) of studies using psychostimulants in ADHD patients, many of whom can be expected to have comorbid bipolar disorder, revealed that psychotic or manic reaction was rarely reported and consisted more of short-lived and possibly toxic reactions than clear manic syndromes [71–75]; see also for recent trials [2•,76]). Additionally, stimulants were overall well tolerated in the few trials with bipolar disorder in which stimulants were given to treat fatigue or cognitive impairments, for example [60,77].

In contrast to the reservation against stimulants, several case reports and case series showed a clear and rapid (within few hours) improvement of the manic symptoms in most manic patients treated with psychostimulants (reviewed in [15,22••], see for example [78]). We recently observed a rapid improvement of manic symptoms together with EEG vigilance stabilization under monotherapy with the stimulant modafinil (Vigil, Cephalon GmbH, Martinsried, Germany; unpublished data). Within 5 days, the Young Mania Rating Scale score (three blind ratings based on video recordings of interviews done by a physician not involved in the study) dropped from 21 to 7.5. Because of the rapid antimanic effect, psychostimulants could be especially beneficial in the initial management of patients with acute mania.

Conclusion

ADHD and mania appear to have in common not only many symptoms but also pathophysiological aspects. Among these is the instability of vigilance, which possibly triggers hyperactivity and sensation seeking as an autoregulatory attempt to stabilize vigilance. In this context, common genetic findings possibly related to vigilance, such as CLOCK genes, are of special interest. Starting from findings about common vigilance deficiency, it was suggested that stimulants might be effective not only in ADHD, but also in the treatment of acute mania. The first evidence of this new treatment option is available and controlled studies should follow.

Acknowledgements

U.H. received sponsorship from Cephalon GmbH, Lilly Deutschland GmbH, Lundbeck, Novartis Pharma GmbH, Wyeth Pharma Deutschland and Sanofi-Aventis for a symposium on vigilance regulation. He is or has been an advisory board member for Lilly, Wyeth, Sanofi-Aventis and Lundbeck.