ADHD exhibits a complex etiology integrating genetic and environmental factors for studied cases [6,7,8,9]. Further updates in the research literature have advanced our understanding of the disorder [10]. Existing family and twin studies support genetics as an important factor in the onset of ADHD [11]. Specifically, twin studies have concluded that the heritability of ADHD is estimated to be 60–90% [11,12,13,14]. However, when evaluated based on isolated genes and risk variants, ADHD demonstrates a poor correlation to any specific gene [15,16].

ADHD typically has had an onset at a young age. In 2013, the DSM V updated the age limit for the onset of qualifying symptoms for ADHD from age 6 to age 12 to prevent the misdiagnosis of normal inattention symptoms in the pediatric population [17]. For diagnosis, adolescents (17 years or older) can display less hyperactive or inattentive symptoms (at least five). Increasingly, it has become accepted that ADHD can exhibit a late manifestation or maintain symptoms throughout adulthood [18,19,20,21]. As a baseline for diagnosis, ADHD must also be present in at least two settings where symptoms present in various environments like the home and school.

Pharmacologic treatments for ADHD can be divided into non-stimulants and stimulants. Stimulants, including amphetamine and methylphenidate-based medications, are considered first-line in treating ADHD in children and adults [40]. These stimulants boost arousal in the prefrontal cortex by increasing norepinephrine and dopamine concentrations in the brain [41]. Increasing synaptic dopamine and catecholamine are main mechanisms of action of both methylphenidate and amphetamine. However, there are specific differences that affect how they alter concentrations [40]. The stimulant methylphenidate exerts its effects by inhibiting the dopamine transporters (DAT) and norepinephrine transporters (NET). It increases dopaminergic neurotransmission by inhibiting presynaptic DAT and, as a result, reuptake at the synapse [40,41].

Studies have demonstrated that methylphenidate directly interacts with adrenergic receptors to stimulate excitability in the cortex via activation of a2 adrenergic receptors [40]. Methylphenidate also exerts agonistic activity at the 5-HT1a receptor [40]. This results in the elevation of extracellular dopamine and norepinephrine levels, and as a result, increased binding to their respective receptors [40].

Another stimulant used in treating ADHD is an amphetamine salt, whose primary mechanism of action is to increase catecholamine release [40]. It acts as a competitive inhibitor of DAT and as a pseudo-substrate at norepinephrine binding sites. It acts to increase dopamine release by inhibiting the VMAT-2, or vesicular monoamine transporter 2, and it also inhibits monoamine oxidase activity to decrease the cytosolic breakdown monoamines [41]. Both methylphenidate and amphetamine increase dopamine release, which increases responsiveness to external stimuli [40,41]. These stimulants have d and l isomers, with the d isomer being more potent than its l counterpart. Specifically, the d isomer is more potent at the norepinephrine transporter and dopamine transporter binding sites b [41].

Non-stimulant medication treatment includes atomoxetine and bupropion. Although the mechanism is not completely clear, atomoxetine is thought to selectivity inhibit norepinephrine uptake and preferentially binds to areas of known high distribution of noradrenergic neurons [42]. Bupropion is an anti-depressant that has a variety of uses, including depression, anxiety, ADHD, and smoking cessation. Its mechanism of action likely involves the reuptake inhibition of the catecholamines, dopamine, and noradrenaline [43]. This mechanism is like the one for psychostimulants, but bupropion is not a controlled substance. Clonidine is another choice, which is an alpha 2 adrenergic receptor agonist. Clonidine is good for impulsivity and hyperactivity but not useful for symptoms of inattention [44]. Guanfacine is a direct alpha 2α subtype agonist within the central nervous system leading to reduced peripheral sympathetic outflow and strengthening of regulation of both attention and behavior within the prefrontal cortex through modulation at norepinephrine receptors [44]. Its actions are found in the locus coeruleus and can result in improved attention [44]. Clonidine and Guanfacine are considered second or third-line treatments after the use of stimulants has failed [45].

There is an overlap in terms of symptoms when looking at ADHD and BD. These two disorders often co-occur, and they are associated with worse outcomes [46]. There is evidence that children with ADHD have a higher risk of being diagnosed with BD later in life [47]. There have been attempts to develop neuropsychological testing that can better identify those with both disorders. However, research has shown that these tests have limited power to differentiate between BD adults with and without childhood ADHD [46].

Symptoms of both ADHD and BD can have overlap which will be further explored in the next section. Mania is associated with bipolar disorder and is highlighted with increased energy and disorganized thinking with the inability to plan which can be seen in the increased goal-related activity. These are things that are also seen in ADHD. Other mood disorders such as depression and anxiety can have decreased concentration, which can also be seen in ADHD. So, at times, it can be hard to separate what diagnosis is correct because of the overlapping symptoms.

Treatment is a question that has been looked at in the research as the overlapping symptoms that cause issues and distress to the patient may be worsened by traditional ADHD treatment of stimulants. There is concern that the use of stimulants may worsen mania and psychosis and further debilitate the patient [47]. A study performed by Galanter et al. suggests that youth treated with stimulants did not have an increase in mania or psychotic symptoms [48]. Furthermore, children in the first month of treatment who had ADHD symptoms and manic symptoms had a more robust response to stimulant treatment. However, the studies in adults are less promising. In a review of three cases, the use of stimulants increased psychosis in patients [49]. The authors concluded that patients need to be monitored for adverse responses to treatment. In the next section, the review will look at the clinical studies regarding the overlap of ADHD and BD.