An Open-label, Flexible Dose, Single Site Study Evaluating the Safety, Efficacy and Tolerability of Cariprazine as an Adjunct to Psychostimulants in Adult Patients With ADHD Who Have Had an Inadequate Response to Psychostimulants Alone

According to the Canadian ADHD Practice Guidelines, psychostimulants are the preferred treatment of ADHD, especially for individuals that require urgent care. Specifically, long-acting psychostimulants are considered the first-line pharmacological treatment for ADHD. Utilizing sustained-release mechanisms, long-acting psychostimulants provide an extended duration of daily symptom relief in addition to overall reductions in ADHD symptoms that are maintained over time. Long-acting psychostimulants minimize several of the limitations of immediate-release psychostimulants including: peak-trough effects, suboptimal duration of action, increased diversion potential, and non-adherence due to multiple dosages.

In accordance with these guidelines, clinicians may combine psychostimulants with other medications when it is deemed necessary. For complex cases, psychostimulants alone are often inadequate for ameliorating the debilitating effects of ADHD and are therefore prescribed in conjunction with other psychotropic medications targeted at the residual symptoms associated with ADHD. Antipsychotics have been deemed appropriate as adjunctive medications, especially for the management of reactive-impulsive behaviours, neurological tics, and/or bipolar disorder. Studies show that most adult cases with ADHD that were undiagnosed or untreated in childhood result in the use of adjunctive medication in adulthood to augment the effects of the psychostimulant. As a result, we propose that adjunct treatment with cariprazine, an atypical antipsychotic, will augment the efficacy of standard ADHD treatment with a long-acting psychostimulant in a subset of the population that achieved little to no response on psychostimulants alone.

Cariprazine is an atypical antipsychotic where the active ingredient is cariprazine hydrochloride (HCl). It is a dopamine D3/D2 receptor partial agonist, with a higher affinity for D3 receptors as demonstrated in both in vitro and in vivo studies. It was approved by the FDA in 2015 for the acute treatment of mania/mixed episodes associated with bipolar I disorder in adults and for the treatment of schizophrenia. Its use is also being explored in the treatment of major depressive disorder. Cariprazine capsules are intended for oral administration and should be stored between 20-25 °C. Each hard gelatin capsule contains a white to off-white powder of cariprazine HCl, which is equivalent to either 1.5, 3, 4.5, or 6 mg of cariprazine base.

Overall efficacy and tolerability of cariprazine appears to be good despite some adverse events including akathisia, insomnia, headache, and weight gain. However, most studies reported that the adverse events were mild to moderate. Prior to discussing the mechanism of action of cariprazine and its utility in the present study, we first present a concise review of dopamine transmission and its relevance to ADHD.

Dopamine (DA) neurons are involved in acquisition and reinforcement learning thought to be maintained in part through the mesolimbic dopaminergic system, with projections from the ventral tegmental area (VTA) to regions such as the nucleus accumbens (NAc). The DAergic neurons in the midbrain are the main source of the neurotransmitter (NT) and mediate a wide range of brain functions and behavioural processes such as voluntary movement, mood, reward, addiction, and stress. In addition to the VTA, dopamine neurons expressing D1 and D2 receptors are typically found in the NAc, substantia nigra (SN), striatum, and hippocampus.