Adjunct Treatment With Cariprazine for Adults With Attention-deficit/Hyperactivity Disorder
Adjunct Treatment With Cariprazine for Adults With Attention-deficit/Hyperactivity Disorder
According to the Canadian ADHD Practice Guidelines, psychostimulants are the preferred
 treatment of attention-deficit/hyperactivity disorder (ADHD), especially for those that
 require urgent care. Specifically, long-acting psychostimulants are considered the
 gold-standard pharmacological treatment for ADHD. Using extended-release formulations,
 long-acting psychostimulants provide an extended duration of daily symptom relief in addition
 to overall reductions in ADHD symptoms that are maintained over time.

 In accordance with these guidelines, clinicians may combine psychostimulants with other
 medications when it is considered necessary. For complex cases, psychostimulants alone are
 often inadequate for improving the effects of ADHD and are therefore prescribed in
 conjunction with other medications. At low doses, antipsychotics have been considered
 appropriate adjunctive medications. Studies show that most adult cases with ADHD that were
 undiagnosed or untreated in childhood result in the need for adjunctive medication in
 adulthood to enhance the effects of the psychostimulant. As a result, it is hypothesized that
 adjunct treatment with a low dose of cariprazine, an atypical antipsychotic, will enhance the
 effectiveness of standard ADHD treatment with a long-acting psychostimulant in a subset of
 the ADHD population that achieved little to no response on 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.

 The DA neurons exhibit two activity states that mediate separate aspects of behavior. Phasic
 DA release mainly activates D1 receptors, whereas tonic DA release mainly activates the
 higher affinity D2 receptors. Phasic activity is thought to facilitate cue-reward acquisition
 and acquisition of incentive salience, whereas tonic activity is involved in response
 inhibition and behavioural flexibility. D2 receptor stimulation has been shown to act in
 opposition to D1 receptors in the regulation of substrates downstream of cyclic adenosine
 monophosphate (AMP). Furthermore, D2 receptor function appears to play a critical role in the
 maintenance of reward functions via the NAc as suggested by pharmacological studies. Recent
 findings also indicate that phasic DA release drives a rapid activation of D2 neurons,
 suggesting that some of the behavioural effects of phasic release may be partially mediated
 by D2 signaling.

 It has been hypothesized that the D1 pathway is involved in promoting reward responses while
 the D2 pathway may mediate the opposite response. Phasic DA events are also proposed to
 indicate the importance of learned reward-predictive cues that drive motivated behavior.
 Moreover, D3 receptors (D3R), a D2-like receptor, are present in high density in the ventral
 striatum, which is a cross-section of neural networks involved in processes of reward,
 motivation, and decision making, and are thought to be tonically occupied by endogenous DA.
 Due to the projections to/from the prefrontal cortex, abnormal activity at these receptors
 may be a potential marker for prefrontal deficits, which underlie the comorbidity between
 ADHD and depression and often contributes to treatment resistance in a subgroup of the
 population. Cariprazine is therefore assumed to act by exerting antagonist-like actions by
 inhibiting the binding of the full agonist DA.

 Cariprazine was found to be unique among antipsychotics in its ability to increase
 dopaminergic D3R levels in D3R-rich brain regions following chronic treatment. The exact
 mechanisms of action underlying cariprazine's effects have not been fully elucidated.
 Zimnisky et al. (2013) found that in D3R knockout mice, cariprazine demonstrated
 D3R-dependent protective effects on cognitive function. In addition, Duric et al. (2017)
 recently reported that cariprazine significantly attenuated chronic unpredictable
 stress-induced anhedonia-like behaviour in wild-type mice. This effect was not observed in
 D3R knockout mice, suggesting that the activity is dependent upon D3Rs.

 This is significant because alterations in reward circuitry, particularly involving the
 prefrontal cortex, have been observed in ADHD. Specifically, neurotransmitter studies have
 revealed abnormalities in DA and norepinephrine (NE) signaling in ADHD. DA and NE activity
 are associated with many prefrontal cortex functions, including those involved in the
 attentional control system, reward acquisition and maintenance and maintenance of hedonic
 tone. Of further interest is the relationship of serotonin (5-HT) to DA and NE because 5-HT
 is hypothesized to decrease DA and NE activity through 5-HT binding to the 5-HT2a and 5-HT2c
 receptors respectively. It appears that at lower doses, cariprazine is considered a DA
 receptor partial agonist, which may serve to increase striatal DA activity, thereby improving
 aberrant reward system functioning in individuals with ADHD. At higher doses, cariprazine,
 like most antipsychotics, functions as a DA receptor antagonist, thereby further reducing DA
 activity. In theory, higher doses of cariprazine should not improve ADHD symptoms.

 The DA theory of ADHD states that ADHD results from DA deficits, specifically lowered
 activity in the frontal cortex and striatum, and is supported by a variety of pharmacological
 and imaging studies. Given the role of this hypothesized deficit in reward maintenance and
 specifically in hedonic tone among ADHD patients, adjunctive treatment with low dose
 cariprazine, a D2/D3R agonist, may have the ability to elevate DA activity in the frontal
 cortex and ventral striatum and help attenuate dysfunction of the reward circuitry in complex
 and severe ADHD patients. For the present study, we are particularly interested in the
 potential action of adjunctive low dose cariprazine in the treatment of ADHD with or without
 comorbidities for individuals who have had inadequate response to psychostimulants alone. The
 trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP)
 guidelines, and with applicable Health Canada regulatory requirements. Site-specific Standard
 Operating Procedures (SOPs) for conducting clinical trials will be followed for the
 recruitment of participants, adverse event reporting, and for the collection, management and
 analysis of data throughout the duration of the study.

 Study Population Participants (N = 15) with a primary diagnosis of ADHD using diagnostic and
 statistical manual of mental disorders (DSM)-5 criteria, with or without comorbid secondary
 illnesses, who meet all other inclusion/exclusion criteria are eligible for entry into the
 study. We have chosen to assign 10 potential patients as the number of desired completers (N
 = 10). Given that the dropout rate with dose adjustment is estimated to be approximately 33
 percent, we will enroll a total of 15 participants to complete the study.

 All participants will be assigned a participant identification number to maintain patient
 confidentiality. Binders will be created for each participant using their unique
 study-specific participant ID in order to store and maintain source documents according to
 the visit number throughout the duration of the study. Physical binders will be stored in a
 locked research office at the site. Source documents both related and unrelated to the
 current study will also be stored electronically in a PHIPA-compliant electronic medical
 record system. All source documents will be de-identified and will be identifiable only to
 members of the study personnel through a password-protected document that contains
 participant names and their corresponding participant IDs. Participant data will be entered
 into the statistical analysis software (SPSS) using the unique participant IDs in order to
 maintain patient confidentiality. The study investigator will permit trial-related
 monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to
 source data and documents.

 Statistical Plan To evaluate the efficacy of adjunct cariprazine (1.5 - 3 mg, daily) in the
 treatment of ADHD with or without comorbidities, each participant will act as his/her own
 control (within-subjects design) and will be evaluated based on pre-treatment and
 post-treatment responses on the primary and secondary outcome measures. The research question
 is as follows: Does treatment with adjunct cariprazine improve ADHD symptoms in participants
 that are on a stable dose of their psychostimulant who have not yet achieved remission? H0
 Adjunct treatment with cariprazine does not improve ADHD symptoms. H1 Adjunct treatment with
 cariprazine improves symptoms of ADHD in outpatients who are on a stable dose of an existing
 psychostimulant and have not yet achieved remission.

 To answer the research question, a within-subjects t-test will be performed to compare
 baseline and post-treatment total scores on the primary ADHD measure.

 Secondary analyses will employ a series of within-subjects t-tests to evaluate the
 relationship between cognition, energy and motivation, and hedonic tone at baseline compared
 to post-treatment of 8 weeks with adjunct cariprazine. There are no plans for interim
 analysis at this time. No pharmacokinetic analyses will be undertaken.

 Response or remission on the primary ADHD outcome measure will be assessed, in addition to
 statistical analyses testing significance of absolute change in total scores. All parametric
 tests will be 2-tailed and performed at a 5 percent alpha level. Descriptive statistics will
 be provided by assessments for the total score and changes from baseline in the total score
 on all of the measures used. Data based on observed cases and last observation carried
 forward will be summarized. Overall, the safety and tolerability of cariprazine in
 participants with ADHD will be assessed by changes from baseline in physical examination,
 clinical laboratory test results, and vital signs. Safety analyses will be presented by means
 of descriptive statistics, frequency tables and graphical presentations as appropriate.
Inclusion Criteria:

 1. The participant has provided signed informed consent.

 2. Males and/or females aged 18-70 (extremes included).

 3. Participants with a primary diagnosis of ADHD according to DSM-5 (314.01) criteria
 (diagnosis to be made using the Mini-International Neuropsychiatric Interview (MINI)
 7.0.2 and confirmed by the Diagnostic Interview for ADHD in Adults (DIVA 5.0).
 Participants with a comorbid anxiety and depressive disorder will be permitted, as
 long as ADHD is judged to be the primary diagnosis.

 4. Participants who score an ASRS of ≥ 4 in Part A at both Screening and Baseline,
 representing non-response to current stable psychostimulant treatment

 5. Participants are on a stable dose (> 4 weeks) of their existing long-acting
 psychostimulant (any type) prior to entry into the study.

 6. Participants are on a stable dose of any other psychotropic medication (> 8 weeks) to
 treat comorbid conditions, except antipsychotics.

 7. On the basis of a physical examination, medical history and basic laboratory
 screening, the patient is, in the investigator's opinion, in a suitable condition.

 Basic laboratory screening includes:

 Chemistry: Electrolytes, ALT, Albumin, Alkaline Phosphatase, AST, Bilirubin Total
 protein, Creatinine, Urea (BUN), CK, GGT, Potassium, Sodium, Calcium, Glucose
 (Fasting), Bilirubin Direct, Bicarbonate, Chloride, Urate (for Uric Acid), LD,
 Magnesium, Phosphorus, Amylase CBC: Hematocrit, Hemoglobin, RBC, WBC + differential,
 abs. Platelet Count Drug Screen (urine-8 tests): amphetamines, benzodiazepines,
 barbiturates, methadone, cocaine, opiates, cannabinoids, PCP Standard Urinalysis Lipid
 Assessment: Cholesterol, HDL, LDL-calc, Triglycerides Prolactin

 8. Willing and able to attend study appointments in the correct time windows.

 Exclusion Criteria:

 Participants meeting one or more of the following criteria cannot be selected for
 inclusion:

 1. Any other primary mental health disorder in the previous six months.

 2. Alcohol or drug abuse as defined in the DSM-5 criteria within the last six months.

 3. Mania, hypomania as defined in the DSM-5 criteria.

 4. Any psychotic disorder.

 5. Eating disorders as defined in the DSM-5 criteria.

 6. Any cognitive disorder or dementia within 3 months before the baseline visit.

 7. A history of Seizure Disorder (Epilepsy or other).

 8. Clinical interpretation of apparent suicide risk.

 9. Commencement of formal psychotherapy for 4 weeks prior to entry into the study and/or
 during the course of the study.

 10. Existing treatment with any antipsychotic as mono- or adjunct therapy at the time of
 the study.

 11. Change in use of medications.

 12. Laboratory values at screening or in medical history that may be considered through
 clinical interpretation to be significant, including positive drug and alcohol tests.

 13. Diseases that could through clinical interpretation interfere with the assessments of
 safety, tolerability and efficacy of study treatment.

 14. Serious illness: liver or renal insufficiency, cardiac, vascular, pulmonary,
 gastrointestinal, endocrine, neurological, infectious, neoplastic or metabolic
 disturbance.

 15. If female, the subject is pregnant or lactating or intending to become pregnant
 before, during, or within 30 days after participating in this study, or intending to
 donate ova during such time period.

 16. The participant has received electroconvulsive therapy, vagal nerve stimulation, or
 repetitive transcranial magnetic stimulation within 6 months prior to Screening.

 17. The participant is, in the opinion of the investigator, unlikely to be able to comply
 with the clinical trial protocol or is unsuitable for any other reasons.

 18. Contraindications and Warning Precautions as per the U.S. Product Monograph will be
 followed.

 Participants must discontinue the use of recreational drugs including cannabis for at least
 2 weeks prior to entry into the study. Participants must limit alcohol intake to a maximum
 of 3 standard drinks per week during the study period.