The improvement of motor symptoms in Huntington's disease during cariprazine treatment.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease, characterised by motor disturbances and non-motor (i.e., psychiatric) symptoms. Motor symptoms are the hallmark features of HD and take many forms. Their emergence is related to alterations in striatal dopaminergic neurotransmission: dopamine levels increase in the early stages of the disease, while more advanced stages are characterised by reduced dopamine levels. Such a biphasic change potentially explains the alterations in motor symptoms: increased dopamine-production induces hyperkinetic movements early in the disease course, while depleted dopamine storage leads to hypokinetic symptoms in the advanced phase. Dopamine D2-D3 partial agonists could be a promising treatment option in HD, as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course. Therefore, the present study aimed at exploring the effects of cariprazine, a dopamine D2-D3 partial agonist with high affinity to D3 receptors, on motor symptoms associated with HD. METHODS: This was a single-centre, retrospective study where sixteen patients received off-label cariprazine treatment for 12 weeks (1.5-3 mg/day). Motor symptoms were evaluated using the Motor Assessment of the Unified Huntington's Disease Rating Scale. Least Square (LS) Mean Changes from Baseline (BL) to Week 8 and Week 12 in the Total Motor Score (TMS) were analysed using the Mixed Model for Repeated Measures method. In addition, improvement from BL to Week 8 and 12 was calculated for all motor items. RESULTS: Data of 16 patients were collected, but data of only 15 patients were analysed as one patient dropped out due to non-compliance. Significant changes were observed from BL to Week 8 (LS Mean Change: -9.4, p < 0.0001) and to Week 12 (LS Mean Change: -12.8, p < 0.0001) in the TMS. The improvement was captured in the majority of motor functions, excluding bradykinesia and gait. Mild akathisia was the most commonly reported side-effect, affecting 3 patients. CONCLUSION: This is the first study investigating the effectiveness of a D2-D3 partial agonist, cariprazine, in the treatment of HD. The findings of this study revealed that cariprazine was effective in the treatment of a wide range of motor symptoms associated with HD.

Real-Life Clinical Experience With Cariprazine: A Systematic Review of Case Studies.

Background: The hierarchy of evidence coming from evidence-based medicine favors meta-analyses and randomized controlled trials over observational studies and clinical cases. Nonetheless, in the field of psychiatry, where conditions are much more complex, additional evidence coming from real-world clinical practice is necessary to complement data from these gold standards. Thus, in this systematic review, the aim is to summarize the evidence coming from clinical case reports regarding cariprazine, a third-generation antipsychotic drug that has been approved for the treatment of schizophrenia and bipolar I disorder with manic, depressive or mixed features in adults. Methods: A systematic review was performed using Embase and Pubmed databases searching for English-language cases published in peer-reviewed journals between 2000 January and 2021 September with the following search terms: (cariprazin* OR "rgh-188" OR rgh188 OR vraylar OR reagila) AND ("case report*" OR "case report"/de OR "case stud*" OR "case study"/de OR "case seri*"). Results: After the removal of duplicates, 49 articles were retrieved via the search, from which 22 were suitable for this review. These 22 articles encompassed 38 cases from which 71% described patients with schizophrenia, 16% patients with psychotic disorders, 5% patients with mood disorder and 8% described patients with other disorders such as Wernicke-Korsakoff syndrome, borderline personality disorder and obsessive-compulsive disorder with paranoid schizophrenia. The median age of patients was 31, and half of them were female. The majority of patients (76%) started cariprazine with 1.5 mg/day, and the most common maintenance dose was 4.5 mg/day (34%) and 3.0 mg/day (29%). Conclusion: Cariprazine was found to be safe and effective in a wide range of psychiatric conditions with different symptom profiles from acute psychotic symptoms through addiction to negative and cognitive symptoms. The results are in-line with the established evidence from clinical trials, however, they also show how cariprazine can be successfully utilized for treating certain symptoms irrespective of the indication.

Reducing Addiction in Bipolar Disorder via Hacking the Dopaminergic System.

The dopaminergic system plays a central and decisive role in substance use disorder (SUD), bipolar disorder (BD), and possibly in a subgroup of patients with refractory depression. Common genetic markers and underlying cellular processes, such as kindling, support the close link between these disorders, which is also expressed by the high rate of comorbidity. Although partial dopamine agonists/antagonists acting on D2 and D3 receptors have an established role in treating BD, their usefulness in SUD is less clear. However, dopamine D3 receptors were shown to play a central role in SUD and BD, making D2/D3 partial agonists/antagonists a potential target for both disorders. This narrative review examines whether these substances bear the promise of a future therapeutic approach especially in patients with comorbid BD and SUD.

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment.

In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5-3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.