Huntington’s disease (HD) is a rare, progressive neurodegenerative disease with autosomal dominant inheritance [1]. It is caused by the expansion of a CAG triplet repeat within the huntingtin (IT15) gene, giving rise to an elongated polyglutamine tract in the resultant protein, therefore causing toxicity through a “gain-of-function” mechanism [2]. The most prominent clinical features include motor symptoms, cognitive impairment (e.g., dysfunction in executive functions, attention, learning and memory), and psychiatric alterations (e.g., depression, apathy, irritability, personality changes). The non-motor symptoms emerge early on and worsen progressively [1, 3]. The longer the polyglutamine repeat, the earlier symptoms start to manifest and the faster they progress. Age of onset ranges from childhood to the eighth decade, but symptoms most commonly appear in the fourth or fifth decades of life. Larger repeats (CAG > 55) are responsible for the juvenile form of HD (JHD), with symptoms appearing before the age of 20. In JHD, 42–94% of patients develop bradykinesia, rigidity, dystonia and psychiatric symptoms [4]. Approximately 30% of JHD patients present with psychiatric or behavioural disturbances (obsessive–compulsive behaviour) at onset [4].

By most, HD is considered predominantly a hyperkinetic movement disorder, as its most obvious and striking features are chorea and dystonia [5]. The early stage of the disease course is dominated by chorea, while dystonia and akinesia become dominant later on [1]. Oculomotor dysfunction can further be observed (e.g., supranuclear gaze palsy, choreatic eye movements) [5]. Despite non-motor symptoms often preceding the emergence of motor symptoms, they are rarely captured as the first signs of HD [6].

Dopamine is a major neurotransmitter playing an essential role in many centrally regulated functions, including attention, learning, memory, mood, motivation, reward and pleasure, motor functions, prolactin production and sleep [7, 8]. The dysregulation of the dopamine system is well-established in the majority of psychiatric and neurological disorders, including HD [9]. Among the five subtypes of dopamine receptors, D1, D2 and D3 play a major role in the pathophysiology of neuropsychiatric disorders and are therefore in the focus of research. Three of the four main dopamine pathways are involved in HD: the mesolimbic (connecting the ventral tegmental area to the ventral striatum), mesocortical (connecting the ventral tegmental area to the prefrontal cortex) and the nigrostriatal pathways (connecting the substantia nigra to the caudate and putamen; responsible for movement) [7].

The basal ganglia, consisting of the substantia nigra, globus pallidus, subthalamic nucleus and of particular importance for HD, the striatum (caudate nucleus and putamen), are a group of deep subcortical nuclei in the brain with extensive interconnections, and are responsible for motor control, cognition and emotion [10, 11].

Neuropathological alterations in HD mainly affect the striatum and the cerebral cortex [12]. Since 90–95% of striatal neurons are comprised of medium-sized spiny neurons (MSNs), the neurodegeneration of the striatum in HD results in a massive loss of these neurons [1, 13]. Two striatal projection pathways are differentiated: the direct (excitatory) and indirect (inhibitory) pathways.

The indirect pathway (Fig. 1A) is responsible for the suppression of undesirable movements and consists of MSNs that express D2 receptors [1]. The indirect pathway originates from the cortex, sending excitatory projections to the striatum, which then sends inhibitory projections to the external globus pallidus (GPe). The GPe provides inhibitory input to the subthalamic nucleus, which in turn projects excitatory input to the internal globus pallidus (GPi). The GPi is connected by an inhibitory loop to the thalamus, from where excitatory connection is established to the cortex. Therefore, the activation of the indirect pathway yields the increased inhibition of the thalamus and the cortex, resulting in movement-suppression [11].

The indirect pathway and its disruption in HD

On the other hand, the direct pathway (Fig. 1B) has been associated with the control and initiation of voluntary movement, and consists of MSNs that express D1 receptors [11]. This pathway originates from the cortex, providing excitatory input to the striatum, from which the inhibitory projections terminate in the GPi. From the GPi, further inhibitory inputs are sent to the thalamus, while the thalamo-cortical projections are excitatory. Therefore, the activation of the MSNs in the direct pathway yields the disinhibition of the thalamus, which projects excitatory input to the cortex, initiating movement [11].

The direct pathway and its disruption in HD

In HD, neurodegeneration affects the MSNs of the indirect pathway early in the disease-course (Fig. 1A): as the number of these neurons decreases, the surplus glutamatergic and dopaminergic excitatory signals that would typically have been directed towards the indirect neurons are funnelled into the direct pathway. As the disease progresses, the direct pathway further becomes impacted by neurodegeneration (Fig. 1B). This biphasic pattern explains the sequence of the appearance of motor symptoms: hyperkinetic movements, such as chorea usually develop in the early phase due to impaired inhibition of motion control by the indirect pathway, while the subsequent impairment of the direct pathway results in hypokinetic state in the advanced stage [11, 14]. Therefore, having balanced dopamine levels is crucial for optimal motor performance: both high and low levels induce malfunction. Based on dopamine’s vital role in the motor symptoms of HD, compounds targeting the dopaminergic system could lead to improvements in motor function, especially dopamine partial agonists that can restore normal dopamine neurotransmission by either increasing or decreasing dopamine receptor activity depending on the amount of dopamine available in the synaptic cleft.

There have been great efforts put into inventing causative treatments for HD, including the reduction of mutant huntingtin concentrations in the central nervous system via gene editing, gene therapy or antisense oligonucleotide approaches [15]. However, no curative or disease-modifying treatments are available yet, therefore symptom control provides the basis of disease-management [16].

The treatment of HD requires a multidisciplinary approach where the combinations of pharmacological and non-pharmacological treatment options are offered to patients tailored to their needs, even prior to the manifestations of symptoms. Pharmacological treatment (for a summary, see Table 1) differs for motor symptoms based on whether they are hyper- or hypokinetic [5]. Hyperkinetic manifestations are treated with medications targeting the dopaminergic system, like dopamine receptor antagonist antipsychotics targeting postsynaptic dopamine receptors, or tetrabenazine (TBZ), a reverse inhibitor of the vesicular monoamine transporter 2 (VMAT2), that concentrates dopamine within presynaptic vesicles [5]. TBZ, and a structurally related molecule with deuterium, deutetrabenazine (deuTBZ), have been shown to be efficacious in the reduction of hyperkinetic movements, such as chorea, dystonia or tardive dyskinesia [17]. However, the FIRST-HD study revealed that despite displaying similar efficacy, deuTBZ is associated with less side-effects compared to TBZ [18]. In line with these findings, a network analysis showed that TBZ was more likely to cause depression and somnolence than deuTBZ [17].

Antipsychotics acting on D2 receptors have demonstrated therapeutic potential as well [11]. Aripiprazole, a D2 receptor partial agonist, had similar efficacy inhibiting chorea as TBZ, although it failed to effectively improve cognition [19]. A D2 receptor antagonist, haloperidol, was shown to improve symptoms of chorea in some HD patients [20], as well as to reduce mutant huntingtin aggregate formation in a rat model of HD [21]. However, it did not yield an increase in functional capacity [22]. Furthermore, risperidone, a D2 receptor antagonist, showed superiority in the management of motor symptoms compared to placebo [23]. Clozapine could not effectively manage chorea, although results are controversial [24]. There is evidence that potentially higher doses of clozapine are required to achieve the desired effect on chorea [24], however, it may result in significant adverse effects, like fatigue, dizziness and gait disturbance [25]. In addition, a new dopaminergic stabiliser, pridopidine, was recently developed for the treatment of motor symptoms associated with HD. A systematic review and meta-analysis of four randomised controlled trials showed that pridopidine significantly outperformed placebo on the Unified Huntington’s Disease Rating Scale (UHDRS)-modified Motor Score (mMS), but not on the Total Motor Score (TMS) [26]. However, for a pridopidine dose of at least 90 mg/day, TMS also showed significant improvements in addition to the mMS, but also increased the occurrence of adverse events compared to placebo, such as nasopharyngitis and insomnia [26].

It is important to take into account that medications used in HD have the propensity to cause deteriorations in mood, cognition, and alertness. Therefore, it is crucial to consider the non-motor symptoms of HD as well when choosing a medication: the most optimal ones address all symptom domains of the disease, including mood, cognitive, psychiatric, and motor symptoms as well.

Cariprazine (CAR) is a dopamine D2-D3 partial agonist with preferential binding to the D3 receptors. It is approved for the treatment of schizophrenia by the European Medicines Agency [27] and by the Food and Drug Administration (FDA) [28], and for the treatment of depressive and manic/mixed episodes associated with bipolar disorder by the FDA. Furthermore, it has been recently approved as an adjunctive therapy in major depressive disorder by the FDA [29]. Cariprazine has a high affinity to D3, D2 and serotonin 5HT1A receptors at which it acts as a partial agonist, and to 5HT2B receptors, at which it acts as an antagonist [30]. Furthermore, it has a moderate affinity to serotonin 5HT2A and 5HT2C receptors, where it exerts antagonist activity [30]. It has two major metabolites, desmethyl CAR and didesmethyl CAR which are pharmacologically equipotent to CAR and they jointly achieve the overall therapeutic effect [31, 32].

The aim of the present study was to determine whether CAR is an effective pharmacological treatment option for controlling motor symptoms associated with HD.