The recommendations of this guideline were established through a Delphi process (strength of consensus > 75–95% for all recommendations), achieved over two rounds of voting. All statements for which consensus strength is not specified separately were met with a consensus of > 95%.
Hyperkinesia/chorea
For the pharmacotherapy of choreatic hyperkinesia, D2/D3-dopamine receptor antagonists (e.g., tiapride) and inhibitors of vesicular monoamine Transporter 2 (VMAT2; e.g., tetrabenazine) are available. The quality of data from RCTs is currently best for VMAT2 inhibitors [
18]. However, the tetrabenazine side effect of depression is clinically relevant since HD patients are prone to depression [
37]. Comparative studies (comparing head-to-head compounds for their ability to suppress hyperkinesias short- and long-term) are unavailable. Therefore, no evidence-based recommendation can be made on best medical practice [
9,
10,
31,
38,
43,
44].
For tiapride, which has been used since the 1970s for treating movement disorders (including HD), the lack of recent RCTs or clinical studies meeting today's quality standards is counterbalanced by many years of clinical real-life experience. Because of the favorable profile of side effects, in particular with regard to extrapyramidal (akathisia, Parkinsonism) and behavioral (depression) symptoms, the consensus in the Delphi group was that tiapride should be considered as first line treatment.
The use of tetrabenazine (in combination or as monotherapy) is recommended if treatment with tiapride is either not tolerated or not efficacious. Combining the two antidopaminergic drugs, tiapride (postsynaptic) and tetrabenazine (presynaptic), might help to reduce the dosage of the respective individual compounds and thereby reduce side effects. There are no studies on combination therapy available (see Table
1).
Table 1
List of compounds used to treat hyperkinesia in Huntington’s disease
Tetrabenazine | Starting dose: 2 × 12,5 mg Target dose: up to 3 × 75 mg per day max. daily dose ~ 200 mg If sedative side effects occur, consider dividing the medication into four separate doses, with the primary dosage administered as the nighttime medication | Depression/suicidality, sedation, sleep disorders, and extrapyramidal side effects, Parkinsonism, akathisia Rare cases of a neuroleptic malignant syndrome Do not combine with MAO inhibitors! |
Tiaprid | Starting dose: 2 × 50 mg Target dose: up to 4 × 300 mg pro Tag Max. Daily dose ~ 300 to 1000 mg. One study used up to 3000 mg daily If sedative side effects occur, consider dividing the medication into four separate doses, with the primary dosage administered at nighttime | Side effects similar to another classic dopamine D2 receptor antagonists, in particular sedation and Parkinsonism |
Atypical neuroleptics, e.g. risperidone, olanzapine and aripiprazole | Similar to psychiatric indications | Only smaller studies and case reports Occasionally Parkinsonism monitoring for impulsivity and impulse control disorders for aripiprazole (Risperidone may also be helpful for the treatment of irritability; Olanzapine may also be beneficial for the treatment of weight loss) |
Haloperidol | Similar to psychiatric indications 5 to 10 mg/day (as evening dose) sufficient in most cases | Side effects of a classic Dopamine receptor antagonists, esp. Parkinsonism not drug of the first choice possibly useful in cases with psychosis or aggressive behavior |
Amantadine | 100 to 400 mg daily dose (divided into 2 to 4 single doses) | Data partially contradictory Caution: Psychosis! (consensus strength 80%) |
Valproate | effect dose-dependent | Rarely indicated in myoclonic Hyperkinesia (action myoclonus; [ 6, 10, 53]) |
Levetiracetam | Up to 2 × 1500 mg per day | Only small studies and case reports Parkinsonism, sedation, cognitive disorders, increased irritability! |
Alternatively, other antipsychotics can be used. Olanzapine (up to 30 mg/day) showed a favorable effect in two out of three small open studies [
9,
10,
43,
44]. For quetiapine, zotepine, ziprasidone, and aripiprazole, only small studies and case reports describing a beneficial effect on motor function are available [
9,
10,
43,
44]. A small study comparing the antichoreatic efficacy of aripiprazole and tetrabenazine describes a similar antichoreatic effect [
11,
14]. For risperidone, a beneficial effect on motor and psychological functions after using a depot preparation was described [
9,
10,
32,
43,
44]. This benefit may also be explained by an improvement of psychomotor restlessness, which may result in a beneficial effect on hyperkinesia. Clozapine did not reduce chorea [
9,
10,
43,
44].
Many other studies investigating classical dopamine receptor antagonists (trifluperidol, thioproperazine, phenothiazine, trifluoperazine, perphenazine, chlorpromazine, melperone) reported no definite effects and these should not be used [
10]. Haloperidol, however, has been shown to be effective in several Level II studies [
9,
10,
43,
44].
Because of the potential to further slow down intended/voluntary movements and the fact that hypo-/brady-kinesia is a common sign in HD, all anti-choreic compounds should be used sparingly and should be prescribed primarily in the case of subjectively disabling hyperkinesias (if necessary, starting with very low dosages, e.g., only half a tablet; [
26]). The impact of antichoreic prescriptions and, therefore, the success of an antichoreatic therapy may become apparent only with some delay, i.e., following a treatment period of four to six weeks for tiaprid and tetrabenazine. Therefore, an increase in dosage and dose reduction should always be done step by step, keeping in mind the delayed effects.
Given the frequently observed sedative side effects of compounds with antichoreatic efficacy, potentially aggravating a reversal of the day-night rhythm in extreme cases (consensus strength 91%), the principal dosage of antichoreatic drugs should be given as a night medication.
As a more hypokinetic-rigid phenotype often emerges in later stages of HD, a dose reduction of antidopaminergic compounds or switching to preparations with a lower risk for hypo-/brady-kinetic side effects might be helpful. A dose reduction of antidopaminergic drugs may also improve swallowing.
Data on the antichoreic efficacy of amantadine are partially contradictory, but amantadine appears to have an antichoreatic effect particularly in paraneoplastic chorea [
10,
25
Levetiracetam has also been described as helpful [
10; consensus strength 90%)].
Evidence for the effectiveness of memantine is lacking [
47]. Ethyl-EPA showed no improvement in motor symptoms after six months of therapy [
10]. A European phase III study confirms this negative result [
19]. An improvement in the clinical signs and symptoms caused by the phosphodiesterase 10a inhibitor PF-02545920 could not be confirmed, the primary endpoint was not reached [
17].
Cannabinoids such as Tetrahydrocannabinol and nabilone are considered potentially helpful in treating motor symptoms and signs [
5,
13,
16]. Tetrahydrocannabinol was safe and well tolerated but without symptomatic effect in a randomized, double-blind cross-over placebo-controlled pilot study over twelve weeks of treatment ([
46], consensus strength 90%).
Deep brain stimulation is experimental and should only be employed in the context of clinical studies. A small German pilot study on deep brain stimulation showed an improvement in chorea after GPi/GPe stimulation in some patients [
63]. A complete analysis of an RTC on deep brain stimulation funded by DFG and the CHDI Foundation is underway. According to preliminary results, the primary endpoint of this clinical trial (UHDRS score at 12 weeks following surgery comparing stimulation on vs. stimulation off) was missed (presentation March 3, 2022, 17th Annual HD Therapeutics Conference, CHDI, Palm Springs; DRKS S00006785, Eudamed no. CIV-13-12-011770; consensus strength 90%). Chorea scores appeared to improve in both study arms in some participants, including the ones with stimulation off. A meta-analysis reported no significant changes in the UHDRS total score after restorative brain graft injections, whereas deep brain stimulation resulted in a substantial reduction of chorea. According to expert opinion in this metaanalysis, GPi-DBS should be considered in cases where the extent of chorea is the primary therapeutic challenge and should therefore be used selectively [
39].
Depression
Depression is a common and clinically significant complaint in HD (consensus strength 91%). An increased rate of suicides is well documented, and the risk may be even higher in families with a history of (frequent) suicides. The time of clinical diagnosis (at the beginning of the disease) and the time when the condition has a functional impact threatening independent living are thought to be phases of increased suicidal risk. For that reason, suicidality should be assessed frequently [
6]. Apathy and loss of motivation may be symptoms of depression, side effects of antidopaminergic drugs (pharmacogenic depression) or may occur independently of pharmacotherapy as part of the natural history of HD. Apathy typically increases over the course of the disease.
There is hardly any data from RCTs or controlled studies on treating mental health problems in HD. Recommendations are therefore based on expert opinion. Therapy, in general, is not different from the principles of psychiatric treatment. MAO inhibitors should be avoided (e.g. contraindication for tetrabenazine).
SSRIs and, in particular, venlafaxine [
29] seem to be effective in patients suffering from severe depressive episodes. In patients with depression and sleep disorders, which may possibly be a part of the neurodegenerative process, the use of mirtazapine and mianserin [
6], possibly also melatonin or melatonin agonists [
1,
61] is recommended. Potent anticholinergic tricyclic antidepressants should be avoided, or only low dosages should be used because of potential side effects on hyperkinesias and cognition. However, tricyclic antidepressants might be helpful in patients suffering from sleep disturbances and simultaneously from hypersalivation.
In patients suffering from mild depression, antidepressant treatment with sulpiride (50–600 mg per day), a nearly selective D2 antagonist, which tends to improve hyperkinesia, might be helpful. Due to the inhibition of mainly presynaptic dopamine D2 receptors in the low dose range of up to 200 mg/day, effects on motivation are possible. To date, there have been few RCTs on antidepressant therapy for HD. A small randomized, double-blind, placebo-controlled study of fluoxetine in nondepressed patients with HD was negative for changes in total functional capacity (TFC) and standardized neurological, cognitive, and behavioral ratings [
15]. There is limited experience with tianeptine, potentially helpful in anxious depression and somatizing complaints. In an animal model for HD, tianeptine improved synaptic plasticity in the hippocampus [
2,
64].
In patients suffering from severe, therapy-refractory depressive episodes, electroconvulsive therapy (ECT) has been used [
6]. However, ECT may cause massive (consensus strength 91%) short-term memory impairment and should, therefore, only be used exceptionally.
Fear, agitation
In patients with mild symptoms, herbal remedies, anxiolytics such as buspirone, hydroxyzine, non-tricyclic antidepressants (e.g., mirtazapine), and sedating antipsychotics with low anticholinergic side effect profile can be used.
For anxious depressive symptoms, using an SSRI or SNRI, such as venlafaxine, may be helpful (Caution is advised: in particular, initially, a worsening of symptoms is possible; [
6]. With amitriptyline and diazepam in HD [
10] and with opipramol, improvements of anxiety and somatoform symptoms have been reported [
62]. As with every tricyclic substance, anticholinergic side effects must be considered. Based on a benefit-risk assessment, the use of benzodiazepines or benzodiazepine receptor agonists (zolpidem, zopiclone) is justified, especially in more advanced stages of the disease. The development of tolerance and rebound effects must be considered.
Irritability, aggressive behaviour, sexual disorders, agitated behavior
Irritability and aggression are common issues in the care for patients with HD. Improvements were reported after treatment with antipsychotics (particularly risperidone), valproate, benzodiazepines, beta-blockers (propranolol), SSRI, possibly in combination with mirtazapine or mianserin, as well as buspirone [
6,
10,
20,
37,
51,
59]. The use of synergistic effects might be helpful. Risperidone, in some cases, not only reduces irritability but also chorea and improves sleep disruption. Olanzapine can also be beneficial for weight loss and chorea treatment, and quetiapine can also be used as a mood stabilizer with an additional antidepressant effect.
It should be noted that SSRIs, especially at the beginning of therapy, can worsen inner tension and irritability. In such a case, the additional administration of a benzodiazepine for 1–2 weeks might be helpful [
3]. In addition, mood-stabilizing drugs and lamotrigine, lithium, or carbamazepine were described to be helpful [
20,
38,
41,
56].
Zuclopenthixol (drops or depot), levomepromazine, and haloperidol [
20,
27,
41] might be helpful in severe irritability and aggression. RCTs for the treatment of irritability in HD are not available. There are only single case reports for using cannabinoids, such as Dronabinol [
54].
Behavior management techniques are helpful in individual cases, such as staying separate instead of arguing in case of a conflict, distraction, and setting a routine. In addition, low-potency neuroleptics might be beneficial. Whether administering the inhalation neuroleptic drug loxapine is helpful needs to be sufficiently explored.
Exhibitionism, which rarely occurs, was successfully treated in one case with leuprorelin. Hypersexuality has been reported to be treated with medroxyprogesterone, cyproterone acetate (note: increased risk of meningioma) in other dementias, and with atypical neuroleptics (as part of impulse control disorders). SSRI (high dose, if in the context of perseverative thinking and behavior) and clomipramine might be helpful [
10,
33,
36,
58].
Often a depressive episode can cause reduced libido. On the other hand, sexual dysfunction is a well recognized potential side effect of SSRIs [
6].
In agitated behavior, causes should be looked for, such as pain, constipation, voiding problems resulting in an overly filled urinary bladder, or environmental factors (stimulus shielding recommended; [
6]).
Sleep disorders
About two-thirds of all HD patients suffer from sleep disorders. The etiology is diverse. Some patients may suffer from a sleep disorder in the context of a depressive episode. These patients should be treated with sedating antidepressants (without pronounced anticholinergic side effects) at night.
Sometimes sleep disorders occur because of sedative side effects of antihyperkinetic medication during daytime, with a day-night reversal. In this situation, it might be helpful to use sedative side effects of these drugs to induce sleep if the primary dosage is administered at nighttime. This dosing regime can also be beneficial for treating disturbing hyperkinesias during the night.
For disease-related alterations in circadian rhythm, melatonin, or sedating antidepressants such as mirtazapine and mianserin, trazodone, or antihistamines might be helpful. In milder cases, herbal remedies (e.g., valerian, lemon balm, passion flower, lavender) can be used. Hypnotics should be avoided or used only for a short time because of the possibility of habituation [
3,
6].
Weight loss, difficulties in swallowing, vomiting, constipation
HD patients are frequently catabolic and therefore require high-caloric supplementation food, possibly up to six to eight meals per day and/or high-caloric food supplements. In the case of difficulties in swallowing, thickening liquids can be helpful. Under certain circumstances, an early percutaneous endoscopic gastrostomy (PEG) system might improve quality of life. Discussions early on with those affected and their relatives about the potential need for a PEG system are recommended. Recurrent vomiting and reflux may be seen in patients on PEG nutrition in the advanced stages of the disease due to a limited absorption capacity of the stomach. Continuous PEG nutrition using an infusomat, dilution of the high-caloric food with water, or appropriate fractioning of meals into several smaller portions may be helpful. In addition, a slight elevation of the upper body—about 30 degrees—can be beneficial in the case of reflux-related vomiting. Furthermore, myocloniform diaphragmatic hyperkinesia may be the cause of recurrent sudden vomiting. In these cases, an increase in antihyperkinetic medication or valproate acid in myocloniform diaphragmatic hyperkinesia might be helpful. On the other hand, reducing neuroleptics can be beneficial in recurrent vomiting [
6]. Always consider the side effects of pharmacotherapy as a possible cause. Proton pump inhibitors should be used in gastric reflux [
4].
Constipation can occur as part of the involvement of the autonomous nervous system, as a side effect of pharmacotherapy, and because of being bedridden. Using laxatives and procedures to improve constipation might be necessary in these cases. High-fiber food (e.g., wheat bran, psyllium husks, flaxseed), adequate drinking (1.5–2 L per day), and physical activity are recommended. Patients should be advised that suppressing the urge to defecate should be avoided. Macrogols (e.g., Movicol), sodium picosulfate, bisacodyl, or prucalopride might be used for acute functional and chronic constipation.