Approach

Optimal management of Huntington's disease requires a multidisciplinary approach.[61]​ The goal of treatment is to reduce the burden of symptoms, maintain/improve quality of life, and provide social and psychological support. Although there are currently no effective disease-modifying therapies, there are symptomatic and supportive treatments.[36][62]

Patients usually benefit from multidisciplinary care, with a combination of pharmacological and non-pharmacological treatments. There is little evidence specific to Huntington’s disease to guide choice of treatment; therefore, recommendations are primarily based on clinical consensus and expert opinion.[32][62]​​[63]​​​[64]

Information and support

Soon after the genetic diagnosis and at various time points along the course of their journey, discussion with patients and family members should address the hereditary nature of the disease, its natural history including variations in speed of progression/sequence of events, behavioural issues, as well as provide safety advice regarding driving, use of firearms, and discarding accumulated prescription drugs. Huntington’s disease can significantly affect family dynamics, often driven by behavioural symptoms, its hereditary nature, as well as the demands placed on carers. If there has been a particularly problematic experience in the family, such information can be comforting.

A significant area of potential intervention by clinicians is carer support. The burden of caring for an affected patient is considerable and taxes families emotionally, physically, and financially. Directing families to community resources, Huntington's disease support groups, and relevant governmental agencies can be of benefit. Huntington’s Disease Association Opens in new window International Huntington Association Opens in new window​ Acknowledging the challenges faced by carers should be part of every clinic visit.

Depression

The most serious treatable problem both in those at risk for the disease or in those who have been diagnosed is depression. Treatment of depression is vital and reduces the risk of suicide.

First-line treatments are antidepressants and/or cognitive behavioural therapy (CBT).[62]​ Depressive symptoms in individuals with Huntington’s disease respond well to antidepressants.[65][66][67]​ Treatment is similar to treating depression in the general population. However, given the increased risk of suicide, additional precaution about the potential of intentional overdose needs to be considered while prescribing.

Comparative studies of antidepressants in Huntington's disease are not available, so choice of agents is based on clinical judgement relating to likely benefit and harms, suicide potential from overdose, and associated behavioural symptoms. Selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, sertraline, escitalopram) are most commonly used.[62]​ Citalopram is frequently used as a first-line choice for patients with depression alone, and sertraline is often used first-line for patients with depression and comorbid irritability or anxiety. Second-line options include escitalopram.

If the patient is likely to be prescribed tetrabenazine (for chorea), then citalopram, sertraline, or escitalopram are the preferred choices. Other SSRIs (fluoxetine, fluvoxamine, paroxetine) are more potent inhibitors of CYP2D6 and may thus reduce clearance of tetrabenazine, causing toxic adverse effects.

In emergent or severe cases, drugs with a more rapid onset of action, such as mirtazapine (a tetracyclic antidepressant), may be considered.[65] Mirtazapine can also be helpful if there is concomitant insomnia.[32]

If there are adverse events or failure of response to any drug, trial another drug or consider referral to a psychiatrist.

Psychotherapy (e.g., CBT) and counselling can be extremely helpful for patients with Huntington’s disease experiencing depressive symptoms. While only small, uncontrolled studies are available to support the use of psychotherapy for depression in patients with Huntington’s disease, guidelines suggest considering it based on evidence from other neurodegenerative diseases and the general population.[62][68][69]

In patients with refractory depression, electroconvulsive therapy can be of significant benefit and does not aggravate other aspects of Huntington's disease.[70][71]

Suicidality should be proactively explored and assessed on a regular basis given higher prevalence among the Huntington’s disease community.

Anxiety

Anxiety is a common symptom and may respond to a variety of treatments, including SSRIs and benzodiazepines.​​ As with depression, psychotherapy can be helpful and complementary to pharmacological intervention.[32]

Obsessive-compulsive behaviours and perseveration

Patients may become obsessive in ways that disrupt family life. Their obsessions may relate to other individuals (recurrent grudges, suspicions of infidelity) or may be self-orientated (obsessions with bowel or bladder habits or fluid intake) or ritualistic (insistence on routines, objects, or hand-washing). Family members usually find these disruptive and often have no choice but to comply as much as possible.

SSRIs, such as citalopram or fluoxetine, may have a role in the management of obsessive-compulsive symptoms.[72][73]​ Longer-duration and higher-dose therapy may be needed for this indication, under consultant supervision. Given the problematic nature of such symptoms in some patients, persistence is warranted.

Clomipramine (a tricyclic antidepressant) has a higher incidence of adverse events but may be considered if SSRIs fail.

Obsessive and compulsive symptoms may be responsive to antipsychotics, such as olanzapine.[74][75] Choosing between antidepressants and antipsychotics should be based on clinical experience and comorbidities. Antipsychotics are more likely to be helpful in patients with problematic chorea and agitation, whereas antidepressants are more appropriate for patients with apathy.

CBT is effective in the general population for obsessions and compulsions, either alone or in combination with drug therapy. It may also be of benefit in people with Huntington's disease, particularly in patients without significant cognitive impairment.[62]

As dementia progresses, the obsessions often remit, perhaps because the patient becomes less able to retain the obsession in active memory. Psychiatric referral may be of benefit.

Behaviour and mood problems (e.g., irritability, mood swings, aggression, frequent temper outbursts)

One problematic behaviour is bad temper.[76][77]​ Patients become increasingly irritable as the disease progresses and can become outspoken and verbally or even physically abusive. Alienation of family can contribute to isolation, divorce, or abandonment, and this increases the likelihood of suicide, neglect, or accidental injury. Guidelines recommend considering environmental causes and behavioural strategies to reduce irritability before initiating pharmacological treatment.[62]​ This may include reducing noise and other sources of overstimulation; addressing pain or other physical sources of discomfort; and instituting regular, structured routines where possible. Psychoeducation for the patient’s family on strategies to help avoid confrontation may also be beneficial.[32][62]​​​​

Although evidence is limited, clinical experience suggests that irritability often responds to treatment with SSRIs, especially in the earlier stages; doses at the upper end of the manufacturer’s recommended range are usually necessary for this indication.[62]​ Other standard approaches to managing temper and irritability include use of atypical antipsychotics (e.g., olanzapine, quetiapine) or anticonvulsants with mood-stabilising properties (e.g., valproic acid). Benzodiazepines may also be helpful, although these may have a disinhibiting effect in some patients. Choosing among these agents is difficult in the absence of definitive studies. However, antipsychotics may be more suitable in circumstances where weight loss and chorea are prominent and symptoms need more acute management; benzodiazepines may be more suitable in situations where anxiety or insomnia is more prominent; and valproic acid more suitable in situations where symptoms are just evolving or where sedating adverse effects are of concern. 

Antipsychotics have been used with success in managing irritability and aggression; however, few published studies are available for specific guidance.[36][78]​ The choice of antipsychotic is based on adverse-effect profile. For patients with behavioural problems co-existent with significant chorea, , involuntary movements, and/or bradykinesia and rigidity, atypical antipsychotics (e.g., olanzapine, quetiapine) may be helpful. Given the adverse effects of antipsychotics, regular monitoring is essential, and occasional dose reductions or drug holidays are appropriate.

Higher starting doses, or parenteral doses, of antipsychotics can be considered for acute, severe behaviour problems. Olanzapine may also be administered parenterally if needed. Severe episodes of aggression or violent behaviour may require intervention by civil authorities, visits to the emergency department, or formal commitment.

Chorea

Chorea is conventionally regarded as the hallmark of Huntington’s disease and can be the source of distress to patients but also to those who are close to the affected individual. However, often the patients themselves are unaware of their movements, and do not feel inconvenienced by them. Therefore, it is vital to establish whether or not the patient feels that chorea is having a significant negative impact on their daily activities, prior to commencing any therapy. When severe, chorea interferes with function and ability to receive personal care; when mild, it can contribute to social isolation, but it varies from one individual to another.[62]​​[79]​​​​ Treating chorea in Huntington's disease is somewhat problematic, and the evidence base for treatments is limited.[80] The drugs that reduce chorea typically have adverse effects on mood, concentration, and coordination, which are factors commonly responsible for functional disability in Huntington's disease.

Treatment options for chorea include tetrabenazine or an atypical antipsychotic.

Tetrabenazine is a selective reversible vesicular monoamine transport 2 (VMAT2) inhibitor that blocks the transport of dopamine into synaptic vesicles in the central nervous system.[81][82]​​ It causes central adverse effects of sedation, bradykinesia, restlessness, and depression. Its action is similar to that of reserpine (which is no longer available), except that reserpine is non-selective and irreversible and therefore has central adverse effects of longer duration and peripheral adverse effects not seen with tetrabenazine, such as hypotension and gastric ulcers. Clinical trials have shown that tetrabenazine significantly reduces chorea.[63][82][83][84]​​ Tetrabenazine has a shorter latency to effect and offset from the institution of therapy compared with antipsychotics, and it is free of any concerns of tardive dyskinesia. However, it is more likely to cause depression and sedation.[82] Patients with chorea in whom it is perceived as a significant problem are suitable candidates for treatment with tetrabenazine, particularly those who cannot tolerate antipsychotics. It is a good first-line choice for patients in whom chorea alone needs management (i.e., patients who do not need the adverse effects of weight gain or night sedation and/or management of irritation or agitation), but it is not suitable for patients with a history of severe depressive symptoms and suicidality/ideation.[62]​ It is contraindicated in patients with active suicidality or untreated or inadequately treated depression. Monitor patients for new or worsening depression or suicidality during treatment. Significant drug-drug interactions exist with tetrabenazine, in particular CYP2D6 inhibitors (e.g., certain SSRIs which may be used to treat other symptoms in patients with Huntington’s disease), and you should consult a drug interaction database before prescribing this drug.

Antipsychotics are among the most effective drugs available for this indication. Atypical antipsychotics (e.g., olanzapine, risperidone) are the preferred drugs in clinical practice because of their improved adverse-effect profile compared with first-generation antipsychotics.[85]

Adverse effects may aggravate underlying features of Huntington's disease, although on occasion they may also be beneficial, such as night sedation and weight gain. These drugs should be reserved for situations in which chorea is problematic for the patient.

Amantadine was previously included in guidelines for treating chorea in Huntington’s disease as ‘probably helpful’. However, its effectiveness is highly debatable, and it is rarely used as a first- or second-line therapy.[86][87][88]​​​​​[89]​ 

The natural history of the movement disorder is such that in later stages of the disease, chorea tends to decline, and bradykinesia and rigidity increase; drug treatments should therefore be regularly reassessed and a reduction considered.

Predominant bradykinesia and rigidity

In general, such symptoms are difficult to treat.[90][91][92]​ Levodopa/carbidopa may be tried.[62]​ A response should be apparent by 1 month, otherwise discontinue. Amantadine may be used for 3 weeks, at which point a therapeutic response should be apparent; discontinue if there is no therapeutic response by this time.[86]

Cognitive impairment

While one small randomised controlled trial has suggested that anticholinesterase drugs may have a beneficial effect on cognition in Huntington's disease, these findings have not been replicated.[93] One randomised, double-blind trial found no effect of citalopram on executive function in non-depressed patients.[94] Further studies are ongoing.

Other supportive interventions

Refer patients for appropriate non-pharmacological care. There is evidence that physical therapy interventions can improve fitness, motor function, and gait in people with Huntington’s disease.[95] Home exercise programmes improve physical function in people with early- to mid-stage Huntington's disease.[96]​ Speech therapy and swallowing therapy have not been tested rigorously in Huntington's disease but may be of transient benefit.

The European Huntington’s Disease Network has published several best practice guidelines on the use of non-pharmacological interventions for Huntington's disease, such as occupational therapy, physiotherapy, speech and language therapy, and nutritional support.[97][98][99][100] EHDN: physiotherapy working group Opens in new window

A driving assessment by an independent assessor can be helpful in deciding whether driving remains safe.

Palliative and end-of-life care

Advance care planning discussion can be helpful at any point in the course of the disease and should form a regular component of clinical review, tailored according to whether the patient is ready and willing to engage in the conversation.[101]​ Topics may include wishes for end-of-life care, appointment of lasting power of attorneys, advance decision to refuse treatment, and advance statements.[101][102]​​

A palliative care approach, integrated through the multidisciplinary team, is appropriate throughout the disease course for patients with Huntington's disease to address symptoms that are difficult to treat.[102][103]​ 

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