Huntington's disease (HD) is known to present with a triad of neuropsychiatric features, including a complex movement disorder, a progressive cognitive decline, and a more variable and wide-ranging set of psychiatric and behavioral disturbances. The latter are among the most common features of HD, and are often the most disturbing, but treatable, aspect of the disease.1
Researchers are challenged by the lack of validated psychiatric and behavioral rating scales specific for HD, and by the impact of patient unawareness and progression of dementia on the accurate reporting of symptoms. It is often necessary to reconcile patient self-reports, family observations, and clinician impressions in making psychiatric diagnoses and rating symptom severity. A recent Movement Disorders Society review of behavioral rating scales used in HD research discussed these issues, and recommended the use of the Beck Depression Inventory-2, the Hospital Anxiety and Depression Scale, and the Irritability Scale for screening of depression and irritability, and was unable to recommend any other rating scales.2
A 2006 review of all pharmacologic studies in HD since 1965 identified 218 such reports.3 These authors found few studies to justify evidence-based recommendations, and concluded that there was low evidence that amitriptyline and mirtazapine are helpful for depression, risperidone for psychosis, and olanzapine, haloperidol, and buspirone for “behavioral symptoms” in HD. A 2009 Cochrane review found no studies that permitted any therapeutic recommendations.4 The situation had not improved by 2016.5
The limited research provides reason for clinical caution, but not for therapeutic nihilism, in the management of patients with HD. Below, we review the management of some specific neuropsychiatric symptoms of HD.
The features, prevalence, and treatment of depression in HD have been reviewed recently.6,7 Depressed mood is present in 33% to 69% of people with a motor diagnosis of HD, and is said to be common before motor diagnosis of HD and in the early to mid-stages of the disease, and less evident later in the course.6,8 However, a review of the minimum data set in a group of people with HD in long-term care showed that almost 60% had depression.9
There have been no randomized controlled trials of treatments for depression in HD (reviewed in Moulton et al.10). In the Neurobiological Predictors of Huntington Disease Onset Study (PREDICT-HD)6 of 1,000 presymptomatic, genetically tested (positive) people, about 20% of participants were taking antidepressants, largely selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).
Electroconvulsive therapy has been reported to benefit depression in patients with intractable depression or depression with psychosis;11,12 its use in HD may be more widespread and effective than the literature allows us to state.
Suicidal Ideation and Suicide
Two large observational studies (REGISTRY and PHAROS)13,14 found rates of suicidal ideation ranging from 5% to 8% in at-risk patients (including a rate of 4.3% in gene-negative patients in PHAROS). Depression/depressed mood, hopelessness, irritability, aggression, anxiety, impulsivity, substance abuse, and use of benzodiazepines were associated with increased suicidality.13,14
In the PREDICT-HD study15 of 735 gene-positive presymptomatic patients and 194 controls, suicide attempts occurred in 12 patients (1.6%) over a mean of 3.7 years of follow-up, and there was one completed suicide (0.1%). History of suicide attempt and presence of depression were the greatest predictors of suicide attempt.
Finally, results from the Huntington Study Group8 patient registry of 1,941 patients identified critical periods of greater suicide risk over the course of HD. The frequency of suicidal ideation ranged from 9.1% in at-risk individuals to 19.8% in patients with “soft motor signs” suggestive of HD, to 23.5% in patients with “possible HD.”8 The frequency of suicidal ideation was 16.7% in stage 1, and 21.6% in stage 2, and declined in the later stages.
Combined, these studies confirm that the rate of suicidal ideation and suicide attempts are high in the HD population, and that the time of greatest risk is the time shortly before or after diagnosis, in the early stages of the disease. Prevention of suicide begins with the recognition of people who are at high risk; along with many other HD researchers, I have found the Columbia Suicide Severity Rating Scale (C-SSRS), a semistructured interview regarding suicidal thoughts and behaviors, to be an excellent screening tool for suicide in both presymptomatic and symptomatic patients with HD.
Aggressive behavior is present in 22% to 66% of patients with HD, and is associated with male sex and possibly with falls, obsessive-compulsive symptoms (OCS), and suicidal ideation.16 A variety of pharmacologic treatments have been used; they have primarily been antipsychotics and nonpharmacologic approaches such as sensory modulation. One recent report documents a reduction in agitation with electroconvulsive therapy (ECT).17
Irritability is also common (affecting 38%–73% of patients), often seen in premanifest gene carriers and can be treated with SSRIs, mood stabilizers such as valproic acid, with the addition of an atypical antipsychotic or buspirone if warranted.18
Echoing van Duijn,18 Groves et al.19 developed a treatment algorithm for the management of irritability, available on the Internet, based on an international survey of HD experts. SSRIs, followed by antipsychotics and antiepileptics, were the clear first- and second-choice therapies, with mirtazapine also sometimes suggested as a second choice. Benzodiazepines were also endorsed as adjunctive therapies. For severe irritability, second-generation antipsychotics, such as olanzapine, risperidone, or quetiapine, were most commonly endorsed.
A thorough review of anxiety in HD has been published that emphasizes the need for improved assessment and evaluation of treatments.20 Anxiety is present in the prodromal period21 in 13% to 71% of diagnosed patients20 and is not related to disease stage. Treatment of anxiety in HD has not been evaluated in clinical trials, but generally includes SSRIs, supportive counseling, cognitive-behavioral therapy, and anxiolytics.
Apathy has long been recognized as a common feature of HD, occurring in about 70% of patients,22 and in 32% to 62% of gene-positive undiagnosed research patients judged to be “far” and “close” to diagnosis, respectively.23 Along with disinhibition and executive dysfunction, apathy is one of the subscales of the Frontal Systems Behavior Scale.24 Apathy correlates with measures of functional and cognitive disease severity,25 with male sex, and use of neuroleptics and benzodiazepines,26 and progresses over time.27,28 In the TRACK-HD study, use of SSRIs and SNRIs by patients early in the course of HD was associated with lower apathy scores.26 Other possible treatments, none proven in HD, have been reviewed.22
Eating/Body Image Disorder
Eating disorder has been reported once as a presenting symptom in an adolescent with juvenile-onset HD.29 We have seen patients with hyperphagia, food obsessions, and with repetitive/perseverative eating behaviors, particularly in later-stage patients with dementia. Weight loss is a concern in HD, as the energy expenditure rate is higher in affected patients,30 and the act of eating is compromised by progressive dysphagia over the course of the disease; coexistent eating disorder would have to be treated aggressively.
Obsessive-compulsive symptoms occur in 20% to 50% of people with HD, and may also be present prior to a motor diagnosis.31,32 Patients often do not meet formal criteria for obsessive-compulsive disorder, so the use of the term “obsessive-compulsive symptoms” seems reasonable. Psychiatric comorbidity is common in patients with OCS; depression, suicidal ideation, aggression, delusions, and hallucinations were all associated with HD in one study, and patients with OCS were older and more functionally and cognitively impaired.33
Case reports have discussed the treatment of OCS with fluoxetine, sertraline, and olanzapine, but no clinical trials have been performed with any pharmacologic or nonpharmacologic therapy.32
Anderson et al.32 developed a treatment algorithm, available on the Internet, for the management of obsessive-compulsive behaviors, based on an international survey of HD experts. SSRIs were the first choice, clomipramine and atypical antipsychotics second choices, and antipsychotics, antiepileptics, and benzodiazepines the most commonly endorsed adjunctive therapies. The presence of psychiatric comorbidities such as anxiety, insomnia, or psychosis significantly influenced medication choice.32
Psychosis is an uncommon complication of HD (delusions in 11.5% and hallucinations in 1.9%).34 The rate can be as low as 1.2%,28 but the symptoms can be severe. In the modern era, antitypical antipsychotics are most commonly used to treat psychosis—including oral35 and intramuscular36 risperidone, olanzapine,37,38 tiapride,38 quetiapine,39 clozapine,40 and aripiprazole.41 The clinical use of these agents greatly exceeds their reporting in the literature.
A 10-year French retrospective review38 of 956 patients with HD found that 63% were taking an antipsychotic, about one-third of those as a treatment for psychiatric or behavioral symptoms (the other two-thirds were taking the drug to treat chorea). The most commonly used antipsychotics were olanzapine, risperidone, and tiapride, which did not differ in their effects on psychosis. Olanzapine outperformed risperidone in the treatment of irritability and aggression, mitigated the tendency to weight loss, and was associated with a lesser decline in total functional capacity over time compared with the other drug classes.38
ECT has been successfully used for medication-refractory psychosis in several cases.12,42,43
Sexual disorders have been reported in HD, including the Kluver-Bucy syndrome, hyper- and hyposexuality, paraphilias, erectile and ejaculatory difficulties, and disruption in stable sexual relationships. Sexual disorders in HD have been reviewed in the literature.44–46
Exhibitionism has been successfully treated with leuprolide,47 and hypersexuality with cyproterone48 and with olanzapine and haloperidol.49
Sleep and circadian rhythm disorders are common in HD,50,51 reported by up to two-thirds of patients and almost three-fourths of caregivers,1 and may predate the onset of motor dysfunction.52 These include disturbances of nighttime sleep such as delayed sleep onset, sleep fragmentation, periodic limb movements, and high amplitude movements upon arousal from rapid eye moment (REM) or non-REM sleep.53 REM behavior disorder and excessive daytime sleepiness are less significant issues. Plasma melatonin levels were decreased in HD patients in one study,54 and the usual evening rise in melatonin was delayed by 1.5 hours in another,55 both implying that melatonin might have specific benefits on HD-related sleep phase and fragmentation disorders. To date, however, there are no reports documenting the use or benefits of melatonin in HD. Therapies for sleep disorders have been reviewed recently.56
Although the frequency of substance abuse in people with HD is not known, about one-third of patients in the Indiana HD Roster (a voluntary registry of about 2,300 patients) who provided information were moderate to high users of alcohol.57
In my view, when treating patients with HD, many clinicians resort to therapeutic nihilism due to the lack of published research. I favor a more optimistic approach, in which a patient with HD is permitted a cautious trial of a medication or treatment that has successfully been used to treat patients without HD with similar symptoms. Given the frequency of psychiatric symptoms in HD and their impact on patients' lives, I recommend the latter approach. At the same time, it is incumbent upon the HD clinical research community to do a better job of reporting outcomes of open-label use of treatments for depression, anxiety, irritability, apathy, psychosis, sleep disorders, and other common features of the disease. The development of a large multinational patient database through the Enroll-HD study should facilitate this process.58
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