Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
Huntington’s Disease: Looking Beyond the Movement Disorder Mary K. Morreale Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Mich., USA
Although Huntington’s disease is classically considered a motor disease, psychiatric, behavioral, and cognitive symptoms are often presenting signs of illness. Even in isolation, these comorbidities can lead to impairment in function and significant distress for patients and their families. Intended for treating psychiatrists, this review discusses the clinical presentation and treatment of Huntington’s disease. © 2015 S. Karger AG, Basel
Introduction
Huntington’s disease (HD) is an autosomal dominant neurodegenerative condition that is classically associated with chorea. Despite classification as a movement disorder, the presenting signs of illness are often unrelated. Although this chapter will discuss the motor indications of HD, the main focus will be on those areas pertinent to a treating psychiatrist, and specifically the cognitive, behavioral, and psychiatric manifestations of the disease.
Patients diagnosed with HD experience neuronal loss and gross atrophy in the caudate and cortex [1]. Symptomatic treatments exist, but there is no cure or mechanism to slow progression. The average survival after diagnosis, which in most cases occurs between the ages of 30 and 50, is 15–20 years [2]. Although individuals of any ethnicity can develop HD, the prevalence is highest in Northern Americans of Caucasian extraction, Europeans, and Australians, with 5.70 per 100,000 people affected [3]. HD is caused by expansion of CAG repeats in the huntingtin gene, which leads to abnormal lengthening of the huntingtin protein. In the general population, the huntingtin gene contains less than 27 repeats. Alleles containing 27–35 repeats do not cause HD but are capable of anticipation or expansion in offspring. While 36–39 repeats may or may not cause HD (reduced penetrance), a number greater than or equal to 40 unequivocally leads to symptoms by age 65 (fully penetrant). At the population level, larger numbers of repeats are associated with an earlier Downloaded by: UCONN Storrs 137.99.31.134 - 5/16/2015 6:53:54 PM
Abstract
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activities of daily living. Although movement is severely impacted in the end stage of illness and patients may be nonverbal, comprehension is not necessarily lost. Juvenile HD will be mentioned briefly but will not be covered in the remainder of this review. Defined as disease diagnosed prior to age 20, this variant differs in many ways from the adult version. In most cases, the number of trinucleotide repeats is above 55, and clinical progression is much more rapid [7]. Juvenile HD occurs in less than 10% diagnosed, and the majority of patients inherit the mutation paternally [7]. The initial manifestations of illness are typically behavioral, and unlike the adult variant, motor symptoms begin with rigidity [7]. Declining school performance may indicate cognitive dysfunction, and attention deficit disorder is a common misdiagnosis [7]. Seizures are seen in 25% of children and adolescents diagnosed with HD and may be the first presenting sign of illness [7].
Motor Dysfunction
The motor symptoms of HD are dynamic and unique to the individual affected. More than 90% of patients develop chorea, which is often the first indication of motor illness [7, 8]. Chorea initially presents in the distal extremities but progresses to the proximal, axial, and facial musculature and, with time, increases in frequency and amplitude [7, 10]. In some patients, chorea plateaus and diminishes, while in others, worsening continues [7]. Dystonia and bradykinesia, which may be masked by comorbid chorea, develop in mid- to late-stage HD [7]. In advanced stages, rigidity is common [7, 10]. In the end stage of illness, nearly all movement-associated functions are affected, including finger dexterity, hand coordination, gait, speech, swallowing, and bowel and bladder control [7]. Effective pharmacotherapy for motor dysfunction depends on the type of abnormality
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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onset of significant motor symptoms and, less significantly, rapidity of progression [4]. There is no association, however, between the number of repeats and the development of psychiatric symptomatology [5]. For the individual diagnosed with HD, nothing can predict the age of onset, which symptoms may appear, how severe the illness will be, or the rate of clinical deterioration [6]. In addition, it is impossible to determine the course of illness based on the experience of affected relatives [6]. Despite the availability of predictive testing, less than 10% of those at risk chose to identify their genetic status [7]. Individuals who test positive but are disease free are considered to be in the pre-manifest phase of illness. Those with cognitive or psychiatric symptoms but no significant motor signs are in the prodromal phase. Manifest illness is diagnosed when significant motor symptoms appear. The Unified Huntington’s Disease Rating Scale (UHDRS), which measures motor, cognitive, and psychiatric symptoms, is the most common clinical and research assessment utilized [8]. Functional decline can begin as early as the prodromal phase of illness. In a study examining 265 individuals during this period, approximately one-third reported some difficulty with activities of daily living [9]. The most common loss cited was in occupational performance (65.1%), followed by the ability to manage finances independently (between 35 and 49.2%, depending on the method of assessment), to drive safely (33.5%), and to supervise children (28.6%). Based on functional impairment, the Huntington’s Disease Society of America (HDSA) divides manifest HD into three stages [7]. In the early stage of illness, the symptoms are minor, and deficits are minimal. Patients are able to drive, handle their finances, and live independently. As the disease progresses, greater impairment in voluntary movements develops, but the ability to dress, bathe, and feed oneself is unaffected. In the final stage of HD, individuals are unable to perform
Cognitive Dysfunction
Like motor dysfunction, cognitive decline has an unpredictable onset and course. Despite discussion in numerous articles, there is little agreement regarding symptomatology and progression [1]. What appears to be clear is that subclinical cognitive changes can occur 15 years prior to motor symptoms and may lead to early functional impairment, independent of other factors [1, 4, 7, 10]. In addition, cognitive decline is prevalent,
with approximately 40% affected in the prodromal period and 75% affected as manifest disease nears [7, 17]. Although initially insidious, the cognitive decline tends to progress [18]. During the beginning of the HD prodrome, the most robust changes are seen in emotional recognition, processing speed, and both working and learning memory [6]. With time, impairments occur in additional areas, including smell identification, cued sequencing, attention, reaction time, and letter fluency [6]. Other domains affected include estimation of time, executive function, initiation and comprehension of conversation, and awareness of one’s own feelings and actions [6]. Researchers emphasize the difference between cognitive dysfunction in HD compared with Alzheimer’s disease and other neurodegenerative disorders and even suggest discrete criteria for diagnosis [19]. In HD, overall memory impairment and ‘rapid forgetting’ are not as pronounced [8]. Implicit memory, which involves coordination of movement in previously learned motor tasks, such as driving a car and chewing, may be affected, while memories of names and dates remain relatively intact [7]. There is no accepted battery of tests recommended to assess cognition in patients diagnosed with HD [6]. The UHDRS, mentioned above, contains three cognitive subtests, one of which evaluates the most sensitive indicator of cognitive function in HD, or the speed of processing [7]. The Mini-Mental Status Exam may detect longitudinal changes in cognition but lacks sensitivity [7]. In comparison, the Montreal Cognitive Assessment, which contains a more comprehensive evaluation of executive function, attention, and visuospatial abilities and relies less on intact verbal skills, may be a more sensitive instrument [20]. There is scant data related to the treatment of cognitive dysfunction. Several pharmacotherapies have been evaluated in small (n = 20–30) randomized placebo-controlled trials, but none
Huntington’s Disease Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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present. Evidence suggests that increased dopamine release leads to chorea, while reductions cause bradykinesia [11]. In 2008, tetrabenazine became the first medication to be Food and Drug Administration approved for the treatment of HD. Indicated solely for chorea, tetrabenazine binds to the vesicular monoamine transporter, resulting in decreased reuptake of dopamine into synaptic vesicles. Although not Food and Drug Administration approved, additional treatments for chorea include typical antipsychotics and atypical agents that provide greater affinity for the D2 receptor (olanzapine and risperidone) [7, 12]. Despite the fact that all pharmacotherapies used to treat chorea potentially cause significant side effects, tetrabenazine is particularly troublesome, as it leads to initiation or exacerbation of depression in 20% of patients [7]. Regarding treatment of tetrabenazine-induced depression, only one case study exists, which reported success with reboxetine [13]. For the treatment of bradykinesia, small studies and case reports have found benefit with the dopaminergic agonists bromocriptine, levodopa, pramipexole, amantadine, and cabergoline [14, 15]. Benzodiazepines, baclofen, and botulinum toxin may be helpful for dystonia [7]. Once rigidity develops, the dose of tetrabenazine and antipsychotics should be reduced [7]. In addition, benzodiazepines, baclofen, and the dopamine agonist, cabergoline may be of value [7, 16].
Behavioral and Psychiatric Dysfunction
Changes in behavior and the development of psychiatric symptoms are quite common in HD and, similar to cognitive impairment, can present years prior to significant motor disease. Although these comorbid conditions can be the most distressing aspect of illness, they tend to be underdiagnosed and inadequately treated [27]. Perhaps part of the difficulty lies in studying these phenomena. First, assessment can be problematic, as symptoms do not always meet the threshold for formal diagnosis. Second, although multi-site studies are available, HD is a rare illness, and sample sizes are often small. Finally, establishing a control population is not always straightforward: should expansion-negative relatives be used, or members of the general population? Methodologies often differ, which makes comparison of information challenging.
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Changes in personality are likely more common than concrete psychiatric diagnoses. HD patients can present with a ‘dysexecutive or frontal lobe syndrome’, which includes both disinhibited and deficit symptoms, possibly at the same time [7]. Disinhibited behaviors include impulsivity, perseveration, and irritability, whereas deficit symptoms consist of apathy, loss of spontaneity, indifference, and lack of insight. Regardless of origin, personality changes are difficult to manage and may respond to behavioral interventions more so than medications. Perseveration can lead to fixation on a specific idea or task and is described as ‘behavioral rigidity’ [7]. This symptom can present in a manner similar to obsessive-compulsive disorder (OCD), although more so the obsessive criteria. Unfortunately, limited evidence is available regarding the treatment of perseveration, although, as in OCD, selective serotonin reuptake inhibitors (SSRIs) may be effective [7]. Per this author’s experience, fluvoxamine has been a particularly effective agent. In addition, case studies have demonstrated improvement with the dopamine agonist amantadine [7]. The majority of patients diagnosed with HD experience irritability, and not surprisingly, this greatly concerns family members [7, 28]. The root of irritability may lie in many causes, including, but not limited to, depression, frustration, and confusion [7]. To minimize escalation toward violence, families should be encouraged to identify and minimize triggers, to redirect their loved one, and to maintain a calm and structured environment [7]. In potentially dangerous situations, the police may need to be summoned. Although no robust evidence exists to guide pharmacologic management of irritability, SSRIs may help if obsessive-compulsive or depressive symptoms are associated [7, 26]. Mood stabilizers can be prescribed as well and, in severe cases, antipsychotics or benzodiazepines [7, 26]. Apathy, which includes disinterest, amotivation, diminished goal-directed behavior, and
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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has been proven to be particularly effective. No effect was seen with modafinil, atomoxetine, or donepezil, although modafinil increased alertness and atomoxetine led to self-reported enhancement of sustained attention [21–23]. Rivastigmine has been evaluated in two small trials, both showing a tendency for improvement [24, 25]. In studies of cognition as an ancillary measure, lamotrigine, fluoxetine, riluzole, amantadine, ketamine, and remacemide all failed to show benefit [26]. The HDSA suggests several behavioral strategies to help those patients who are cognitively compromised [7]. As estimation of time, initiation of activity, and attention may be impaired, distractions should be minimized, and extra time should be allowed for activities. Patients may need reminders of schedules, and calendars and clocks should be readily visible. In addition, a structured routine can be beneficial. Given the possibility of diminished insight, interventions to enhance adherence are vital.
creased cognitive impairment, perceived stress, and negative life experience [32–34]. Whereas unipolar depression is relatively common in HD, bipolarity is infrequently seen [7]. Irritability and impulsivity may look like symptoms of mania but tend to occur in the absence of additional criteria. The rate of suicidal behavior in patients with HD is higher than in any other neurodegenerative disorder [35]. In the same 1,941 patients mentioned above, approximately 25% reported a history of suicidal ideation; 19%, of current suicidal ideation; and 9.5%, of at least one suicide attempt [31]. To put these data into perspective, in the general population, suicidal ideation exists in 3.3%, and a history of a suicide attempt exists in less than 1% [36]. Per Wetzel et al., no demographic, motor, or cognitive variables predict suicidal behavior, but there is a significant association with depression, anxiety, and aggression, as assessed by the UHDRS [31]. When looking at those with the most severe suicidal ideation, a past or current history of alcohol abuse becomes a predictive measure as well [31]. Suicidal risk increases during periods of functional loss, such as when work becomes too difficult or driving is no longer possible [31]. As the disease worsens and reductions in awareness occur, this risk decreases [31]. As stated earlier, although elevations in scales related to psychoticism occur in HD, chronic psychosis and schizophrenia are uncommon [7]. When psychotic symptoms do present, they tend to follow the diagnosis of manifest disease and develop in tandem with cognitive impairment, mood disorders, or delirium [37]. Per the HDSA, some HD patients suffer from resistant delusions, which are difficult to discern from perseveration [7]. As is the case with all delusional thinking, confrontation is rarely beneficial. While elevations in anxiety levels are possible, there is little in the literature regarding the diagnosis and treatment of anxiety disorders. The probability of obsessive and compulsive
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emotional blunting, is extremely common as well, occurring in 34–76% of patients, depending on the stage of illness and the method of assessment [7, 29]. The prevalence and severity of apathy increase as HD progresses [29]. Apathy may be mistaken for depression but can be distinguished from a mood disorder diagnosis by the absence of neurovegetative symptoms [7]. Activating antidepressants may be helpful for apathy, but additional medications may be needed as well, including stimulants, amantadine, bromocriptine, and selegiline [7]. In this author’s clinical experience, stimulants help somewhat with amotivation and may secondarily benefit difficulties with attention and initiation of activity. Antipsychotics and benzodiazepines may worsen apathy by further blunting emotion and cognition [7]. Collaborating investigators have studied discrete psychiatric symptoms during both prodromal and manifest illness. Compared with controls, individuals with prodromal HD (n = 589) display elevations in scales related to depression, obsessive-compulsiveness, anxiety, and psychoticism [30]. These symptoms are directly correlated to the severity of motor and cognitive impairments and inversely associated with overall function. In individuals (n = 1,941) with ‘probable’ or ‘definite’ manifest disease, 48.2% report treatment for past depression; 8.1%, for obsessivecompulsive disorder; and 5.2%, for psychosis [31]. Given the nature of retrospective reporting, it is impossible to know if full DSM criteria were met for the diagnoses specified. Per Epping et al., clinically significant depression (Beck Depression Inventory score >13) is noted in 20–30% of gene-expanded individuals, which is slightly more frequent than in controls [32]. Depressive symptoms can occur at any time during prodromal HD and are not associated with proximity to genetic testing or the expected time to diagnosis [32]. Not surprisingly, geneexpanded females have a higher frequency of depression when compared with similar males, and the severity of symptoms contributes to in-
Conclusion
Although typically understood as a movement disorder, HD has significant cognitive, behavioral, and psychiatric comorbidity. Symptoms
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from any of these domains may present prior to motor abnormalities and alone can cause distress and functional impairment. The HDSA acknowledges that HD is more than a neurologic illness and necessitates that its Centers of Excellence provide psychiatric and psychological services. Unfortunately, there are considerable limitations in the research related to the treatment of nonmotor manifestations of HD. Randomized placebo-controlled trials of medications have been small, and the bulk of information available comes from case studies and anecdotal evidence. Thankfully, there is no evidence to suggest that HD patients are less likely to benefit from psychiatric medications than non-HD populations. Hopefully, in the future, the work of collaborative investigators will help us to fine-tune our approach. Behavioral interventions are a key component of managing patients with HD. As described above, the HDSA suggests several strategies to minimize both patient and family distress. Although there is no literature regarding psychotherapeutic strategies, psychoeducation, supportive therapy, cognitive-behavioral therapy, and family sessions should all be considered. In addition, all those affected by HD can potentially benefit from support groups, which are offered through multiple organizations. In this author’s opinion, it would be helpful for physicians, patients, and families if the diagnosis of manifest HD were expanded to reflect the significance of cognitive, behavioral, and psychiatric symptoms. The current standard, which only requires involuntary movement in the presence of a positive genetic test, minimizes the impact of these comorbid conditions. In a disease in which patients struggle with so many ambiguities, including which symptoms they will develop and how their illness might progress, an increase in diagnostic clarity could be a relief for all.
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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symptoms, as assessed by the UHDRS, has been measured and shown to increase with disease severity, with a peak of 24% for obsessions and 12% for compulsions in advanced stages of illness [38]. The full criteria for OCD, however, are rarely met [38]. Unfortunately, scarce evidence exists regarding the treatment of psychiatric comorbidity in HD. In general, choosing a medication for a patient with HD is similar to doing so for any psychiatric patient, with the theoretical exception of a propensity toward increased side effects in the HD population. As with the use of antidepressants in all depressive illness, there are no concrete data to suggest the superiority of any one agent over another [7]. If the diagnostic criterion is met for mania, lithium should be avoided, as potential fluctuations in fluid intake can lead to toxicity [7]. It is important to distinguish mania from isolated irritability and impulsivity, as the latter do not typically respond to mood-stabilizing medications [7]. Expert consensus supports the use of SSRIs and clomipramine for obsessive-compulsive behaviors [39]. If psychosis is present, antipsychotics are indicated. As with psychotic illness in general, no particular agent is preferred [7]. If chorea exists, the high-potency typical agents may be of benefit, as they decrease movement via parkinsonism. In contrast, if the patient has either bradykinesia or rigidity, atypical antipsychotics are a better choice. Although there are only case studies regarding electroconvulsive therapy, evidence indicates improvement in mood and psychosis as well as decreased suicidality [40]. Interestingly, decreased cognition is not always the norm.
References 13 Schreiber W, Krieg JC, Eichhorn T: Reversal of tetrabenazine induced depression by selective noradrenaline (norepinephrine) reuptake inhibition. J Neurol Neurosurg Psychiatry 1999;67: 550. 14 White RF: Clinical Syndromes in Adult Neuropsychology: The Practitioner’s Handbook. Amsterdam/New York, Elsevier, 1992. 15 Phillips W, Shannon KM, Barker RA: The current clinical management of Huntington’s disease. Mov Disord 2008; 23:1491–1504. 16 Martin B, Golden E, Keselman A, et al: Therapeutic perspectives for the treatment of Huntington’s disease: treating the whole body. Histol Histopathol 2008;23:237–250. 17 Duff K, Paulsen J, Mills J, et al: Mild cognitive impairment in prediagnosed Huntington disease. Neurol 2010;75: 500–507. 18 Paulsen JS, Langbehn DR, Stout JC, et al: Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 2008;79:874–880. 19 Peavy GM, Jacobson MW, Goldstein JL, et al: Cognitive and functional decline in Huntington’s disease: dementia criteria revisited. Mov Disord 2010;25:1163– 1169. 20 Mickes L, Jacobson M, Peavy G, et al: A comparison of two brief screening measures of cognitive impairment in Huntington’s disease. Mov Disord 2010;25: 2229–2233. 21 Beglinger LJ, Adams WH, Paulson H, et al: Randomized controlled trial of atomoxetine for cognitive dysfunction in early Huntington disease. J Clin Psychopharmacol 2009;29:484– 487. 22 Cubo E, Shannon KM, Tracy D, et al: Effect of donepezil on motor and cognitive function in Huntington disease. Neurology 2006;67:1268–1271. 23 Blackwell AD, Paterson NS, Barker RA, Robbins TW, Sahakian BJ: The effects of modafinil on mood and cognition in Huntington’s disease. Psychopharmacology (Berl) 2008;199:29–36.
24 de Tommaso M, Specchio N, Sciruicchio V, Difruscolo O, Specchio LM: Effects of rivastigmine on motor and cognitive impairment in Huntington’s disease. Mov Disord 2004;19:1516–1518. 25 Rot U, Kobal J, Sever A, Pirtosek Z, Mesec A: Rivastigmine in the treatment of Huntington’s disease. Eur J Neurol 2002; 9:689–690. 26 Mestre TA, Ferreira JJ: An evidencebased approach in the treatment of Huntington’s disease. Parkinsonism Relat Disord 2012;18:316–320. 27 Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC: Suicidality in Huntington’s disease. J Affect Disord 2012;136:550–557. 28 Pflanz S, Besson JA, Ebmeier KP, Simpson S: The clinical manifestation of mental disorder in Huntington’s disease: a retrospective case record study of disease progression. Acta Psychiatr Scand 1991;83:53–60. 29 van Duijn E, Reedeker N, Giltay EJ, Roos RA, van der Mast RC: Correlates of apathy in Huntington’s disease. J Neuropsychiatry Clin Neurosci 2010;22:287– 294. 30 Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC, Predict-HD Investigators of the Huntington Study Group. Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 2007;62:1341– 1346. 31 Wetzel HH, Gehl CR, Dellefave-Castillo L, et al: Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res 2011;188:372–376. 32 Epping EA, Mills JA, Beglinger LJ, et al: Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study. J Psychiatric Res 2013;47:1423–1431. 33 Smith MM, Mills JA, Epping EA, Westervelt HJ, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group. Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease. Neuropsychology 2012;26:664–669. 34 Downing N, Smith MM, Beglinger LJ, et al: Perceived stress in prodromal Huntington disease. Psychol Health 2012;27: 196–209.
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1 Papp KV, Kaplan RF, Snyder PJ: Biological markers of cognition in prodromal Huntington’s disease: a review. Brain Cogn 2011;77:280–291. 2 Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C: Therapeutic interventions for symptomatic treatment in Huntington’s disease. Cochrane Database Syst Rev 2009;3:CD006456. 3 Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N: The incidence and prevalence of Huntington’s disease: a systematic review and metaanalysis. Mov Disord 2012;27:1083– 1091. 4 Novak MJ, Tabrizi SJ: Huntington’s disease. BMJ 2010;340:c3109. 5 Vassos E, Panas M, Kladi A, Vassilopoulos D: Effect of CAG repeat length on psychiatric disorders in Huntington’s disease. J Psychiatr Res 2008;42:544– 549. 6 Paulsen JS: Cognitive impairment in Huntington disease: diagnosis and treatment. Curr Neurol Neurosci 2011;11: 474–483. 7 Nance M, Paulsen JS, Rosenblatt A, Wheelock V, Huntington’s Disease Society of America. A Physician’s Guide to the Management of Huntington’s Disease, ed. 3. New York, Huntington’s Disease Society of America, 2013. 8 Ross CA, Aylward EH, Wild EJ, et al: Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 2014;10: 204–216. 9 Beglinger LJ, O’Rourke JJ, Wang C, et al: Earliest functional declines in Huntington disease. Psychiatry Res 2010;178: 414–418. 10 Roos RA: Huntington’s disease: a clinical review. Orphanet J Rare Dis 2010;5: 40. 11 Chen JY, Wang EA, Cepeda C, Levine MS: Dopamine imbalance in Huntington’s disease: a mechanism for the lack of behavioral flexibility. Front Neurosci 2013;7:114. 12 Kapur S, Seeman P: Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. AJP 2001; 158:360–369.
35 Harris EC, Barraclough B: Suicide as an outcome for mental disorders. A metaanalysis. Br J Psychiatry 1997;170:205– 228. 36 Kessler RC, Berglund P, Borges G, Nock M, Wang PS: Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990–1992 to 2001–2003. JAMA 2005;293:2487–2495.
37 Nagel M, Rumpf HJ, Kasten M: Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis. Gen Hosp Psychiatry 2014;36:361.e3–e4. 38 Beglinger LJ, Langbehn DR, Duff K, et al: Probability of obsessive and compulsive symptoms in Huntington’s disease. Biol Psychiatry 2007;61:415–418. 39 Anderson K, Craufurd D, Edmondson MC, et al: An international survey-based algorithm for the pharmacologic treatment of obsessive-compulsive behaviors in Huntington’s disease. PLoS Curr 2011;3:RRN1261.
40 Cusin C, Franco FB, Fernandez-Robles C, DuBois CM, Welch CA: Rapid improvement of depression and psychotic symptoms in Huntington’s disease: a retrospective chart review of seven patients treated with electroconvulsive therapy. Gen Hosp Psychiatry 2013;35: 678.e3–e5.
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Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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Mary K. Morreale, MD Department of Psychiatry 3901 Chrysler Service Dr. Detroit, MI 48201 (USA) E-Mail [email protected]
Huntington’s Disease: Looking Beyond the Movement Disorder Mary K. Morreale Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Mich., USA
Although Huntington’s disease is classically considered a motor disease, psychiatric, behavioral, and cognitive symptoms are often presenting signs of illness. Even in isolation, these comorbidities can lead to impairment in function and significant distress for patients and their families. Intended for treating psychiatrists, this review discusses the clinical presentation and treatment of Huntington’s disease. © 2015 S. Karger AG, Basel
Introduction
Huntington’s disease (HD) is an autosomal dominant neurodegenerative condition that is classically associated with chorea. Despite classification as a movement disorder, the presenting signs of illness are often unrelated. Although this chapter will discuss the motor indications of HD, the main focus will be on those areas pertinent to a treating psychiatrist, and specifically the cognitive, behavioral, and psychiatric manifestations of the disease.
Patients diagnosed with HD experience neuronal loss and gross atrophy in the caudate and cortex [1]. Symptomatic treatments exist, but there is no cure or mechanism to slow progression. The average survival after diagnosis, which in most cases occurs between the ages of 30 and 50, is 15–20 years [2]. Although individuals of any ethnicity can develop HD, the prevalence is highest in Northern Americans of Caucasian extraction, Europeans, and Australians, with 5.70 per 100,000 people affected [3]. HD is caused by expansion of CAG repeats in the huntingtin gene, which leads to abnormal lengthening of the huntingtin protein. In the general population, the huntingtin gene contains less than 27 repeats. Alleles containing 27–35 repeats do not cause HD but are capable of anticipation or expansion in offspring. While 36–39 repeats may or may not cause HD (reduced penetrance), a number greater than or equal to 40 unequivocally leads to symptoms by age 65 (fully penetrant). At the population level, larger numbers of repeats are associated with an earlier Downloaded by: UCONN Storrs 137.99.31.134 - 5/16/2015 6:53:54 PM
Abstract
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activities of daily living. Although movement is severely impacted in the end stage of illness and patients may be nonverbal, comprehension is not necessarily lost. Juvenile HD will be mentioned briefly but will not be covered in the remainder of this review. Defined as disease diagnosed prior to age 20, this variant differs in many ways from the adult version. In most cases, the number of trinucleotide repeats is above 55, and clinical progression is much more rapid [7]. Juvenile HD occurs in less than 10% diagnosed, and the majority of patients inherit the mutation paternally [7]. The initial manifestations of illness are typically behavioral, and unlike the adult variant, motor symptoms begin with rigidity [7]. Declining school performance may indicate cognitive dysfunction, and attention deficit disorder is a common misdiagnosis [7]. Seizures are seen in 25% of children and adolescents diagnosed with HD and may be the first presenting sign of illness [7].
Motor Dysfunction
The motor symptoms of HD are dynamic and unique to the individual affected. More than 90% of patients develop chorea, which is often the first indication of motor illness [7, 8]. Chorea initially presents in the distal extremities but progresses to the proximal, axial, and facial musculature and, with time, increases in frequency and amplitude [7, 10]. In some patients, chorea plateaus and diminishes, while in others, worsening continues [7]. Dystonia and bradykinesia, which may be masked by comorbid chorea, develop in mid- to late-stage HD [7]. In advanced stages, rigidity is common [7, 10]. In the end stage of illness, nearly all movement-associated functions are affected, including finger dexterity, hand coordination, gait, speech, swallowing, and bowel and bladder control [7]. Effective pharmacotherapy for motor dysfunction depends on the type of abnormality
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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onset of significant motor symptoms and, less significantly, rapidity of progression [4]. There is no association, however, between the number of repeats and the development of psychiatric symptomatology [5]. For the individual diagnosed with HD, nothing can predict the age of onset, which symptoms may appear, how severe the illness will be, or the rate of clinical deterioration [6]. In addition, it is impossible to determine the course of illness based on the experience of affected relatives [6]. Despite the availability of predictive testing, less than 10% of those at risk chose to identify their genetic status [7]. Individuals who test positive but are disease free are considered to be in the pre-manifest phase of illness. Those with cognitive or psychiatric symptoms but no significant motor signs are in the prodromal phase. Manifest illness is diagnosed when significant motor symptoms appear. The Unified Huntington’s Disease Rating Scale (UHDRS), which measures motor, cognitive, and psychiatric symptoms, is the most common clinical and research assessment utilized [8]. Functional decline can begin as early as the prodromal phase of illness. In a study examining 265 individuals during this period, approximately one-third reported some difficulty with activities of daily living [9]. The most common loss cited was in occupational performance (65.1%), followed by the ability to manage finances independently (between 35 and 49.2%, depending on the method of assessment), to drive safely (33.5%), and to supervise children (28.6%). Based on functional impairment, the Huntington’s Disease Society of America (HDSA) divides manifest HD into three stages [7]. In the early stage of illness, the symptoms are minor, and deficits are minimal. Patients are able to drive, handle their finances, and live independently. As the disease progresses, greater impairment in voluntary movements develops, but the ability to dress, bathe, and feed oneself is unaffected. In the final stage of HD, individuals are unable to perform
Cognitive Dysfunction
Like motor dysfunction, cognitive decline has an unpredictable onset and course. Despite discussion in numerous articles, there is little agreement regarding symptomatology and progression [1]. What appears to be clear is that subclinical cognitive changes can occur 15 years prior to motor symptoms and may lead to early functional impairment, independent of other factors [1, 4, 7, 10]. In addition, cognitive decline is prevalent,
with approximately 40% affected in the prodromal period and 75% affected as manifest disease nears [7, 17]. Although initially insidious, the cognitive decline tends to progress [18]. During the beginning of the HD prodrome, the most robust changes are seen in emotional recognition, processing speed, and both working and learning memory [6]. With time, impairments occur in additional areas, including smell identification, cued sequencing, attention, reaction time, and letter fluency [6]. Other domains affected include estimation of time, executive function, initiation and comprehension of conversation, and awareness of one’s own feelings and actions [6]. Researchers emphasize the difference between cognitive dysfunction in HD compared with Alzheimer’s disease and other neurodegenerative disorders and even suggest discrete criteria for diagnosis [19]. In HD, overall memory impairment and ‘rapid forgetting’ are not as pronounced [8]. Implicit memory, which involves coordination of movement in previously learned motor tasks, such as driving a car and chewing, may be affected, while memories of names and dates remain relatively intact [7]. There is no accepted battery of tests recommended to assess cognition in patients diagnosed with HD [6]. The UHDRS, mentioned above, contains three cognitive subtests, one of which evaluates the most sensitive indicator of cognitive function in HD, or the speed of processing [7]. The Mini-Mental Status Exam may detect longitudinal changes in cognition but lacks sensitivity [7]. In comparison, the Montreal Cognitive Assessment, which contains a more comprehensive evaluation of executive function, attention, and visuospatial abilities and relies less on intact verbal skills, may be a more sensitive instrument [20]. There is scant data related to the treatment of cognitive dysfunction. Several pharmacotherapies have been evaluated in small (n = 20–30) randomized placebo-controlled trials, but none
Huntington’s Disease Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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present. Evidence suggests that increased dopamine release leads to chorea, while reductions cause bradykinesia [11]. In 2008, tetrabenazine became the first medication to be Food and Drug Administration approved for the treatment of HD. Indicated solely for chorea, tetrabenazine binds to the vesicular monoamine transporter, resulting in decreased reuptake of dopamine into synaptic vesicles. Although not Food and Drug Administration approved, additional treatments for chorea include typical antipsychotics and atypical agents that provide greater affinity for the D2 receptor (olanzapine and risperidone) [7, 12]. Despite the fact that all pharmacotherapies used to treat chorea potentially cause significant side effects, tetrabenazine is particularly troublesome, as it leads to initiation or exacerbation of depression in 20% of patients [7]. Regarding treatment of tetrabenazine-induced depression, only one case study exists, which reported success with reboxetine [13]. For the treatment of bradykinesia, small studies and case reports have found benefit with the dopaminergic agonists bromocriptine, levodopa, pramipexole, amantadine, and cabergoline [14, 15]. Benzodiazepines, baclofen, and botulinum toxin may be helpful for dystonia [7]. Once rigidity develops, the dose of tetrabenazine and antipsychotics should be reduced [7]. In addition, benzodiazepines, baclofen, and the dopamine agonist, cabergoline may be of value [7, 16].
Behavioral and Psychiatric Dysfunction
Changes in behavior and the development of psychiatric symptoms are quite common in HD and, similar to cognitive impairment, can present years prior to significant motor disease. Although these comorbid conditions can be the most distressing aspect of illness, they tend to be underdiagnosed and inadequately treated [27]. Perhaps part of the difficulty lies in studying these phenomena. First, assessment can be problematic, as symptoms do not always meet the threshold for formal diagnosis. Second, although multi-site studies are available, HD is a rare illness, and sample sizes are often small. Finally, establishing a control population is not always straightforward: should expansion-negative relatives be used, or members of the general population? Methodologies often differ, which makes comparison of information challenging.
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Changes in personality are likely more common than concrete psychiatric diagnoses. HD patients can present with a ‘dysexecutive or frontal lobe syndrome’, which includes both disinhibited and deficit symptoms, possibly at the same time [7]. Disinhibited behaviors include impulsivity, perseveration, and irritability, whereas deficit symptoms consist of apathy, loss of spontaneity, indifference, and lack of insight. Regardless of origin, personality changes are difficult to manage and may respond to behavioral interventions more so than medications. Perseveration can lead to fixation on a specific idea or task and is described as ‘behavioral rigidity’ [7]. This symptom can present in a manner similar to obsessive-compulsive disorder (OCD), although more so the obsessive criteria. Unfortunately, limited evidence is available regarding the treatment of perseveration, although, as in OCD, selective serotonin reuptake inhibitors (SSRIs) may be effective [7]. Per this author’s experience, fluvoxamine has been a particularly effective agent. In addition, case studies have demonstrated improvement with the dopamine agonist amantadine [7]. The majority of patients diagnosed with HD experience irritability, and not surprisingly, this greatly concerns family members [7, 28]. The root of irritability may lie in many causes, including, but not limited to, depression, frustration, and confusion [7]. To minimize escalation toward violence, families should be encouraged to identify and minimize triggers, to redirect their loved one, and to maintain a calm and structured environment [7]. In potentially dangerous situations, the police may need to be summoned. Although no robust evidence exists to guide pharmacologic management of irritability, SSRIs may help if obsessive-compulsive or depressive symptoms are associated [7, 26]. Mood stabilizers can be prescribed as well and, in severe cases, antipsychotics or benzodiazepines [7, 26]. Apathy, which includes disinterest, amotivation, diminished goal-directed behavior, and
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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has been proven to be particularly effective. No effect was seen with modafinil, atomoxetine, or donepezil, although modafinil increased alertness and atomoxetine led to self-reported enhancement of sustained attention [21–23]. Rivastigmine has been evaluated in two small trials, both showing a tendency for improvement [24, 25]. In studies of cognition as an ancillary measure, lamotrigine, fluoxetine, riluzole, amantadine, ketamine, and remacemide all failed to show benefit [26]. The HDSA suggests several behavioral strategies to help those patients who are cognitively compromised [7]. As estimation of time, initiation of activity, and attention may be impaired, distractions should be minimized, and extra time should be allowed for activities. Patients may need reminders of schedules, and calendars and clocks should be readily visible. In addition, a structured routine can be beneficial. Given the possibility of diminished insight, interventions to enhance adherence are vital.
creased cognitive impairment, perceived stress, and negative life experience [32–34]. Whereas unipolar depression is relatively common in HD, bipolarity is infrequently seen [7]. Irritability and impulsivity may look like symptoms of mania but tend to occur in the absence of additional criteria. The rate of suicidal behavior in patients with HD is higher than in any other neurodegenerative disorder [35]. In the same 1,941 patients mentioned above, approximately 25% reported a history of suicidal ideation; 19%, of current suicidal ideation; and 9.5%, of at least one suicide attempt [31]. To put these data into perspective, in the general population, suicidal ideation exists in 3.3%, and a history of a suicide attempt exists in less than 1% [36]. Per Wetzel et al., no demographic, motor, or cognitive variables predict suicidal behavior, but there is a significant association with depression, anxiety, and aggression, as assessed by the UHDRS [31]. When looking at those with the most severe suicidal ideation, a past or current history of alcohol abuse becomes a predictive measure as well [31]. Suicidal risk increases during periods of functional loss, such as when work becomes too difficult or driving is no longer possible [31]. As the disease worsens and reductions in awareness occur, this risk decreases [31]. As stated earlier, although elevations in scales related to psychoticism occur in HD, chronic psychosis and schizophrenia are uncommon [7]. When psychotic symptoms do present, they tend to follow the diagnosis of manifest disease and develop in tandem with cognitive impairment, mood disorders, or delirium [37]. Per the HDSA, some HD patients suffer from resistant delusions, which are difficult to discern from perseveration [7]. As is the case with all delusional thinking, confrontation is rarely beneficial. While elevations in anxiety levels are possible, there is little in the literature regarding the diagnosis and treatment of anxiety disorders. The probability of obsessive and compulsive
Huntington’s Disease Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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emotional blunting, is extremely common as well, occurring in 34–76% of patients, depending on the stage of illness and the method of assessment [7, 29]. The prevalence and severity of apathy increase as HD progresses [29]. Apathy may be mistaken for depression but can be distinguished from a mood disorder diagnosis by the absence of neurovegetative symptoms [7]. Activating antidepressants may be helpful for apathy, but additional medications may be needed as well, including stimulants, amantadine, bromocriptine, and selegiline [7]. In this author’s clinical experience, stimulants help somewhat with amotivation and may secondarily benefit difficulties with attention and initiation of activity. Antipsychotics and benzodiazepines may worsen apathy by further blunting emotion and cognition [7]. Collaborating investigators have studied discrete psychiatric symptoms during both prodromal and manifest illness. Compared with controls, individuals with prodromal HD (n = 589) display elevations in scales related to depression, obsessive-compulsiveness, anxiety, and psychoticism [30]. These symptoms are directly correlated to the severity of motor and cognitive impairments and inversely associated with overall function. In individuals (n = 1,941) with ‘probable’ or ‘definite’ manifest disease, 48.2% report treatment for past depression; 8.1%, for obsessivecompulsive disorder; and 5.2%, for psychosis [31]. Given the nature of retrospective reporting, it is impossible to know if full DSM criteria were met for the diagnoses specified. Per Epping et al., clinically significant depression (Beck Depression Inventory score >13) is noted in 20–30% of gene-expanded individuals, which is slightly more frequent than in controls [32]. Depressive symptoms can occur at any time during prodromal HD and are not associated with proximity to genetic testing or the expected time to diagnosis [32]. Not surprisingly, geneexpanded females have a higher frequency of depression when compared with similar males, and the severity of symptoms contributes to in-
Conclusion
Although typically understood as a movement disorder, HD has significant cognitive, behavioral, and psychiatric comorbidity. Symptoms
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from any of these domains may present prior to motor abnormalities and alone can cause distress and functional impairment. The HDSA acknowledges that HD is more than a neurologic illness and necessitates that its Centers of Excellence provide psychiatric and psychological services. Unfortunately, there are considerable limitations in the research related to the treatment of nonmotor manifestations of HD. Randomized placebo-controlled trials of medications have been small, and the bulk of information available comes from case studies and anecdotal evidence. Thankfully, there is no evidence to suggest that HD patients are less likely to benefit from psychiatric medications than non-HD populations. Hopefully, in the future, the work of collaborative investigators will help us to fine-tune our approach. Behavioral interventions are a key component of managing patients with HD. As described above, the HDSA suggests several strategies to minimize both patient and family distress. Although there is no literature regarding psychotherapeutic strategies, psychoeducation, supportive therapy, cognitive-behavioral therapy, and family sessions should all be considered. In addition, all those affected by HD can potentially benefit from support groups, which are offered through multiple organizations. In this author’s opinion, it would be helpful for physicians, patients, and families if the diagnosis of manifest HD were expanded to reflect the significance of cognitive, behavioral, and psychiatric symptoms. The current standard, which only requires involuntary movement in the presence of a positive genetic test, minimizes the impact of these comorbid conditions. In a disease in which patients struggle with so many ambiguities, including which symptoms they will develop and how their illness might progress, an increase in diagnostic clarity could be a relief for all.
Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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symptoms, as assessed by the UHDRS, has been measured and shown to increase with disease severity, with a peak of 24% for obsessions and 12% for compulsions in advanced stages of illness [38]. The full criteria for OCD, however, are rarely met [38]. Unfortunately, scarce evidence exists regarding the treatment of psychiatric comorbidity in HD. In general, choosing a medication for a patient with HD is similar to doing so for any psychiatric patient, with the theoretical exception of a propensity toward increased side effects in the HD population. As with the use of antidepressants in all depressive illness, there are no concrete data to suggest the superiority of any one agent over another [7]. If the diagnostic criterion is met for mania, lithium should be avoided, as potential fluctuations in fluid intake can lead to toxicity [7]. It is important to distinguish mania from isolated irritability and impulsivity, as the latter do not typically respond to mood-stabilizing medications [7]. Expert consensus supports the use of SSRIs and clomipramine for obsessive-compulsive behaviors [39]. If psychosis is present, antipsychotics are indicated. As with psychotic illness in general, no particular agent is preferred [7]. If chorea exists, the high-potency typical agents may be of benefit, as they decrease movement via parkinsonism. In contrast, if the patient has either bradykinesia or rigidity, atypical antipsychotics are a better choice. Although there are only case studies regarding electroconvulsive therapy, evidence indicates improvement in mood and psychosis as well as decreased suicidality [40]. Interestingly, decreased cognition is not always the norm.
References 13 Schreiber W, Krieg JC, Eichhorn T: Reversal of tetrabenazine induced depression by selective noradrenaline (norepinephrine) reuptake inhibition. J Neurol Neurosurg Psychiatry 1999;67: 550. 14 White RF: Clinical Syndromes in Adult Neuropsychology: The Practitioner’s Handbook. Amsterdam/New York, Elsevier, 1992. 15 Phillips W, Shannon KM, Barker RA: The current clinical management of Huntington’s disease. Mov Disord 2008; 23:1491–1504. 16 Martin B, Golden E, Keselman A, et al: Therapeutic perspectives for the treatment of Huntington’s disease: treating the whole body. Histol Histopathol 2008;23:237–250. 17 Duff K, Paulsen J, Mills J, et al: Mild cognitive impairment in prediagnosed Huntington disease. Neurol 2010;75: 500–507. 18 Paulsen JS, Langbehn DR, Stout JC, et al: Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 2008;79:874–880. 19 Peavy GM, Jacobson MW, Goldstein JL, et al: Cognitive and functional decline in Huntington’s disease: dementia criteria revisited. Mov Disord 2010;25:1163– 1169. 20 Mickes L, Jacobson M, Peavy G, et al: A comparison of two brief screening measures of cognitive impairment in Huntington’s disease. Mov Disord 2010;25: 2229–2233. 21 Beglinger LJ, Adams WH, Paulson H, et al: Randomized controlled trial of atomoxetine for cognitive dysfunction in early Huntington disease. J Clin Psychopharmacol 2009;29:484– 487. 22 Cubo E, Shannon KM, Tracy D, et al: Effect of donepezil on motor and cognitive function in Huntington disease. Neurology 2006;67:1268–1271. 23 Blackwell AD, Paterson NS, Barker RA, Robbins TW, Sahakian BJ: The effects of modafinil on mood and cognition in Huntington’s disease. Psychopharmacology (Berl) 2008;199:29–36.
24 de Tommaso M, Specchio N, Sciruicchio V, Difruscolo O, Specchio LM: Effects of rivastigmine on motor and cognitive impairment in Huntington’s disease. Mov Disord 2004;19:1516–1518. 25 Rot U, Kobal J, Sever A, Pirtosek Z, Mesec A: Rivastigmine in the treatment of Huntington’s disease. Eur J Neurol 2002; 9:689–690. 26 Mestre TA, Ferreira JJ: An evidencebased approach in the treatment of Huntington’s disease. Parkinsonism Relat Disord 2012;18:316–320. 27 Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC: Suicidality in Huntington’s disease. J Affect Disord 2012;136:550–557. 28 Pflanz S, Besson JA, Ebmeier KP, Simpson S: The clinical manifestation of mental disorder in Huntington’s disease: a retrospective case record study of disease progression. Acta Psychiatr Scand 1991;83:53–60. 29 van Duijn E, Reedeker N, Giltay EJ, Roos RA, van der Mast RC: Correlates of apathy in Huntington’s disease. J Neuropsychiatry Clin Neurosci 2010;22:287– 294. 30 Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC, Predict-HD Investigators of the Huntington Study Group. Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 2007;62:1341– 1346. 31 Wetzel HH, Gehl CR, Dellefave-Castillo L, et al: Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res 2011;188:372–376. 32 Epping EA, Mills JA, Beglinger LJ, et al: Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study. J Psychiatric Res 2013;47:1423–1431. 33 Smith MM, Mills JA, Epping EA, Westervelt HJ, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group. Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease. Neuropsychology 2012;26:664–669. 34 Downing N, Smith MM, Beglinger LJ, et al: Perceived stress in prodromal Huntington disease. Psychol Health 2012;27: 196–209.
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1 Papp KV, Kaplan RF, Snyder PJ: Biological markers of cognition in prodromal Huntington’s disease: a review. Brain Cogn 2011;77:280–291. 2 Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C: Therapeutic interventions for symptomatic treatment in Huntington’s disease. Cochrane Database Syst Rev 2009;3:CD006456. 3 Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N: The incidence and prevalence of Huntington’s disease: a systematic review and metaanalysis. Mov Disord 2012;27:1083– 1091. 4 Novak MJ, Tabrizi SJ: Huntington’s disease. BMJ 2010;340:c3109. 5 Vassos E, Panas M, Kladi A, Vassilopoulos D: Effect of CAG repeat length on psychiatric disorders in Huntington’s disease. J Psychiatr Res 2008;42:544– 549. 6 Paulsen JS: Cognitive impairment in Huntington disease: diagnosis and treatment. Curr Neurol Neurosci 2011;11: 474–483. 7 Nance M, Paulsen JS, Rosenblatt A, Wheelock V, Huntington’s Disease Society of America. A Physician’s Guide to the Management of Huntington’s Disease, ed. 3. New York, Huntington’s Disease Society of America, 2013. 8 Ross CA, Aylward EH, Wild EJ, et al: Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 2014;10: 204–216. 9 Beglinger LJ, O’Rourke JJ, Wang C, et al: Earliest functional declines in Huntington disease. Psychiatry Res 2010;178: 414–418. 10 Roos RA: Huntington’s disease: a clinical review. Orphanet J Rare Dis 2010;5: 40. 11 Chen JY, Wang EA, Cepeda C, Levine MS: Dopamine imbalance in Huntington’s disease: a mechanism for the lack of behavioral flexibility. Front Neurosci 2013;7:114. 12 Kapur S, Seeman P: Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. AJP 2001; 158:360–369.
35 Harris EC, Barraclough B: Suicide as an outcome for mental disorders. A metaanalysis. Br J Psychiatry 1997;170:205– 228. 36 Kessler RC, Berglund P, Borges G, Nock M, Wang PS: Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990–1992 to 2001–2003. JAMA 2005;293:2487–2495.
37 Nagel M, Rumpf HJ, Kasten M: Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis. Gen Hosp Psychiatry 2014;36:361.e3–e4. 38 Beglinger LJ, Langbehn DR, Duff K, et al: Probability of obsessive and compulsive symptoms in Huntington’s disease. Biol Psychiatry 2007;61:415–418. 39 Anderson K, Craufurd D, Edmondson MC, et al: An international survey-based algorithm for the pharmacologic treatment of obsessive-compulsive behaviors in Huntington’s disease. PLoS Curr 2011;3:RRN1261.
40 Cusin C, Franco FB, Fernandez-Robles C, DuBois CM, Welch CA: Rapid improvement of depression and psychotic symptoms in Huntington’s disease: a retrospective chart review of seven patients treated with electroconvulsive therapy. Gen Hosp Psychiatry 2013;35: 678.e3–e5.
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Morreale Balon R, Wise TN (eds): Clinical Challenges in the Biopsychosocial Interface. Update on Psychosomatics for the 21st Century. Adv Psychosom Med. Basel, Karger, 2015, vol 34, pp 135–142 (DOI: 10.1159/000369111)
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Mary K. Morreale, MD Department of Psychiatry 3901 Chrysler Service Dr. Detroit, MI 48201 (USA) E-Mail [email protected]
