Recognizing the Neuropsychiatric Symptoms of Huntington Disease

TALES FROM THE CLINIC

Series Editor Nidal Moukaddam, MD, PhD

In this installment of Tales From the Clinic: The Art of Psychiatry, we explore the neuropsychiatric symptoms and presentation of Huntington disease (HD). While the motor pathology is easily clinically recognizable, associated neuropsychiatric manifestations are not well understood and lack systematic treatment trials, despite representing a significant burden on patients. There is also a lack of disease-modifying therapies for HD, adding to the problem.

Case Study

“Mr Blake” is a 44-year-old man with a 5-year history of major depressive disorder who presented to his psychiatrist after a referral from his primary care physician. He presented with concerns regarding a new onset of cognitive deficits. He reported that he had recently noticed difficulty focusing and had become very forgetful, missing appointments for his job. Mr Blake stated that this had been ongoing for several weeks, and he had been experiencing trouble at work because of it. He worried that it might be because of the recent increase in his fluoxetine dose from 20 to 30 mg daily for his worsening depressive symptoms. Mr Blake denied any physical or motor symptoms, such as tremors or involuntary movements, and headaches. He reported that he had become more anxious and irritable. Family history is positive for the suicide of his mother at age 44.

His psychiatrist performed the Montreal Cognitive Assessment (MoCA), and Mr Blake received a score of 21, indicating mild cognitive impairment. In light of this, his psychiatrist referred him to a neurologist to address this new onset of cognitive symptoms. Upon his visit to the clinic, the neurologist performed a full neurological exam and noted no major deficits in motor function. The neurologist asked Mr Blake again about his family history. Mr Blake reported that his mother had regular mood swings and committed suicide around his age. When asked about his grandparents, he stated that he does not remember much aside from his maternal grandfather often making random “jerky” movements.

The neurologist ordered a genetic test that came back positive for a HTT mutation, confirming that Mr Blake has HD. The neurologist counseled Mr Blake about the prognosis of HD and the progression of its symptomology to the triad of motor, psychiatric, and cognitive symptoms. He was prescribed 20 mg of memantine daily for his cognitive deficits and continues taking 30 mg of fluoxetine daily. His neurologist and psychiatrist work together and monitor Mr Blake’s disease progression, prepared to add new medications as needed.

Five-Year Follow-Up 

Mr Blake presents to his neurologist, having now developed full HD pathology. He is on an extensive medication regimen with dopamine modulators, N-methyl-D-aspartate (NMDA) receptor antagonists, antidepressants, and anxiolytics. Mr Blake’s neurologist informs him of an upcoming clinical trial for gene therapy with the potential of inactivating mHTT and helps him get enrolled.

An Overview of HD

HD is a progressive neurodegenerative disease of the basal ganglia that manifests in disturbances of cognitive, motor, and behavioral/psychiatric functions, leading to severe disability and ultimately death.1,2 It occurs with its highest prevalence in Western populations at 10.6 to 13.7 individuals per 100,000, with a global rise over the past 2 decades.^1,2 The disease is caused by a CAG trinucleotide repeat expansion on chromosome 4 of the HTT gene, creating a mutant huntingtin (mHTT) protein responsible for the disease pathology.^1,2 Several proposed mechanisms, including glutamine excitotoxicity, mitochondrial dysfunction, oxidative stress, and neuroinflammation, have been advanced to explain the clinical manifestations.^2,3 Ultimately, the striatum’s neuronal population of medium spiny neurons (MSNs) becomes vulnerable due to the mHTT protein and undergoes neurodegeneration. Because HD is a disease of the basal ganglia, its molecular progression is biphasic, starting with the loss of the indirect pathway of the basal ganglia and progressing to the direct pathway. The neurodegeneration and subsequent inactivation of the basal ganglia pathways lead to atrophy of the caudate nucleus and putamen. HD also displays monogenic autosomal dominant inheritance with full penetrance, meaning the disease is always expressed if an individual has at least 1 copy of the gene/allele.²

HD symptomology follows a triad of motor, cognitive, and psychiatric/behavioral disturbances, usually manifesting during midadulthood.^1-3 The biphasic progression of HD manifests to an early hyperkinetic phase of involuntary movements (ie, chorea) and a later hypokinetic phase in which voluntary movements become inhibited, resulting in bradykinesia, dystonia, gait disturbances, etc.^1,2 Cognitively, HD results in impaired emotional processing as well as executive function (eg, attention, concentration, decision-making, etc) with some evidence of indirect peripheral nervous system impairment.^1,2 HD has a wide psychiatric manifestation, with notable effects on anxiety, depression, obsessive-compulsive behavior, irritability, aggression, and psychosis.^1,2 The actual diagnosis of HD can be made at any time, but it is typically done during middle adulthood after the onset of symptoms.³ Given the genetic nature of HD, clinical diagnosis is usually evaluated by a positive genetic test for the HTT mutation in combination with cognitive tests and neuroimaging.^1,2 Predictive testing before symptom onset could also be done for individuals at risk of inheriting the mutation, typically for reproductive purposes.¹

Currently, there are no approved disease-modifying treatments for HD; therefore, the therapeutic interventions only address the symptoms.³ Treatment for motor symptoms (eg, hyperkinesia and chorea) is limited to supplementing the indirect pathway via dopamine modulators/antagonists and antiglutamatergic drugs. Given the mechanism of the basal ganglia pathways, the therapy for the indirect pathway could exacerbate the symptoms of the direct pathways (eg, hypokinesia and rigidity). Dopamine agonists have been studied, although they have a limited effect.³ Cognitive impairment is typically treated with NMDA receptor antagonists (eg, memantine), which reduce the glutamate-mediated excitotoxicity.³ Psychiatric and behavioral treatment options typically follow the general therapeutics of the specific symptoms (eg, antidepressants, antipsychotics, etc).³

Advancements in gene therapies, specifically clustered regularly interspaced short palindromic repeats (CRISPR)–associated protein 9 (Cas9), show promise in possible disease-modifying therapies via inactivation of mHTT.³ HD is a fully penetrant disease with a very poor prognosis. The disease is progressive, and the symptomatology has a profound effect on quality of life.^1,2 While the specific gene of HTT has been identified, the mechanism leading to the neurodegeneration of striatal MSNs remains unclear, leading to limited treatment options aside from developing gene therapies and addressing the symptoms.^1-3

HD Management and Treatment

While HD is certainly an area of academic interest, the management of its neuropsychiatric symptoms is not as well explored as its motor or cognitive manifestations.⁴ Psychiatric—or rather, neuropsychiatric—symptoms are not just common in patients with HD, but are part of the full disease spectrum (ie, triad) and cause serious emotional toll and distress.⁵ In fact, neuropsychiatric symptoms (NPS) are often the first manifestation of HD, occurring in atypical phases as early as 20 years before the onset of motor symptoms (eg, chorea).⁶ Regarding the mechanism, studies point toward the neuronal loss of the basal ganglia and eventual cerebral degeneration as a core contributor to NPS. The resulting neurodegeneration seems to affect other neuronal pathways such as the limbic system, the orbitofrontal-subcortical circuit, and the anterior cingulate-subcortical circuit structures, to name a few.⁶ As far as the scope of NPS, we see a wide range of symptomatology, including affective and nonaffective disorders such as depression, mania, and anxiety.^6,7 Furthermore, other behavioral symptoms such as apathy, impulsivity, disinhibition, and sexual dysfunction, as well as obsessive and psychotic symptoms, are reported.^6,7 The heterogeneous and complex nature of NPS manifestation in HD makes it especially difficult to manage in terms of pharmacotherapy.⁵ On top of that, there is a severe lack of evidence-based clinical trials for disease-modifying therapies, which makes pharmacological treatment especially limited.⁸

Generally, it is imperative for the physician to identify any NPS as early as possible and begin treatment, following the multidisciplinary approach of pharmacological interventions as well as counseling, behavioral therapy, and support.⁴ Depression is the most common NPS seen in HD, appearing in atypical stages throughout the disease, normally preceding any motor symptoms as a prodrome and eventually increasing during the disease course.⁹ Anxiety in HD is also common, usually coexisting with depression in the prodromal stage, and can actually worsen the eventual motor and cognitive HD symptoms.⁵ Irritability/aggression is another especially common NPS in HD, where patients are very quick to anger despite minimal triggers.⁹ On the other side of the coin, we see apathy as another extremely frequent NPS that occurs in the middle and later stages of the disease. In these cases, patients will greatly lose interest and motivation in daily activities.⁹ These specific NPS are typically linked together and contribute to a significant increase in the risk factors for suicide in patients with HD, with a suicide rate 4 to 5 times higher than the general population.⁶ Obsessive-compulsive symptoms and psychotic symptoms have also been documented in patients with HD, although they are less common than other NPS.⁶ The recommended pharmacological therapies follow the standard guidelines per psychiatric symptom (eg, selective serotonin reuptake inhibitors for depression), with disease-modifying treatment being severely understudied.⁸ Furthermore, with the diverse scope of NPS, it is imperative to always monitor drug interactions to prevent adverse reactions or exacerbated symptoms.⁶ It is also important to consider the guidelines on behavioral therapies as treatments for specific NPS in patients with HD.⁵ Cognitive symptoms can also occur and present in a dementia-like picture in advanced stages. The Figure outlines first-line pharmacological treatments as well as alternative drug classes and behavioral interventions.^4,5,10

Concluding Thoughts

While HD is often characterized by its motor symptoms of hyperkinetic movement and chorea, it has major psychiatric manifestations that are just as common and extremely burdensome on the patient. Psychiatrists treating patients with HD can expect to find symptoms of depression, anxiety, agitation, apathy, obsessive-compulsive disorder, and even psychosis; however, the actual range of neuropsychiatric symptoms is even broader. When treating patients with HD for their psychiatric manifestations, it is imperative to follow the most up-to-date guidelines on pharmacological therapies, paying close attention to drug-drug interactions and paradoxical effects.¹⁰ Given the extensive symptomology, certain drug classes may alleviate one set of symptoms while exacerbating another. Furthermore, physicians must always take an interdisciplinary approach to care and help the patient manage symptoms through traditional behavioral/psychological therapies.

In HD, neuropsychiatric symptoms often precede any motor symptoms, which can make psychiatrists the first responders. With that said, psychiatrists must be able to spot the pattern of HD NPS and make the necessary orders and referrals to ensure the best patient outcome. For example, a psychiatrist may note that a patient presents as presymptomatic for HD and can order a genetic test. Throughout their treatment, patients with HD can see several different physicians at a time, as well as take multiple medications simultaneously. As such, psychiatrists, neurologists, and their patients must work in deep collaboration to ensure efficient drug management and proper care.

The mechanism behind HD is unfortunately elusive, and there is no actual disease-modifying therapy available for patients, with only symptom-addressing therapeutic interventions available. Even so, pharmacological treatment plans also lack the evidence from clinical trials to adequately address the neuropsychiatric symptoms of HD. Current research points toward gene therapies such as Cas9 as having the potential to treat patients with HD at the molecular level. With limited treatment options available, physicians must dedicate their support to advancing HD research in clinical trials and beyond. Support for families may also be welcome as symptoms become more pronounced.

Mr Saadah is a student at Texas A&M University College of Medicine, interested in the neurology/psychiatry interface. Dr Moukaddam is a professor of psychiatry at Baylor College of Medicine, Department of Psychiatry, and the director of Outpatient Psychiatry at Harris Health. She also serves on the Psychiatric Times Editorial Board.

References

1. McColgan P, Tabrizi SJ. Huntington’s disease: a clinical review. Eur J Neurol. 2018;25(1):24-34.

2. Jiang A, Handley RR, Lehnert K, Snell RG. From pathogenesis to therapeutics: a review of 150 years of Huntington’s disease research. Int J Mol Sci. 2023;24(16):13021.

3. Kim A, Lalonde K, Truesdell A, et al. New avenues for the treatment of Huntington’s disease. Int J Mol Sci. 2021;22(16):8363.

4. Jay JA, Kumar V, Garrels E, et al. Management of neuropsychiatric disturbances in Huntington’s disease: a literature review and case report. Prim Care Companion CNS Disord. 2023;25(1):22cr03265.

5. Anderson KE, van Duijn E, Craufurd D, et al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-based consensus guidelines on agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis. 2018;7(3):355-366.

6. Paoli RA, Botturi A, Ciammola A, et al. Neuropsychiatric burden in Huntington’s disease. Brain Sci. 2017;7(6):67.

7. Saft C, Burgunder JM, Dose M, et al. Symptomatic treatment options for Huntington’s disease (guidelines of the German Neurological Society). Neurol Res Pract. 2023;5(1):61.

8. Andriessen RL, Oosterloo M, Molema J, et al. Pharmacological treatment of neuropsychiatric symptoms in Huntington’s disease: a systematic review. Mov Disord Clin Pract. 2025;12(4):418-431.

9. Bachoud-Lévi AC, Ferreira J, Massart R, et al. International guidelines for the treatment of Huntington’s disease. Front Neurol. 2019;10:710.

10. Huntington disease (HD). Rare Disease Advisor. Updated June 24, 2025. Accessed August 5, 2025. https://www.rarediseaseadvisor.com/junction-hub-pages/huntington-disease/