Huntington's disease (HD) is a rare, autosomal dominant, neurodegenerative disorder with an estimated worldwide prevalence of approximately 5 per 100,000 people.1 The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the Huntingtin gene (IT15) results in cognitive decline, behavioral changes, and motor abnormalities such as chorea and athetosis, with the most common age of onset between 30 and 50 years.2 Cognitive and behavioral changes may precede motor symptoms by up to 15 years and most often present as impaired executive function, irritability, apathy, and depression.3
The lifetime prevalence of psychiatric disorders in patients with HD is estimated to be between 33% and 76%, and the most common symptoms include psychosis, mood instability, depressed mood, mania, anxiety, apathy, and obsessions/compulsions.4 Prevalence of specific symptoms in patients with HD are as follows: depression 9% to 63%; anxiety disorder independent of gender 17% to 61%; irritability 35% to 73%; obsessive and compulsive symptoms 7% to 50%; psychosis 3% to 11%.4 Completed suicide rates have been reported to be as high as 13%, which is 7 to 12 times higher than that of the general population.5 Anxiety, worsening depression, irritability, aggression, and impulsivity have been associated with high rates of suicidal behavior and suicidality in patients with HD. The mechanism is not fully known, but one can argue that abnormality in tryptophan metabolism leads to lower cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, which could account for high rates of suicidality. Despite these statistics, there are no established guidelines for treating depression in HD. Moreover, treatment of these patients may be complicated by the side effects of other medications used in HD, such as tetrabenazine, which has been shown to increase the risk of depression and suicidality in patients with HD.6 This case illustrates the psychiatric manifestations of HD, specifically depression and suicidality, and provides clinical evidence and advice to treating clinicians.
A 42-year-old woman presented to the psychiatric emergency department with active suicidal ideation with intent and a plan to overdose on heroin. She had a past medical history of HD with progressive dementia, seizure disorder, bipolar disorder II, borderline personality disorder, polysubstance abuse, and approximately 30 psychiatric hospitalizations including multiple suicide attempts.
On admission to the inpatient unit, the patient exhibited mild dysarthria and distal chorea as well as signs of anxiety, mood swings, irritability, and symptoms of severe depression, which she reported had worsened over the last month. She claimed adherence to her medication regimen, which included lithium at a dose of 300 mg twice daily, valproic acid at dose of 2,000 mg once daily, and quetiapine at a dose of 600 mg at bedtime. She had previously used tetrabenazine to manage her movement disorder but discontinued it due to increased suicidality, and she was not taking any medication for her movement disorder at the time of admission.
Collateral history obtained from the patient's outpatient psychiatrist revealed that the patient had a history of chronic bipolar II depression with predominant symptoms of sadness, lack of interest, insomnia, mood instability, irritability, and suicidal ideations. The outpatient psychiatrist had tried fluoxetine at a dose of 60 mg daily for a sufficient period with minimal clinical response. The patient was not prescribed any other antidepressant due to her concern as well as her psychiatrist's concern of “switching” depression into mania. A medication management plan and the risks versus benefits were discussed with the patient and she was prescribed lithium at a dose of 300 mg twice daily for depressive symptoms and mood instability, with the added benefit of decreasing suicidality. Clonazepam at a dose of 0.5 mg twice daily was added to address her overt anxiety. After discussion with the patient's neurologist, valproic acid at a dose of 2,000 mg at bedtime was continued for her seizures, with an added benefit of mood stabilization.
The patient's lithium dose was titrated to 300 mg thrice daily during the first week and to 600 mg twice daily in the second week. The patient's anxiety gradually improved, but she continued to display depressive symptoms, mood swings, and suicidal ideations. Her hospitalization was complicated by an episode of seizure, after which she was transferred to the medical floor and given phenytoin at a dose of 100 mg during the day and another 150 mg at bedtime. Her dose of valproic acid was tapered to 500 mg twice daily and her lithium dose was maintained at 600 mg thrice daily.
After stabilization of her seizure disorder, she returned to the psychiatry inpatient unit and was started on paroxetine at a dose of 10 mg once daily for persistent depression. After 2 months in the hospital, her depression showed marked improvement as measured by patient feedback and interviews. She was no longer irritable or exhibiting mood swings and no longer experiencing thoughts of self-harm or suicidal ideation.
In summary, the patient's depressive symptoms and suicidal ideation, which had not been responsive to fluoxetine and had worsened with tetrabenazine, improved with lithium and the addition of paroxetine. Lithium was chosen because it helps in relieving bipolar depression and significantly reduces suicide risk. Paroxetine was chosen based partly on studies suggesting its neuroprotective effects in genetic mouse models of HD.7
Depression and suicidality are common psychiatric manifestations in HD. Suicidality is an important and potentially devastating clinical aspect of HD. Patients with HD have a lifetime prevalence of suicidal behavior up to 20% and are at 12 times greater risk than the general population.8 In 6.6% of deaths in patients with HD, the cause was reported as suicide.9 Prior studies have shown an association between suicidal behavior and psychiatric comorbidities (especially depression), antidepressant use, and benzodiazepine use.8,9 Treatment with lithium has demonstrated significant reduction in suicidal ideation and behavior.10 An explanation for this is that lithium may reduce impulsivity and aggression, which are both associated with an increased risk of suicide.11
Recent studies have demonstrated that neuroinflammation plays a vital role in pathogenesis of HD. In one study, increased levels of proinflammatory markers (interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha) and activity of microglia and macrophages were found in the striatum of patients with HD.12 Another study has also shown the role of neuroinflammation in development of symptoms of depression in susceptible patients.13 Modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention.14
Selective serotonin reuptake inhibitors (SSRIs), and especially paroxetine, are thought to have some therapeutic potential in patients with HD because of their antidepressant and neuroprotective properties.7,15,16 SSRIs such as sertraline have demonstrated potential as they act as a mitochondrial protectant, increase brain-derived neurotrophic factor, and produce neurogenic effects.17,18
Chorea can present as involuntary jerking or writhing movements that may put the patient at risk for falls and aspiration as the disease progresses.19 Tetrabenazine and deutetrabenazine are the only US Food and Drug Administration-approved treatments for chorea in HD.10,20 These drugs are vesicular monoamine transporter 2 inhibitors, which reduce the concentration of dopamine in the synaptic cleft. Although valbenazine is an isomer of tetrabenazine and has a similar mechanism of action, it has not been studied for the treatment of chorea.21 Treatment of chorea in HD with these medications could be beneficial, although it can be complicated by the fact that both tetrabenazine and deutetrabenazine may increase the risk of depression and suicidality.22 However, according to a recent review of clinical trials, deutetrabenazine was found to have a better safety profile, demonstrating a lack of worsening of neuropsychiatric symptoms compared to placebo.21
Current treatment guidelines regarding coexisting psychiatric illnesses are limited. Neuroleptics such as haloperidol, risperidone, and olanzapine are also frequently used in practice for treatment of chorea and concomitant psychosis, aggression, and irritability,10 but side effects such as dyskinesia, parkinsonism, and metabolic syndrome limit their use.10 Treatment may also be complicated by comorbid substance use disorder, which can independently contribute to depression and suicidality.23
If depressive symptoms in patients with HD persist after a trial with SSRIs, we suggest using an alternative antidepressant, such as paroxetine (as in this case), a tricyclic antidepressant, or a combination of antidepressants. For example, success has been reported in case studies after introducing mirtazapine and fluoxetine.15 Drug-resistant depression may also be treated with electroconvulsive therapy but its effectiveness in treating suicidal behavior lacks evidence.9 Psychotherapy in HD has not been formally studied, but there is extensive evidence of its benefit for depression in other settings, which makes it another treatment option.24 As for chorea, if side effects occur with tetrabenazine, we suggest considering deutetrabenazine, amantadine, or riluzole.25 As a novel drug, deutetrabenazine has shown significant improvement in chorea and a better safety profile compared to tetrabenazine in clinical trials.20 Amantadine use has demonstrated improvement in mood, apathy, and fatigue.10 Neither amantadine or riluzole raise any major safety concerns, and both have been effective in treating chorea. Treating patients with HD often requires a multidisciplinary approach involving both psychiatry and neurology evidenced by index cases as these patients often suffer from psychiatric as well as neurological disorders.
As this is a single case report, it may not be sufficient to provide strong clinical evidence at a larger scale that can be generalized. The current case report also suffered from lack of conventional methodology as well as eligibility or exclusion criteria, which we often see in credible clinical research articles. Also, there could be publication bias because we the authors looked at a positive outcome of a given treatment. Therefore, further research at larger scale is required to gain a better understanding of the etiologies, pathophysiology of psychiatric comorbidities, and associated manifestations related to suicidality in HD patients.
Depression, whether stemming from major depressive disorder or bipolar disorder, is a common psychiatric symptom in patients with HD, who are also at an increased risk of suicide. Unfortunately, there are no established consensus guidelines for the treatment of psychiatric manifestations in HD. For these patients, we recommend the same initial treatment used in patients without HD, which is a trial of SSRIs. In SSRI-resistant patients, alternative antidepressants, combinations of antidepressants, or electroconvulsive therapy may be used. For the mood instability and bipolar spectrum, especially with suicidality, lithium should be tried, as it often seems to have good clinical response (as in this case). It is critical to assess the risk-benefit ratio on an individual basis and carefully monitor patients throughout the course of treatment.
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- Paulsen JS. Cognitive impairment in Huntington disease: diagnosis and treatment. Curr Neurol Neurosci Rep. 2011;11(5):474–483. doi:10.1007/s11910-011-0215-x [CrossRef] PMID:21861097
- Paoli RA, Botturi A, Ciammola A, et al. Neuropsychiatric burden in Huntington's disease. Brain Sci. 2017;7(6):e67. doi:10.3390/brainsci7060067 [CrossRef] PMID:28621715
- Wetzel HH, Gehl CR, Dellefave-Castillo L, Schiffman JF, Shannon KM, Paulsen JSHuntington Study Group. Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res. 2011;188(3):372–376. doi:10.1016/j.psychres.2011.05.006 [CrossRef] PMID:21605914
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- Kachian ZR, Cohen-Zimerman S, Bega D, Gordon B, Grafman J. Suicidal ideation and behavior in Huntington's disease: systematic review and recommendations. J Affect Disord. 2019;250:319–329. doi:10.1016/j.jad.2019.03.043 [CrossRef] PMID:30875675
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