Treating Depression and Suicidality in Huntington’s Disease

Treating Depression and Suicidality in Huntington’s Disease

Publication date: Feb 07, 2020

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.

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.

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.

Concepts Keywords
Acid Fluoxetine
Adenine Suicidal ideation
Amantadine Mood disorders
Antidepressant Antidepressants
Antidepressants RTT
Anxiety Psychiatry
Anxiety Disorder Depression
Athetosis Psychoactive drugs
Autosomal Dominant Electroconvulsive therapy
Benzodiazepine Psychotherapy
Bipolar Depression Bipolar disorder
Bipolar Disorder Bipolar disorder II
Borderline Personality Disorder Practice treatment chorea
Cerebrospinal Fluid Beta tumor necrosis
Chorea Significant improvement chorea
Clinical Trials Treatment chorea
Clonazepam Chronic bipolar depression
Cognitive Bipolar depression
Comorbid Months hospital depression
Comorbidities Seizures
Compulsions Comorbid substance disorder
Cytosine Athetosis
Dementia Paroxetine
Depressed Mood Daily persistent depression
Depression Major depressive disorder
Distal Medication movement disorder
Dopamine Anxiety disorder
Dysarthria Drug resistant depression
Dyskinesia Neuroinflammation symptoms depression
Electroconvulsive Therapy Alpha
Executive Function Major depressive disorder
Interleukin 1
Interleukin 6
Lifetime Prevalence
Metabolic Syndrome
Movement Disorder
Neurodegenerative Disorder
Obsessive Compulsive
Patient History
Psychiatric Disorders
Seizure Disorder
Suicidal Behavior
Suicidal Ideation
Suicidal Ideations
Synaptic Cleft
Tricyclic Antidepressant
Trinucleotide Repeats
Tryptophan Metabolism
Valproic Acid


Type Source Name
disease MESH major depressive disorder
disease MESH neurological disorders
drug DRUGBANK Riluzole
drug DRUGBANK Amantadine
drug DRUGBANK Mirtazapine
drug DRUGBANK Spinosad
disease MESH dyskinesia
disease MESH development
drug DRUGBANK Serotonin
drug DRUGBANK Benzodiazepine
drug DRUGBANK Paroxetine
disease MESH seizure disorder
drug DRUGBANK Phenytoin
disease MESH seizures
drug DRUGBANK Clonazepam
disease MESH substance use disorder
disease MESH metabolic syndrome
drug DRUGBANK Fluoxetine
disease MESH insomnia
disease MESH movement disorder
drug DRUGBANK Quetiapine
drug DRUGBANK Valproic Acid
drug DRUGBANK Olanzapine
drug DRUGBANK Risperidone
drug DRUGBANK Sertraline
drug DRUGBANK Deutetrabenazine
drug DRUGBANK Dopamine
drug DRUGBANK Valbenazine
drug DRUGBANK Tropicamide
drug DRUGBANK Haloperidol
disease MESH dysarthria
disease MESH suicide
disease MESH borderline personality disorder
disease MESH dementia
drug DRUGBANK Diamorphine
disease MESH suicidal ideation
disease MESH emergency
drug DRUGBANK Tetrabenazine
pathway KEGG Tryptophan metabolism
disease MESH impulsivity
disease MESH Completed suicide
disease MESH anxiety disorder
disease MESH obsessions
disease MESH anxiety
disease MESH mania
disease MESH psychosis
disease MESH psychiatric disorders
disease MESH apathy
disease MESH athetosis
disease MESH chorea
disease MESH abnormalities
disease MESH cognitive decline
drug DRUGBANK Guanine
drug DRUGBANK Adenine
disease MESH neurodegenerative disorder
disease MESH Depression


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