Is maintenance therapy warranted for recurrent mania in a woman with a positive family history of Huntington's disease?

Abstract

A 63-year-old woman visited our outpatient clinic 2 months after being involuntarily admitted for a manic psychotic episode. She had been convinced that a bomb would hit her home and that she could talk to angels. When she was admitted, she was initially reluctant to take medication, but she quickly recovered with 10 mg of olanzapine per day and she was discharged after 3 weeks and 2 days. Her physical health is good except for osteoporosis and hypothyroid function. She does not use alcohol or drugs. She works as a legal assistant and will retire soon. She is divorced and has two daughters and two grandchildren.

Her psychiatric history revealed several (hypo)manic episodes (Figure 1). Her first manic episode likely resulted from sleep deprivation when she was 23 years old, and she recovered without needing medication after being admitted to a psychiatric ward. Her second episode of mania occurred at the age of 42 and was attributed to stress as a result of her divorce. This time around, she had to be admitted involuntarily. Then, she had three hypomanic episodes at ages 48, 51, and 58 of which she recovered without any intervention by mental healthcare professionals. She did not recall the duration of any of these last three episodes.

Despite her doubts about having bipolar disorder, she attended a psychoeducational course and attributed her episodes to psychosocial stressors, such as work-related problems and worries about her grandchild. There is no family history of psychiatric disorders, but she has a positive family history of Huntington's disease (HD), comprising seven genetically confirmed cases in one generation and symptomatic suspected cases in three successive generations. Her mother passed away at the age of 84, without an official HD diagnosis as shown in Figure 2. Our patient chose not to be genetically tested for HD as there is no cure yet. However, her two daughters decided to be tested. One of her daughters tested positive for HD, with a relatively low number of trinucleotide CAG repeats. While the exact number is not known, she was informed that a very late onset of HD was to be expected. The other daughter tested negative.

Since HD is an autosomal-dominant hereditary disease, it is highly probable that our patient has an HD gene expansion in a similar range as her daughter's. Although she had decided not to be tested for HD, our patient wondered if this could explain her vulnerability to developing psychiatric symptoms in response to psychosocial triggers and whether maintenance therapy with medication would be warranted.

Unipolar mania is classified as bipolar disorder in DSM 5 and is typically defined by three manic episodes without a depressive episode over the course of more than 5 years. Unipolar mania is a rare disorder and is clinically distinct with male predominance, earlier age at onset, shorter episodes, fewer suicide attempts, and lower lifetime comorbidities. The prevalence of unipolar mania varies between studies (prevalence 0.18%–3.1%), likely as a result of methodological differences.¹ Mania can be a manifestation of bipolar disorder or due to the use of psychotropics or a physical condition, including neurological disorders.

HD is a neurodegenerative disorder resulting from an expanded CAG trinucleotide repeat in the Htt gene on chromosome 4. A high number of repeats is correlated with earlier onset of symptoms. Patients with more than 39 repeats will develop HD, whereas patients with 36–39 CAG repeats have a reduced penetration, and patients with 27–35 CAG repeats have intermediate expansion. Behavioral changes and psychiatric disorders may be present prior to the onset of the classical movement symptoms (chorea, hypokinesia) and cognitive deterioration. Of all neuropsychiatric symptoms in HD, apathy is the most frequent symptom, but depression, anxiety, irritability, aggression, perseverative, and obsessive-compulsive behavior, and psychosis are prevalent as well.²

Our patient has recurrent unipolar mania with a first episode occurring over 40 years ago. It is unlikely she will convert to bipolar mania as she has not experienced any depressive episodes in her lifetime. As her daughter is a genetically confirmed HD gene expansion carrier—although in the lower repeat range—it is likely that she is an HD gene carrier as well. Although mood changes can be a neuropsychiatric manifestation of HD, we argue that this is unlikely in our patient as the first mania episode occurred at the young age of 40 years ago, and progressive cognitive or motor symptoms are absent. In our patient all episodes were triggered by stressful events and sleep deprivation, and she has fully recovered after every episode.

In recent years, there has been an increased interest in preclinical symptoms in C9ORF repeat expansion carriers (associated with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis) and intermediate CAG repeat carriers. These repeat expansions cause neurodegenerative changes that result in motor, cognitive, or neuropsychiatric symptoms. These repeat expansions may also influence personality traits early in life^{3, 4} and lead to a lifelong neuropsychiatric vulnerability.⁵ Collaborative efforts of psychiatrists, neurologists, and clinical neuropsychologists are warranted to define lifespan symptomatology of these carriers and to possibly unravel a genetic contribution of neuropsychiatric symptoms.

Clinical guidance on maintenance therapy for mania in HD gene expansion carriers, as is relevant for our patient, cannot be given based on scientific evidence. It is understandable that our patient prefers to strengthen her coping skills over the long-term use of mood stabilizers. Following a shared decision-making process our patient visited our outpatient clinic for an additional 6 months with a focus on her crisis management plan and on coping with psychosocial stressors.

None of the authors reported a conflict of interest.