Dr. O'Leary reviews one of the most frustrating diseases that a patient and their family might approach a psychiatrist with: Huntington’s Disease. Huntington’s Disease is a neurodegenerative disorder, which means that over the course of the disease neurons die or cease to function correctly and this worsens over time. The death of neurons in the caudate nucleus and putamen results in choreiform or dance-like movements of the extremities which earned it the moniker “Huntington’s Chorea." Huntington's Disease can result in many psychiatric symptoms and these may start to occur during the prodromal stage before the choreiform movements develop. Sleep disturbances, apathy, executive dysfunction, memory impairment, personality change, irritability and aggression, disinhibition and impulsivity (including hyper-sexuality), depression, mania, delusions, paranoia and other psychotic symptoms, obsessions and compulsions, and most prominently a high risk of suicide.
Please leave feedback at https://www.psydactic.com. References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
Welcome to PsyDactic - Residency Edition. I am Dr. O’Leary, a 3rd year psychiatry resident in the national capital region. I love making this podcast, but my love for it far outstrips my credentials and doesn’t magically make more time for me to make. I do this podcast to help me understand more deeply the patients that wander into my office, what is causing their dysfunction and what we can do together to improve their life, or at the very least, prevent things from getting worse. No one else that I know of endorses or approves my opinions. If they do, then the are as likely to be as wrong, as I am likely to be. My opinions are certainly not to be confused with those of the National Capital Consortium Psychiatry Residency Program, the Department of Defense, the Federal Government, the Society for the Preservation and Encouragement of Barbershop Quartets Singing in America, or anyone else for that matter. Today I want to review one of the most frustrating diseases that a patient and their family might approach a psychiatrist with: Huntington’s Disease.
Huntington’s Disease is a neurodegenerative disorder, which means that over the course of the disease neurons die or cease to function correctly and this worsens over time. It can have a long, insidious prodromal phase, or seem to develop more rapidly. The death of neurons in the caudate nucleus and putamen results in choreiform or dance-like movements of the extremities which earned it the moniker “Huntington’s Chorea:” chorea meaning dance (like choreographer) and Huntington’s after the first researcher to fully characterize the phenotype of the illness. Choreiform movements are large amplitude movements that are most noticeable in the limbs, but though they are the most conspicuous movements in the disease, they are often accompanied by other movement difficulties that affect a person's ability to swallow or to fix their gaze on an object. Over the course of the disease motor problems can progress to more difficulty moving and rigidity like in Parkinson’s Disease. There are also likely personality changes, cognitive impairments, and behavioral disturbances associated with impaired emotional regulation.
Huntington’s Disease is caused by a trinucleotide repeat of CAG on chromosome 4 in an exon that encodes the protein called huntingtin. You may remember that exons are parts of a gene that ultimately exit the nucleus to be translated into a protein, resulting, in this case, in a malformed protein. The function of this protein is not known, but when there are enough repeats in this area it causes the protein to build up over time and this results in neuronal death and dysfunction. Huntington’s is considered an autosomal dominant disease because if it is inherited from a parent, it will be present in offspring regardless of sex. However, its expression can vary primarily based on the number of repeats in the region. In general, having more than 26 repeats can result in the disease, and its penetrance (or likelihood of being expressed as a disease) increases to 100% when reaching 39 repeats. Having more repeats generally means that the disease will be present earlier in life and may progress more rapidly. This is because repeats tend to accumulate and expand over generations. This earlier onset due to expanded repeats is a phenomenon known as anticipation. This genetic anticipation can also result in a different kind of anticipation, when children with an affected parent anticipate developing the disease themselves, either because they had genetic testing to verify the variant, or they know there is a 50% chance that they carry it.
Images of the brain will most likely show atrophy in the caudate and putamen, which are the regions that control motor behaviors. In some cases it can result in something called “boxcar ventricles” which is a squaring and enlargement of the 3rd ventricles due to loss of neurons in caudate and putamen. The cortex also atrophies, and the involvement of the cortex can help explain some of the neuropsychiatric components. Imaging may also be within normal limits and this does not exclude the disease.
HD can result in many psychiatric symptoms and these may start to occur during the prodromal stage before the choreiform movements develop. Sleep disturbances, apathy, executive dysfunction, memory impairment, personality change, irritability and aggression, disinhibition and impulsivity (including hyper-sexuality), depression, mania, delusions, paranoia and other psychotic symptoms, obsessions and compulsions, and most prominantly a high risk of suicide.
Basic screening instruments and structured interviews can be useful for identifying symptoms of concern. Be sure to ask about the timeline of symptoms, and if treating someone who has already begun to experience motor symptoms, be sure to ask about prodromal psychiatric symptoms. Because the brains of patients with HD have some level of diffuse dysfunction throughout many regions, the diagnostic criteria that we apply to the general population should be interpreted in the context of the patient. Depression can result in poor sleep, executive dysfunction, low motivation, psychomotor agitation and suicidality. In HD these symptoms could be present for very different reasons. Also, the symptoms may have a variable course, spontaneously occur and then remit.
It is critically important whenever possible to include a spouse or other companion or long term caregiver of the patient when reporting and rating symptoms because individuals with Huntington's disease often have a decreased awareness of symptoms and insight may become progressively poor as the disease advances. The companion can help to fill in those blanks or provide a more objective report. This is true even in the prodromal phase (before motor onset). Many of the prodromal psychiatric changes may be subtle and not noticeable to the patient, but more obvious to their loved ones.
Another principle when considering symptoms is whether these are a side effect of medications that they are already on. For example Tetrabenazine or deutetrabenazine may be prescribed to help with hyperkinetic motor activity. They are human vesicular monoamine transporter type 2 inhibitors and result in depletion of the monoamines serotonin, norepinephrine, and dopamine. Therefore, they can also worsen depressive symptoms and result in higher rates of suicidality. These drugs do exactly the opposite of what many of our antidepressants and psychostimulants are thought to do (increase available serotonin, norepinephrine, or dopamine), so use of these medications can result in low energy, low motivation, suicidal thoughts, akathisia (or agitation) and anxiety. All of these are also not unexpected results of the disease itself. Although FDA approve, tetrabenazine is not used regularly and is often reserved for cases of uncontrolled motor function.
A paper titled Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines
on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders published in the Journal of Huntington’s Disease in 2018, reported the results of an expert committee's recommendations that relied heavily on responses to a survey of clinicians. They reported a high level of consensus between these physicians. Being relatively rare and highly variable in presentation, HD does not lend itself well to numerous clinical trials, and many trials that do exist are conducted by drug companies trying to find support for their pharmacological agents. There are also a number of case series in the literature. The previously mentioned paper divided treatment strategies into 5 domains including general treatment, apathy, anxiety, agitation and sleep disorders. I will highlight some of their recommendations here. I have also included other readings at the end of the transcript for this podcast which is located at psydactic.buzzsprout.com.
Because the inheritance of HD CAG repeats results in genetic anticipation, it can present early in life, rarely in adolescence or childhood, but more commonly in middle adulthood. This means that the patient has had time to develop other comorbid medical conditions such as diabetes, cardiovascular disease, other brain or bodily injuries and even other psychiatric injuries. At the time that they present with a life story, the patient also is in a socioeconomic and cultural context that has folded into it many other challenges, strengths and determinants of health. Be sure to have a good grasp on what a patient is already bringing to the table and their resources and challenges for the future. As a treating physician, you will be responsible for educating the patient and their family on what to expect and how to cope with it, so be prepared for an alignment with them that goes beyond mere office visits for medication refills.
One of the prominent challenges that families and patients will face is agitation. If you listened to my podcast in the past, you might remember that I have complained about the use of the word agitation in medicine. It is frequently poorly defined and its definition seems highly contextual. When families come to us and report agitation it might look something like this: Inability to sit still, resistance to requests, talking too much, not listening, yelling and screaming, insulting others, physically attacking or resisting interventions by others. That's a lot of very different things and its not a comprehensive list. One thing that defines agitation is that it is something that makes itself obviously a problem in the moment, unlike apathy that might take days or weeks to identify as a problem. It constitutes a broad range of actions that are not socially acceptable at the time they occur. Similar to agitation in delirious patients, it is important to make sure that the environment is not exacerbating the problem. First educate families in calming measures and how to use distraction or reorientation to help prevent worsening of whatever is happening. It may be that the family member needs to calm and reorient themselves before they attempt to help their loved one. Providing familiar, trusted voices or calming stimuli like favorite music might help. It may be best not to engage at all, but to provide a safe, quiet place where the patient can calm down. Remove noxious stimuli that might be overwhelming the patient. Be sure to check for deficits in senses, such as problems with vision or hearing. HD patients may also be experiencing hallucinations or delusions that need to be identified as sources of distress. Assess for pain and treat it appropriately. Someone who is agitated may not be perceiving at the moment the pain that is disturbing them. A trial of acetaminophen in patients with good liver function or NSAIDs in those with adequate renal function can be safe and helpful.
For acute agitation that doesn’t respond to reorientation, distraction, or calming, low dose antipsychotics can be helpful. Benzodiazepines can also help, but care should be taken because benzos might cause paradoxical agitation and as I will repeat later, should not be used as chronic treatment in HD unless everything else has failed. Antipsychotics on the other hand, may be helpful not only for agitation, but also as chronic treatment to reduce motor symptoms, delusions and paranoia. If agitation is frequent, then there might be underlying irritability, obsessions, or depression that needs to be treated with an antidepressant like an SSRI, SNRI, or tricyclic like clomipramine, or even an anticonvulsant (which we psychiatrists often refer to as mood stabilizers - Dr. DePietro, I can hear you groaning as I use the term mood stabilizer.)
Clinicians often focus on agitation because it is an obvious symptom and can result from the other problems that patients with HD often experience. Other symptoms to be aware of are apathy and depression, intense anxiety, psychosis, and chronic sleep disturbances.
Let’s look at Apathy and depression. Apathy can look like anhedonic depression and in different surveys has been present in ¼ to ¾ of patients with HD. It tends to become more frequent after motor symptoms are “manifested” especially because motor symptoms tend to progress from hyperkinetic and involuntary movements to more bradykinesia and rigidity later. Apathy can be seen as a lack of emotion or motivation in many areas. Anhedonia is specifically the inability to experience pleasure. Abulia may be present as well and this describes the inability to make decisions or to act decisively. Alexithymia may be another component of apathy and literally means having no words for feelings, or the inability to put one’s emotions into words. Apathy in HD is not necessarily the same as depressive symptoms you have seen in other patients. Apathy may result in a patient apparently lacking motivation to do anything, even to eat, and to be true apathy the symptoms need to be distinct from the patient’s inability to do this because of motor dysfunction. Catatonia can also result and there are case studies that demonstrate that ECT (electro-convulsive therapy) is effective in HD as well. In one review, 18 out of 19 HD patients experienced improvement of catatonia, psychosis, or depression and overall functioning with ECT, but one patient in particular experienced worsening of motor symptoms. For a more thorough review of ECT see the first 3 episodes of this podcast.
We don’t know why apathy develops in HD, but it can develop early. The most prominent early changes on imaging in HD are in the striatum, so it is natural to suspect this. One of our main emotion processing networks involves what has been called the “limbic loop.” The ventral striatum receives projections from the anterior cingulate, the orbitofrontal cortex and dorso-lateral and ventro-medial prefrontal cortex. These regions are involved in the experience of emotion and of motivation, but also in obsessions and compulsions. There are not enough studies to be able to draw any definitive conclusions about what kind of network dysfunction causes apathy in HD.
There may be more classical features of low mood, poor appetite, low energy, poor concentration and difficulty thinking or making decisions, and possibly psychomotor agitation or retardation, feelings of guilt and worthlessness or suicidal ideation. Patients with HD are at least 6 times as likely to attempt suicide as the general population, and one review I read reported a risk 12 times higher. Frequent screening for depression and apathy is important and SSRIs are the first line for both. I have not been able to find much evidence that would help me decide which SSRI is the most effective. Fluoxetine has been called an “activating” antidepressant, but I wouldn’t trust that general responses like these are helpful predictors in HD. All I can say is that I would avoid SSRIs that are more anticholinergic, like paroxetine, at the onset unless you have another good reason for this. Don’t be shy switching to another SSRI if the first was ineffective. If you started escitalopram and it didn’t work or had intolerable side effects, then it would be reasonable to switch to sertraline before abandoning SSRIs altogether. For comorbid sleep problems, expert opinion seems to favor mirtazapine or clomipramine if there are obsessional components that two trials of an SSRI did not address. As a reminder, don’t be afraid to stop or taper a drug that is not working and try something else.
It may be tempting to start a psychostimulant like methylphenidate, atomoxetine, modafinil, amantadine, or bromocriptine to treat apathy. These all have different mechanisms of action, and may be helpful adjunctively or at low doses. However, evidence for their effectiveness in depression in HD has not been studied in randomized controlled trials and they present the risk of worsening other psychiatric symptoms, so care should be taken with close follow-up if you choose these. When first seeing a patient with HD, you may notice that the neurologist has already started amantadine, because it can help treat some of the motor symptoms and have the expected effect of improving cognitive symptoms as well.
Not surprisingly, anxiety often accompanies depression in HD. It can contribute to agitation and depression and be exacerbated by psychotic symptoms. The first line treatments for anxiety overlap with depression, so you won’t have to choose to treat one or the other. However, it can be tempting to give benzodiazepines, which are a double edged sword. Chronic treatment with benzos is associated with worse outcomes, so be judicious.
Psychotic and obsessional symptoms can result from HD. Increasing degeneration of the striatum and the orbitofrontal-subcortical circuit contributes to the development of socially inappropriate behaviors. The damage to cortico-striatal circuits also likely contributes to obsessions and compulsions. However, there is a lot more malfunctioning in the brain of an individual with HD than someone whose primary complaint is obsessions and compulsions. Obsessions may respond to SSRIs, but severe obsessions or psychotic symptoms require use of antipsychotics. If there is a large obsessional component with difficulty falling asleep, you can try the tricyclic antidepressant clomipramine, which is both highly sedating and has demonstrated efficacy for obsessions. You may choose antipsychotics because they can also reduce the motor symptoms of HD by slowing down traffic in the striatum. Atypicals are preferred, but there is little guidance on which to choose. Side effects should be considered and may be helpful. Sleep is another huge issue for HD patients, so sedating antipsychotics like quetiapine may be helpful. Also, don’t push doses up high quickly. Monitor for responses at lower doses and maintain these if there is a good response. If psychosis does not respond to two different antipsychotics, then reach for clozapine. We often wait too long to start this drug because of the need to monitor patients for neutropenia, myocarditis, and severe constipation or ileus (all of which can be fatal), but it remains the most effective antipsychotic there is. So, if you can monitor your patient, then use it.
After starting an antipsychotic you have to be aware of side effects, which can be hard to distinguish from the disease itself. HD is known for chorea or large amplitude involuntary muscle contractions, but dystonias and rigidity can also be present. Akathisia or restlessness can also be either medication induced or are part of the degenerative process. When adjusting medications in HD it is reasonable to slowly adjust doses up and down to see if there is improvement or worsening. Someone with HD may have been on an antipsychotic for a very long time in order to better control involuntary movements, and this might be masking brain network dysfunction that might otherwise result in psychosis, so be aware that reducing an antipsychotic might also unmask obsessions, delusions, or hallucinations.
I want to pause and reinforce here that care should be taken to avoid unnecessary polypharmacy to treat side effects of other meds, which can confound the picture even more. Instead of adding a med, try reducing one. It may take some skill to develop a good therapeutic alliance with HD patients and their families so that when the inevitable setbacks and challenges arise, they know they have an advocate in you.
Today I reviewed Huntington disease because I expect to have patients come to me in the future with this illness. I am not an expert in Huntington’s and my clinical experience leaves much to be desired. I just want to be prepared and I hope this review will help residents or other psychiatrists early in their practice to at least have a good place to start if a patient with HD arrives in their care.
Thank you for listening. I am Dr. O and this has been an episode of PsyDactic - Residency Edition.
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