Introduction

Patients with Huntington's disease who have psychiatric disorders generally suffer from underdiagnosis and undertreatment. It is important to remember that psychiatric problems, particularly depression, are very common and very devastating in Huntington's disease, but they are also very treatable. Relieving a depression in someone with Huntington's disease may be the single most effective intervention a physician can perform.

Psychiatric disturbances in Huntington's disease are varied. Some patients suffer from conditions such as Major Depression, Bipolar Disorder, or Obsessive-Compulsive Disorder which are specific well-described syndromes, found in all sorts of patients. Many, if not most people with Huntington's disease also experience less well defined, non-specific changes in personality and mood, such as irritability, apathy, or disinhibition. Most of these psychiatric problems are believed to be related directly to the central nervous system injury caused by Huntington's disease. This issue is discussed further in the chapter on cognition.

Specific psychiatric diagnoses

Major depression is a clinical syndrome, a constellation of signs and symptoms which, taken together, suggest the diagnosis. Use of diagnostic criteria helps to distinguish major depression from demoralization, transient changes in mood caused by negative life events, such as bereavement, and from some of the symptoms of Huntington's disease itself, such as weight loss, trouble with concentration, and apathy. Patients with major depression have a sustained low mood, often accompanied by changes in self-attitude, such as feelings of worthlessness or guilt, a loss of interest or pleasure in activities, changes in sleep, particularly early morning awakening, and appetite, loss of energy, and hopelessness. Depressed patients often feel worse in the morning than in the afternoon.

In severe cases of depression, patients may have delusions or hallucinations, which tend to match their depressed mood. A patient may hear voices berating him or urging him to commit suicide, or may have the delusion that he will be going to jail, or that he has killed his family. Depressed patients often display psychomotor retardation, a slowing of speech and movement as a result of depression. In extreme cases they can appear stuporous or catatonic.

It is important to remember that because depression is a syndrome, with various symptoms and manifestations, the presenting complaint may be something other than a low mood. For example a depressed patient may complain of insomnia, anxiety, or pain, with each problem only a symptom of the depression which is the underlying cause. It is vital to get the whole story, because symptomatic treatment for any of these complaints, e.g. sleeping pills, tranquilizers, or narcotics, could be worse than no treatment at all.

A specific complaint of depressed mood is not necessary to make the diagnosis if the patient has the other symptoms. In fact patients with Huntington's disease often have trouble identifying or describing their emotional state. Depression in such a patient may be characterized by changes in sleep or appetite patterns, agitation, tearfulness, or a drop-off in functional abilities. In such circumstances the diagnosis should be considered.

In evaluating an Huntington's disease patient with depression the physician also needs to consider whether some physical problem, other than Huntington's disease, might be the cause. The patient's medical history should be reviewed for conditions such as hypothyroidism, stroke, or exposure to certain drugs associated with mood changes, such as steroids, reserpine, beta-blockers, and particularly alcohol.

Pharmacotherapy of Depression
Depressed people with Huntington's disease can usually be treated with the same agents as any other patient with depression, but certain factors may make some drugs easier to use. Many new medications have become available since the first edition of thePhysician's Guide and the tricyclic antidepressants, while highly effective, should no longer be considered the standard first-line choice. Instead, the physician should consider the Selective Serotonin Re-uptake Inhibitors (SSRIs), such as sertraline (Zoloft), paroxetine (Paxil), fluoxetine (Prozac), and fluvoxamine (Luvox). These offer the advantages of low side effect profile, once-a-day dosing, and safety in the event of overdose. Of these drugs, fluoxetine has a much longer half-life. If a patient develops an unpleasant side effect it will take longer to wear off. On the other hand this may make it a good choice for patients who sometimes forget to take their medicine.

The SSRIs are sometimes stimulating and most patients should take them in the morning rather than at bedtime. Initial side effects may be Gl upset or diarrhea, and increased anxiety or insomnia (although, if they are part of a depression, these symptoms will eventually respond to the treatment).

SSRI-induced insomnia may respond to 25-50 mg of trazodone (Desyrel) qhs. A small number of patients will develop sexual problems on SSRIs, particularly anorgasmia or ejaculatory delay. These symptoms are highly dependent on the dose. Some people have asserted that SSRIs, particularly fluoxetine, cause violence or suicide in psychiatric patients. There is no valid evidence to support this claim.

Patients with Huntington's disease are sensitive to the potential side effects of CNS drugs. Any new drug should be started carefully, and increased gradually. Sertraline 25-50 mg, paroxetine lO mg, or fluoxetine lO mg are appropriate starting doses. If well tolerated, the dose can be increased after a few days or a week to sertraline 50-IOO mg, paroxetine 20 mg, or fluoxetine 20 mg. Most patients will respond to these doses, but sometimes higher doses will be necessary. As we will discuss, SSRIs may also be particularly useful for some of the more nonspecific psychiatric symptoms found in patients with HD, such as irritability, apathy, and obsessiveness.

Other, newer antidepressants we have used with success in patients with Huntington's disease include buproprion (Wellbutrin), venlafaxine (Effexor), and nefazodone (Serzone). These all require dosing several times a day. A new formulation of venlafaxine, Effexor XR, may be given once a day, and nefazodone is sometimes given in a single bedtime dose, despite the short half-life. It is often difficult for depressed patients, especially those with cognitive impairment, to adhere to a complex medication regimen. Therefore these drugs may not be good first choices if there is no responsible family member who will help make sure that the patient takes his medicine.

Tricyclic antidepressants (TCA's) such as Nortiptyline (Pamelor), Imipramine (Tofranil) or Amitryptiline (Elavil) remain an important class of drugs for depression in Huntington's disease. They can be given once a day (usually at bedtime because of sedative properties). Common side effects of TCA's include constipation, dry mouth, tachycardia, and orthostasis. We tend to favor nortriptyline over the others because of the relatively low incidence of these side effects and because of the well-established range of blood levels which have been associated with efficacy. It is not necessary to reach the target blood level if the patient has already responded to a lower dose, but the availability of meaningful blood levels for the TCA's can serve as a useful check of compliance, and a reassurance that a patient's dose is optimal. Since TCA's can worsen conduction delays, an EKG is indicated prior to treatment if the patient's cardiac status is unknown. TCA's are extremely dangerous in overdose. As little as a week's supply may be fatal if taken at once. They are a poor choice in patients with a history of deliberate overdoses and may have to be dispensed only a few pills at a time if this is a concern.

If the patient's depression is accompanied by delusions, hallucinations, or significant agitation, it may be necessary to add an antipsychotic medication to the regimen, preferably in low doses to minimize the risk of sedation, rigidity, or parkinsonism. If the neuroleptic is being used for a purely psychiatric purpose, and is not required for suppression of chorea, the physician may want to prescribe one of the newer agents such as risperidone (Risperdal), olanzepine (Zyprexa), or quetiapine (Seroquel). These drugs may have a lower incidence of side effects and appear to be just as effective. Among the older neuroleptics, high potency agents such as haloperidol (Haldol) or fluphenazine (Prolixin) tend to be less sedating, but cause more parkinsonism. Lower potency agents such as thioridazine (Mellaril) may aid with overactivity and sleeplessness, but tend to be constipating and can cause orthostasis.

Benzodiazepines, particularly short acting drugs such as lorazepam (Ativan) may be another good choice for the short-term management of agitation. In any case neuroleptics and benzodiazepines used for acute agitation should be tapered as soon as the clinical picture allows.

Electroconvulsive therapy (ECT) has also been found effective in depressed patients with Huntington's disease. This treatment should be considered if a patient does not respond to several good trials of medication, or if an immediate intervention is needed for reasons of safety. For example a severely depressed patient may be refusing food and fluids, or may be very actively suicidal. ECT may be particularly effective in treating delusional depression.

Depressed patients should always be asked about substance abuse. Substance abuse, particularly of alcohol, can be both a consequence or a cause of depression, makes treatment difficult or impossible if not addressed, and significantly increases the risk of suicide.

Suicide
Depressed patients should always be asked about suicide, and this should be regularly reassessed. It is a misconception that suicidal patients will not admit to these feelings. The question should be asked in a non-intimidating, matter-of-fact way, such as "have you been feeling so bad that you sometimes think life isn't worth living?" Or, "have you even thought about suicide?" If the patient acknowledges these feelings, the clinician needs to ask more questions to evaluate their severity and decide on the best course of action. Are the feelings just a passive wish to die or has the patient actually thought out a specific suicidal plan? Does the patient have the means to commit suicide? Has she prepared for a suicide, such as by loading a gun or hoarding pills? Can the patient identify any factors which are preventing her from killing herself? What social supports are present? Some patients, although having suicidal thoughts, may be at low risk if they have a good relationship with their doctor, have family support, and have no specific plans. Others may be so dangerous to themselves that they require emergent hospitalization.

Although there have been cases of non-depressed patients with Huntington's disease harboring chronic suicidal feelings, we feel that most, if not all, suicidal patients with Huntington's disease suffer from Major Depression and can be treated successfully. So as not to miss such cases, it is helpful to think of all patients with Huntington's disease who are suicidal as depressed until proven otherwise. If the clinician is unsure, the patient should be treated presumptively. This is not to say that a person with Huntington's disease, particularly early in the course of the disease may not express a fear of becoming helpless one day, or a desire not to live past a certain degree of impairment. A physician should listen supportively to these concerns, realizing that most patients will be able to adapt if they are not suffering from depression.

Mania
While depression is the most common psychiatric problem in Huntington's disease, a smaller number of patients will become manic, displaying elevated or irritable mood, overactivity, decreased need for sleep, impulsiveness, and grandiosity. Some may alternate between spells of depression and spells of mania with times of normal mood in between, a condition known as bipolar disorder. Patients with these conditions are usually treated with a mood stabilizer.

Lithium is probably still the most popular mood stabilizer for people with idiopathic bipolar disorder, but we have not found it to be as helpful in patients with Huntington's disease. It is not known why this is the case. Lithium has a narrow therapeutic range, particularly in patients whose food and fluid intake may be spotty, but there may be some other aspect to the mood disorders found in Huntington's disease patients which make them poor lithium responders.

We recommend beginning with the anticonvulsant divalproex sodium (Depakote) or valproic acid (Depekene) at a low dose such as 125 to 250 mg po bid and gradually increasing to efficacy, or to reach a blood level of 50-150mcg/ml. A dose of 500 mg po bid is fairly typical, but some patients will require as much as several grams per day.

Another anticonvulsant, carbamazepine (Tegretol), is also an effective mood stabilizer. This can be started at 100-ZOO mg per day, and gradually increased by lOO mg/day to reach an effect or a therapeutic level of 5-IZmcg/ml, which may require a dose of 800-1 ZOO mg/day. Therapeutic ranges for these drugs were established on the basis of their anticonvulsant properties, so it is important to remember that a patient may show a good psychiatric response below the minimum "therapeutic" level (but generally should not exceed the maximum level in any case).

Both drugs carry a small risk of liver function abnormalities (particularly divalproex sodium) and blood dyscrasias (particularly carbamazepine), and so LFT's, and CBC should be routinely monitored every few months and clinicians should be alert for suggestive symptoms. Valproic acid may cause thrombocytopenia, and both drugs are associated with neural tube defects when used during pregnancy.

Manic patients with Huntington's disease who have delusions and hallucinations may require a neuroleptic, and patients who are very agitated may need a neuroleptic or a benzodiazepine for immediate control of these symptoms. As discussed for depression, the doctor may wish to prescribe one of the newer antipsychotics which have fewer parkinsonian side effects, such as risperidone, olanzepine, or quetiapine. In cases of extreme agitation, a rapidly acting injectable agent, such as droperidol (Inapsine) or lorazepam may be necessary. Finally, ECT is known to be a very effective treatment for idiopathic mania and should be considered when other treatments fail, or when the individual is extremely dangerous.

Obsessive-compulsive disorders
Obsessions are recurrent, intrusive thoughts or impulses which are experienced as being senseless, at least initially. A compulsion is a repetitive performance of the same activity, a stereotyped routine which must be followed, often in response to an obsession, such as handwashing because of an obsessive concern with germs. Obsessions are usually a source of anxiety and the patient may struggle to put them aside, whereas the acting out of compulsions generally relieves anxiety and may not be as strongly resisted.

True Obsessive-compulsive disorder (OCD) is rare in Huntington's disease, but Huntington's disease patients often display an obsessive preoccupation with particular ideas. Patients may worry about germs or contamination, or engage in excessive checking of switches or locks. Sometimes patients will become fixated on an episode of being wronged in the past (e.g. fired from a job, divorced, driver's license revoked), and then bring it up constantly, or become preoccupied with some perceived need, such as a desire to go shopping, or to eat a certain food.

Serotonergic antidepressants are used to treat OCD and may ameliorate obsessions and compulsions in Huntington's disease patients that do not meet the criteria for the full syndrome. The use of the tricyclic antidepressant clomipramine (Anafranil) has largely been superceded by the SSRIs fluoxetine, sertraline, paroxetine and fluvoxamine (Luvox) which have milder side effects and lower lethality in overdose. Patients may require higher doses than those needed for depression, e.g. 40-60 mg of fluoxetine. For relentless perseverative behavior unresponsive to these agents, one might consider neuroleptics, keeping in mind that the newer, atypical drugs may be better tolerated.

Schizophrenia-like disorders
Schizophrenia and schizophrenia-like conditions are much less common than affective disorder in Huntington's disease. The new onset of delusions and hallucinations should prompt a search for specific causes or precipitating factors, including mood disorders, delirium related to metabolic or neurologic derangements and intoxication with or withdrawal from illicit or prescription drugs.

Once these possibilities of mood disorder, drug intoxication, and delirium have been considered, neuroleptics may be employed for Huntington's disease patients with schizophrenia-like syndromes. The doses used for treatment of psychosis may be somewhat higher than those used for treatment of chorea. As mentioned before, if neuroleptics are not needed for the control of involuntary movements, patients may do better on newer agents such as risperidone, olanzepine or quetiapine which do not cause as many extrapyramidal side effects.

Some patients will respond completely and others only partly, reporting that "voices" have been reduced to a mumble, or becoming less preoccupied with delusional concerns. Patients with delusions will rarely respond to being argued with, but a clinician may certainly express skepticism regarding a delusional belief and explain to the patient that it may be the product of a mental illness.

Caregivers should be encouraged to respond diplomatically, to appreciate that the delusions are symptoms of a disease, and to avoid direct confrontation if the issue is not crucial.

Delirium
Delirium, an abnormal change in a patient's level of consciousness, may result from a variety of toxic, structural or metabolic causes. Delirious patients may have waxing and waning of consciousness, may be agitated or lethargic, and frequently have disturbed sleep. Patients in the later stages of Huntington's disease, are particularly vulnerable to delirium. Common causes of delirium in Huntington's disease include prescription medications, particularly benzodiazepines and anticholinergic agents, alcohol or illicit drugs, and medical problems such as dehydration and respiratory or urinary tract infections. It is important to ask about over the counter medicines such as cold tablets and sleep aids, which patients and families may forget to mention. Subdural hematoma, due to a recognized or unrecognized fall should also be considered if the patient suffers a sudden change in mental status.

Delirium can also come about gradually as an underlying problem worsens. For example, a dehydrated patient may no longer be able to tolerate his usual medication regimen. Delirium can also be mistaken for a number of other conditions in Huntington's disease. As mentioned previously, it may be accompanied by hallucinations or paranoia.

Clinicians usually expect delirious patients to exhibit agitation or hyperarousal and may overlook the delirious patient who is somnolent or obtunded. Such patients may seem depressed to their families, but when questioned will not report a low mood.

Physicians should consider a diagnosis of delirium whenever confronted with an acute behavioral change in someone with Huntington's disease and should review the medication list, examine the patient, and obtain necessary laboratory studies, including a toxicology screen if indicated. Identification and correction of the underlying cause is the definitive treatment for delirium. Low doses of neuroleptics may be helpful in managing the agitation of a delirious patient temporarily.

Psychiatric symptoms not belonging to a specific diagnostic category
Patients with Huntington's disease may suffer from a variety of emotional symptoms which do not fit any specific psychiatric diagnosis, but may nevertheless be a source of distress and a focus of treatment including irritability, anxiety and apathy. Some of these symptoms are related to the disease itself, and others can be seen as a response to changing circumstances, such as a patient who becomes anxious about going to the market because her involuntary movements attract attention.

Patients with Huntington's disease may undergo personality changes, becoming irritable, disinhibited, or obsessional. In some cases these changes represent an accentuation, or coarsening of personality characteristics the person already had. Other times they will be a radical departure from the patient's usual state, which can be very distressing to families. Families should be reassured, as patients can usually be helped by better communication, environmental interventions, and judicious use of medications.

Other patients may not be irritable under most circumstances, but will develop a kind of rigidity of thinking which will cause them to perseverate relentlessly on a particular desire or idea, becoming progressively more irritable if their demands are not met. One woman, for example, insists on having 10 to 12 varieties of juice in the refrigerator at all times and was markedly irritable during a recent visit to the clinic. Her husband had started the car to drive to the clinic and had refused to go back into the house to get her another glass of juice. Hours later she was still dwelling on it and kept interrupting the interview to say that she wanted to go home to have a drink.

Irritability in Huntington's disease may have a variety of triggers and exacerbating causes. It is important to understand it in context and avoid premature use of medications. One must first understand exactly what the informant means by saying the patient is irritable or agitated.

Does the patient appear restless? Is the patient yelling or verbally abusive? Is there potential for violence? Many factors can precipitate an irritable episode, such as hunger, pain, inability to communicate, frustration with failing capabilities, boredom, and changes in expected routine. Family members and caregivers should learn to respond diplomatically, appreciating the patient's irritability as a symptom. Confrontations and ultimatums should be avoided if the issue is not crucial.

The environment should be made as calm and structured as possible. Some families achieve this more easily than others. Family settings in which there are children and adolescents, unpredictable working hours, noise, or general chaos may lead to irritability and aggressiveness in persons with Huntington's disease. Caretaker and family support groups can provide emotional support and are a forum for sharing strategies that members have found useful in their own households.

When irritability is severe, or enduring, or is expressed physically, patients are often described as agitated. A great deal of overtreatment, particularly with neuroleptics, stems from continuous use of a drug for an episodic problem. It is always necessary to revisit the situation and see whether the drug has actually reduced the frequency of outbursts.

For episodic outbursts, success often results from combining drug therapy with a careful analysis of the context and precipitants of the outburst.

Nevertheless, we have found a number of medications helpful in treating enduring irritability. Patients may respond to antidepressants, particularly the SSRIs (sertraline, fluoxetine, and paroxetine) even if they do not meet all the criteria for major depression.

The optimal doses for treating irritability are not known but one should start at a low dose and increase gradually as in the treatment of depression (see table 13). These agents may be particularly useful when the irritability seems tied to obsessions and perseveration on a particular topic. As in the treatment of depression, improvement may not occur for several weeks.

Mood stabilizers such as divalproex sodium and carbamazepine have also been helpful and could be administered as outlined for bipolar disorder (see table 15).

Low dose neuroleptics may be helpful, particularly the newer, "atypical" ones which have fewer side effects. Long-acting benzodiazepines, such as clonazepam (Klonopin), starting at low doses, e.g. 0.5 mg/day, have also been helpful. The clinician must carefully monitor patients treated with these agents, as overdosing can lead to falls or aspiration.

Apathy
Apathy is common in Huntington's disease and is probably related to frontal lobe dysfunction. Apathetic patients become unmotivated and uninterested in their surroundings. They lose enthusiasm and spontaneity. Performance at work or school becomes sluggish. The symptom of apathy can be very troubling to families, if they see the active person they knew slipping away. It can be a source of conflict for caregivers, who know the person is physically capable of activities but "won't" do them.

Families need much education and support in this regard and should learn to practice a combination of exhortation and accommodation. While apathetic patients have trouble initiating actions, they will often participate if someone else suggests an activity and works along with them to sustain energy and attention. For example, a man with Huntington's disease had always loved fishing, but when his brother came to take him fishing for his birthday he wanted to stay home in front of the television. The brother insisted, and when they left the house, he had a good time fishing all day. When he returned, he immediately turned the television back on.

Apathy can be hard to distinguish from depression. Apathetic patients, like those with depression, may be sluggish, quiet, and disengaged. They may talk slowly, or not at all. By and large apathetic patients will deny being sad, but in distinguishing the two it is important to ask not only about the patient's mood, but about other depressive symptoms as well, such as a change in sleeping or eating patterns, feelings of guilt, or suicidal thoughts. Neuroleptics and benzodiazepines can cause or worsen apathy. The need for these medications should be reexamined if the patient is apathetic.

Depressed patients with apathy should be treated aggressively for their depression, which may cause the other symptoms to remit. It can be very difficult to distinguish depression from primary apathy, but patients with primary apathy sometimes respond to psychostimulants such as methylphenidate (Ritalin), pemoline (Cylert) or dextroamphetamine (Dexedrine). These medicines are highly abusable and may exacerbate irritability.

They should be used with caution. It may be more prudent to make a trial of a non-sedating antidepressant, such as an SSRI, first even if the patient does not seem to meet the criteria for depression, as these agents have also occasionally been helpful.

Anxiety
Patients with Huntington's disease are vulnerable to anxiety because of life circumstances, but also because of physical changes in the brain. Patients may develop a social phobia related to embarrassment about visible symptoms. As thought processes become less flexible, patients may be made anxious by trivial departures from the usual routine. Patients may worry for days in advance about what to wear when going to the hairdresser or whether to attend a family function.

In addressing anxiety, attempts should be made to decrease the complexity of the patient's environment. Stopping a job that has become too difficult may result in a remarkable decline in symptoms. Assisting the caregiver in establishing a predictable routine for the patient is helpful. Some caregivers find it useful to refrain from- discussing any special events until the day before they are to occur. Patients who are very fearful of going to the doctor may need to be told only that they are going on an errand until they reach the clinic.

Some patients will not improve with counseling and environmental interventions and will require pharmacotherapy. The clinician should first assess whether the anxiety is a symptom of some other psychiatric condition, such as a major depression. Patients with obsessive-compulsive disorder may be made anxious by obsessions about danger or "germs," or if their rituals are interrupted.

Panic disorder, although uncommon in Huntington's disease, is a highly treatable condition. It is characterized by the acute onset of overwhelming anxiety and dread, accompanied by physiological symptoms of rapid heartbeat, sweating, hyperventilation, lightheadedness, or paraesthesias. Panic attacks usually last only fifteen or twenty minutes, may begin during sleep, and may result in syncope. Suspected panic attacks require a good medical work-up, because most of the other possible explanations for the symptoms represent highly dangerous conditions. Once these other causes have been ruled out, the usual treatment consists of SSRIs, sometimes temporarily supplemented with benzodiazepines. SSRIs are usually mildly stimulating and may need to start at a lower dose than that used for depression.

Benzodiazepines should be used judiciously in anxious persons with Huntington's disease because of the vulnerability of these patients to delirium and falls and because of their potential for abuse, especially in patients whose judgement may already be impaired. PRN medications may have to be controlled by a family member. Some patients will respond to the non-benzodiazepine anxiolytic buspirone, which can be started at 5 mg two to three times per day and advanced to 20-30 mg per day in divided doses.

Sexual disorders
Many patients with Huntington's disease become uninterested in sexual activity. Others may continue to enjoy healthy sexual activity well into the course of the illness. Occasional patients may desire and pursue excessive sexual activity or engage in inappropriate sexual behaviors, such as public masturbation, or voyeurism. The spouse, usually the wife, may be distressed and fearful because the individual with Huntington's disease may become aggressive if sexual demands are not met. Spouses may be afraid to talk about the problem unless interviewed alone. Interventions are difficult in these circumstances, probably because of the patient's impaired judgement and the strength of the drive.

Open communication about sex between the doctor and the family can help to destigmatize this sensitive topic. With open discussion among the parties, distressing sexual behaviors can sometimes be adapted into more acceptable acts. Patients engaging in these behaviors should be assessed and treated for comorbid conditions, such as mania. We have found antiandrogenic therapy helpful in a few of these cases.

Disclaimer: The indications and dosages of this material have either been recommended in the medical literature or conform to the practices of physicians expert in the care of people with Huntington's disease. The indications do not necessarily have specific approval forth Food and Drug Administration (FDA) for the indications and dosages for which they are recommended. The package insert for each drug should be consulted for uses and dosage approved by the FDA. Because standards for dosage change, it is advisable to keep abreast of revised recommendations, particularly those concerning new drugs. Statements and opinions expressed in this book are not necessarily those of the Huntington's disease Society of America, Inc. nor does HDSA promote, endorse, or recommend any treatment or therapy mentioned herein. The lay reader should consult a physician or other appropriate health care professional concerning any advice, treatment or therapy set forth in this book.