Huntington Disease
Fredy J Revilla, MD
Synonyms, Key Words, and Related Terms: 
Huntington's chorea, hereditary chorea 

Background: 

Huntington disease (HD) is an incurable, adult-onset, autosomal dominant disorder associated with cell loss within a specific subset of neurons in the basal ganglia 
and cortex. 

HD is named after George Huntington, the physician who described it as hereditary 
chorea in 1872. Characteristic features of HD include involuntary movements, 
dementia, and behavioral changes. 

Pathophysiology: 

The most striking neuropathology in HD occurs within the neostriatum, in which there is gross atrophy of the caudate nucleus and putamen, accompanied by selective neuronal 
loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. 
Other regions, including the globus pallidus, thalamus, sub-thalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic 
grade.

The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4). 

No gross striatal atrophy is observed in grades 0 and 1. 

Grade 0 cases have no detectable histological neuropathology in the presence of a typical clinical picture and positive family history suggesting HD. 

Grade 1 cases have neuropathological changes that can be detected microscopically but without gross atrophy. 

Grade 2 striatal atrophy is present, but the caudate nucleus remains convex. 

Grade 3 striatal atrophy is more severe, and the caudate nucleus is flat. 

Grade 4 striatal atrophy is most severe, and the medial surface of the caudate nucleus is concave. 

The genetic basis of HD is the expansion of a cysteine- adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin. 

The function of huntingtin is not known. Normally, it is located in the cytoplasm. The
association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neurodegeneration. 

N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD. 

The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence, pathogenic. More recent data from striatal neuronal cultures transfected 
with mutant huntingtin and transgenic mice carrying the spinocerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient 
to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death. Caspase inhibition in clonal striatal cells showed no correlation between the reduction of aggregates in the cells and increased survival. 

Furthermore, postmortem studies reveal that NIIs are quite rare in the striatum of patients with HD as compared to the cortex, and most of the aggregates within the striatum are observed in populations of interneurons that are typically spared in individuals with HD. 

Frequency: 

In the US: 
Estimates of the prevalence of HD in the US range from 4.1-8.4 per 100,000 people. Accurate estimates of the incidence of HD are not available. 

Internationally: 
The frequency of HD in different countries varies greatly. A few isolated populations of western European origin have an unusually high prevalence of HD that appears to have 
resulted from a founder effect. 

These include the 

•	Lake Maracaibo region in Venezuela 700 per 100,000 people
•	The island of Mauritius off the South African coast 46 per 
100,000 people and
•	Tasmania 17.4 per 100,000 people
•	The prevalence in most European countries ranges from 1.63-9.95 
          per 100,000 people. 
•	The prevalence of HD in Finland and Japan is less than 1 per 100,000 people. 

Mortality/Morbidity 

HD is a relentlessly progressive disorder, leading to disability and death, usually from an intercurrent illness. The mean age at death in all major series ranges from 51-57 years, but the range may be broader. Duration of illness varies considerably, with a mean of approximately 19 years. Most patients survive for 10-25 years after the onset of illness. In a large study, pneumonia and cardiovascular disease were the most common primary causes of death. 

Juvenile HD 
(ie, onset of HD in patients younger than 20 years) account for approximately 5-10% of all affected patients. Most patients with juvenile HD inherit the disease from their father, whereas patients with onset of the disease after the age of 20 years are more likely to have inherited the gene from their mother. 

Inheritance through the father can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. This is caused by greater instability of the HD allele during spermatogenesis. CAG repeat length correlates inversely with age of onset, and the correlation is stronger when the onset of symptoms occurs earlier. 

A small number of homozygotes for the HD mutation have been identified, and they seem to be phenotypically indistinguishable from heterozygotes, making HD a truly autosomal dominant disorder.
 
Sex: No sex predilection has been reported. 

Age: Most studies show a mean age at onset ranging from 35-44 years. However, the range is large and varies from 2 years to older than 80 years. Onset in patients younger than 10 years and in patients older than 70 years is rare. 

CLINICAL 

History: 
The clinical features of HD include a movement disorder, a cognitive disorder, and a behavioral disorder. 

Patients may present with one or all disorders in varying degrees. Chorea (derived from the Greek word, which means to dance) is the most common movement disorder seen in HD.
Initially, mild chorea may pass for fidgetiness. Severe chorea may appear as uncontrollable flailing of the extremities (ie, ballism), which interferes with function.

As the disease progresses, chorea coexists with and is gradually replaced by dystonia and parkinsonian features, such as bradykinesia, rigidity, and postural instability, which 
are usually more disabling than the choreic syndrome per se.

In advanced disease, patients develop an akinetic-rigid syndrome, with minimal or no chorea. Other late features are spasticity, clonus, and extensor plantar responses.

Dysarthria and dysphagia are common. Abnormal eye movements may be seen early in the disease. Other movement disorders, such as tics and myoclonus, may be seen in patients with HD.

Juvenile HD (Westphal variant), defined as having an age of onset of younger than 20 years, is characterized by parkinsonian features, dystonia, long-tract signs, dementia, epilepsy, and mild or even absent chorea.

Cognitive decline is characteristic of HD, but the rate of progression among individual patients can vary considerably. Dementia and the psychiatric features of HD are perhaps the earliest and most important indicators of functional impairment.

The dementia syndrome associated with HD includes early-onset behavioral changes, such as irritability, untidiness, and loss of interest. Slowing of cognition, impairment of intellectual function, and memory disturbances are seen later. This pattern corresponds 
well to the syndrome of subcortical dementia, and it has been suggested to reflect dysfunction of frontal-subcortical neuronal circuitry. (The so-called cortical dementias primarily involve the cerebral cortex and are associated with aphasia, agnosia, apraxia, 
and severe amnesia.)

Early stages of HD are characterized by deficits in short-term memory, followed by motor dysfunction and a variety of cognitive changes in the intermediate stages of dementia. These deficits include diminished verbal fluency, problems with attention, executive function, visuospatial processing, and abstract reasoning. 

Language skills become affected in the final stages of the illness, resulting in a marked word-retrieval deficit.

The behavioral disorder of HD is most commonly represented by affective illness.

Depression is more prevalent, with a small percentage of patients experiencing episodic bouts of mania characteristic of bipolar disorder.

Patients with HD and persons at risk for HD may have an increased rate of suicide.

Patients with HD also can develop psychosis, obsessive-compulsive symptoms, sexual and sleep disorders, and changes in personality.

Physical

Most patients with HD have a mixed pattern of neurological and psychiatric abnormalities. Understanding of the clinical signs must take into account the fact that signs change during the course of the illness and that different patterns may be observed, depending on the age of onset. 

Chorea is a characteristic feature of HD and, until recently, the disorder was commonly called Huntington chorea. Chorea, as defined by the World Federation of Neurology, is a state of excessive, spontaneous movements, irregularly timed, randomly distributed, and abrupt. 

Severity of chorea may vary from restlessness with mild intermittent exaggeration of gesture and expression, fidgeting movements of the hands, and unstable dancelike gait to a 
continuous flow of disabling violent movements. Chorea in cases of HD usually is generalized.

o Patients may incorporate involuntary choreiform movements into apparently purposeful gestures, a phenomenon referred to as parakinesia.

o Ballism is characterized by large amplitude, usually proximal, flinging movements of a limb or body part. Ballism is considered to be a severe form of chorea by most authors.

o Chorea may coexist with slower, distal, writhing, sinuous movements called athetosis; it is then described as choreoathetosis. 

o Chorea is less prominent in juvenile HD and in advanced stages of the illness.

Bradykinesia and akinesia are frequent features of HD and may explain some of the abnormalities of voluntary movement observed clinically.

o Bradykinesia may be a major source of disability of voluntary movement, though it commonly is overshadowed by the hyperkinetic movement disorder.

o Other parkinsonian signs, such as rigidity and postural instability, may be seen. Patients may become akinetic and rigid in the terminal stages of the illness.

Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures.

o Mild dystonia, in combination with chorea, may give the writhing appearance of choreoathetosis.

o Sustained dystonic posturing may result in contractures, immobility, and breakdown of skin

o Dystonia may be prominent in juvenile HD.

o Eye movement abnormalities can be seen early in the disease.

o Initiation of saccadic movements is slow and uncoordinated. Patients have difficulty suppressing head movements or blinking in order to break fixation and generate saccadic movements.

o Smooth pursuit is interrupted by saccadic intrusions.

o Patients with HD are unable to inhibit saccades toward a peripheral stimulus when instructed to look in the opposite direction.

o Tendon reflexes are variable in HD, ranging from reduced in some patients to pathologically brisk with clonus in other patients. The plantar response usually is flexor, but it may be extensor in advanced stages of the illness.

o Other hyperkinesias, such as tics and myoclonus, may be seen in HD.

o Dementia, depression, and other psychiatric manifestations may be seen at the time of examination as well.

Causes

The selective neuronal dysfunction and subsequent loss of neurons in the striatum, the cerebral cortex, and other parts of the brain can explain the clinical picture seen in cases of HD. Several mechanisms of neuronal cell death have been proposed for HD, mainly including excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis. 

Excitotoxicity
Excitotoxicity refers to the neurotoxic effect of excitatory amino acids in the presence of excessive activation of postsynaptic receptors.

Intrastriatal injections of kainic acid, an agonist of a subtype of glutamate receptor, produce lesions similar to those seen in HD.

Intrastriatal injections of quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist, selectively affects medium-sized GABA-ergic spiny projection neurons, sparing the striatal interneurons and closely mimicking the neuropathology seen in HD.

NMDA receptors are depleted in the striatum of patients with HD, suggesting a role of NMDA receptor-mediated excitotoxicity, but no correlation exists between the distribution of neuronal loss and the density of such receptors.

The theory that reduced uptake of glutamate by glial cells may play a role in the pathogenesis of HD also has been proposed. 

Oxidative stress 

Oxidative stress is caused by the presence of free radicals (ie, highly reactive oxygen derivatives) in large amounts. This may occur as a consequence of mitochondrial 
or excitotoxicity and can trigger apoptosis.

Striatal damage induced by quinolinic acid can be ameliorated by the administration of spin-trap agents, which reduce oxidative stress, providing indirect evidence for the 
of free radicals in excitotoxic cell death. 

Impaired energy metabolism 

Impaired energy metabolism reduces the threshold for glutamate toxicity and can lead to activation of excitotoxic mechanisms as well as an increased production of reactive oxygen species.

Nuclear magnetic resonance spectroscopy studies have shown elevated lactate levels in the basal ganglia and occipital cortex of patients with HD.

Patients with HD have an elevated lactate-pyruvate ratio in the cerebrospinal fluid.

A reduction in the activity of the respiratory chain complex II and III (and less in complex IV) of mitochondria of caudate neurons in patients with HD has been reported.

In rats, intrastriatal injections of 3-nitroproprionic acid (3-NP), an inhibitor of succinate dehydrogenase or complex II of the respiratory chain, cause a dose-dependent ATP depletion, increased lactate concentration, and neuronal loss in the striatum. Systemic injections of 3-NP into rats produce a selective loss of medium spiny neurons in the striatum. 

Apoptosis 

Apoptosis is the programmed cell death that is normally activated in the nervous system during embryogenesis to remove supernumerary neurons as part of the natural development.

Morphological features of apoptosis have been well characterized. Oxidative stress, excitotoxicity, and partial energy failure can lead to apoptosis.

A subset of neurons and glia in the neostriatum of patients with HD appears to undergo apoptosis, as shown by in situ DNA nick end labeling (TUNEL) staining, but clear morphological evidence for an apoptotic process in HD is still missing

It has been hypothesized that expanded polyglutamine repeats cause neuronal degeneration through abnormal interactions with other proteins containing short polyglutamine tracts. Recent work suggests that polyglutamine interference with transcription of CREB binding protein (CBP), a major mediator of survival signals in mature neurons, may constitute a genetic gain of function underlying polyglutamine disorders including HD.

Other Problems to be Considered 

Sydenham chorea
Antiphospholipid antibody syndrome
Benign hereditary chorea
Dentatorubropallidoluysian atrophy (DRPLA)
Senile chorea
Vascular chorea, hemichorea, and hemiballismus
Hyperthyroidism
Polycythemia vera
Paroxysmal dyskinesias
Drugs 

Presymptomatic genetic testing for HD is now available. It should only be performed in specialized centers following strict protocols because of the ethical and legal implications of a positive (or negative) result. 

WORKUP 

Imaging Studies: 
No single imaging technique is necessary or sufficient for diagnosis. Measurement of the bicaudate diameter (ie, the distance between the heads of the 2 caudate nuclei) by CT scan or MRI is a reliable marker of HD.

Abnormalities in positron emission tomography (PET) scanning and proton MR spectroscopy have been reported; however, their use in clinical practice is limited. 

Other Tests: 

Genetic testing (reported as the CAG repeat number for each allele) is now commercially available.Genetic testing may not be necessary in a patient with a typical clinical picture and a genetically proven family history of HD.

In the absence of a family history of HD, patients with a suggestive clinical presentation should undergo genetic testing to exclude or confirm HD.

Persons at risk for HD who request presymptomatic testing should undergo extensive genetic counseling and neurological and psychiatric evaluation, given the implications of receiving a positive (or negative) result for an untreatable, familial, progressive, neurodegenerative disease. Most testing centers follow strict protocols, such as the one put forth by the Huntington's Disease Society of America (HDSA).

If the genetic test is negative for HD, then depending on each individual case, it may be reasonable to test for systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, thyroid disease, neuroacanthocytosis, DRPLA, Wilson disease, and other less common causes of chorea.

Staging: The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4). See Pathophysiology. 

TREATMENT 

Medical Care: 
Consider general safety measures and nonpharmacologic interventions first. 

If chorea is severe enough to interfere with function, consider treatment with benzodiazepines, such as clonazepam or diazepam; valproic acid; dopamine-
depleting agents, such as reserpine or tetrabenazine (not available in the US but can be obtained from Canada); and finally, neuroleptics. Carefully weigh potential adverse effects against the benefits from each drug.

Patients who have HD and predominant features of bradykinesia and rigidity may benefit from treatment with L-dopa or dopamine agonists.

Depression in patients with HD is treatable and should be recognized promptly. Selective serotonin reuptake inhibitors (SSRIs) should be considered as first-line 
therapy. Other antidepressants, including bupropion, venlafaxine, nefazodone, and tricyclic antidepressants, also can be used. Electroconvulsive therapy (ECT) can be used in patients with refractory depression.

Antipsychotic medications may be necessary in patients with hallucinations, delusions, or schizophrenialike syndromes. As compared to the older agents, the newer agents, such as quetiapine, clozapine, olanzapine, and risperidone, are preferred because of the lower incidence of extrapyramidal side effects and the decreased risk for tardive syndromes.

Irritability may be treated with antidepressants, particularly the SSRIs; mood stabilizers, such as valproic acid or carbamazepine; and, if needed, atypical neuroleptics.

Other less frequent aspects of HD that may require pharmacologic treatment are mania, obsessive-compulsive disorder, anxiety, sexual disorders, myoclonus, tics, dystonia, and epilepsy.

Surgical Care

Ablative surgical procedures and fetal cell transplantation have been attempted in patients with HD. Currently, enough data to support this type of treatment is not available. It is still 
experimental. 

Consultations 

Physical therapist 
Occupational therapist 
Speech therapist 
Psychiatrist 
Genetic counselor

MEDICATION 

Although no therapy to delay the onset of symptoms or prevent the progression of the disease is currently available, symptomatic treatment of patients with HD may improve the quality of life and prevent complications. 

As is the case with other neurological diseases, HD makes individuals more vulnerable to side effects from medications, particularly cognitive adverse effects. 

Avoid polypharmacy if possible. 

Symptomatic treatment for HD can be divided into drugs to treat the movement disorder and drugs to treat psychiatric or behavioral problems. 

Experimental therapies for HD are currently being tested in animal models and human trials. Awareness of ongoing research to find an effective cure for HD must be a part of the care plan of an individual patient and the patients family. Therapeutic options include dopamine 
-depleting agents (eg, reserpine, tetrabenazine) and dopamine -receptor antagonists (eg, neuroleptics). 

Long-term use of these drugs may carry a high risk of side effects. Pharmacologically treat choreic movements in patients with HD only if they become disabling to the patient. Neuroleptics, may worsen other features of the disease, such as bradykinesia and rigidity, leading to further functional decline. 

Results of some studies have suggested that valproic acid and clonazepam may be effective in the treatment of chorea, while results of other studies have been less conclusive. 

In the authors experience, it may be worthwhile to use valproic acid and clonazepam first because of their safer adverse-effect profile. 

Tetrabenazine is a dopamine-depleting agent, not available in the US, which can be obtained from the UK through special arrangements. May be more effective in the treatment of chorea and less likely to cause hypotension than reserpine. Administer 12.5 mg bid or tid initially. May increase dose over several weeks to maximum 75-100 mg/d in divided doses

Drug Treament Category: see below website 

MISCELLANEOUS

Medical/Legal Pitfalls: 

The usual medicolegal pitfalls of missed diagnosis, delayed diagnosis, and complications of medication therapy are pertinent in those with Huntington disease.

With the increasing amount of genetic/hereditary information available in Huntington disease the question of whether patients and/or family members should be made aware of the genetic risks is becoming an increasingly important issue

Article Source:
eMedicine Journal, September 11 2001, Volume 2, Number 9
http://www.emedicine.com/NEURO/topic81.htm

Very thorough workup on HD Authored by Fredy J Revilla, MD, Instructor,Department of Neurology, Washington University in Saint Louis School of Medicine

Information on medications follow. 

Drug Category: Anticonvulsant 
These agents are used to manage muscle spasms in chorea. 
Drug Name
	Valproic acid (Depakote, Depakene, Depacon) -- Carboxylic acid commonly used as antiepileptic drug, mood stabilizer in mania, and prophylactic agent for migraine. When combined with sodium valproate in 1:1 molar relationship, called divalproex sodium. Mechanism by which valproate exerts its antiepileptic effects has not been established; its activity may be related to increased brain levels of GABA. No large clinical trials exist to support its use for hyperkinetic movement disorders, but it may be effective, as suggested by a few small studies in patients with chorea of different etiologies.
Daily maximum dose of 2000 mg in divided doses (bid or tid) is enough to determine whether drug is going to be effective for individual patient. 	
Adult Dose	250 mg/d PO initially; not to exceed 60 mg/kg/d 	
Pediatric Dose	Not established 	
Contraindications	Documented hypersensitivity; hepatic disease 	

Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism of valproate; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either one may decrease valproate levels; may displace warfarin from protein binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients 	
Pregnancy	D - Unsafe in pregnancy 	
Precautions	Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; before initiating therapy, at periodic intervals, and prior to surgery determine platelet counts and bleeding time; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness	

Drug Name
	Clonazepam (Klonopin) -- Belongs to benzodiazepine class of drugs. Enhances activity of GABA, major inhibitory neurotransmitter in CNS. Used commonly as antiepileptic drug. May be useful in treatment of chorea, but no large clinical trials exist to support its use. Does not induce parkinsonism or carry risk of tardive syndromes, as neuroleptics do; therefore, an adequate trial with this medication is reasonable before using dopamine antagonists.
Maximum daily dose of 2-4 mg divided bid/tid usually is enough to determine effectiveness for individual patient. 	
Adult Dose	0.25-0.5 mg/d PO initially; increase dose very slowly to avoid sedation 	
Pediatric Dose	Not established 	
Contraindications	Documented sensitivity; significant hepatic disease; acute narrow-angle glaucoma (may use in open-angle glaucoma if patient receiving appropriate therapy) 	
Interactions	Phenytoin and barbiturates may reduce effects; CNS depressants increase toxicity 	
Pregnancy	C - Safety for use during pregnancy has not been established. 	
Precautions	Data from several sources raise concerns about use during pregnancy; withdrawal symptoms may occur after abrupt discontinuation; most common adverse effects include sedation, ataxia, and other cognitive adverse effects
Caution in chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation of medication	

Drug Category: Antipsychotic agents 
 These agents may improve choreic movements in patients. 
Drug Name
	Risperidone (Risperdal) -- Antipsychotic agent that belongs to new chemical class, benzisoxazole derivatives. 
Antagonist of type 2 dopamine and serotonin receptors. 
Less likely than typical neuroleptics to cause parkinsonism. 	
Adult Dose	0.5-1 mg/d PO initially; increase dose until benefit achieved or adverse effects appear; not to exceed 6 mg/d divided bid 	
Pediatric Dose	Not established 	
Contraindications	Documented hypersensitivity 	
Interactions	May enhance hypotensive effects of other therapeutic agents because of potential for inducing hypotension; may antagonize effects of levodopa and dopamine agonists; long-term administration of carbamazepine may increase clearance of risperidone; long-term administration of clozapine may decrease clearance; fluoxetine may increase plasma concentration of antipsychotic fraction (ie, risperidone and 9-hydroxyrisperidone) by raising concentration of risperidone but not active metabolite, 9-hydroxyrisperidone 	
Pregnancy	C - Safety for use during pregnancy has not been established. 	
Precautions	Adverse effects include extrapyramidal symptoms, dizziness, hyperkinesia, somnolence, and nausea; advise patients to notify their physicians if they become pregnant or intend to become pregnant during therapy; caution when taking in combination with other centrally acting drugs and alcohol	

Drug Category: Antipsychotic agents continued
 These agents may improve choreic movements in patients.

Note: Most families do not like affects of Haldol/Jean

Drug Name
	Haloperidol (Haldol) -- First of butyrophenone class of major tranquilizers. Typical neuroleptics, such as haloperidol, are potent dopamine-receptor antagonists and should be used only as last resort to treat chorea. 	
Adult Dose	0.5 mg/d PO initially; may increase cautiously to 6-8 mg/d; gradually reduce dose to lowest effective maintenance dose upon achieving satisfactory response 	
Pediatric Dose	Not established 	
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; bone-marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage 	
Interactions	May increase tricyclic antidepressant serum concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; anticholinergics may increase intraocular pressure; lithium may cause encephalopathy-like syndrome 	
Pregnancy	C - Safety for use during pregnancy has not been established. 	
Precautions	Caution in severe cardiovascular disorders because of possibility of transient hypotension and/or precipitation of anginal pain; potentially serious adverse effects include tardive dyskinesia (and other tardive syndromes) and neuroleptic malignant syndrome; other common adverse effects include extrapyramidal symptoms (eg, parkinsonism, akathisia, dystonia), insomnia, restlessness, anxiety, agitation, drowsiness, depression, and confusion	

Drug Category: Rauwolfia alkaloids 
These agents may improve choreic movements in patients. 
Drug Name
	Reserpine -- Dopamine-depleting agent. Used in past to treat hypertension. 	
Adult Dose	0.05-0.1 mg/d PO initially; increase cautiously at weekly intervals until benefit achieved or adverse effects appear 	
Pediatric Dose	Not established 	
Contraindications	Documented hypersensitivity; hypotension; severe depression 	
Interactions	Tricyclic antidepressants may decrease antihypertensive effects; digitalis or quinidine may cause cardiac arrhythmias 	
Pregnancy	C - Safety for use during pregnancy has not been established. 	
Precautions	Caution in patients with renal impairment or peptic ulcer disease; parkinsonism, sedation, and depression are adverse effects that may be deleterious particularly in patients with HD; restlessness, hypotension, and dizziness may occur	

Drug Category: Antidepressants 
Depression is relatively common in patients with HD and should be treated pharmacologically as soon as diagnosis of depression is made. Depression in patients with HD can be treated with the same agents used for treatment of depression of any other cause. SSRIs may be used as first-line therapy because of their low adverse-effect profile, convenient dosing, and safety in the event of overdose. Other antidepressants can be used, including bupropion, venlafaxine, nefazodone, and the tricyclic antidepressants. Electroconvulsive therapy can be effective if an immediate intervention is required and in patients who do not respond to several good trials of medication. 
Drug Name
	Paroxetine (Paxil) -- SSRI that can be used once daily. Most patients should take it in morning because can be stimulating and may cause insomnia. If sedation occurs, drug should be taken at bedtime. A few patients develop sexual problems, such as decreased libido, anorgasmia, or ejaculatory delay. 	
Adult Dose	10-20 mg/d PO initially; not to exceed 40-60 mg/d 	
Pediatric Dose	Not established 	
Contraindications	Documented hypersensitivity; concurrent MAOIs 	
Interactions	Phenobarbital and phenytoin decrease effects; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity 	
Pregnancy	B - Usually safe but benefits must outweigh the risks. 	
Precautions	Possibility of suicide attempt has to be adequately assessed, and close supervision of high-risk patients should accompany initial drug therapy; hypomania or mania can occur after use of SSRIs; caution in history of seizures, mania, renal disease, or cardiac disease