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Irritability is a common neuropsychiatric feature of Huntington’s disease (HD), with prevalences varying from 38% to 73%. Similar prevalences of irritability are reported in other neurodegenerative disorders and traumatic brain injury, especially when the frontal lobe is involved. Before therapeutic interventions are initiated, the clinician should analyze the severity and frequency of the irritable behavior. By examining irritability in a broader spectrum, a tailor-made treatment can be provided.
In general, I recommend as a first step a selective serotonin reuptake inhibitor (SSRI), such as sertraline, or the mood stabilizer valproate; they both have a mild side effect profile. Next, if the result is insufficient, I advise a switch between these two medications. As an alternative, I recommend a switch to a low dose of an atypical antipsychotic, preferably twice daily. Buspirone may be another alternative. Both antipsychotics and buspirone are also used as an add-on. Other mood stabilizers and beta-adrenergic receptor antagonists should only be used when earlier treatments are ineffective. The use of acetylcholinesterase inhibitors for the treatment of irritability is discouraged, as results are unclear. Synthetic cannabinoids are an interesting new therapeutic option, though their “illicit” compound and side effect profile make them not a first-line option.
It is important to identify possible comorbid psychiatric disorders, because irritability may be secondary to a psychiatric condition, and the choice of medication partly depends on the co-occurrence of a specific psychiatric disorder. For example, antipsychotic medication would be the treatment of choice in delusional HD patients with excessive irritability, instead of an SSRI or valproate.
Besides psychiatric comorbidity, the choice of medication also depends on the general medical condition, the side effect profile, and drug-drug interactions with other medications in concomitant use. Patients with advanced disease are particularly likely to be using various other types of medications.
In addition to pharmacotherapy, behavioral therapy or other psychotherapeutic interventions may be helpful to reduce levels of stress and should be considered.
Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor symptoms, cognitive decline, and psychiatric disorders . HD is caused by a trinucleotide expansion in the IT15 gene, coding for the mutant protein huntingtin, and has an autosomal dominant hereditary pattern. Neurodegeneration occurs primarily in the striatum and cerebral cortex. The onset of HD most commonly occurs between 30 and 50 years of age, and the average disease duration is 16 years.
Although motor symptoms remain at the forefront of the clinical diagnosis, neuropsychiatric symptoms often precede the onset of motor symptoms. Next to depression, obsessive-compulsive disorder, and anxiety, irritability and aggression are frequent neuropsychiatric symptoms in HD [2,3,4]. Irritable patients are frequently hard to get along with, have emotional lability and eruptions, and demonstrate outbursts in response to minor provocations. The burden of this neuropsychiatric symptom is highly associated with functional disability.
The term irritability is often poorly defined and is used as synonym for agitation, hostility, aggressive behavior, and violent outbursts. Irritability is best defined as a temporary mood state characterized by impatience, intolerance, and reduced control over temper, which usually results in verbal or behavioral outbursts. It includes elements of anger, aggression, and reduced impulse control and can occur independently of other neuropsychiatric conditions [5,6].
A variety of psychotropic medications are used to treat irritability in HD, although no medication is officially approved for this indication. In this review of the literature, we aimed to investigate all reported treatments for irritability in HD.
The present level of evidence is based on small studies, with different definitions of irritability and measurement tools, and many patients used concomitant medications that may have affected the clinical outcome. In addition to these methodologic shortcomings, the choice of the medications in the studies examined seems to be rather arbitrary. For example, only one publication is available on the use of a selective serotonin reuptake inhibitor (SSRI) [7, Class IV], whereas in clinical practice, SSRIs are often prescribed as a first-choice treatment for irritability.
Most of the studies discuss the use of antipsychotics, in particular olanzapine [8,9,10,11, Class IV]. Relatively large case series show an improvement of irritability after initiating treatment with olanzapine, indicating that olanzapine may be an effective treatment for irritability. However, olanzapine has not been compared with other medications, so the results are inconclusive.
So far, only one study comparing the effect of two different medications (lithium carbonate and haloperidol, in a crossover study), and their combination, has been published [12, Class III]. Recently, a placebo-controlled study measuring the effect of nabilone was published, showing an overall improvement in behavior [13•, Class III].
In conclusion, there is a low level of evidence for current treatments of irritability, and systematic research with randomized controlled trials is warranted to measure the effect of medication.
Sertraline A hospitalized patient showed a “dramatic improvement” in irritability shortly after starting sertraline (100 mg), in combination with an ongoing treatment of haloperidol, whereas earlier treatment with carbamazepine was not effective [7, Class IV]. Another patient improved with sertraline after treatments with several other psychotropic medications had been ineffective [7, Class IV].
Buspirone Episodic aggression that was due to a subjective sense of anger and irritability in a patient with juvenile-onset HD was effectively treated with 60 mg of buspirone per day [15, Class IV]. Agitation and aggressive behavior also abated in a 74-year-old patient treated with buspirone (10 mg three times per day) [16, Class IV]. Dramatic responses on buspirone at a dosage of 20 mg daily were described after initial treatments with haloperidol and carbamazepine [17, Class IV].
Olanzapine In an open-label study, 11 HD patients were treated with olanzapine for several indications, including disruptive behavior and “psychomotor agitation” [11, Class IV]. After 6 and 12 months, the behavioral score of the Unified Huntington’s Disease Rating Scale (UHDRS)  was significantly reduced, whereas the UHDRS motor score was unchanged.Olanzapine (5 mg) was a useful antipsychotic drug in an open-label study with 10 patients, with significant changes in behavior, including irritability [8, Class IV]. Reported dosages of olanzapine as a treatment for agitation vary between 5 mg and 10 mg daily in combination with valproate [9, Class IV]. Impulsivity and aggressive behavior diminished with 5 mg of olanzapine. Chorea movements and functioning in activities of daily life improved when the dose was increased to 10 mg per day [10, Class IV].
Risperidone In a patient with anger, anxiety, and impulsive behavior, risperidone was initiated after a treatment with haloperidol. The dosage was titrated gradually up to 1 mg twice daily, giving a moderate improvement in movement and overall psychiatric symptoms [19, Class IV]. Another case report described a late-onset HD patient who showed behavioral changes with temper outbursts and psychotic symptoms, which disappeared after starting risperidone at a dosage of 1 mg twice daily [20, Class IV]. A retrospective review of a group of HD patients treated with risperidone (average dose, 2.5 mg) for an average of 15 months showed improved psychiatric functioning measured with the UHDRS behavioral score, but the effect on irritability was not specified [21•, Class III].
Quetiapine With dosages varying from 150 mg to 300 mg daily, improvement of behavioral symptoms, including irritability, was noted in five HD patients without worsening of motor functioning [22, Class IV]. However, all patients had multiple psychiatric symptoms and were treated with several types of medications. In a case report concerning an elderly HD patient with hypersexuality, the addition of quetiapine (25 mg at bedtime) to cyproterone for his deviant sexual behavior was effective in reducing agitation [23, Class IV].
Aripiprazole In a patient with irritability and delusions, aripiprazole (20 mg per day) gave an improvement of his psychotic symptoms and his personal hygiene, though the effect on irritability remained unclear [24, Class IV]. One advanced symptomatic patient with agitation showed an improvement of agitation with aripiprazole (15 mg per day), with good control of motor symptoms and without adverse effects [25, Class IV]. However, precise assessment of behavioral functioning in this patient was not possible because of severe cognitive dysfunction.
Valproate One study reported an effective treatment of agitation with valproate, 1500 mg daily, with a plasma concentration range from 60 to 80 μg/mL, in combination with olanzapine [19, Class IV].
Carbamazepine Carbamazepine (500 mg/d) was effectively used in combination with haloperidol, clonazepam, and a strict behavior modification plan in a patient with aggressive and disinhibited behavior [26, Class IV].
Lamotrigine Only one study describes an effective treatment with lamotrigine (300 mg/d), together with clonazepam (4 mg/d) in a patient with irritability, mood swings, and depression [27, Class IV].
Lithium carbonate In a small, double-blind, crossover trial with six female patients, a combination of lithium and haloperidol during 3 weeks resulted in a decrease of irritability and angry outbursts, but this effect did not occur when either drug was administered separately [12, Class III].
Donepezil No clinical or statistical improvement in behavioral, cognitive, or functional assessment was measured in an open-label study with 10 mg per day of donepezil in eight symptomatic HD patients [28, Class IV]. However, a high dropout rate of 50% was noted after 6 weeks of treatment.
Rivastigmine Data on the effect of rivastigmine (3 mg twice daily) show a tendency to improvement of the total score of the UHDRS behavioral scale [29, Class IV].
Propranolol With dosage varying from 30 to 240 mg daily, propranolol was an effective treatment for aggression in three patients [30, Class IV], but propranolol also precipitated paradoxic aggression in a patient with HD [31, Class IV].
Nabilone One HD patient had an improvement of mood, was calmer and more relaxed after she started smoking of cannabis [32, Class IV]. Nabilone, a synthetic 9-keto cannabinoid, was given in a larger study, resulting in an overall improvement of UHDRS behavioral and the Neuropsychiatric Inventory scores [13•, Class III].
Behavioral therapy Both classical and operant conditioning are useful in managing irritability. Operant conditioning involves the reinforcement of more appropriate behaviors and discouragement of inappropriate behaviors . Furthermore, limits and consequences of deviant behavior need to be clearly defined to the patient . Especially for patients in an advanced disease stage, a behavior modification plan may include a structured daily schedule and reinforcement of desired behaviors .
Nursing interventions Stressful psychosocial factors may result in irritability. After identification of stressors, the patient should be helped to look for ways to avoid these stressors and to develop concrete ways of coping, in order to decrease the level of stress within the nursing home or day care setting. Patients may be advised to break tasks down into simpler components.Adaptive devices and specialized equipment are valuable in maintaining comfort, thereby decreasing the expression of problematic behaviors .
No potential conflicts of interest relevant to this article were reported.
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