Of the 66 expert clinicians contacted, 55 responded. Not all respondents answered all individual questions. Of these 55 expert respondents, 26 were from Europe, 23 from the United States, 4 from Canada,and 2 from Australia. Most respondents were neurologists (39) or psychiatrists (10). There were 2 respondents who were double boarded in neurology and psychiatry and 2 respondents in neurogenetics. Clinical experience was quite substantial among the surveyed experts: over half reported treating more than 100 HD patients annually.
Practice patterns by drug or drug class: The first set of treatment questions concerned drug selection and was phrased as follows: “Assuming there are no comorbid symptoms to influence your decision, what is your practice pattern with the use of [drug or drug class] for the treatment of irritability in Huntington’s disease?” Drugs/drug classes included SSRIs, APDs, AEDs, BZDs, and tricyclic antidepressants (TCAs)) and 4 specific drugs (propranolol, clomipramine (CMI), buspirone, and mirtazapine. Alternative usage included: first choice, alternative monotherapy, adjunctive therapy, not an appropriate use, or insufficient experience. Interpretation of this first set of questions was complicated by limitations in the survey branching logic which allowed for the respondent to check more than 1 first choice or no first choice. Five respondents checked no first choice, while 2 had more than 1 first choice. See figures 1-3 and table 1.
Figure 1. Choice of irritability drug across all geographic regions. Vertical axis is number of responses. See box 1 for abbreviations.
Figure 2. Choice of irritability drug, European respondents. Vertical axis is number of responses. See box 1 for abbreviations.
Figure 3. Choice of irritability drug, North American and Australian respondents. Vertical axis is number of responses. See box 1 for abbreviations.
Table 1. Choice of drug for treating irritability across all geographic regions. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.
Results from this set of questions, when no comorbid symptoms influenced treatment decisions revealed some variation in practice patterns. Across all geographic regions SSRIs were most frequently chosen as the first drug for treating mild to moderate HD irritability. Though a less frequent choice than the SSRIs overall, APD usage for treatment of mild or moderate irritability was more common in Europe than in North America and Australia. AEDs were less frequently endorsed as first choice drug. When combining monotherapy choices (first and alternative), SSRIs were most frequently endorsed (80%), followed by APDs (53%) and AEDs (43%). No respondent chose buspirone, mirtazapine, propranolol or TCAs as first choice drugs, but each was cited as an alternative monotherapy choice by a minority of respondents. Many cited lack of experience with these drugs for treating irritability. The BZDs were most frequently used as an adjunctive drug. Though many (43%) were not familiar with the use of mirtazapine for irritabilty, half of those familiar with the drug chose it as an alternative monotherapy.
Perceived efficacy of drug choice: Most experts indicated that efficacy of APDs was somewhat higher than SSRIs. Table 2 summarizes expert views about the relative efficacy of surveyed drugs.
Table 2. Expert opinion of drug efficacy for treating irritability. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.
Perceived benefit of high dose SSRI optimization: Respondents were also asked about SSRI dosing optimization for treating irritability in HD to upper limits of manufacturer recommended dosage for depression. Though all respondents perceived a level of increased effectiveness with higher dosing, the degree of effectiveness varied widely. Subsequent to the survey, the Federal Drug Administration issued a directive to change manufacturer recommended high dosage of citalopram from 60 mg to 40 mg per day, based on an increase in heart arrhythmias, and lack of larger dose benefit in treating depression. However, for treatment of irritability, six respondents reported beneficial result in selected patients exceeding the highest dose recommended for depression.
Dosing interval choices: Respondents were asked about dosing titration intervals for the drug/drug class alternatives. Preferred titration intervals varied greatly within each drug or drug class. See table 3.
Table 3. Choice of dosing titration intervals for drugs used to treat irritability. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.
Adding or switching drugs for inadequate response to initial drug choice: The next set of iterative questions regarded strategies for adding or switching drug when an initial drug choice failed to adequately treat irritability in HD in the setting of no comorbid symptom to influence choice. The most notable result to this set of questions is that no consistent pattern was demonstrated for either SSRI or APD, the preferred initial choices. When SSRI was chosen as initial monotherapy but gave no or only partial benefit, the experts reported adding: an APD (30%), AED (16%) or BZD (7%), or switching to another SSRI (14%), or switching to an APD (12%), AED (7%), or BZD (5%). Similarly when an APD was chosen as initial monotherapy and did not give adequate response, the experts reported switching to another APD (28%), adding an SSRI (15%), AED (15%) or BZD (11%), or switching to an AED (8%) or SSRI (6%).
Table 4. Alternate choice of drug for treating irritability when inadequate response to initial therapy. N is number of responses. Percentages are relative to N. Alternate listed only if chosen by 5% or more of respondents. See box 1 for abbreviations.
Specific drugs favored within class: Preferred drugs within class for use in HD irritability included the SSRIs citalopram (35%), sertraline (25%) and paroxetine (15%); the APDs olanzapine (51%), risperidone (32%), and quetiapine (30%). Sulpiride and tiapride available only in parts of Europe were preferred by 7 European respondents. Insufficient experience was reported by many for clozapine, aripiprazole, ziprasidone, and pimozide. A high percentage of respondents (83.7%) preferred second-generation over first-generation antipsychotics. AED preferences included valproate derivatives (74%) and carbamazipine (23%), with a few others choosing each of the following: lamotrigine, gabapentin, topiramate and levetiracetam.
Other choices: The mood stabilizer lithium was an option for treating HD irritability. Only one expert rated lithium to be his/her first choice, but a substantial number of experts (23.6%) had no experience in using lithium for HD irritability, and 17.4% rated it as inappropriate. Only one respondent reported using benzodiazepines (BDZs) as first choice of treatment for irritability in HD. Most respondents prescribed BDZs as adjunctive therapy (70.6%). No one endorsed propranolol as a first-choice medication, 6 chose it as alternative monotherapy, and 13 as adjunctive therapy for irritability in HD. Almost half of the experts reported insufficient experience with propranolol for this indication.
Preferred medication choices for irritability with comorbid psychiatric symptoms: Given comorbid depression, anxiety, or perseverative behaviors, an SSRI was the first choice of the experts for treating HD irritability. Antipsychotic drugs were the first choice when comorbid psychosis, aggression, impulsivity, or hypersexuality were present. When patients who were irritable also suffered from insomnia, the favored medication choices were BDZs or mirtazapine. See figure 4 and table 5.
Figure 4. Choice of drug for irritability that occurs with a given comorbid symptom. Blue bars indicate the number of experts who selected the drug as first choice; red bars indicate the number who selected the drug as alternative monotherapy. See (more ...)
Table 5. Choice of drug for treating irritability that occurs with a given comorbid symptom. Percentages are relative to the number of experts who provided information for any symptom x drug combination (47). The last column is the sum of the previous two; the percentages do not always match precisely because of roundoff. The table only includes drugs chosen by 10% or more of the experts. See box 1 for abbreviations.