Long-term follow-up of impulse control disorders in Parkinson's disease
Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson's disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = −3.1, P = 0.002) and a higher daily levodopa dosage (Z = −1.9, P = 0.05), but a similar total LEDD dosage (Z = −0.47, P = 0.64) with no changes in Unified Parkinson's Disease Rating Scale motor score (Z = −1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms. © 2007 Movement Disorder Society
Multiple impulse control disorders (ICDs), including compulsive gambling,1 sexual behavior,2–4 buying,3, 5 and eating,6 have been reported to occur frequently in Parkinson's disease (PD). Estimates of ICDs in PD typically exceed those in the general population,7 in total affecting ∼5% of patients at any given time3, 8 and between 5 and 10% at some point during the course of the disease.2, 3
Case reporting4, 5, 8–10 and prospective studies3, 11 have implicated dopamine agonist (DA) use as a primary risk factor for the development of ICDs in PD, although these disorders have also been linked with levodopa (L-dopa) use.12 Other risk factors for the development of ICDs may be younger age at PD onset11 and a pre-PD history of ICD behaviors3 or substance use disorders.11
Little is known about the optimal management strategies for or long-term outcomes of PD patients with ICDs. Anecdotally, there are reports of ICD symptom improvement or resolution with changes in DA therapy, including discontinuation of DA therapy, lowering the dose of the existing DA, or switching to a different DA.4, 6, 9, 10 Case reports suggest that atypical antipsychotics,4, 13, 14 antidepressants,4, 12 mood stabilizers,4, 9 and a variety of psychosocial interventions9, 12 may be beneficial in the treatment of ICD behaviors in PD. However, as these treatments are often administered concurrently with changes in dopamine replacement therapy, their respective efficacies are unclear. Finally, in a case series reporting on the outcomes of PD patients (N = 598) who underwent subthalamic nucleus (STN) deep-brain stimulation (DBS) surgery as part of routine clinical care, all patients who had pathological gambling pre-DBS surgery (N = 7) experienced a resolution of symptoms post-DBS surgery.15 The authors hypothesized that the physiological effects of DBS stimulation in conjunction with the concomitant decrease in overall dopaminergic treatment was responsible for the improvement in ICD symptoms. However, the results of this last study did not differentiate between changes in L-dopa versus DA therapy, and reflected the experience of a small number of ICD patients who all underwent STN DBS. Thus, the findings may not generalize to PD patients overall.
We previously reported3 on 18 PD patients of a sample of 273 who developed an ICD during the course of PD, all of whom were taking a DA when symptomatic. Here we report on the long-term outcomes of these patients' ICD behaviors. Information was collected on changes in dopamine replacement therapy or PD management that were made over time, and on clinical interventions for ICD behaviors. We hypothesized that discontinuation of or decreases in DA therapy dosage would be associated with ICD improvement or resolution.
SUBJECTS AND METHODS
PD subjects with an active ICD during the course of PD were identified using a database from a study examining the frequency and correlates of depression in PD (methods previously described3). On initial assessment, 18 subjects were identified as having an ICD during PD (11 subjects with active ICDs and 7 with ICDs in remission). Of these subjects, 15 (83.3%) participated in the follow-up telephone interview. The patients who participated in the follow-up had the following clinical and demographic characteristics at the time when their ICD symptoms were most severe based on self-report and chart review: sex = 73.3% male, marital status = 86.7% married, mean (SD) age = 60.9 (11.1) years, mean (SD) education = 14.8 (3.0) years, and mean (SD) PD duration = 9.4 (4.6) years.
Patients were contacted by one of the authors (EM) for the follow-up interview. The mean (SD) time interval between either original screening (for patients with an active ICD) or self-reported time period of maximal ICD symptomatology (for patients with an inactive ICD) (Time 1) and the follow-up interview (Time 2) was 29.2 (16.5) months.
The follow-up interview consisted of both a semi-structured clinical interview and the administration of a modified Minnesota Impulse Disorder Interview (MIDI)16 for compulsive buying, gambling, and sexuality. This same methodology was used in the original reporting of this ICD cohort.3 Subjects were asked to self-rate whether their ICD disorder was in full remission (i.e., no symptoms present), partial remission (i.e., still symptomatic but not causing significant functional impairment), or remained fully symptomatic (i.e., no change in symptomatology over time).
As part of the interview, subjects were asked to provide information regarding starting and end dates for ICD symptomatology, any interventions targeting ICD symptomatology (e.g., increase or decrease of PD pharmacotherapy, use of psychotropic medication, or engagement in psychosocial treatment), and both past and current PD and psychiatric medication regimen, all of which was confirmed by chart review and reviewed by another study author (DW). Unified Parkinson's Disease Rating Scale (UPDRS)17 motor scores for Time 1 and Time 2 (±6 months) were obtained by chart review. For the purposes of this study, a significant change in DA dosage was determined a priori to be a >30% decrease.
The Wilcoxon Signed Ranks Test for two related samples was used to determine changes in daily L-dopa dosage, daily L-dopa equivalent daily dosage (LEDD) for DAs, total daily LEDD (L-dopa + LEDD for DAs), and UPDRS motor score between Time 1 and Time 2. LEDDs were calculated on the basis of the following formula, similar to that previously reported18, 19: 100 mg L-dopa = 130 mg controlled-release L-dopa = 70 mg L-dopa + COMT inhibitor = 1 mg pergolide = 1 mg pramipexole = 5 mg ropinirole. Significance was set at P ≤ 0.05.
At Time 1 all 15 subjects were on a DA (Table 1). The distribution for specific DAs was as follows: pramipexole (40%), ropinirole (47%), and pergolide (13%). Thirteen (87%) subjects had a single ICD, while two subjects had two or more ICDs. Approximately half (53%) of subjects were compulsive gamblers, 40% experienced compulsive sexual behavior, and 20% had compulsive buying. Mean (SD) daily dosages of PD medications and UPDRS motor score were as follows: L-dopa = 349.7 (381.3) mg, DA LEDD = 358.7 (179.4) mg, total LEDD = 708.3 (482.9) mg, and UPDRS motor score = 22.6 (8.7).
Table 1. Changes in clinical management and ICD status over time
|1||Compulsive sexuality||Yes||Pergolide (5)||500||16||25 mo||No||Not applicable||400||24||Discontinued pergolide; attended sex addiction support group||Full remission||Full remission|
|2||Compulsive gambling||Yes||Pramipexole (3)||210||13||46 mo||No||Not applicable||720||17||Discontinued pramipexole||Full remission||Full remission|
|3||Compulsive gambling||Yes||Pramipexole (4)||800||24||22 mo||Yes||Pramipexole (1.5)||700||31||Decreased pramipexole dosage; Switched antidepressant||Partial remission||Compulsive gambling|
|4||Compulsive gambling||Yes||Pergolide (8)||800||29||16 mo||Yes||Pergolide (8)||1,010||19||None||Fully symptomatic||Compulsive gambling|
|5||Compulsive buying||Yes||Ropinirole (18)||210||20||35 mo||No||Not applicable||140||22||Discontinued ropinirole||Full remission||Full remission|
|6||Compulsive buying||Yes||Ropinirole (12)||0||24||29 mo||Yes||Pramipexole (1.25)||0||32||Decreased DA dosage (switched from ropinirole to pramipexole)||Full remission||Full remission|
|7||Compulsive gambling, buying, sexuality||Yes||Ropinirole (15)||1,320||26||24 mo||No||Not applicable||1,310||35||Discontinued ropinirole||Full remission||Full remission|
|8||Compulsive gambling||Yes||Ropinirole (4.5)||390||30||23 mo||No||Not applicable||520||28||Discontinued ropinirole; increased antidepressant dosage||Full remission||Full remission|
|9||Compulsive sexuality||Yes||Pramipexole (4.5)||425||29||20 mo||Yes||Pramipexole (4.5)||390||12||Underwent DBS surgery; decreased amantadine||Full remission||Full remission|
|10||Compulsive gambling||Yes||Pramipexole (2.25)||0||10||71 mo||No||Not applicable||390||10||Discontinued pramipexole||Full remission||Full remission|
|11||Compulsive gambling, sexuality||Yes||Ropinirole (21)||0||32||18 mo||Yes||Ropinirole (21)||300||42||None||Partial remission||Compulsive gambling|
|12||Compulsive sexuality||Yes||Pramipexole (6)||400||36||18 mo||Yes||Pramipexole (1)||700||38||Decreased pramipexole||Partial remission||Compulsive sexuality|
|13||Compulsive sexuality||Yes||Ropinirole (12)||280||–||58 mo||Yes||Ropinirole (6)||330||–||Decreased ropinirole||Full remission||Full remission|
|14||Compulsive gambling||Yes||Ropinirole (9)||0||21||17 mo||No||Not applicable||325||23||Discontinued ropinirole||Full remission||Full remission|
|15||Compulsive sexuality||Yes||Pramipexole (2.75)||0||7||17 mo||Yes||Pramipexole (1.875)||0||11||Decreased pramipexole||Full remission||Full remission|
At Time 2 approximately half (53%) of the sample remained on a DA. Of the subjects remaining on a DA, 63% were on pramipexole, 25% on ropinirole, and 13% on pergolide. Mean (SD) daily dosages of PD medications and UPDRS motor score were as follows: L-dopa = 482.3 (358.9) mg, DA LEDD = 170.2 (233.3) mg, total LEDD = 652.5 (465.3) mg, and UPDRS motor score = 24.6 (10.2). Over time there was a statistically significant increase in L-dopa dosage (Z = −1.9, P = 0.05) and a statistically significant decrease in DA LEDD (Z = −3.1, P = 0.002), with no change in total LEDD (Z = −0.5, P = 0.64). There was no change in UPDRS motor score over time (Z = 1.3, P = 0.19) (Table 2).
Table 2. Changes in levodopa equivalent daily dosages (LEDDs) and UPDRS score over time
|Dopamine agonist LEDD||358.7 (179.4)||170.2 (233.3)||−52.6||−3.1 (0.002)|
|Levodopa daily dosage||349.7 (381.3)||482.3 (358.9)||+37.9||−1.9 (0.05)|
|Total LEDD||708.3 (482.9)||652.5 (465.3)||−7.9||−0.5 (0.64)|
|UPDRS motor scorea||22.6(8.7)||24.6(10.2)||+8.8||−1.3(0.19)|
As part of clinical management for the ICD, 12 (80%) patients either discontinued DA treatment or significantly decreased their DA dosage. Of these patients, all reported experiencing full or partial remission of their ICD symptoms, and 10 (83%) no longer met criteria for an active ICD. Of the 7 (47%) patients who discontinued DA treatment, all reported full remission of ICD symptoms over time and none still met diagnostic criteria for an active ICD.
Only 3 (20%) patients remained on the exact same DA and dosage over time. One was in full remission post-DBS surgery and other medication adjustments, one was in partial remission, and one remained fully symptomatic.
Four patients who experienced full or partial remission reported clinical interventions for their ICD symptoms in addition to (N = 3) or instead of (N = 1) changes in DA treatment. As a supplemental treatment, one subject attended a sex addiction support group, and two subjects changed antidepressant treatment or increased their antidepressant dosage. The remaining patient continued on the same DA and dosage post-DBS surgery, but did discontinue amantadine post-DBS surgery.
To our knowledge this is the first case series examining in the context of routine care the long-term clinical outcomes of PD patients with ICDs. We found that on average patients had a significant change in their specific dopamine replacement therapies once their ICD was identified, and that all patients who discontinued or significantly decreased DA treatment experienced full remission or a clinically significant reduction in ICD symptomatology. This was consistent with our hypothesis that decreases in exposure to DA therapy would be associated with improvement in ICD symptoms.
There are several limitations to this study. First, we were unable to contact all eligible subjects, although over 80% of the original ICD sample did participate in the follow-up interview. Second, the sample size was relatively small, only identified ICD patients on a DA, and involved patients at two movement disorders centers with a research focus on the psychiatric complications of PD, limiting the generalizability of the findings. Third, the data were obtained primarily via telephone interview. In-person interviews may have yielded more accurate and complete information. Finally, this study was not controlled, limiting conclusions that could be drawn. For example, it is possible that the overall decrease in DA exposure was unrelated to improvement in ICD symptoms, as the natural histories of ICDs in PD and non-PD individuals are not well understood.
The results of this study results provide further evidence of the association between DA treatment and ICD behaviors in PD. Because of the long lag-time reported in many cases between DA initiation and development of ICD behaviors, it is not practical to conduct a randomized trial to definitively determine the association between DA treatment and ICDs. Additionally, given the existing evidence in support of the association between ICDs and DA treatment, it does not seem ethical to conduct a randomized DA discontinuation study in PD patients with an ICD. Thus, the best available evidence regarding the impact of DA treatment on ICD behaviors is likely to come from cross-sectional studies and careful long-term follow-up of clinical populations.
Our results are consistent with previous case reporting that discontinuation or reduction in DA treatment leads to a reduction or resolution of ICD symptoms. They are also similar to the outcomes of the small group of ICD patients who underwent STN DBS surgery, all of whom experienced resolution of ICD symptomatology post-DBS surgery and in the context of treatment with significantly lower total LEDD.15
We found that patients overall were being treated with similar total LEDDs at the two time periods, but that there was an overall shift in the balance between L-dopa and DA treatment. At Time 1, patients were on essentially the same daily L-dopa and DA LEDD dosage, but at Time 2 the balance shifted in favor of L-dopa treatment, with the daily L-dopa dosage being nearly four times as high as the DA LEDD dosage. The lack of change in UPDRS motor score over time suggests that overall it is possible to adequately manage motor symptoms in ICD patients by shifting the balance away from DA treatment to L-dopa treatment. Though there may be long-term adverse effects (e.g., dyskinesias or motor fluctuations) from chronic, higher-dose L-dopa treatment,20 our results in conjunction with those of patients undergoing surgery suggest that two possible management strategies for ICD symptoms in PD are shifting the L-dopa:DA balance in favor of L-dopa and STN DBS surgery, the latter leading to a decrease in overall dopaminergic treatment. However, it is important to note a recent case report of a patient on long-term DA treatment who developed pathological gambling only after post-bilateral STN DBS and in the context of cognitive decline.21 The urge to gamble resolved after switching off the neurostimulation. Upon restimulation with different parameters, ICD symptoms reoccurred, and only with discontinuation of DA treatment was the patient able to continue with STN stimulation. Thus, the relationship between ICD symptomatology and PD treatments, particularly within the context of individual patient characteristics, requires additional investigation.
It is also important to determine if other treatment strategies may be effective for ICDs in PD that arise in the context of DA use. One of the patients in this study experienced partial remission of ICD symptomatology in spite of continuing the same DA at the same dosage, suggesting that other factors may contribute to changes in ICD symptoms over time. In addition, many PD patients are reluctant to discontinue DA treatment because of the motor benefits associated with their use. Thus, randomized treatment studies using psychiatric medications that have been reported to be helpful in the treatment of ICDs in PD, such as atypical antipsychotics and antidepressants, are needed. Finally, the role for psychosocial interventions, such as participation in Gamblers' Anonymous, has yet to be studied. However, while waiting for other treatment strategies to be tested, one relatively simple and apparently effective way to manage ICDs that occur during DA treatment is to decrease DA exposure and consider a concomitant increase in L-dopa treatment.
Supported by a grant from the National Institute of Mental Health, No. 067894.