Ropinirole-Associated Psychotic Symptoms in an Outpatient Population
Ropinirole-Associated Psychotic Symptoms in an Outpatient Population
Background: Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinson's disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms.
Objective: To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD.
Methods: Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis.
Results: A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003).
Discussion: Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms.
Conclusions: Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.
Traditional pharmacologic treatment approaches for the management of Parkinson's disease (PD) include the use of the dopamine precursor levodopa, as well as other direct and indirect dopamine agonists, monoamine oxidase inhibitors (MAOIs), catechol-O-methyltransferase (COMT) inhibitors, and anticholinergics. The treatment for restless leg syndrome (RLS) also often includes the use of dopamine agonists. When treating either PD or RLS in psychiatric patients, there is an inherent concern that dopaminergic agents used to treat and manage neurologic symptoms may contribute to the development or exacerbation of preexisting psychiatric features. Dopamine agonists are used in PD and RLS based on the idea that action on dopamine receptors will provide relief of neurologic symptoms through agonistic activity on striatal dopamine receptors. One theoretical benefit of dopamine agonists that are selective for the D3 receptor (eg, ropinirole) is the ability to circumvent excessive stimulation of D2 receptors in the mesolimbic regions of the brain.
Data are limited regarding the stimulation of targeted individual dopamine receptors and subsequent differences in the rates or prevalence of psychosis, although case reports suggest the potential for development of psychosis and mania with ropinirole. There is also little information to identify whether concurrent antipsychotic treatment provides a protective benefit against development of psychosis, particularly in patients already being treated for psychotic symptoms. Early studies of ropinirole in patients with PD found an estimated 5% prevalence rate of hallucinations in patients not concurrently being treated with levodopa, although more recent studies suggest rates of up to 17%. Early trials found that when ropinirole was combined with levodopa, the rate of reported hallucinations nearly doubled. The results of one study conflict with these results and suggest a low incidence of hallucinations, confusion, and psychosis with the combination of ropinirole and levodopa. In part, this finding may be the result of the study design, which allowed for reduction of the levodopa dosage in response to clinical benefits observed with dual therapy.
In contrast to findings in PD trials, the reported incidence of hallucinations from early ropinirole RLS studies was dramatically less, with hallucinations reported at a rate of less than 1% of patients in both short- and long-term trials. These findings are of particular interest when considering possible dose relationships and implementation of single-agent versus dual therapy. Attention should be given to the dosing of drugs being used, recognizing that doses of ropinirole in patients with RLS are typically lower than those used in patients with PD.
The pathophysiology of each disease state may also be an important variable when examining the prevalence of psychotic symptoms and adverse events in each patient group. One common link between the disorders is that the regulation of dopamine plays a critical role in response rates and adverse events. PD is a degenerative disorder of the central nervous system caused by neuronal impairment and dysfunctional dopamine activity in the substantia nigra and corpus striatum. Alterations in dopaminergic function contribute to the classical presentation of PD characterized by rigidity, tremor, masked facies, drooling, and shuffled gait. RLS is also a neurologic disorder that is, in part, the consequence of reduced dopamine levels and diminished dopamine activity. The clinical presentation of RLS differs from that of PD in that patients report unpleasant feelings in the legs followed by the urge to move in an effort to relieve the discomfort.
One common treatment approach for both PD and RLS is based on increasing dopamine activity. This can be accomplished through the use of the combination of levodopa/carbidopa, although the potential for developing dyskinesias and other motor symptoms within a few years of starting these agents has led practitioners to consider alternative treatment modalities as first-line drugs. Dopamine agonists have been shown to be effective treatments and are categorized as ergolinic (ergot; eg, bromocriptine, cabergoline) and nonergolinic (nonergot; eg, ropinirole, pramipexole, rotigotine). The ergot and nonergot derivatives differ not only in chemical structure, but also in receptor affinity, half-life, and duration of action. As stated previously, other alternative treatments for PD include MAO-B inhibitors (eg, selegiline, rasagiline), anticholinergics (eg, benztropine), amantadine, and COMT inhibitors (eg, entacapone, tolcapone). Additional treatments for RLS include the use of benzodiazepines, anticonvulsants, and opioids.
The development of psychotic features can be a major limitation for the effective treatment of PD. The presence of psychotic features can be a part of the physiologic progression of PD and is estimated to occur naturally in 20–40% of patients with PD, usually in the latter stages of the disease process. The most common psychotic features occur in the form of paranoid ideations and visual hallucinations, although other symptoms may present. A second mechanism for psychosis-related symptoms in PD patients is the overstimulation or activation of the D2 receptor from drugs, which may contribute to the development of hallucinations, delusions, agitation, and paranoid ideations. Although other dopamine receptors have been identified and studied, there have not been any trials that definitively describe the clinical implications of stimulating the D1, D3, and D4 receptor sites and possible correlation with development or exacerbation of psychosis. It is hypothesized that ropinirole is less likely to amplify or initiate the development of psychotic features due to its high selective affinity for the D3 receptor compared with the D2 receptor. In vitro studies have shown that ropinirole is 10–20 times more selective for the D3 receptor than for the D2 receptor. This activity more closely resembles endogenous dopamine than does the activity of nonselective treatments, as dopamine is estimated to be 17 times more selective for the D3 receptor. This theoretically implies that ropinirole should reduce the risk of psychotic symptoms compared with nonselective dopamine agonists during the treatment of PD or RLS. Additionally, increased activity at the D3 receptor has been associated with improvement of depressed mood, amotivation, and bradykinetic movement. Dependent upon disease state, the dosing ranges vary for symptomatic treatment of PD, starting at 0.75 mg/day and increasing to 24 mg/day, while RLS treatment starts at 0.25 mg/day and may be increased to 4 mg/day. Safety data compiled from clinical trials in both PD and RLS patients conclude that hallucinations and other psychiatric features are more often associated with doses of ropinirole that are larger than those commonly used in the management of RLS.
Despite the theory, this has not been addressed as the primary outcome measure in any published clinical trials. This naturalistic, retrospective study will provide information about patients who have been given ropinirole for up to 2 years to help determine whether there is a significant risk of developing new or worsening psychotic features during treatment.
Abstract and Introduction
Abstract
Background: Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinson's disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms.
Objective: To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD.
Methods: Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis.
Results: A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003).
Discussion: Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms.
Conclusions: Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.
Introduction
Traditional pharmacologic treatment approaches for the management of Parkinson's disease (PD) include the use of the dopamine precursor levodopa, as well as other direct and indirect dopamine agonists, monoamine oxidase inhibitors (MAOIs), catechol-O-methyltransferase (COMT) inhibitors, and anticholinergics. The treatment for restless leg syndrome (RLS) also often includes the use of dopamine agonists. When treating either PD or RLS in psychiatric patients, there is an inherent concern that dopaminergic agents used to treat and manage neurologic symptoms may contribute to the development or exacerbation of preexisting psychiatric features. Dopamine agonists are used in PD and RLS based on the idea that action on dopamine receptors will provide relief of neurologic symptoms through agonistic activity on striatal dopamine receptors. One theoretical benefit of dopamine agonists that are selective for the D3 receptor (eg, ropinirole) is the ability to circumvent excessive stimulation of D2 receptors in the mesolimbic regions of the brain.
Data are limited regarding the stimulation of targeted individual dopamine receptors and subsequent differences in the rates or prevalence of psychosis, although case reports suggest the potential for development of psychosis and mania with ropinirole. There is also little information to identify whether concurrent antipsychotic treatment provides a protective benefit against development of psychosis, particularly in patients already being treated for psychotic symptoms. Early studies of ropinirole in patients with PD found an estimated 5% prevalence rate of hallucinations in patients not concurrently being treated with levodopa, although more recent studies suggest rates of up to 17%. Early trials found that when ropinirole was combined with levodopa, the rate of reported hallucinations nearly doubled. The results of one study conflict with these results and suggest a low incidence of hallucinations, confusion, and psychosis with the combination of ropinirole and levodopa. In part, this finding may be the result of the study design, which allowed for reduction of the levodopa dosage in response to clinical benefits observed with dual therapy.
In contrast to findings in PD trials, the reported incidence of hallucinations from early ropinirole RLS studies was dramatically less, with hallucinations reported at a rate of less than 1% of patients in both short- and long-term trials. These findings are of particular interest when considering possible dose relationships and implementation of single-agent versus dual therapy. Attention should be given to the dosing of drugs being used, recognizing that doses of ropinirole in patients with RLS are typically lower than those used in patients with PD.
The pathophysiology of each disease state may also be an important variable when examining the prevalence of psychotic symptoms and adverse events in each patient group. One common link between the disorders is that the regulation of dopamine plays a critical role in response rates and adverse events. PD is a degenerative disorder of the central nervous system caused by neuronal impairment and dysfunctional dopamine activity in the substantia nigra and corpus striatum. Alterations in dopaminergic function contribute to the classical presentation of PD characterized by rigidity, tremor, masked facies, drooling, and shuffled gait. RLS is also a neurologic disorder that is, in part, the consequence of reduced dopamine levels and diminished dopamine activity. The clinical presentation of RLS differs from that of PD in that patients report unpleasant feelings in the legs followed by the urge to move in an effort to relieve the discomfort.
One common treatment approach for both PD and RLS is based on increasing dopamine activity. This can be accomplished through the use of the combination of levodopa/carbidopa, although the potential for developing dyskinesias and other motor symptoms within a few years of starting these agents has led practitioners to consider alternative treatment modalities as first-line drugs. Dopamine agonists have been shown to be effective treatments and are categorized as ergolinic (ergot; eg, bromocriptine, cabergoline) and nonergolinic (nonergot; eg, ropinirole, pramipexole, rotigotine). The ergot and nonergot derivatives differ not only in chemical structure, but also in receptor affinity, half-life, and duration of action. As stated previously, other alternative treatments for PD include MAO-B inhibitors (eg, selegiline, rasagiline), anticholinergics (eg, benztropine), amantadine, and COMT inhibitors (eg, entacapone, tolcapone). Additional treatments for RLS include the use of benzodiazepines, anticonvulsants, and opioids.
The development of psychotic features can be a major limitation for the effective treatment of PD. The presence of psychotic features can be a part of the physiologic progression of PD and is estimated to occur naturally in 20–40% of patients with PD, usually in the latter stages of the disease process. The most common psychotic features occur in the form of paranoid ideations and visual hallucinations, although other symptoms may present. A second mechanism for psychosis-related symptoms in PD patients is the overstimulation or activation of the D2 receptor from drugs, which may contribute to the development of hallucinations, delusions, agitation, and paranoid ideations. Although other dopamine receptors have been identified and studied, there have not been any trials that definitively describe the clinical implications of stimulating the D1, D3, and D4 receptor sites and possible correlation with development or exacerbation of psychosis. It is hypothesized that ropinirole is less likely to amplify or initiate the development of psychotic features due to its high selective affinity for the D3 receptor compared with the D2 receptor. In vitro studies have shown that ropinirole is 10–20 times more selective for the D3 receptor than for the D2 receptor. This activity more closely resembles endogenous dopamine than does the activity of nonselective treatments, as dopamine is estimated to be 17 times more selective for the D3 receptor. This theoretically implies that ropinirole should reduce the risk of psychotic symptoms compared with nonselective dopamine agonists during the treatment of PD or RLS. Additionally, increased activity at the D3 receptor has been associated with improvement of depressed mood, amotivation, and bradykinetic movement. Dependent upon disease state, the dosing ranges vary for symptomatic treatment of PD, starting at 0.75 mg/day and increasing to 24 mg/day, while RLS treatment starts at 0.25 mg/day and may be increased to 4 mg/day. Safety data compiled from clinical trials in both PD and RLS patients conclude that hallucinations and other psychiatric features are more often associated with doses of ropinirole that are larger than those commonly used in the management of RLS.
Despite the theory, this has not been addressed as the primary outcome measure in any published clinical trials. This naturalistic, retrospective study will provide information about patients who have been given ropinirole for up to 2 years to help determine whether there is a significant risk of developing new or worsening psychotic features during treatment.
