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A case of transient hallucination with ropinirole augmentation antidepressant in a patient with treatment-resistant depression: Is there differential effect of ropinirole dose on developing psychotic symptom?
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1087–1088
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report) A case of transient hallucination with ropinirole augmentation antidepressant in a patient with treatment-resistant depression: Is there differential effect of ropinirole dose on developing psychotic symptom?
Sir: Ropinirole has been shown to have antidepressant actions, presumably via D2/D3 receptor agonist effects which in turn modulate serotonergic and sigma receptor activity (Dhir and Kulkarni, 2007). A recent report provided the first case of acute psychosis in a patient who was treated with ropinirole for restless legs syndrome: the patient developed paranoid delusions, auditory/visual hallucinations, and thought process disorganization within a week after initiating ropinirole. Her psychotic symptoms substantially improved or resolved within a few days of discontinuing ropinirole, although treatment was simultaneously initiated with quetiapine and citalopram (Perea et al., 2006). In an earlier controlled clinical trial for Parkinson's disease, ropinirole was found to be associated with mild hallucinations as well (Schrag et al., 1998). Given the etiological relationship between enhanced dopaminergic function and psychotic symptoms (particularly demonstrated by consistent efficacy of currently available antipsychotics having dopamine antagonistic properties), exacerbation or onset of psychosis by a dopamine agonist appears to be predictable. However, to our knowledge, there have been no case reports of the development of psychotic symptoms in relation to ropinirole augmentation with antidepressants in the treatment of major depressive disorder. Ms. A was a 58-year-old woman without a family history of any psychiatric disorders who presented with an approximately 10-year history of major depressive disorder and dysthymic disorder. She had no clinically significant comorbid medical conditions. Her depressive symptoms were moderate without psychotic features, and they included anhedonia such that Ms. A withdrew from social interaction and had no meaningful interpersonal relationships. She had been compliant with fluoxetine, and at her intake appointment with the undersigned it was felt that she might benefit from antidepressant augmentation. Ropinirol was initiated at 2 mg/day and up-titrated to 4 mg/day within 4 weeks. Tolerability issues were not reported. Ms. A's depressive symptoms responded well, and in particular her social interaction and motivation dramatically improved. According to her subjective report, she felt improvement by 60% after a month of ropinirole treatment. At week 6, ropinirole was increased to 6 mg/day to target residual depressive symptoms. She subsequently began to experience visual hallucinations of her deceased mother which began 2 days after the increase in her ropinirole dose to 6 mg/day; these hallucinations occurred 3 times in the week following her dose increase, and they resolved completely after her ropinirole dose was decreased back to 4 mg/day. Her depressive symptoms remained markedly improved compared to prior to the initiation of ropinirole augmentation. 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.02.011
To date there have been no systematic controlled clinical trials of ropinirole for augmentation treatment of depression, although several open-label pilot or retrospective studies have demonstrated the benefit of ropinirole for treating treatment-resistant depression and bipolar II depression (Cassano et al., 2005; Perugi et al., 2001). Meanwhile two previous studies investigating the augmentation effect of another dopamine agonist, pramipexol, reported the development of psychosis in patients with mood disorder (Goldberg et al., 2004; Szegedi et al., 1997), in which one study found the resolution of psychotic symptoms with dose reduction (Szegedi et al., 1997). In addition, a recent review(Aiken, 2007) also advised the risk to develop psychotic symptoms in both Parkinson's disease and mood disorders when prescribing pramipexol. In a longer-term study (48 weeks) with pramipexol, it was associated with the development of psychotic symptom along with conversion to mania in two patients, indicating a possibility of late development of psychotic symptom after augmentation of pramipexol (Cassano et al., 2004). These previous literatures are largely similar to our case report in that clinicians need to be careful and to monitor patients' symptomatic changes after prescription of dopamine agonists. The intriguing point in our case is that the onset of hallucinations started after increasing the dose of ropinirole to 6 mg/day and disappeared upon reducing the dose to 4 mg/day. This suggests that ropinirole may have a dose-dependent propensity for inducing psychotic symptoms. Positron emission tomography (PET) studies have shown that the differential occupancy of antipsychotics on dopamine (D)-2 receptors may determine clinical efficacy and side effect profile in the treatment of schizophrenia (Seeman, 2006). Hence we may inversely assume that the differential dose-effect of the D-2 agonist ropinirole might determine its potential to provoke brief psychotic symptoms, particularly in susceptible individuals. In fact a significant correlation between the D-2 density (Bmax) values and severity of psychotic symptoms has been demonstrated in PET studies with drug-naïve bipolar psychotic patients (Pearlson et al., 1995). The previous report of psychosis induced by ropinirole involved a patient with a family history of schizophrenia. Our case does not share such a family history. However, it is plausible that nonpsychotic individuals vary in their susceptibility to induced psychosis, perhaps in relationship to their sensitivity to dopamine agonism. Our case suggests that ropinirole augmentation of antidepressants should be carefully monitored and tailored based on individuals' potential vulnerability. Acknowledgements Dr. Pae has received research grant from GlaxoSmithKline Korea, GlaxoSmithKline, AstraZeneca Korea, Jansssen Pharmaceutcals Korea, Eli Lilly and Company Korea, Korean Research Foundation, Otsuka Korea, Wyeth Korea, and Korean Institute of Science and Technology Evaluation and Planning; has received honoraria and is on the speaker's bureaus of GlaxoSmithKline Korea, Lundbeck Korea, AstraZeneca Korea, Jansssen Pharmaceutcals Korea, Eli Lilly and Company Korea, McNeil Consumer and Specialty Inc, and Otsuka Korea. Dr. Han
1088
Letter to the Editor (Case report)
has received research support from Korea Research Foundation Grant (MOEHRD) (KRF-2007-013-E00033) and from Korea University Neuropsychiatric Alumni Grant. Dr. Marks has no financial disclosures. Dr. Patkar is a consultant for Bristol-Myers Squibb, GlaxoSmithKline, and Reckitt Benckiser; is on the speaker's bureau of Bristol-Myers Squibb, GlaxoSmithKline, and Reckitt Benckiser; has received research support from National Institutes of Health, AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, McNeil Consumer and Specialty Inc, Organon, Jazz Pharmaceuticals, and Pfizer. References Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry 2007;68:1230–6. Cassano P, Lattanzi L, Fava M, Navari S, Battistini G, Abelli M, et al. Ropinirole in treatment-resistant depression: a 16-week pilot study. Can J Psychiatry 2005;50: 357–60. Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, et al. Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety 2004;20: 131–8. Dhir A, Kulkarni SK. Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist. Brain Res Bull 2007;74:58–65. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebocontrolled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004;161:564–6. Pearlson GD, Wong DF, Tune LE, Ross CA, Chase GA, Links JM, et al. In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch Gen Psychiatry 1995;52:471–7. Perea E, Robbins BV, Hutto B. Psychosis related to ropinirole. Am J Psychiatry 2006;163: 547–8.
Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 2001;34:137–41. Schrag AE, Brooks DJ, Brunt E, Fuell D, Korczyn A, Poewe W, et al. The safety of ropinirole, a selective nonergoline dopamine agonist, in patients with Parkinson's disease. Clin Neuropharmacol 1998;21:169–75. Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 2006;10:515–31. Szegedi A, Hillert A, Wetzel H, Klieser E, Gaebel W, Benkert O. Pramipexole, a dopamine agonist, in major deoression: antidepressant effects and tolerability in an openlable study with multiple doses. Clin Neuropharmacol 1997;20:236–45.
Chi-Un Pae* David M. Marks Changsu Han Ashwin A. Patkar Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA *Corresponding author. Department of Psychiatry, Kangnam St. Mary's Hospital, The Catholic University of Korea, College of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Korea. Tel.: +82 2 590 2780; fax: +82 2 6442 2789. E-mail address: [email protected]. Changsu Han Department of Psychiatry Korea University, College of Medicine, Seoul, South Korea 1 February 2008
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report) A case of transient hallucination with ropinirole augmentation antidepressant in a patient with treatment-resistant depression: Is there differential effect of ropinirole dose on developing psychotic symptom?
Sir: Ropinirole has been shown to have antidepressant actions, presumably via D2/D3 receptor agonist effects which in turn modulate serotonergic and sigma receptor activity (Dhir and Kulkarni, 2007). A recent report provided the first case of acute psychosis in a patient who was treated with ropinirole for restless legs syndrome: the patient developed paranoid delusions, auditory/visual hallucinations, and thought process disorganization within a week after initiating ropinirole. Her psychotic symptoms substantially improved or resolved within a few days of discontinuing ropinirole, although treatment was simultaneously initiated with quetiapine and citalopram (Perea et al., 2006). In an earlier controlled clinical trial for Parkinson's disease, ropinirole was found to be associated with mild hallucinations as well (Schrag et al., 1998). Given the etiological relationship between enhanced dopaminergic function and psychotic symptoms (particularly demonstrated by consistent efficacy of currently available antipsychotics having dopamine antagonistic properties), exacerbation or onset of psychosis by a dopamine agonist appears to be predictable. However, to our knowledge, there have been no case reports of the development of psychotic symptoms in relation to ropinirole augmentation with antidepressants in the treatment of major depressive disorder. Ms. A was a 58-year-old woman without a family history of any psychiatric disorders who presented with an approximately 10-year history of major depressive disorder and dysthymic disorder. She had no clinically significant comorbid medical conditions. Her depressive symptoms were moderate without psychotic features, and they included anhedonia such that Ms. A withdrew from social interaction and had no meaningful interpersonal relationships. She had been compliant with fluoxetine, and at her intake appointment with the undersigned it was felt that she might benefit from antidepressant augmentation. Ropinirol was initiated at 2 mg/day and up-titrated to 4 mg/day within 4 weeks. Tolerability issues were not reported. Ms. A's depressive symptoms responded well, and in particular her social interaction and motivation dramatically improved. According to her subjective report, she felt improvement by 60% after a month of ropinirole treatment. At week 6, ropinirole was increased to 6 mg/day to target residual depressive symptoms. She subsequently began to experience visual hallucinations of her deceased mother which began 2 days after the increase in her ropinirole dose to 6 mg/day; these hallucinations occurred 3 times in the week following her dose increase, and they resolved completely after her ropinirole dose was decreased back to 4 mg/day. Her depressive symptoms remained markedly improved compared to prior to the initiation of ropinirole augmentation. 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.02.011
To date there have been no systematic controlled clinical trials of ropinirole for augmentation treatment of depression, although several open-label pilot or retrospective studies have demonstrated the benefit of ropinirole for treating treatment-resistant depression and bipolar II depression (Cassano et al., 2005; Perugi et al., 2001). Meanwhile two previous studies investigating the augmentation effect of another dopamine agonist, pramipexol, reported the development of psychosis in patients with mood disorder (Goldberg et al., 2004; Szegedi et al., 1997), in which one study found the resolution of psychotic symptoms with dose reduction (Szegedi et al., 1997). In addition, a recent review(Aiken, 2007) also advised the risk to develop psychotic symptoms in both Parkinson's disease and mood disorders when prescribing pramipexol. In a longer-term study (48 weeks) with pramipexol, it was associated with the development of psychotic symptom along with conversion to mania in two patients, indicating a possibility of late development of psychotic symptom after augmentation of pramipexol (Cassano et al., 2004). These previous literatures are largely similar to our case report in that clinicians need to be careful and to monitor patients' symptomatic changes after prescription of dopamine agonists. The intriguing point in our case is that the onset of hallucinations started after increasing the dose of ropinirole to 6 mg/day and disappeared upon reducing the dose to 4 mg/day. This suggests that ropinirole may have a dose-dependent propensity for inducing psychotic symptoms. Positron emission tomography (PET) studies have shown that the differential occupancy of antipsychotics on dopamine (D)-2 receptors may determine clinical efficacy and side effect profile in the treatment of schizophrenia (Seeman, 2006). Hence we may inversely assume that the differential dose-effect of the D-2 agonist ropinirole might determine its potential to provoke brief psychotic symptoms, particularly in susceptible individuals. In fact a significant correlation between the D-2 density (Bmax) values and severity of psychotic symptoms has been demonstrated in PET studies with drug-naïve bipolar psychotic patients (Pearlson et al., 1995). The previous report of psychosis induced by ropinirole involved a patient with a family history of schizophrenia. Our case does not share such a family history. However, it is plausible that nonpsychotic individuals vary in their susceptibility to induced psychosis, perhaps in relationship to their sensitivity to dopamine agonism. Our case suggests that ropinirole augmentation of antidepressants should be carefully monitored and tailored based on individuals' potential vulnerability. Acknowledgements Dr. Pae has received research grant from GlaxoSmithKline Korea, GlaxoSmithKline, AstraZeneca Korea, Jansssen Pharmaceutcals Korea, Eli Lilly and Company Korea, Korean Research Foundation, Otsuka Korea, Wyeth Korea, and Korean Institute of Science and Technology Evaluation and Planning; has received honoraria and is on the speaker's bureaus of GlaxoSmithKline Korea, Lundbeck Korea, AstraZeneca Korea, Jansssen Pharmaceutcals Korea, Eli Lilly and Company Korea, McNeil Consumer and Specialty Inc, and Otsuka Korea. Dr. Han
1088
Letter to the Editor (Case report)
has received research support from Korea Research Foundation Grant (MOEHRD) (KRF-2007-013-E00033) and from Korea University Neuropsychiatric Alumni Grant. Dr. Marks has no financial disclosures. Dr. Patkar is a consultant for Bristol-Myers Squibb, GlaxoSmithKline, and Reckitt Benckiser; is on the speaker's bureau of Bristol-Myers Squibb, GlaxoSmithKline, and Reckitt Benckiser; has received research support from National Institutes of Health, AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, McNeil Consumer and Specialty Inc, Organon, Jazz Pharmaceuticals, and Pfizer. References Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry 2007;68:1230–6. Cassano P, Lattanzi L, Fava M, Navari S, Battistini G, Abelli M, et al. Ropinirole in treatment-resistant depression: a 16-week pilot study. Can J Psychiatry 2005;50: 357–60. Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, et al. Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety 2004;20: 131–8. Dhir A, Kulkarni SK. Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist. Brain Res Bull 2007;74:58–65. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebocontrolled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004;161:564–6. Pearlson GD, Wong DF, Tune LE, Ross CA, Chase GA, Links JM, et al. In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch Gen Psychiatry 1995;52:471–7. Perea E, Robbins BV, Hutto B. Psychosis related to ropinirole. Am J Psychiatry 2006;163: 547–8.
Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 2001;34:137–41. Schrag AE, Brooks DJ, Brunt E, Fuell D, Korczyn A, Poewe W, et al. The safety of ropinirole, a selective nonergoline dopamine agonist, in patients with Parkinson's disease. Clin Neuropharmacol 1998;21:169–75. Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 2006;10:515–31. Szegedi A, Hillert A, Wetzel H, Klieser E, Gaebel W, Benkert O. Pramipexole, a dopamine agonist, in major deoression: antidepressant effects and tolerability in an openlable study with multiple doses. Clin Neuropharmacol 1997;20:236–45.
Chi-Un Pae* David M. Marks Changsu Han Ashwin A. Patkar Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA *Corresponding author. Department of Psychiatry, Kangnam St. Mary's Hospital, The Catholic University of Korea, College of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Korea. Tel.: +82 2 590 2780; fax: +82 2 6442 2789. E-mail address: [email protected]. Changsu Han Department of Psychiatry Korea University, College of Medicine, Seoul, South Korea 1 February 2008