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1 Blackwell Publishing AsiaMelbourne, AustraliaPCNPsychiatry and Clinical Neurosciences Folia Publishing SocietyJune Short CommunicationAdd-on risperidone in OCDR. Yoshimura et al. Psychiatry and Clinical Neurosciences (2006), 60, doi: /j x Short Communication Successful treatment for obsessive-compulsive disorder with addition of low-dose risperidone to fluvoxamine: Implications for plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor levels REIJI YOSHIMURA, MD, phd, SACHIKO KANEKO, MD, KOJI SHINKAI, MD, phd AND JUN NAKAMURA, MD, phd Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan Abstract The authors report on the successful treatment of obsessive-compulsive disorder (OCD) in three patients with the addition of risperidone to ongoing fluvoxamine treatment. Plasma homovanillic acid (HVA), but not 3-methoxy-4-hydroxyphenylglycol (MHPG) levels decreased after risperidone administration, and plasma levels of fluvoxamine did not change. In addition, serum brainderived neurotrophic factor (BDNF) levels were not altered after the recovery from obsessivecompulsive symptoms, indicating that serum BDNF levels might not predict the patient s response to risperidone treatment. Taken together, a combination treatment of risperdone and fluvoxamine might improve obsessive-compulsive symptoms. In short, fluvoxamine enhances the activity of the serotonergic system by inhibiting serotonin transporters, and risperidone decreases that of the dopaminergic system by blocking D 2 receptors. Key words brain-derived neurotrophic factor (BDNF), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), obsessive-compulsive disorder, risperidone. INTRODUCTION The efficacy of serotonin re-uptake inhibitors (SRI) has been established in controlled studies in patients with obsessive-compulsive disorder (OCD). 1 However, 40 60% of OCD patients seem to be refractory to SRI monotherapy. 2 In such cases, lithium, 3,4 buspirone 5 and pindolol 6 are added to ongoing treatment with SRI. Augmentation of antipsychotic drugs such as haloperidol 7 and pimozide 8 to SRI is also effective, especially in patients with a comorbid schizotypal personality disorder. McDougle et al. report three cases of Correspondence address: Reiji Yoshimura, MD, PhD, Department of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka , Japan. yoshi621@med.uoeh-u.ac.jp Received 19 July 2005; revised 14 November 2005; accepted 20 November fluvoxamine-refractory OCD responsive to risperidone with ongoing fluvoxamine treatment. 9 Moreover, Erzegovesi et al. recently carried out a double-blind, placebo-controlled study in which they found that even very low (0.5 mg) doses of risperidone are effective in OCD patients who are non-responders to fluvoxamine treatment. 10 However, the pharmacological mechanisms of the combination treatment of risperidone and fluvoxamine for ameliorating OCD symptoms still remain unknown. Here we present the cases of three OCD patients who were successfully treated with the addition of low doses of risperidone to fluvoxamine. We also analyzed plasma levels of fluvoxamine, catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and serum levels of brainderived neurotrophic factor (BDNF) in each case. All blood samples were taken at 7:00 am before breakfast (at least 12 h after the last medication), just before

2 390 R. Yoshimura et al. and 2 weeks after the risperidone administration. Fifteen milliliters of venous blood was drawn with the patient in the supine position, after the patient had been lying at rest overnight. The plasma samples were quickly separated in a centrifuge (2000 g, 10 min, 4 C) and stored at 80 C until assay. Plasma levels of MHPG and HVA were analyzed by high-performance liquid chromatography (HPLC) as previously described. 11 The plasma level of fluvoxamine was also measured by HPLC according to van der Meersch Mougeot and Diquet. 12 The intra-assay and interassay coefficients of variation were 3% and 5% with respect to the assay for HVA, MHPG, and fluvoxamine, respectively. Serum BDNF levels were measured using the BDNF Emax Immunoassay System Kit (Promega, Madison, WI, USA) according to the manufacturer s instructions. Intra- and interassay coefficients of variation were 5% and 7%, respectively. The protocol of the present study was approved by the Ethics Committee of the University of Occupational Environmental Health. Written informed consent was obtained from all subjects. CASE REPORTS Case 1 Ms A, a 30-year-old woman, after she had trouble in her engagement, developed primary obsessive-compulsive symptoms consisting of contamination and sexual obsessions, that is, she was afraid of having AIDS and being pregnant after she went to a toilet, and had repeating and washing compulsions. She was treated subsequently with sulpiride 400 mg/day, haloperidol 3 mg/day, clomipramine 150 mg/day, and clomipramine 150 mg/day plus lithium 400 mg/day, but her obsessivecompulsive symptoms persisted without significant improvement. She was started on fluvoxamine from 50 mg/day and gradually increased to 300 mg/day, and she was maintained on the same dosage for 3 months but her obsessive-compulsive symptoms still did not improve (Yale Brown Obsessive Compulsive Scale [Y- BOCS] score: 24 points). Then, risperidone 1 mg/day was added to fluvoxamine 300 mg/day, and within 2 weeks her obsessive-compulsive symptoms markedly improved (Y-BOCS score: 9 point). No extrapyramidal side-effects were seen after risperidone augmentation. In this case, plasma fluvoxamine levels (fluvoxamine 300 mg/day) before and 2 weeks after risperidone addition (1 mg/day) were 198 ng/ml and 210 ng/ml, respectively. Plasma levels of MHPG and HVA before and 2 weeks after risperidone addition were 4.8 ng/ml (MHPG), 7.1 ng/ml (HVA) and 5.1 ng/ml (MHPG), 5.8 ng/ml (HVA), respectively. Serum BDNF levels before and 2 weeks after risperidone addition were 22 ng/ml and 24 ng/ml, respectively. Case 2 Ms B, a 31-year-old woman, first experienced obsessive-compulsive symptoms consisting of sexual and contamination obsessions as well as obsessions about her appearance, that is, she was afraid that her nose hair extended out under her nose, and began washing and checking her face in the mirror, and pulling out her nose hair at the age of 25 years. Before presenting to the University Hospital in University of Occupational and Environmental Health for treatment, she had received clomipramine up to 200 mg/day, and clomipramine 200 mg/day plus haloperidol 1.5 mg/day, but her obsessive-compulsive symptoms remained unchanged. Subsequently, she was treated with fluvoxamine up to 300 mg/day for 4 months without marked improvement of her obsessive-compulsive symptoms (Y-BOCS score, 20 points). Risperidone liquid 0.5 mg/ day was then added to the ongoing fluvoxamine 300 mg/day. After 1 week of risperidone augmentation, the patient s obsessive-compulsive symptoms dramatically improved (Y-BOCS score, 5 points), and no extrapyramidal symptoms were found after risperidone addition. In this case, the patient s plasma levels of fluvoxamine (300 mg/day) before and 2 weeks after risperidone augmentation were 242 ng/ml and 227 ng/ ml, respectively; plasma levels of MHPG and HVA before and 2 weeks after risperidone augmentation were 7.4 ng/ml (MHPG), 6.9 ng/ml (HVA) and 7.0 ng/ml (MHPG), 5.2 ng/ml (HVA), respectively; and serum BDNF levels before and 2 weeks after risperidone augmentation were 18 ng/ml and 21 ng/ml, respectively. Case 3 Mr C, a 42-year-old man, first experienced obsessivecompulsive symptoms at the age of 30 years. After he had suffered a traffic accident he was afraid of hitting people with his car, and he repeatedly stopped his car to check around it. He was given amoxapine 150 mg/ day, amoxapine 150 plus lithium 600 mg/day, and haloperidol 1.5 mg/day, but his obsessive-compulsive symptoms were not reduced. He was subsequently started with fluvoxamine, which was gradually increased up to 300 mg/day for 4 months with no marked improvement of his obsessive-compulsive symptoms (Y-BOCS score, 18 points). Therefore, risperidone 1 mg/day was added to the ongoing fluvoxamine treatment. After 2 weeks of risperidone addition, the patient s obsessive-compulsive symptoms improved markedly (Y-BOCS score,

3 Add-on risperidone in OCD points). No extrapyramidal symptoms were found after risperidone addition. In this case, the patient s plasma levels of fluvoxamine (300 mg/day) before and 2 weeks after risperidone addition were 188 ng/ml and 199 ng/ml, respectively; plasma levels of MHPG and HVA before and 2 weeks after risperidone addition were 4.9 ng/ml (MHPG), 6.1 ng/ml (HVA) and 5.2 ng/ml (MHPG), 4.8 ng/ml (HVA), respectively; and serum BDNF levels before and 2 weeks after risperidone addition were 29 ng/ml and 26 ng/ml, respectively. DISCUSSION Low doses of risperidone (0.5 1 mg/day) were found to result in a robust improvement in obsessive-compulsive symptoms without evidence of extrapyramidal symptoms or other significant adverse events in all three cases. Several open-label studies have demonstrated that the administration of risperidone in SRIrefractory OCD patients brings about significant improvement of obsessive-compulsive symptoms Additionally, a double-blind placebo-controlled study performed by McDougle et al. 15 reconfirmed the results of these open-label studies. Erzegovesi et al. performed a double-blind, placebo-controlled study and concluded that very low risperidone doses (0.5 mg/day) are effective in OCD patients who are non-responders to a standardized treatment with fluvoxamine. 10 The present three cases are thus consistent with the previous reports, which demonstrated the efficacy of an add-on risperidone treatment to ongoing fluvoxamine. We measured plasma levels of catecholamine metabolites. Plasma levels of HVA were found to decrease, but plasma MHPG levels did not change before and 2 weeks after risperidone administration. Benkelfat et al. report that no difference was found in mean plasma concentrations of MHPG and HVA between OCD patients and normal controls. 16 Thoren et al. measured cerebrospinal fluid (CSF) levels of MHPG and HVA before and 3 weeks after clomipramine treatment, but found no change. 17 Swedo et al. examined CSF levels of HVA and found that they were not significantly related to OCD symptoms and did not correlate with improvement following 5 weeks of treatment with clomipramine, suggesting that the role of catecholamine metabolites in OCD patients, for the most part, yields no evidence for an abnormal dopamine and/or norepinephrine function in OCD. 18 Our results were similar to those in the previous reports regarding MHPG levels. In contrast, plasma HVA levels decreased to some extent after risperidone administration, suggesting that decreased dopaminergic activity by risperidone is in part associated with the improvement of obsessive-compulsive symptoms. In the present study, however, we demonstrated that plasma levels of HVA decreased 2 weeks after addition of low-dose risperidone (0.5 1 mg) in three patients. These results suggest that a low dosage of risperidone (0.5 1 mg) is enough to change plasma levels of HVA in OCD patients. In other words, it might not be necessary to occupy a large number of D 2 receptors in order to reduce plasma levels of HVA. In addition, effects of serotonergic neurons on dopaminergic neurons may influence plasma HVA levels to some extent. It is hard to clarify whether decreasing HVA is related to the improvement of the OCD symptoms or to non-specific effects of risperidone on dopaminergic neurons. It is suggested that the D 2 receptor antagonism reduces obsessive-compulsive symptoms through the inhibition of the dopamine neurons. 19 Enhancement of the serotonergic neurotransmission via inhibition of the serotonin transporter by fluvoxamine and the decreasing activity of the dopaminergic system via the blocking of the D 2 receptor by risperidone may be involved in improving obsessive-compulsive symptoms. Our results demonstrate that plasma levels of fluvoxamine do not change before and 2 weeks after risperidone addition, indicating that the efficacy of low-dose risperidone addition is unlikely to be due to pharmacokinetic interactions. Indeed, experimental pharmacology data show a different cytochrome P450 metabolism for fluvoxamine (CYP1A2) and risperidone (CYP2D6, CYP3A4). 11,20 22 We also measured serum BDNF levels in each patient, and found no change after risperidone treatment. Dysregulation of serotonergic neurons might be involved in the pathophysiology of depression as well as OCD, and comorbidity exists between OCD and depression. 23 Karege et al. reported that serum BDNF levels were significantly decreased in antidepressantfree depressed patients, and that serum BDNF levels were negatively correlated with scores of Montgomery-Åsberg Depression Rating Scale. 24 Shimizu et al. also demonstrated that serum BDNF was significantly lower in an antidepressant-naïve group than in either a treated or in a control group, and that there was a significant negative correlation between serum BDNF and scores of Hamilton Rating Scale for Depression (Ham-D) in all patients. 25 In the present cases, no patients were comorbid with a depressive state at the time of serum BDNF measurement, which might be associated with the finding of no change in BDNF levels. In any case, these results indicate that serum BDNF level is not a predictor for response to risperidone treatment.

4 392 R. Yoshimura et al. It is not plausible that the fluvoxamine or the risperidone alone, rather than the combination of drugs, led to the improvement, because all three patients had been taking fluvoxamine for more than 3 months without significant improvement in their obsessive-compulsive symptoms. In addition, there have been numerous case reports demonstrating that risperidone monotherapy induces or exacerbates obsessive-compulsive symptoms. 26 Therefore, it is reasonable to believe that it was the combination therapy of fluvoxamine and risperidone that brought about the improvement in obsessive-compulsive symptoms. ACKNOWLEDGMENTS The authors gratefully thank Professor Kenji Hashimoto (Center for Forensic Mental Health, Ciba University, Division of Clinical Neurosciences) and Professor Masaomi Iyo (Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan) for instruction in the method of analyzing serum BDNF levels. REFERENCES 1. McDougle CJ, Goodman WK, Leckman JF. The psychopharmacology of obsessive-compulsive disorder: implications for treatment and pathogenesis. In: Dunner DL (ed.). Psychiatric Clinics of North America, Vol. 16, 4th edn. Saunders, Philadelphia, PA, 1993; Erzegovesi S, Cavallini MC, Cavadini P, Diaferia G, Locatelli Bellodi L. Clinical predictors of drugs response in obsessive-compulsive disorder. J. Clin. Psychopharmacol. 2001; 21: McDougle CJ, Price LH, Goodman WK, Charney DS, Heninger GR. A controlled clinical trial of lithium augmentation in fluvoxamine refractory obsessive-compulsive disorder: lack of efficacy. J. Clin. Psychopharmacol. 1991; 11: Pigott TA, Pato MT, L Heureux F et al. A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine treated patients with obsessive-compulsive disorder. J. Clin. Psychopharmacol. 1991; 11: Pigott TA, L Heureux F, Hill JL, Bihari K, Bernstein SE, Murphy DL. A double blind study of adjuvant buspirone hydrochloride in clomipramine treated patients with obsessive-compulsive disorder. J. Clin. Psychopharmacol. 1992; 12: Mundo E, Guglielmo E, Bellodi L. Effect of adjuvant pindolol on the antiobsessional response to fluvoxamine: a double-blind, placebo-controlled study. Int. Clin. Psychopharmacol. 1998; 13: McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH. Haloperidol addition in fluvoxamine-refractory obsessive compulsive disorder: a double-blind, placebo-controlled study in patients with and without tics. Arch. Gen. Psychiatry 1994; 51: McDougle CJ, Goodman WK, Price LH et al. Neuroleptic addition in fluvoxamine-refractory obsessive compulsive disorder. Am. J. Psychiatry 1990; 147: McDougle CJ, Fleishmann RL, Epperson CN, Wasylink S, Leckman JF, Price LH. Risperidone addition in fluvoxamine-refractory obsessive-compulsive disorder: three cases. J. Clin. Psychiatry 1995; 56: Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a doubleblind, placebo-controlled study. Eur. Neuropsychopharmacol. 2005; 15: Kakihara S, Yoshimura R, Shinkai K et al. Prediction of response to risperidone treatment with respect to plasma concentrations of risperdone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int. Clin. Psychopharmacol. 2005; 20: van der Meersch-Mougeot V, Diquet B. Sensitive onestep extraction procedure for column liquid chromatographic determination of fluvoxamine in human and rat plasma. J. Chromatgr. 1991; 567: Jacobsen FM. Risperidone in the treatment of affective illness and obsessive-compulsive disorder. J. Clin. Psychiatry 1995; 56: Stein DJ, Bouwer C, Hawkridge S, Emsley RA. Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive disorder. J. Clin. Psychiatry 1997; 58: McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitorrefractory obsessive-compulsive disorder. Arch. Gen. Psychiatry 2000; 57: Benkelfat C, Mefford IN, Masters CF, Nordahl TE, King AC, Cohen RM. Plasma catecholamines and their metabolites in obsessive-compulsive disorder. Psychiatry Res. 1991; 37: Thoren P, Asberg M, Bertilsson L, Mellstrom B, Sjoquvist F, Traskman L. Clomipramine treatment of obsessive-compulsive disorder 2: biochemical aspects. Arch. Gen. Psychiatry 1980; 37: Swedo SE, Leonard HL, Kruesi MJ et al. Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder. Arch. Gen. Psychiatry 1992; 49: Denys D, Zohar J, Westenberg HG. The role of dopamine in obsessive-compulsive disorder. Preclinical and clinical evidence. J. Clin. Psychiatry 2004; 65 (Suppl. 14): Yoshimura R, Ueda N, Nakamura J. Low dosage of levomepromazine did not increase plasma concentrations of fluvoxamine. Int. Clin. Psychopharmacol. 2000; 15: DeVane CL, Nemeroff CB. An evaluation of risperdone drug interactions. J. Clin. Psychopharmacol. 2001; 21:

5 Add-on risperidone in OCD Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo MG, Tybring G. Different enantioselective 9- hydroxyrisperidone of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab. Dispos. 2001; 29: Hollander E, Simeon D, Gorman JM. Anxiety disorders. In: Hales RE, Yudofsky SC, Talbott JA (eds). Textbook of Psychiatry, 3rd edn. American Psychiatric Press, Washington DC, 1999; Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002; 109: Shimizu E, Hashimoto K, Okamura N et al. Alternations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 2003; 54: Sareen J, Kirshner A, Lander M, Kjernisted KD, Eleff MK, Reiss JP. Do antipsychotics ameliorate or exacerbate obsessive compulsive disorder symptoms? A systematic review. J. Affect. Disord. 2004; 82: