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Associations between side effects of nemonapride and plasma concentrations of the drug and prolactin
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 287 – 291
Associations between side effects of nemonapride and plasma concentrations of the drug and prolactin Tsuyoshi Kondo*, Masayuki Ishida, Noboru Tokinaga, Kazuo Mihara, Norio Yasui-Furukori, Shingo Ono, Sunao Kaneko Department of Neuropsychiatry, Hirosaki University Hospital, Hirosaki 036-8562, Japan
Abstract Associations between neuroleptic side effects and plasma concentrations of the drug and prolactin were investigated in 33 acutely exacerbated schizophrenic patients (16 males and 17 females) treated with a fixed dose of nemonapride (18 mg/day), a new substituted benzamide, for 3 weeks. The most frequently observed side effects during nemonapride treatment were extrapyramidal symptoms such as akathisia (69.7%), dystonia (48.5%), hypokinesia (45.5%), tremor (39.4%) and increased salivation (36.4%). There were positive correlations between prolactin response and extrapyramidal side effects (EPS) scores after 1 week (Spearman rank correlation rs=.651, P < .01), 2 weeks (rs=.567, P < .05) and 3 weeks (rs=.670, P < .01) in male patients although no significant correlations were found in female or total patients. No significant correlations were found between plasma concentrations of the drug and total or any subscale side effects scores. The present study thus suggests that the spectrum of nemonapride-induced side effects is characterized by predominant extrapyramidal symptoms, and that prolactin response as an index of dopamine blockade reflects severity of EPS at least in male patients treated with nemonapride. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Nemonapride; Plasma drug concentrations; Prolactin; Side effects
1. Introduction Nemonapride, cis-N-(1-benzyl-2-methyl-3-pyrrolidinyl)5-chloro-2-methoxy-4-methyl aminobenzamide, is a new substituted benzamide neuroleptic developed in Japan. This drug has selective and potent antagonistic effects for dopamine D2-like receptors such as D2, D3 and D4 whereas it has very weak affinity for other receptors of such neurotransmitters as dopamine D1, 5-HT2, noradrenaline and acetylcholine (Terai et al., 1989; Schotte et al., 1995). Daily doses recommended for clinical use are 9– 27 mg/day in the treatment of schizophrenia. Some studies (Mori et al., 1989; Satoh et al., 1996) have shown that nemonapride is effective in treating both positive and negative symptoms of schizophrenia. We also reported that nemonapride had a broad therapeutic spectrum in the treatment of acute schizophrenia, and that the improvement in positive and anxiety-
Abbreviations: EPS, extrapyramidal side effects; UKU, Udvalg for Kliniske Unders\ = gelser * Corresponding author. Tel.: +81-172-39-5066; fax: +81-172-395067.
depression symptoms were regarded as determinant factors for total response to this drug (Kondo et al., 2000). Meanwhile, our previous study showed that nemonapride treatment markedly increased prolactin concentrations in schizophrenic patients, demonstrating a strong D2 receptor blockade property of this drug (Otani et al., 1997). This finding together with the neuroleptic profiles of nemonapride suggest that side effects of nemonapride associated with dopamine blockade, e.g., extrapyramidal side effects (EPS), are primarily warned of. We previously reported the high incidence of acute dystonia during nemonapride treatment and the highest risk of this side effect in young male patients (Kondo et al., 1999). However, there is no comprehensive study on the precise spectrum and quantitative analysis of various side effects of nemonapride. Both plasma drug concentrations and prolactin response have been regarded as plausible markers for the prediction of side effects of some neuroleptics. Positive correlations between plasma concentrations of antipsychotic drugs and EPS have been shown in some studies (Wode-Helgodt et al., 1978; Bolvig Hansen and Larsen, 1985; Spina et al., 2000) but not in others (Papadopoulos et al., 1980; Volavoka et al., 1992). Likewise, it is still controversial whether positive
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correlations between prolactin concentrations and EPS exist during neuroleptic treatment (Kolakowska et al., 1979; Rao et al., 1980; Johnstone et al., 1983; Bartko et al., 1988). Therefore, the present study aimed to investigate the spectrum of side effects of nemonapride and its relationship with plasma concentrations of the drug and prolactin in schizophrenic patients receiving a fixed dose of nemonapride.
turbances, orthostatic dizziness, palpitation) side effects. The UKU scale has four scale steps according to the severity of side effects (0, absence; 1, mild; 2, moderate; 3, severe). A pretreatment score was subtracted from one obtained during treatment and was recorded as a drug-associated side effect. Thus, a symptom that occurred or was more exacerbated during treatment was defined as a side effect. 2.3. Assays for drug and prolactin
2. Methods 2.1. Subjects The subjects were 33 schizophrenic patients (16 males and 17 females), who fulfilled the DSM-III-R criteria (American Psychiatric Association, 1987) for schizophrenia (17 paranoid type, 1 catatonic type and 15 undifferentiated type). They suffered from first-time or recurrent episodes of schizophrenia, and all had received no oral or depot medication for at least 1 month. Among patients with recurrent episodes, various types and doses of neuroleptics were administered prior to nemonapride treatment, although no specific difference was found between those in male and female patients. The means (ranges) of age, body weight and duration of illness were 35.1 (17 – 58) years, 57.0 (38.0 – 88.7) kg and 68.8 (6 – 240) months, respectively. All patients were physically healthy, and none had any past history of substance abuse. This study was approved by the Ethics Committee of Hirosaki University Hospital, and written informed consent to participate in this study was obtained from the patients or their families. 2.2. Study design Nemonapride (Emilace, Yamanouchi Pharmaceutical, Tokyo, Japan) was administered in three equally divided doses at 0700, 1200 and 1800 h for 3 weeks. The daily dose of nemonapride was 18 mg, and was fixed during the 3-week study period. Intramuscular biperiden 5 – 10 mg was administered immediately after the development of acute dystonia, followed by oral biperiden 6 mg/day in 16 patients. The same dose of biperiden was also coadministered to other six patients who showed moderate to severe EPS other than acute dystonia. No other drugs were coadministered except for flunitrazepam 2– 4 mg/day for insomnia (17 patients) and sennnoside 12 – 24 mg/day for constipation (5 patients). Nineteen items were selected from the Udvalg for Kliniske Unders\ = gelser (UKU) side effects rating scale (Lingjaerde et al., 1987) and used for assessment of side effects. These items were divided into three subgroups: psychic (difficulties concentrating, asthenia, sleepiness, failing memory, depression, tension); extrapyramidal (dystonia, rigidity, hypokinesia, hyperkinesia, tremor, akathisia, increased salivation); and autonomic (accommodation disturbances, reduced salivation, constipation, micturition dis-
Blood samplings were performed before treatment and weekly during treatment, just before the morning dose. Plasma concentrations of nemonapride and desmethylnemonapride, which is a pharmacologically active metabolite and has one third of the potency of nemonapride in the inhibition of [3H]nemonapride binding (Terai et al., 1989), were determined in duplicate by a high-performance liquid chromatography method with solid-phase extraction (Nagasaki et al., 1998). Coefficients of variations for nemonapride and desmethylnemonapride were 7.2% and 10.3%, respectively. The limit of detection was 0.1 ng/ml for each compound. Plasma prolactin concentrations were measured in duplicate by enzyme immunoassay (IMX Prolactin Dainapack, Dainabot, Tokyo, Japan). The lowest limit of detection was 0.6 ng/ml, and interassay coefficients of variation were 3.7%, 3.5% and 3.5% at the concentrations of 8, 20 and 40 ng/ml for prolactin, respectively. 2.4. Statistical analyses Statistical analyses were performed by Wilcoxon rank sum test and Spearman rank test. A P value of .05 or less was regarded as statistically significant. SPSS 6.1J for Windows (SPSS Japan, Tokyo, Japan) was used for these statistical analyses.
3. Results Such factors as age, duration of illness, subtypes of schizophrenia and coadministered drugs did not affect either development of side effects of nemonapride or plasma concentrations of the drug and prolactin. There was no gender difference in occurrence of side effects except for the higher incidence of acute dystonia in males (12 out of 16 cases) than in females (4 out of 17 cases), which was more precisely reported in our previous study (Kondo et al., 1999). Frequent side effects throughout the 3-week nemonapride treatment were EPS such as akathisia (69.7%), dystonia (48.5%), hypokinesia (45.5%), tremor (39.4%) and increased salivation (36.4%). Regarding the time courses of side effects (Table 1), the incidences of EPS consistently increased during 3-week treatment except for dystonia, which was mainly observed in the initial phase of the treatment. In contrast, psychic and autonomic side effects
T. Kondo et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 287–291 Table 1 Occurrence (%) of side effects of nemonapride 1 Week
2 Weeks
3 Weeks
Psychic Asthenia Sleepiness Tension Failing memory Depression Difficulties concentrating
23.1 15.4 12.8 10.3 15.4 10.3
28.2 7.7 12.8 7.7 12.8 12.8
23.1 10.3 7.7 7.7 7.7 5.1
Extrapyramidal Akathisia Dystonia Hypokinesia Tremor Increased salivation Hyperkinesia
28.2 48.7 28.5 15.4 20.5 0
56.5 2.6 38.5 30.8 25.6 2.6
59.0 2.6 43.6 38.5 35.9 5.1
Autonomic Constipation Orthostatic dizziness Reduced salivation Palpitation Mictrurition disturbances Accommodation disturbances
12.8 12.8 5.1 12.8 0 0
10.3 12.8 5.1 0 0 0
7.7 5.1 2.6 0 0 0
were relatively infrequent, and the incidences gradually decreased throughout the study period (Table 1). Mean plasma concentrations of the drug (nemonapride plus desmethylnemonapride) during nemonapride treatment ranged from 0.2 to 2.1 ng/ml (mean ± S.D.: 0.7 ± 0.4 ng/ml) and the mean concentration of desmethylnemonapride was about 70% of that of nemonapride. There was no significant correlation between the plasma drug concentration and any
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subscale scores or items of side effects in male, female or total patients at any week. Mean plasma concentrations during nemonapride treatment did not significantly differ in subjects with and without EPS, i.e., 0.9 ± 0.5 ng/ml (n = 12) vs. 0.5 ± 0.1 ng/ml (n = 3) in males, 0.4 ± 0.1 ng/ml (n = 10) vs. 0.7 ± 0.4 ng/ml (n = 4) in females, and 0.7 ± 0.4 ng/ml (n = 22) vs. 0.6 ± 0.3 ng/ml (n = 7) in total patients. Prolactin response (Dprolactin) was estimated by the change in plasma prolactin concentration caused by nemonapride treatment. Female patients had the significantly higher (Wilcoxon rank sum test: P < .01) Dprolactin than male patients (71.4 ± 41.6 vs. 29.5 ± 18.4 ng/ml at 1 week, 82.7 ± 58.9 vs. 37.0 ± 23.2 ng/ml at 2 weeks, 82.6 ± 73.9 vs. 27.9 ± 18.2 ng/ml at 3 weeks). Accordingly, the relationships between weekly Dprolactin and side effects scores were analyzed separately in male and female patients. Significant correlations between weekly Dprolactin and EPS scores were found in male patients (Fig. 1: Spearman rank correlation: rs=.651, P < .01 at 1 week; rs=.567, P < .05 at 2 weeks; rs=.670, P < .01 at 3 weeks), while the correlations were not significant in female or total patients at any weeks. No significant relationships were found between Dprolactin and scores of psychic or autonomic side effects in total subjects or either gender group at any week.
4. Discussion 4.1. Side effect spectrum of nemonapride Side effects of nemonapride were characterized by high incidences of EPS in contrast to fewer psychic and auto-
Fig. 1. Relationships between weekly prolactin response (Dprolactin) and extrapyramidal side effect scores in 16 male schizophrenic patients. Significant correlations were observed (Spearman rank correlation: rs=.651, P < .01 at 1 week; rs=.567, P < .05 at 2 weeks; rs=.670, P < .01 at 3 weeks).
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nomic side effects. The spectrum of these side effects well reflect pharmacological profiles of nemonapride, i.e., potent antagonistic effects for dopamine D2-like receptors and weak affinities for other receptors for 5-HT2, noradrenaline and acetylcholine (Terai et al., 1989; Schotte et al., 1995). Therefore, the present study suggests that EPS should be mainly targeted as likely side effects during nemonapride treatment. 4.2. Time courses of side effects As shown in Table 1, EPS that should be warned of the most during the first week is acute dystonia while thereafter one should pay more attention to akathisia and parkinsonian symptoms during nemonapride treatment. Psychic and autonomic side effects were almost negligible after 3-week nemonapride treatment (Table 1). Thus, fewer sedative and anticholinergic side effects are regarded as an advantage of nemonapride because these side effects are frequently observed in the treatment with other neuroleptics that block multiple receptors (Kondo et al., 1994). 4.3. Relationship with drug concentrations Monitoring of plasma concentrations of antipsychotics would be useful for the prediction of side effects as well as therapeutic effects if strong correlations between plasma concentrations and side effects are consistent. Positive correlations between plasma concentrations of drugs and EPS have been shown in studies on chlorpromazine (WodeHelgodt et al., 1978), perphenazine (Bolvig Hansen and Larsen, 1985) and risperidone (Spina et al., 2000). On the other hand, no definite correlation was found in other studies on thioridazine (Papadopoulos et al., 1980) and haloperidol (Volavoka et al., 1992). To investigate the relationships between plasma drug concentrations and clinical effects precisely, pharmacologically active metabolites of the drug should be also taken into consideration. In the present study, a pharmacologically active moiety (nemonapride plus desmethylnemonapride) was regarded as plasma drug concentration. Nevertheless, no correlation was observed between plasma drug concentrations and total or any subscale side effects scores. Therefore, plasma drug concentration does not appear to be a useful marker for the prediction of side effects of nemonapride. 4.4. Relationship with prolactin response Meanwhile, several previous studies have focused on the relationship between prolactin response and EPS during neuroleptic treatment since the prolactin response to antipsychotic drugs is an index of their effects on dopamine activity (Rubin, 1987). Some of these reports pointed out that plasma prolactin concentrations were positively correlated to development of EPS (Kolakowska et al., 1979; Rao et al., 1980) while other reports showed no significant
correlation between prolactin response and EPS (Johnstone et al., 1983; Bartko et al., 1988). These conflicting results may be partly due to the heterogeneity of the subjects, e.g., gender difference in prolactin response to neuroleptic treatment, which was consistent with findings in previous studies (Harnryd et al., 1984; Linkowski et al., 1984). The present study also showed greater prolactin response to nemonapride in females than in males. This phenomenon may be ascribable to higher concentrations of estrogen in females than in males since estrogen stimulates prolactin response (Rubin, 1987) and may have a neuroleptic-enhancing property (Seeman and Lang, 1990). Therefore, we analyzed the relationship between prolactin response and side effects separately in male and female patients. Despite the greater and wider prolactin response in females, no correlations were observed between prolactin response and EPS scores. As a reason for the lack of the significant relationship, it is suggested that prolactin response in females does not simply reflect antidopaminergic effects of neuroleptics because prolactin response may be rather influenced by varied estrogen concentrations in females. On the other hand, prolactin response was significantly correlated to the severity of EPS in males, which was consistent throughout the study period (Fig. 1). Therefore, prolactin response may reflect vulnerability to the development of EPS at least in male patients treated with nemonapride. This finding together with the data on plasma drug concentrations suggest that pharmacodynamic factors rather than pharmacokinetic factors are more important to predict the development of nemonapride-induced EPS in male schizophrenic patients.
5. Conclusion The present study thus suggests that the spectrum of nemonapride-induced side effects is mainly characterized by EPS, and that prolactin response as an index of dopamine blockade reflects severity of EPS, at least in male patients treated with nemonapride.
Acknowledgments This study was supported by a grant from the Hirosaki Research Institute for Neurosciences.
References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R). American Psychiatric Association, Washington, DC. Bartko, G., Sztaniszlav, D., Olajos, S., Bekesy, M., 1988. Serum chlorpromazine and prolactin levels in paranoid schizophrenic patients and clinical response. Eur. J. Psychiatry, 109 – 117.
T. Kondo et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 287–291 Bolvig Hansen, L., Larsen, L.-E., 1985. Therapeutic advantages of monitoring plasma concentrations of perphenazine in clinical practice. Psychopharmacology 87, 16 – 19. Harnryd, C., Bjerkenstedt, L., Gullberg, B., Oxenstierna, G., Sedvall, G., Wiesel, F.-A., 1984. Time course for effects of sulpiride and chlorpromazine on monoamine metabolite and prolactin levels in cerebrospinal fluid from schizophrenic patients. Acta Psychiatr. Scand. 69 (Suppl. 311), 75 – 92. Johnstone, E.C., Crow, T.M., Frith, C.D., Owens, D.G.C., 1983. Adverse effects of anticholinergic medication in positive schizophrenic symptoms: theoretical and practical considerations. Psychol. Med. 13, 513 – 527. Kolakowska, T., Orr, M., Gelder, M., Heggie, M., Wiles, D., Franklin, M., 1979. Clinical significance of plasma drug and prolactin levels during acute chlorpromazine treatment: a replication study. Br. J. Psychiatry 135, 352 – 359. Kondo, T., Otani, K., Ishida, M., Tanaka, O., Kaneko, S., Fukushima, Y., 1994. Adverse effects of zotepine and their relationship to serum concentrations of the drugs and prolactin. Ther. Drug Monit. 16, 120 – 124. Kondo, T., Otani, K., Tokinaga, N., Ishida, M., Yasui, N., Kaneko, S., 1999. Characteristics and risk factors of acute dystonia in schizophrenic patients treated with nemonapride, a selective dopamine antagonist. J. Clin. Psychopharmacol. 19, 45 – 50. Kondo, T., Mihara, K., Yasui, N., Nagashima, U., Ono, S., Kaneko, S., Ohkubo, T., Osanai, T., Sugawara, K., Otani, K., 2000. Therapeutic spectrum of nemonapride and its relationship with plasma concentrations of the drug and prolactin. J. Clin. Psychopharmacol. 20, 404 – 409. Lingjaerde, O., Ahlfors, U.G., Bech, P., Dencker, S.J., Elgen, K., 1987. The UKU side effect rating scale. Acta. Psychiatr. Scand. 76 (Suppl. 334), 11 – 100. Linkowski, P., Hubain, P., Von Frenckell, R., Mendlewicz, J., 1984. Haloperidol plasma levels and clinical response in paranoid schizophrenics. Eur. Arch. Psychiat. Neurol. Sci. 234, 231 – 236. Mori, A., Kazamatsuri, H., Kaneko, S., Kamijima, K., Kariya, T., Murasaki, M., Yagi, G., 1989. A double-blind comparison of a new benzamide compound YM-09151 with haloperidol in the treatment of schizophrenia. Clin. Eval. 17, 349 – 377 (in Japanese, abstract in English). Nagasaki, T., Ohkubo, T., Sugawara, K., Yasui, N., Otani, K., Kaneko, S., 1998. High-performance liquid chromatographic determination of nem-
291
onapride and desmethylnemonapride in human plasma using an electrochemical detection. J. Chromatogr., B 714, 293 – 298. Otani, K., Kondo, T., Yasui, N., Suzuki, A., Furukori, H., Kaneko, S., Ohkubo, T., Nagasaki, T., Sugawara, K., Hayashi, K., 1997. Prolactin response to nemonapride, a new antipsychotic drug, in schizophrenic patients. Hum. Psychopharmacol. 12, 591 – 594. Papadopoulos, A.S., Chand, T.G., Crammer, J.L., Lader, S., 1980. A pilot study of plasma thioridazine and metabolites in chronically treated patients. Br. J. Psychiatry 136, 591 – 596. Rao, V.A.R., Bishop, M., Coppen, A., 1980. Clinical state, plasma levels of haloperidol and prolactin: a correlation study in chronic schizophrenia. Br. J. Psychiatry 137, 518 – 521. Rubin, R.T., 1987. Prolactin and schizophrenia. In: Meltzer, H.Y. (Ed.), Psychopharmacology, 3rd Generation of Progress. Raven Press, New York, pp. 803 – 808. Satoh, K., Someya, T., Shibasaki, M., 1996. Effects of nemonapride on positive and negative symptoms of schizophrenia. Int. Clin. Psychopharmacol. 11, 279 – 281. Schotte, A., Bonaventure, P., Janssen, P.F.M., Leysen, J.E., 1995. In vitro receptor binding and in vivo receptor occupancy in rat and guinea pig brain: risperidone compared with antipsychotics hitherto used. Jpn. J. Pharmacol. 69, 399 – 412. Seeman, M.V., Lang, M., 1990. The role of estrogens in schizophrenia gender differences. Schizophr. Bull. 16, 185 – 194. Spina, E., Avenoso, A., Facciola, G., Salemi, M., Scordo, M.G., Ancione, M., Madia, A.G., Perucca, E., 2000. Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology 153, 238 – 243. Terai, M., Hidaka, K., Nakamura, Y., 1989. Comparison of [3H] YM09151-2 with [3H] spiperone and [3H] raclopride for dopamine D-2 receptor binding to rat striatum. Eur. J. Pharmacol. 173, 177 – 182. Volavoka, J., Cooper, T., Czobor, P., Bitter, I., Meisner, M., Laska, E., Gastanaga, P., Krakowski, M., Chou, J.C.Y., Crowner, M., Douyon, R., 1992. Haloperidol blood levels and clinical effects. Arch. Gen. Psychiatry 49, 354 – 361. Wode-Helgodt, B., Borg, S., Fyro, B., Sedvall, G., 1978. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Acta Psychiatr. Scand. 58, 149 – 173.
Associations between side effects of nemonapride and plasma concentrations of the drug and prolactin Tsuyoshi Kondo*, Masayuki Ishida, Noboru Tokinaga, Kazuo Mihara, Norio Yasui-Furukori, Shingo Ono, Sunao Kaneko Department of Neuropsychiatry, Hirosaki University Hospital, Hirosaki 036-8562, Japan
Abstract Associations between neuroleptic side effects and plasma concentrations of the drug and prolactin were investigated in 33 acutely exacerbated schizophrenic patients (16 males and 17 females) treated with a fixed dose of nemonapride (18 mg/day), a new substituted benzamide, for 3 weeks. The most frequently observed side effects during nemonapride treatment were extrapyramidal symptoms such as akathisia (69.7%), dystonia (48.5%), hypokinesia (45.5%), tremor (39.4%) and increased salivation (36.4%). There were positive correlations between prolactin response and extrapyramidal side effects (EPS) scores after 1 week (Spearman rank correlation rs=.651, P < .01), 2 weeks (rs=.567, P < .05) and 3 weeks (rs=.670, P < .01) in male patients although no significant correlations were found in female or total patients. No significant correlations were found between plasma concentrations of the drug and total or any subscale side effects scores. The present study thus suggests that the spectrum of nemonapride-induced side effects is characterized by predominant extrapyramidal symptoms, and that prolactin response as an index of dopamine blockade reflects severity of EPS at least in male patients treated with nemonapride. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Nemonapride; Plasma drug concentrations; Prolactin; Side effects
1. Introduction Nemonapride, cis-N-(1-benzyl-2-methyl-3-pyrrolidinyl)5-chloro-2-methoxy-4-methyl aminobenzamide, is a new substituted benzamide neuroleptic developed in Japan. This drug has selective and potent antagonistic effects for dopamine D2-like receptors such as D2, D3 and D4 whereas it has very weak affinity for other receptors of such neurotransmitters as dopamine D1, 5-HT2, noradrenaline and acetylcholine (Terai et al., 1989; Schotte et al., 1995). Daily doses recommended for clinical use are 9– 27 mg/day in the treatment of schizophrenia. Some studies (Mori et al., 1989; Satoh et al., 1996) have shown that nemonapride is effective in treating both positive and negative symptoms of schizophrenia. We also reported that nemonapride had a broad therapeutic spectrum in the treatment of acute schizophrenia, and that the improvement in positive and anxiety-
Abbreviations: EPS, extrapyramidal side effects; UKU, Udvalg for Kliniske Unders\ = gelser * Corresponding author. Tel.: +81-172-39-5066; fax: +81-172-395067.
depression symptoms were regarded as determinant factors for total response to this drug (Kondo et al., 2000). Meanwhile, our previous study showed that nemonapride treatment markedly increased prolactin concentrations in schizophrenic patients, demonstrating a strong D2 receptor blockade property of this drug (Otani et al., 1997). This finding together with the neuroleptic profiles of nemonapride suggest that side effects of nemonapride associated with dopamine blockade, e.g., extrapyramidal side effects (EPS), are primarily warned of. We previously reported the high incidence of acute dystonia during nemonapride treatment and the highest risk of this side effect in young male patients (Kondo et al., 1999). However, there is no comprehensive study on the precise spectrum and quantitative analysis of various side effects of nemonapride. Both plasma drug concentrations and prolactin response have been regarded as plausible markers for the prediction of side effects of some neuroleptics. Positive correlations between plasma concentrations of antipsychotic drugs and EPS have been shown in some studies (Wode-Helgodt et al., 1978; Bolvig Hansen and Larsen, 1985; Spina et al., 2000) but not in others (Papadopoulos et al., 1980; Volavoka et al., 1992). Likewise, it is still controversial whether positive
0278-5846/02/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 6 7 - 6
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correlations between prolactin concentrations and EPS exist during neuroleptic treatment (Kolakowska et al., 1979; Rao et al., 1980; Johnstone et al., 1983; Bartko et al., 1988). Therefore, the present study aimed to investigate the spectrum of side effects of nemonapride and its relationship with plasma concentrations of the drug and prolactin in schizophrenic patients receiving a fixed dose of nemonapride.
turbances, orthostatic dizziness, palpitation) side effects. The UKU scale has four scale steps according to the severity of side effects (0, absence; 1, mild; 2, moderate; 3, severe). A pretreatment score was subtracted from one obtained during treatment and was recorded as a drug-associated side effect. Thus, a symptom that occurred or was more exacerbated during treatment was defined as a side effect. 2.3. Assays for drug and prolactin
2. Methods 2.1. Subjects The subjects were 33 schizophrenic patients (16 males and 17 females), who fulfilled the DSM-III-R criteria (American Psychiatric Association, 1987) for schizophrenia (17 paranoid type, 1 catatonic type and 15 undifferentiated type). They suffered from first-time or recurrent episodes of schizophrenia, and all had received no oral or depot medication for at least 1 month. Among patients with recurrent episodes, various types and doses of neuroleptics were administered prior to nemonapride treatment, although no specific difference was found between those in male and female patients. The means (ranges) of age, body weight and duration of illness were 35.1 (17 – 58) years, 57.0 (38.0 – 88.7) kg and 68.8 (6 – 240) months, respectively. All patients were physically healthy, and none had any past history of substance abuse. This study was approved by the Ethics Committee of Hirosaki University Hospital, and written informed consent to participate in this study was obtained from the patients or their families. 2.2. Study design Nemonapride (Emilace, Yamanouchi Pharmaceutical, Tokyo, Japan) was administered in three equally divided doses at 0700, 1200 and 1800 h for 3 weeks. The daily dose of nemonapride was 18 mg, and was fixed during the 3-week study period. Intramuscular biperiden 5 – 10 mg was administered immediately after the development of acute dystonia, followed by oral biperiden 6 mg/day in 16 patients. The same dose of biperiden was also coadministered to other six patients who showed moderate to severe EPS other than acute dystonia. No other drugs were coadministered except for flunitrazepam 2– 4 mg/day for insomnia (17 patients) and sennnoside 12 – 24 mg/day for constipation (5 patients). Nineteen items were selected from the Udvalg for Kliniske Unders\ = gelser (UKU) side effects rating scale (Lingjaerde et al., 1987) and used for assessment of side effects. These items were divided into three subgroups: psychic (difficulties concentrating, asthenia, sleepiness, failing memory, depression, tension); extrapyramidal (dystonia, rigidity, hypokinesia, hyperkinesia, tremor, akathisia, increased salivation); and autonomic (accommodation disturbances, reduced salivation, constipation, micturition dis-
Blood samplings were performed before treatment and weekly during treatment, just before the morning dose. Plasma concentrations of nemonapride and desmethylnemonapride, which is a pharmacologically active metabolite and has one third of the potency of nemonapride in the inhibition of [3H]nemonapride binding (Terai et al., 1989), were determined in duplicate by a high-performance liquid chromatography method with solid-phase extraction (Nagasaki et al., 1998). Coefficients of variations for nemonapride and desmethylnemonapride were 7.2% and 10.3%, respectively. The limit of detection was 0.1 ng/ml for each compound. Plasma prolactin concentrations were measured in duplicate by enzyme immunoassay (IMX Prolactin Dainapack, Dainabot, Tokyo, Japan). The lowest limit of detection was 0.6 ng/ml, and interassay coefficients of variation were 3.7%, 3.5% and 3.5% at the concentrations of 8, 20 and 40 ng/ml for prolactin, respectively. 2.4. Statistical analyses Statistical analyses were performed by Wilcoxon rank sum test and Spearman rank test. A P value of .05 or less was regarded as statistically significant. SPSS 6.1J for Windows (SPSS Japan, Tokyo, Japan) was used for these statistical analyses.
3. Results Such factors as age, duration of illness, subtypes of schizophrenia and coadministered drugs did not affect either development of side effects of nemonapride or plasma concentrations of the drug and prolactin. There was no gender difference in occurrence of side effects except for the higher incidence of acute dystonia in males (12 out of 16 cases) than in females (4 out of 17 cases), which was more precisely reported in our previous study (Kondo et al., 1999). Frequent side effects throughout the 3-week nemonapride treatment were EPS such as akathisia (69.7%), dystonia (48.5%), hypokinesia (45.5%), tremor (39.4%) and increased salivation (36.4%). Regarding the time courses of side effects (Table 1), the incidences of EPS consistently increased during 3-week treatment except for dystonia, which was mainly observed in the initial phase of the treatment. In contrast, psychic and autonomic side effects
T. Kondo et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 287–291 Table 1 Occurrence (%) of side effects of nemonapride 1 Week
2 Weeks
3 Weeks
Psychic Asthenia Sleepiness Tension Failing memory Depression Difficulties concentrating
23.1 15.4 12.8 10.3 15.4 10.3
28.2 7.7 12.8 7.7 12.8 12.8
23.1 10.3 7.7 7.7 7.7 5.1
Extrapyramidal Akathisia Dystonia Hypokinesia Tremor Increased salivation Hyperkinesia
28.2 48.7 28.5 15.4 20.5 0
56.5 2.6 38.5 30.8 25.6 2.6
59.0 2.6 43.6 38.5 35.9 5.1
Autonomic Constipation Orthostatic dizziness Reduced salivation Palpitation Mictrurition disturbances Accommodation disturbances
12.8 12.8 5.1 12.8 0 0
10.3 12.8 5.1 0 0 0
7.7 5.1 2.6 0 0 0
were relatively infrequent, and the incidences gradually decreased throughout the study period (Table 1). Mean plasma concentrations of the drug (nemonapride plus desmethylnemonapride) during nemonapride treatment ranged from 0.2 to 2.1 ng/ml (mean ± S.D.: 0.7 ± 0.4 ng/ml) and the mean concentration of desmethylnemonapride was about 70% of that of nemonapride. There was no significant correlation between the plasma drug concentration and any
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subscale scores or items of side effects in male, female or total patients at any week. Mean plasma concentrations during nemonapride treatment did not significantly differ in subjects with and without EPS, i.e., 0.9 ± 0.5 ng/ml (n = 12) vs. 0.5 ± 0.1 ng/ml (n = 3) in males, 0.4 ± 0.1 ng/ml (n = 10) vs. 0.7 ± 0.4 ng/ml (n = 4) in females, and 0.7 ± 0.4 ng/ml (n = 22) vs. 0.6 ± 0.3 ng/ml (n = 7) in total patients. Prolactin response (Dprolactin) was estimated by the change in plasma prolactin concentration caused by nemonapride treatment. Female patients had the significantly higher (Wilcoxon rank sum test: P < .01) Dprolactin than male patients (71.4 ± 41.6 vs. 29.5 ± 18.4 ng/ml at 1 week, 82.7 ± 58.9 vs. 37.0 ± 23.2 ng/ml at 2 weeks, 82.6 ± 73.9 vs. 27.9 ± 18.2 ng/ml at 3 weeks). Accordingly, the relationships between weekly Dprolactin and side effects scores were analyzed separately in male and female patients. Significant correlations between weekly Dprolactin and EPS scores were found in male patients (Fig. 1: Spearman rank correlation: rs=.651, P < .01 at 1 week; rs=.567, P < .05 at 2 weeks; rs=.670, P < .01 at 3 weeks), while the correlations were not significant in female or total patients at any weeks. No significant relationships were found between Dprolactin and scores of psychic or autonomic side effects in total subjects or either gender group at any week.
4. Discussion 4.1. Side effect spectrum of nemonapride Side effects of nemonapride were characterized by high incidences of EPS in contrast to fewer psychic and auto-
Fig. 1. Relationships between weekly prolactin response (Dprolactin) and extrapyramidal side effect scores in 16 male schizophrenic patients. Significant correlations were observed (Spearman rank correlation: rs=.651, P < .01 at 1 week; rs=.567, P < .05 at 2 weeks; rs=.670, P < .01 at 3 weeks).
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nomic side effects. The spectrum of these side effects well reflect pharmacological profiles of nemonapride, i.e., potent antagonistic effects for dopamine D2-like receptors and weak affinities for other receptors for 5-HT2, noradrenaline and acetylcholine (Terai et al., 1989; Schotte et al., 1995). Therefore, the present study suggests that EPS should be mainly targeted as likely side effects during nemonapride treatment. 4.2. Time courses of side effects As shown in Table 1, EPS that should be warned of the most during the first week is acute dystonia while thereafter one should pay more attention to akathisia and parkinsonian symptoms during nemonapride treatment. Psychic and autonomic side effects were almost negligible after 3-week nemonapride treatment (Table 1). Thus, fewer sedative and anticholinergic side effects are regarded as an advantage of nemonapride because these side effects are frequently observed in the treatment with other neuroleptics that block multiple receptors (Kondo et al., 1994). 4.3. Relationship with drug concentrations Monitoring of plasma concentrations of antipsychotics would be useful for the prediction of side effects as well as therapeutic effects if strong correlations between plasma concentrations and side effects are consistent. Positive correlations between plasma concentrations of drugs and EPS have been shown in studies on chlorpromazine (WodeHelgodt et al., 1978), perphenazine (Bolvig Hansen and Larsen, 1985) and risperidone (Spina et al., 2000). On the other hand, no definite correlation was found in other studies on thioridazine (Papadopoulos et al., 1980) and haloperidol (Volavoka et al., 1992). To investigate the relationships between plasma drug concentrations and clinical effects precisely, pharmacologically active metabolites of the drug should be also taken into consideration. In the present study, a pharmacologically active moiety (nemonapride plus desmethylnemonapride) was regarded as plasma drug concentration. Nevertheless, no correlation was observed between plasma drug concentrations and total or any subscale side effects scores. Therefore, plasma drug concentration does not appear to be a useful marker for the prediction of side effects of nemonapride. 4.4. Relationship with prolactin response Meanwhile, several previous studies have focused on the relationship between prolactin response and EPS during neuroleptic treatment since the prolactin response to antipsychotic drugs is an index of their effects on dopamine activity (Rubin, 1987). Some of these reports pointed out that plasma prolactin concentrations were positively correlated to development of EPS (Kolakowska et al., 1979; Rao et al., 1980) while other reports showed no significant
correlation between prolactin response and EPS (Johnstone et al., 1983; Bartko et al., 1988). These conflicting results may be partly due to the heterogeneity of the subjects, e.g., gender difference in prolactin response to neuroleptic treatment, which was consistent with findings in previous studies (Harnryd et al., 1984; Linkowski et al., 1984). The present study also showed greater prolactin response to nemonapride in females than in males. This phenomenon may be ascribable to higher concentrations of estrogen in females than in males since estrogen stimulates prolactin response (Rubin, 1987) and may have a neuroleptic-enhancing property (Seeman and Lang, 1990). Therefore, we analyzed the relationship between prolactin response and side effects separately in male and female patients. Despite the greater and wider prolactin response in females, no correlations were observed between prolactin response and EPS scores. As a reason for the lack of the significant relationship, it is suggested that prolactin response in females does not simply reflect antidopaminergic effects of neuroleptics because prolactin response may be rather influenced by varied estrogen concentrations in females. On the other hand, prolactin response was significantly correlated to the severity of EPS in males, which was consistent throughout the study period (Fig. 1). Therefore, prolactin response may reflect vulnerability to the development of EPS at least in male patients treated with nemonapride. This finding together with the data on plasma drug concentrations suggest that pharmacodynamic factors rather than pharmacokinetic factors are more important to predict the development of nemonapride-induced EPS in male schizophrenic patients.
5. Conclusion The present study thus suggests that the spectrum of nemonapride-induced side effects is mainly characterized by EPS, and that prolactin response as an index of dopamine blockade reflects severity of EPS, at least in male patients treated with nemonapride.
Acknowledgments This study was supported by a grant from the Hirosaki Research Institute for Neurosciences.
References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R). American Psychiatric Association, Washington, DC. Bartko, G., Sztaniszlav, D., Olajos, S., Bekesy, M., 1988. Serum chlorpromazine and prolactin levels in paranoid schizophrenic patients and clinical response. Eur. J. Psychiatry, 109 – 117.
T. Kondo et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 287–291 Bolvig Hansen, L., Larsen, L.-E., 1985. Therapeutic advantages of monitoring plasma concentrations of perphenazine in clinical practice. Psychopharmacology 87, 16 – 19. Harnryd, C., Bjerkenstedt, L., Gullberg, B., Oxenstierna, G., Sedvall, G., Wiesel, F.-A., 1984. Time course for effects of sulpiride and chlorpromazine on monoamine metabolite and prolactin levels in cerebrospinal fluid from schizophrenic patients. Acta Psychiatr. Scand. 69 (Suppl. 311), 75 – 92. Johnstone, E.C., Crow, T.M., Frith, C.D., Owens, D.G.C., 1983. Adverse effects of anticholinergic medication in positive schizophrenic symptoms: theoretical and practical considerations. Psychol. Med. 13, 513 – 527. Kolakowska, T., Orr, M., Gelder, M., Heggie, M., Wiles, D., Franklin, M., 1979. Clinical significance of plasma drug and prolactin levels during acute chlorpromazine treatment: a replication study. Br. J. Psychiatry 135, 352 – 359. Kondo, T., Otani, K., Ishida, M., Tanaka, O., Kaneko, S., Fukushima, Y., 1994. Adverse effects of zotepine and their relationship to serum concentrations of the drugs and prolactin. Ther. Drug Monit. 16, 120 – 124. Kondo, T., Otani, K., Tokinaga, N., Ishida, M., Yasui, N., Kaneko, S., 1999. Characteristics and risk factors of acute dystonia in schizophrenic patients treated with nemonapride, a selective dopamine antagonist. J. Clin. Psychopharmacol. 19, 45 – 50. Kondo, T., Mihara, K., Yasui, N., Nagashima, U., Ono, S., Kaneko, S., Ohkubo, T., Osanai, T., Sugawara, K., Otani, K., 2000. Therapeutic spectrum of nemonapride and its relationship with plasma concentrations of the drug and prolactin. J. Clin. Psychopharmacol. 20, 404 – 409. Lingjaerde, O., Ahlfors, U.G., Bech, P., Dencker, S.J., Elgen, K., 1987. The UKU side effect rating scale. Acta. Psychiatr. Scand. 76 (Suppl. 334), 11 – 100. Linkowski, P., Hubain, P., Von Frenckell, R., Mendlewicz, J., 1984. Haloperidol plasma levels and clinical response in paranoid schizophrenics. Eur. Arch. Psychiat. Neurol. Sci. 234, 231 – 236. Mori, A., Kazamatsuri, H., Kaneko, S., Kamijima, K., Kariya, T., Murasaki, M., Yagi, G., 1989. A double-blind comparison of a new benzamide compound YM-09151 with haloperidol in the treatment of schizophrenia. Clin. Eval. 17, 349 – 377 (in Japanese, abstract in English). Nagasaki, T., Ohkubo, T., Sugawara, K., Yasui, N., Otani, K., Kaneko, S., 1998. High-performance liquid chromatographic determination of nem-
291
onapride and desmethylnemonapride in human plasma using an electrochemical detection. J. Chromatogr., B 714, 293 – 298. Otani, K., Kondo, T., Yasui, N., Suzuki, A., Furukori, H., Kaneko, S., Ohkubo, T., Nagasaki, T., Sugawara, K., Hayashi, K., 1997. Prolactin response to nemonapride, a new antipsychotic drug, in schizophrenic patients. Hum. Psychopharmacol. 12, 591 – 594. Papadopoulos, A.S., Chand, T.G., Crammer, J.L., Lader, S., 1980. A pilot study of plasma thioridazine and metabolites in chronically treated patients. Br. J. Psychiatry 136, 591 – 596. Rao, V.A.R., Bishop, M., Coppen, A., 1980. Clinical state, plasma levels of haloperidol and prolactin: a correlation study in chronic schizophrenia. Br. J. Psychiatry 137, 518 – 521. Rubin, R.T., 1987. Prolactin and schizophrenia. In: Meltzer, H.Y. (Ed.), Psychopharmacology, 3rd Generation of Progress. Raven Press, New York, pp. 803 – 808. Satoh, K., Someya, T., Shibasaki, M., 1996. Effects of nemonapride on positive and negative symptoms of schizophrenia. Int. Clin. Psychopharmacol. 11, 279 – 281. Schotte, A., Bonaventure, P., Janssen, P.F.M., Leysen, J.E., 1995. In vitro receptor binding and in vivo receptor occupancy in rat and guinea pig brain: risperidone compared with antipsychotics hitherto used. Jpn. J. Pharmacol. 69, 399 – 412. Seeman, M.V., Lang, M., 1990. The role of estrogens in schizophrenia gender differences. Schizophr. Bull. 16, 185 – 194. Spina, E., Avenoso, A., Facciola, G., Salemi, M., Scordo, M.G., Ancione, M., Madia, A.G., Perucca, E., 2000. Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology 153, 238 – 243. Terai, M., Hidaka, K., Nakamura, Y., 1989. Comparison of [3H] YM09151-2 with [3H] spiperone and [3H] raclopride for dopamine D-2 receptor binding to rat striatum. Eur. J. Pharmacol. 173, 177 – 182. Volavoka, J., Cooper, T., Czobor, P., Bitter, I., Meisner, M., Laska, E., Gastanaga, P., Krakowski, M., Chou, J.C.Y., Crowner, M., Douyon, R., 1992. Haloperidol blood levels and clinical effects. Arch. Gen. Psychiatry 49, 354 – 361. Wode-Helgodt, B., Borg, S., Fyro, B., Sedvall, G., 1978. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Acta Psychiatr. Scand. 58, 149 – 173.