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The effect of smoking status on the plasma concentration of prolactin already elevated by risperidone treatment in schizophrenia patients
Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 573–576
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 ev i e r. c o m / l o c a t e / p n p
The effect of smoking status on the plasma concentration of prolactin already elevated by risperidone treatment in schizophrenia patients Chikako Ohta, Norio Yasui-Furukori ⁎, Hanako Furukori, Shoko Tsuchimine, Manabu Saito, Taku Nakagami, Kaori Yoshizawa, Sunao Kaneko Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
a r t i c l e
i n f o
Article history: Received 15 August 2010 Received in revised form 25 December 2010 Accepted 25 December 2010 Available online 6 January 2011 Keywords: Gender Prolactin Risperidone Smoking status
a b s t r a c t Smoking prevalence for schizophrenic patients is higher than for the general population. Inter-individual variability in hyperprolactinemia induced antipsychotics particularly risperidone can be explained by smoking status to some extent. We therefore studied the effects of smoking status on the plasma concentration of prolactin. Subjects included 154 schizophrenia patients (61 males, 93 females) who had received 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in the females were significantly higher than in the males (117.6± 69.3 ng/ml vs. 52.9± 30.7 ng/ml, p b 0.001). The mean (±SD) plasma concentrations of prolactin did not differ between smokers and nonsmokers in the males (59.5 ± 31.2 ng/ml vs. 47.6± 29.3 ng/ml, not significant (ns)), but there was a significant difference in the females (100.2± 59.1 vs. 134.0 ± 74.6, ng/ml, p b 0.05). Multiple regression analyses including gender, plasma drug concentration and age revealed that the plasma concentration of prolactin positively correlated with gender (standardized beta= 0.452, p b 0.001) and negatively with age (standardized beta = −0.171, p b 0.05) and smoking status (standardized beta = −0.232, p b 0.01). These findings suggest that smoking status has an impact on prolactin concentration during risperidone treatment. However, further study is required to determine whether these findings have clinical implications. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Hyperprolactinemia has been observed as a frequent consequence of treatment with antipsychotic agents (Rubin, 1987; Petty, 1999). The major effects of hyperprolactinemia in women include amenorrhea, galactorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism (Rubin, 1987; Petty, 1999) and a long-term risk of osteoporosis (Meaney et al., 2004). The effects in men include impotence, loss of libido, hypospermatogenesis (Rubin, 1987; Petty, 1999) and a long-term risk of low bone density (Meaney et al., 2004). Risperidone shows potent serotonin 5HT2 activity and milder dopamine D2 antagonistic activity (Schotte et al., 1995). Numerous studies have reported that the adverse effects of risperidone are associated with hyperprolactinemia (Dickson et al., 1995; Popli et al., 1998; Kim et al., 1999). With the exception of one retrospective analysis (Kleinberg et al., 1999), it has generally been demonstrated that pronounced hyperprolactinemia (Shiwach and Carmody, 1998; Caracci and Ananthamoorthy, 1999; Lavalaye et al., 1999; David et al., 2000; Yasui-Furukori et al., 2002) is consistently induced by risperi-
Abbreviations: 5-HT, 5-hydroxytryptamine; CNS, central nervous system; CV, coefficient of variation; CYP, cytochrome P450; DRD2, Dopamine D2 Receptor; GABA, gamma-aminobutyric acid; MDR1, Multidrug resistance 1. ⁎ Corresponding author. Tel.: + 81 172 39 5352; fax: + 81 172 39 5352. E-mail address: [email protected] (N. Yasui-Furukori). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.12.025
done treatment when compared with treatment using conventional antipsychotic agents. However, inter-individual variability in plasma concentration during risperidone treatments has been implied (YasuiFurukori et al., 2002). In addition, among women, risperidone has not been shown to correlate with adverse events and adverse events have not been shown to correlate with endpoint prolactin levels (Kleinberg et al., 1999). Smoking prevalence for schizophrenic patients is higher than for the general population (Sagud et al., 2009). More than 60% of schizophrenic patients are current smokers, which contributes to excessive mortality in these patients (Sagud et al., 2009). Several studies have demonstrated that cigarette smoking status influences the hormonal regulation of prolactin (Xue et al., 2010), but the mechanism of this relationship seems to be complex. Some studies have suggested that cigarette smoking increases the prolactin response (Kirschbaum et al., 1994; Mendelson et al., 2003), while others have reported lower prolactin responses in smokers than in nonsmokers (Corona et al., 2005; Trummer et al., 2002). Based on these findings, we hypothesized that inter-individual variability in the hyperprolactinemia induced by antipsychotics, such as risperidone, can be explained to some extent by smoking status. However, no studies have examined the effect of smoking on hyperprolactinemia induced by antipsychotics. Therefore, in this study, we examined the effect of smoking status on the plasma prolactin concentrations induced by risperidone treatment in schizophrenia patients.
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C. Ohta et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 573–576
2. Methods 2.1. Subjects The subjects were 154 schizophrenic Japanese inpatients (61 males and 93 females) who met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Some of the patients had participated in our previous studies on the relationship between steady-state plasma drug concentrations and the CYP2D6, DRD2 and MDR1 genotypes (Mihara et al., 2003; Yasui-Furukori et al., 2003, 2004, 2007, 2008). Demographic data is shown in Table 1. The mean ± SD (range) of age, body weight and duration of illness were 45.3 ± 19.9 (18−75) years, 56.1 ± 11.8 (37−105)kg and 160 ± 126 (4−448) months, respectively. The 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 and their families. 2.2. Protocol The subjects had received 3 mg risperidone twice daily (8 a.m. and 8 p.m.) for 4 to 79 weeks. The elimination half-lives of risperidone and 9-hydroxyrisperidone were reported to be 3 to 20 h and 20 to 29 h, respectively. Therefore, the plasma concentrations of these compounds had already reached a steady state in all of the subjects before the initiation of the study. Blood samplings for drug concentrations and prolactin concentration were performed at 8:00 a.m. just before taking risperidone. The drugs co-administered were flunitrazepam (1−6 mg/day in 60 cases), diazepam (2−15 mg/day in 15 cases), lorazepam (1−3 mg/day in 10 cases), alprazolam (0.8−2.4 mg/day in 12 cases), biperiden (4−6 mg/day in 48 cases), trihexyphenidyl (4−10 mg/day in 13 cases) and sennoside (12−60 mg/day in 58 cases). Patients with clinically significant abnormal laboratory or electrocardiography findings, histories of mental disorder other than schizophrenia, epilepsy, alcoholism or drug abuse, or clinically significant organic or neurological disease like thyroid disease, CNS or pituitary disorder, chronic renal failure, and liver cirrhosis were excluded. The patients receiving prolactin-influencing medication such as sulpiride and patients with history of depot antipsychotics were also excluded. Smokers were defined as subjects receiving over 10 cigarettes daily. Nonsmokers were defined as subjects who had not received any cigarettes at least for a year. 2.3. Assays The plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-mass spectrometry–mass spectrometry (LC-MS–MS). The extraction procedure was as follows:
Table 1 The characteristics of smokers and nonsmokers in males and females. Males
Age (years) Body weight (kg) Drug concentration (ng/ml) Risperidone 9-hyroxyrisperidone Active moiety Prolactin level (ng/ml) Prolactin level/active moiety level
Females
Smokers (n = 36)
Nonsmokers (n = 23)
46.0 ± 14.5 60.8 ± 10.6
49.2 ± 18.3 65.1 ± 13.1
47.9 ± 13.4 58.4 ± 9.1
51.6 ± 12.6 58.3 ± 11.5
9.1 ± 13.0 38.2 ± 13.1 47.3 ± 21.9 47.6 ± 29.3 1.2 ± 0.9
8.5 ± 18.3 50.3 ± 27.6 57.6 ± 37.8 59.5 ± 31.2 1.4 ± 1.0
5.6 ± 6.1 42.0 ± 20.8 47.6 ± 23.2 100.2 ± 59.1⁎ 2.6 ± 2.0
6.7 ± 8.6 54.4 ± 57.8 53.4 ± 24.7 134.0 ± 76.7 3.1 ± 2.8
⁎ p b 0.05 compared with nonsmokers.
Smokers (n = 45)
Nonsmokers (n = 48)
200 μl of 0.1 M phosphate buffer (pH 7), 50 μl of internal standard solution (R068808: Jansen Research Foundation) and 100 μl of methanol were added to 200 μl of plasma sample. Thereafter, 400 μl of 0.1 M Borax was added. The mixture was vortexed and poured over an Extrelut NT 1 (Merck) column, which was eluted with 7 ml of ethyl acetate. The eluate was evaporated under a nitrogen stream at 65 °C and was redissolved in 100 μl of methanol, which was again evaporated under a nitrogen stream at 65 °C. The residues were redissolved in 200 μl of acetonitrile/0.01 M ammonium acetate (50/50, pH 9.0), and 5 μl were injected onto the LC-MS–MS system. The system consisted of an API 3000 (Sciex) and a column (Hypersil BDS C18 100 × 4.6, 3 μm). The mobile phase consisted of a gradient of ammonium acetate (0.01 M, pH 9.0)-acetonitrile. Among the fragment ions of the compounds, the mass-to-charge ratio (m/z) was 207.0 for risperidone, 191.0 for 9-hydroxyrisperidone, and 201.0 for the internal standard, all three of which were selected for ion monitoring. The lower limit of detection was 0.1 ng/ml for risperidone and 9hydroxyrisperidone, and the values of the intra-assay and inter-assay coefficient of variation were less than 5% at all concentrations (0.1– 100 ng/ml) of the calibration curves for both compounds. The plasma prolactin concentration was determined using an enzyme immunoassay (IMX Prolactin Dainapack, Dainabot, Osaka, Japan). The lowest limit of detection was 0.6 ng/ml, and the interassay CVs were 3.7%, 3.5% and 3.5% at the prolactin concentrations of 8, 20 and 40 ng/ml, respectively. 2.4. Data analyses and statistics The comparison of several factors, including the plasma concentration of prolactin and smoking status, was performed using a t-test and a chi-square test. Multiple regression analyses were used to examine the correlation between the plasma concentration of prolactin and several factors including gender, smoking status, plasma drug concentration and age. Smoking status and gender difference were analyzed using dummy variables (nonsmoking = 0, smoking = 1 and male = 0, female = 1). A p value less than 0.05 was regarded as statistically significant. All analyses were performed using SPSS 15.0J for windows (SPSS Japan Inc., Tokyo, Japan). 3. Results The plasma concentration of prolactin in females was dramatically higher than in males (117.6 ± 69.3 ng/ml vs. 52.9 ± 30.7 ng/ml, respectively; p b 0.001). We therefore analyzed the prolactin concentrations in males and females separately. The prolactin concentration in males did not differ between smokers and nonsmokers, but it did differ significantly between the two in females (Table 1). Although the plasma concentrations of risperidone in males were significantly higher than those in females (8.7 ± 14.9 ng/ml vs. 4.1 ± 5.2 ng/ml, p b 0.05), no difference between males and females was found in the plasma concentrations of 9-hydroxyrisperidone (42.4 ± 20.3 ng/ml vs. 48.5 ± 44.4 ng/ml, ns) or in the active moiety (50.8 ± 29.0 ng/ml vs. 49.8 ± 44.7 ng/ml, ns). There was no significant difference in the plasma concentration of risperidone, 9-hydroxyrisperidone or active moiety between the smokers and the nonsmokers in males or females (Table 1). Multiple regression analyses including smoking status, gender difference, age, plasma drug concentration (active moiety) and plasma prolactin concentration correlated positively with gender (standardized beta = 0.452, p b 0.001) and negatively with smoking status (standardized beta = −0.232, p b 0.01) and age (standardized beta = −0.171, p b 0.05) (Table 2). When the multiple regression analyses without gender difference were further analyzed, the plasma prolactin concentration correlated negatively with smoking status in females (standardized beta = −0.298, p b 0.01) and negatively with age in males (standardized beta = −0.455, p b 0.01) (Table 2).
C. Ohta et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 573–576 Table 2 Partial correlation efficient (standardized beta) and multiple correlation coefficients between prolactin concentrations and potential variables. Variable
Total (n = 154)
Males (n = 61)
Females (n = 93)
Gender Age Body weight Smoking status Drug concentration R
0.452*** − 0.171* − 0.144 − 0.232** − 0.066 0.578***
− 0.455** − 0.231 − 0.161 0.110 0.421*
− 0.160 − 0.161 − 0.298** 0.061 0.361*
R: multiple correlation coefficient. *P b 0.05, **P b 0.01, ***p b 0.001.
4. Discussion The results of these findings show that smoking status does not affect the prolactin concentration in males but does in females, while the ratio of prolactin concentration to active moiety concentration in nonsmokers was similar in smokers. To our knowledge, this is the first study indicating an effect of smoking on hyperprolactinemia. These findings suggest that, at the least, smoking status affects prolactin concentration in females during risperidone treatment and does not induce a pharmacodynamic change in the prolactin response to risperidone. However, further studies will be required to confirm the association between smoking status and higher prolactin concentration-related adverse effects. The regulation of prolactin secretion in the pituitary gland is complex. Nicotine enhances dopaminergic, serotonergic, GABAergic and glutaminergic synaptic transmission (Mansvelder et al., 2002). In a previous study using healthy subjects, an evaluation of smoking patients demonstrated that acute nicotine intervention induces prolactin secretion (Mendelson et al., 2003). However, chronic cigarette smoking is associated with a lower prolactin level (Kirschbaum et al., 1994; Corona et al., 2005). In addition, a smoking habit induces a lower prolactin response after physiological and psychological stress (Kirschbaum et al., 1994). Our findings showing a lower prolactin concentration in smokers than in nonsmokers might therefore be explained by a lower response to several stresses in smokers than in nonsmokers, although the prolactin response to risperidone, as defined by the ratio of prolactin concentration to active moiety concentration, did not differ between smokers and nonsmokers in males or females. It is known that smoking induces some metabolic enzymes, such as CYP1A2 Walter-Sack and Klotz, 1996. CYP1A2 is not a major metabolic enzyme of risperidone. In the present study, there was no significant difference in plasma risperidone concentration (Fang et al., 1999). Meanwhile, olanzapine is metabolized by CYP1A2 (Callaghan et al., 1999), and smoking has a significant effect on olanzapine metabolism (Carrillo et al., 2003). During olanzapine treatment, plasma concentrations of olanzapine in smokers are thus assumed to be lower than those in nonsmokers. In addition, the prolactin response in smokers might be lower than in nonsmokers. Taken together, it is more likely that the plasma concentration of prolactin in smokers is lower than that in nonsmokers. The plasma concentrations of prolactin did not correlate with plasma drug concentrations of risperidone or the active moiety, although our previous studies showed a positive correlation between plasma drug concentrations and prolactin concentrations during bromperidol and haloperidol treatments in males (Yasui et al., 1998; Yasui-Furukori et al., 2001). This discrepancy may be due to the relatively complex pharmacological profile of risperidone and its active metabolite, 9-hydroxyrisperidone. Risperidone has a potent serotonin 5HT2 activity and a milder dopamine D2 antagonistic activity, (Schotte et al., 1995) and its 5HT2 antagonistic effect has been associated with the inhibition of prolactin secretion (Rubin, 1987).
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It should be noted that the incidence of adverse effects related to hyperprolactinemia was not evaluated in the present study. In large clinical trials, a risperidone-associated increase in serum prolactin levels did not correlate significantly with the emergence of possible prolactin-related adverse effects (Kleinberg et al., 1999). This may be due to the considerable number of patients who are without adverse effects despite having a high prolactin level. Nevertheless, prolactin monitoring during risperidone treatment should be conducted, especially in premenopausal women who may suffer from the potentially adverse effects associated with hyperprolactinemia. Patients receiving 6 mg/day of risperidone might have around 90% dopamine D2 receptor occupancy due to tight binding to the dopamine D2 receptor (Kapur and Seeman, 2001). According to the rapid dissociation model, tight-binding atypical agents are hypothesized to have antipsychotic action when they cause other effects of dopamine blockade, including raised prolactin levels or extrapyramidal adverse effects (Kapur and Seeman, 2001). The present study had several limitations. First, the incidence of adverse effects related to hyperprolactinemia was not evaluated. In large clinical trials, the risperidone-associated increase in serum prolactin levels was not significantly correlated with the emergence of possible prolactin-related adverse effects (Kleinberg et al., 1999). This may result from the considerable number of patients who had no adverse effects despite having high prolactin levels. Nevertheless, prolactin monitoring during risperidone treatment should be conducted or physicians should ask about the possible prolactin-related adverse effects, especially to premenopausal women who may suffer from potential adverse effects associated with hyperprolactinemia. Second, the small number of patients in this study greatly limited secondary comparisons because the prolactin response to antipsychotics varies, particularly in females. Third, since the study was not designed to assess the hormone levels associated with menstrual cycle phases in premenopausal females, blood sampling failed to capture the anticipated normalization of reproductive hormone levels with the return to euprolactinemia. Blood sampling throughout the menstrual cycle would have allowed more definitive conclusions about the effects of risperidone and olanzapine on gonadal hormone levels. Further studies are required to clarify the relationship of prolactin kinetics to plasma drug concentrations. Fourth, the dosages in this study were relatively higher than the typical dosages and were administered at night; the dosage should be 4 mg for risperidone. As a result, prolactin concentrations in this study might not be the same as those in the usual clinical situation. Finally, only four weeks of testing may be insufficient for some of the patients in the present study. The period of testing in further studies should be much longer than four weeks. 5. Conclusion The present results indicate that smoking status is associated with prolactin concentration during risperidone treatment in female schizophrenia patients. Further studies will be valuable in determining whether smoking status is clinically relevant in treatment with antipsychotics. Acknowledgement All authors indicate no conflict of interest that might serve to bias this work. This study was supported by a grant from the Hirosaki Research Institute for Neurosciences, and Health and Labour Sciences Research Grants (Research on Psychiatric and Neurological Diseases and Mental Health) (H22-Seishin-Ippan-011). References Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999;37(3):177–93 Sep.
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Caracci G, Ananthamoorthy R. Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics. J Clin Psychopharmacol 1999;19:194–6. Carrillo JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J. Role of the smokinginduced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003;23(2):119–27 Apr. Corona G, Mannucci E, Petrone L, Ricca V, Mansani R, Cilotti A, et al. Psychobiological correlates of smoking in patients with erectile dysfunction. Int J Impot Res 2005;17(6): 527–34 Nov-Dec. David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085–96. Dickson RA, Dalby JT, Williams R, Edwards AL. Risperidone-induced prolactin elevations in premenopausal women with schizophrenia. Am J Psychiatry 1995;152:1102–3. Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999;359(2):147–51 Feb. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 2001;158:360–9. Kim YK, Kim L, Lee MS. Risperidone and associated amenorrhea: a report of 5 cases. J Clin Psychiatry 1999;60:315–7. Kirschbaum C, Scherer G, Strasburger CJ. Pituitary and adrenal hormone responses to pharmacological, physical, and psychological stimulation in habitual smokers and nonsmokers. Clin Investig 1994;72(10):804–10 Oct. Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57–61. Lavalaye J, Linszen DH, Booij J, Reneman L, Gersons BP, van Royen EA. Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia. Psychiatry Res 1999;92:33–44. Mansvelder HD, Keath JR, McGehee DS. Synaptic mechanisms underlie nicotineinduced excitability of brain reward areas. Neuron 2002;33(6):905–19 Mar 14. Meaney AM, Smith S, Howes OD, O'Brien M, Murray RM, O'Keane V. Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia. Br J Psychiatry 2004;184:503–8 Jun. Mendelson JH, Sholar MB, Mutschler NH, Jaszyna-Gasior M, Goletiani NV, Siegel AJ, et al. Effects of intravenous cocaine and cigarette smoking on luteinizing hormone, testosterone, and prolactin in men. J Pharmacol Exp Ther 2003;307(1):339–48 Oct. Mihara K, Kondo T, Yasui-Furukori N, Suzuki A, Ishida M, Ono S, et al. Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther Drug Monit 2003;25:287–93. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 1999;35:S67–73.
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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 ev i e r. c o m / l o c a t e / p n p
The effect of smoking status on the plasma concentration of prolactin already elevated by risperidone treatment in schizophrenia patients Chikako Ohta, Norio Yasui-Furukori ⁎, Hanako Furukori, Shoko Tsuchimine, Manabu Saito, Taku Nakagami, Kaori Yoshizawa, Sunao Kaneko Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
a r t i c l e
i n f o
Article history: Received 15 August 2010 Received in revised form 25 December 2010 Accepted 25 December 2010 Available online 6 January 2011 Keywords: Gender Prolactin Risperidone Smoking status
a b s t r a c t Smoking prevalence for schizophrenic patients is higher than for the general population. Inter-individual variability in hyperprolactinemia induced antipsychotics particularly risperidone can be explained by smoking status to some extent. We therefore studied the effects of smoking status on the plasma concentration of prolactin. Subjects included 154 schizophrenia patients (61 males, 93 females) who had received 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in the females were significantly higher than in the males (117.6± 69.3 ng/ml vs. 52.9± 30.7 ng/ml, p b 0.001). The mean (±SD) plasma concentrations of prolactin did not differ between smokers and nonsmokers in the males (59.5 ± 31.2 ng/ml vs. 47.6± 29.3 ng/ml, not significant (ns)), but there was a significant difference in the females (100.2± 59.1 vs. 134.0 ± 74.6, ng/ml, p b 0.05). Multiple regression analyses including gender, plasma drug concentration and age revealed that the plasma concentration of prolactin positively correlated with gender (standardized beta= 0.452, p b 0.001) and negatively with age (standardized beta = −0.171, p b 0.05) and smoking status (standardized beta = −0.232, p b 0.01). These findings suggest that smoking status has an impact on prolactin concentration during risperidone treatment. However, further study is required to determine whether these findings have clinical implications. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Hyperprolactinemia has been observed as a frequent consequence of treatment with antipsychotic agents (Rubin, 1987; Petty, 1999). The major effects of hyperprolactinemia in women include amenorrhea, galactorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism (Rubin, 1987; Petty, 1999) and a long-term risk of osteoporosis (Meaney et al., 2004). The effects in men include impotence, loss of libido, hypospermatogenesis (Rubin, 1987; Petty, 1999) and a long-term risk of low bone density (Meaney et al., 2004). Risperidone shows potent serotonin 5HT2 activity and milder dopamine D2 antagonistic activity (Schotte et al., 1995). Numerous studies have reported that the adverse effects of risperidone are associated with hyperprolactinemia (Dickson et al., 1995; Popli et al., 1998; Kim et al., 1999). With the exception of one retrospective analysis (Kleinberg et al., 1999), it has generally been demonstrated that pronounced hyperprolactinemia (Shiwach and Carmody, 1998; Caracci and Ananthamoorthy, 1999; Lavalaye et al., 1999; David et al., 2000; Yasui-Furukori et al., 2002) is consistently induced by risperi-
Abbreviations: 5-HT, 5-hydroxytryptamine; CNS, central nervous system; CV, coefficient of variation; CYP, cytochrome P450; DRD2, Dopamine D2 Receptor; GABA, gamma-aminobutyric acid; MDR1, Multidrug resistance 1. ⁎ Corresponding author. Tel.: + 81 172 39 5352; fax: + 81 172 39 5352. E-mail address: [email protected] (N. Yasui-Furukori). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.12.025
done treatment when compared with treatment using conventional antipsychotic agents. However, inter-individual variability in plasma concentration during risperidone treatments has been implied (YasuiFurukori et al., 2002). In addition, among women, risperidone has not been shown to correlate with adverse events and adverse events have not been shown to correlate with endpoint prolactin levels (Kleinberg et al., 1999). Smoking prevalence for schizophrenic patients is higher than for the general population (Sagud et al., 2009). More than 60% of schizophrenic patients are current smokers, which contributes to excessive mortality in these patients (Sagud et al., 2009). Several studies have demonstrated that cigarette smoking status influences the hormonal regulation of prolactin (Xue et al., 2010), but the mechanism of this relationship seems to be complex. Some studies have suggested that cigarette smoking increases the prolactin response (Kirschbaum et al., 1994; Mendelson et al., 2003), while others have reported lower prolactin responses in smokers than in nonsmokers (Corona et al., 2005; Trummer et al., 2002). Based on these findings, we hypothesized that inter-individual variability in the hyperprolactinemia induced by antipsychotics, such as risperidone, can be explained to some extent by smoking status. However, no studies have examined the effect of smoking on hyperprolactinemia induced by antipsychotics. Therefore, in this study, we examined the effect of smoking status on the plasma prolactin concentrations induced by risperidone treatment in schizophrenia patients.
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2. Methods 2.1. Subjects The subjects were 154 schizophrenic Japanese inpatients (61 males and 93 females) who met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Some of the patients had participated in our previous studies on the relationship between steady-state plasma drug concentrations and the CYP2D6, DRD2 and MDR1 genotypes (Mihara et al., 2003; Yasui-Furukori et al., 2003, 2004, 2007, 2008). Demographic data is shown in Table 1. The mean ± SD (range) of age, body weight and duration of illness were 45.3 ± 19.9 (18−75) years, 56.1 ± 11.8 (37−105)kg and 160 ± 126 (4−448) months, respectively. The 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 and their families. 2.2. Protocol The subjects had received 3 mg risperidone twice daily (8 a.m. and 8 p.m.) for 4 to 79 weeks. The elimination half-lives of risperidone and 9-hydroxyrisperidone were reported to be 3 to 20 h and 20 to 29 h, respectively. Therefore, the plasma concentrations of these compounds had already reached a steady state in all of the subjects before the initiation of the study. Blood samplings for drug concentrations and prolactin concentration were performed at 8:00 a.m. just before taking risperidone. The drugs co-administered were flunitrazepam (1−6 mg/day in 60 cases), diazepam (2−15 mg/day in 15 cases), lorazepam (1−3 mg/day in 10 cases), alprazolam (0.8−2.4 mg/day in 12 cases), biperiden (4−6 mg/day in 48 cases), trihexyphenidyl (4−10 mg/day in 13 cases) and sennoside (12−60 mg/day in 58 cases). Patients with clinically significant abnormal laboratory or electrocardiography findings, histories of mental disorder other than schizophrenia, epilepsy, alcoholism or drug abuse, or clinically significant organic or neurological disease like thyroid disease, CNS or pituitary disorder, chronic renal failure, and liver cirrhosis were excluded. The patients receiving prolactin-influencing medication such as sulpiride and patients with history of depot antipsychotics were also excluded. Smokers were defined as subjects receiving over 10 cigarettes daily. Nonsmokers were defined as subjects who had not received any cigarettes at least for a year. 2.3. Assays The plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-mass spectrometry–mass spectrometry (LC-MS–MS). The extraction procedure was as follows:
Table 1 The characteristics of smokers and nonsmokers in males and females. Males
Age (years) Body weight (kg) Drug concentration (ng/ml) Risperidone 9-hyroxyrisperidone Active moiety Prolactin level (ng/ml) Prolactin level/active moiety level
Females
Smokers (n = 36)
Nonsmokers (n = 23)
46.0 ± 14.5 60.8 ± 10.6
49.2 ± 18.3 65.1 ± 13.1
47.9 ± 13.4 58.4 ± 9.1
51.6 ± 12.6 58.3 ± 11.5
9.1 ± 13.0 38.2 ± 13.1 47.3 ± 21.9 47.6 ± 29.3 1.2 ± 0.9
8.5 ± 18.3 50.3 ± 27.6 57.6 ± 37.8 59.5 ± 31.2 1.4 ± 1.0
5.6 ± 6.1 42.0 ± 20.8 47.6 ± 23.2 100.2 ± 59.1⁎ 2.6 ± 2.0
6.7 ± 8.6 54.4 ± 57.8 53.4 ± 24.7 134.0 ± 76.7 3.1 ± 2.8
⁎ p b 0.05 compared with nonsmokers.
Smokers (n = 45)
Nonsmokers (n = 48)
200 μl of 0.1 M phosphate buffer (pH 7), 50 μl of internal standard solution (R068808: Jansen Research Foundation) and 100 μl of methanol were added to 200 μl of plasma sample. Thereafter, 400 μl of 0.1 M Borax was added. The mixture was vortexed and poured over an Extrelut NT 1 (Merck) column, which was eluted with 7 ml of ethyl acetate. The eluate was evaporated under a nitrogen stream at 65 °C and was redissolved in 100 μl of methanol, which was again evaporated under a nitrogen stream at 65 °C. The residues were redissolved in 200 μl of acetonitrile/0.01 M ammonium acetate (50/50, pH 9.0), and 5 μl were injected onto the LC-MS–MS system. The system consisted of an API 3000 (Sciex) and a column (Hypersil BDS C18 100 × 4.6, 3 μm). The mobile phase consisted of a gradient of ammonium acetate (0.01 M, pH 9.0)-acetonitrile. Among the fragment ions of the compounds, the mass-to-charge ratio (m/z) was 207.0 for risperidone, 191.0 for 9-hydroxyrisperidone, and 201.0 for the internal standard, all three of which were selected for ion monitoring. The lower limit of detection was 0.1 ng/ml for risperidone and 9hydroxyrisperidone, and the values of the intra-assay and inter-assay coefficient of variation were less than 5% at all concentrations (0.1– 100 ng/ml) of the calibration curves for both compounds. The plasma prolactin concentration was determined using an enzyme immunoassay (IMX Prolactin Dainapack, Dainabot, Osaka, Japan). The lowest limit of detection was 0.6 ng/ml, and the interassay CVs were 3.7%, 3.5% and 3.5% at the prolactin concentrations of 8, 20 and 40 ng/ml, respectively. 2.4. Data analyses and statistics The comparison of several factors, including the plasma concentration of prolactin and smoking status, was performed using a t-test and a chi-square test. Multiple regression analyses were used to examine the correlation between the plasma concentration of prolactin and several factors including gender, smoking status, plasma drug concentration and age. Smoking status and gender difference were analyzed using dummy variables (nonsmoking = 0, smoking = 1 and male = 0, female = 1). A p value less than 0.05 was regarded as statistically significant. All analyses were performed using SPSS 15.0J for windows (SPSS Japan Inc., Tokyo, Japan). 3. Results The plasma concentration of prolactin in females was dramatically higher than in males (117.6 ± 69.3 ng/ml vs. 52.9 ± 30.7 ng/ml, respectively; p b 0.001). We therefore analyzed the prolactin concentrations in males and females separately. The prolactin concentration in males did not differ between smokers and nonsmokers, but it did differ significantly between the two in females (Table 1). Although the plasma concentrations of risperidone in males were significantly higher than those in females (8.7 ± 14.9 ng/ml vs. 4.1 ± 5.2 ng/ml, p b 0.05), no difference between males and females was found in the plasma concentrations of 9-hydroxyrisperidone (42.4 ± 20.3 ng/ml vs. 48.5 ± 44.4 ng/ml, ns) or in the active moiety (50.8 ± 29.0 ng/ml vs. 49.8 ± 44.7 ng/ml, ns). There was no significant difference in the plasma concentration of risperidone, 9-hydroxyrisperidone or active moiety between the smokers and the nonsmokers in males or females (Table 1). Multiple regression analyses including smoking status, gender difference, age, plasma drug concentration (active moiety) and plasma prolactin concentration correlated positively with gender (standardized beta = 0.452, p b 0.001) and negatively with smoking status (standardized beta = −0.232, p b 0.01) and age (standardized beta = −0.171, p b 0.05) (Table 2). When the multiple regression analyses without gender difference were further analyzed, the plasma prolactin concentration correlated negatively with smoking status in females (standardized beta = −0.298, p b 0.01) and negatively with age in males (standardized beta = −0.455, p b 0.01) (Table 2).
C. Ohta et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 573–576 Table 2 Partial correlation efficient (standardized beta) and multiple correlation coefficients between prolactin concentrations and potential variables. Variable
Total (n = 154)
Males (n = 61)
Females (n = 93)
Gender Age Body weight Smoking status Drug concentration R
0.452*** − 0.171* − 0.144 − 0.232** − 0.066 0.578***
− 0.455** − 0.231 − 0.161 0.110 0.421*
− 0.160 − 0.161 − 0.298** 0.061 0.361*
R: multiple correlation coefficient. *P b 0.05, **P b 0.01, ***p b 0.001.
4. Discussion The results of these findings show that smoking status does not affect the prolactin concentration in males but does in females, while the ratio of prolactin concentration to active moiety concentration in nonsmokers was similar in smokers. To our knowledge, this is the first study indicating an effect of smoking on hyperprolactinemia. These findings suggest that, at the least, smoking status affects prolactin concentration in females during risperidone treatment and does not induce a pharmacodynamic change in the prolactin response to risperidone. However, further studies will be required to confirm the association between smoking status and higher prolactin concentration-related adverse effects. The regulation of prolactin secretion in the pituitary gland is complex. Nicotine enhances dopaminergic, serotonergic, GABAergic and glutaminergic synaptic transmission (Mansvelder et al., 2002). In a previous study using healthy subjects, an evaluation of smoking patients demonstrated that acute nicotine intervention induces prolactin secretion (Mendelson et al., 2003). However, chronic cigarette smoking is associated with a lower prolactin level (Kirschbaum et al., 1994; Corona et al., 2005). In addition, a smoking habit induces a lower prolactin response after physiological and psychological stress (Kirschbaum et al., 1994). Our findings showing a lower prolactin concentration in smokers than in nonsmokers might therefore be explained by a lower response to several stresses in smokers than in nonsmokers, although the prolactin response to risperidone, as defined by the ratio of prolactin concentration to active moiety concentration, did not differ between smokers and nonsmokers in males or females. It is known that smoking induces some metabolic enzymes, such as CYP1A2 Walter-Sack and Klotz, 1996. CYP1A2 is not a major metabolic enzyme of risperidone. In the present study, there was no significant difference in plasma risperidone concentration (Fang et al., 1999). Meanwhile, olanzapine is metabolized by CYP1A2 (Callaghan et al., 1999), and smoking has a significant effect on olanzapine metabolism (Carrillo et al., 2003). During olanzapine treatment, plasma concentrations of olanzapine in smokers are thus assumed to be lower than those in nonsmokers. In addition, the prolactin response in smokers might be lower than in nonsmokers. Taken together, it is more likely that the plasma concentration of prolactin in smokers is lower than that in nonsmokers. The plasma concentrations of prolactin did not correlate with plasma drug concentrations of risperidone or the active moiety, although our previous studies showed a positive correlation between plasma drug concentrations and prolactin concentrations during bromperidol and haloperidol treatments in males (Yasui et al., 1998; Yasui-Furukori et al., 2001). This discrepancy may be due to the relatively complex pharmacological profile of risperidone and its active metabolite, 9-hydroxyrisperidone. Risperidone has a potent serotonin 5HT2 activity and a milder dopamine D2 antagonistic activity, (Schotte et al., 1995) and its 5HT2 antagonistic effect has been associated with the inhibition of prolactin secretion (Rubin, 1987).
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It should be noted that the incidence of adverse effects related to hyperprolactinemia was not evaluated in the present study. In large clinical trials, a risperidone-associated increase in serum prolactin levels did not correlate significantly with the emergence of possible prolactin-related adverse effects (Kleinberg et al., 1999). This may be due to the considerable number of patients who are without adverse effects despite having a high prolactin level. Nevertheless, prolactin monitoring during risperidone treatment should be conducted, especially in premenopausal women who may suffer from the potentially adverse effects associated with hyperprolactinemia. Patients receiving 6 mg/day of risperidone might have around 90% dopamine D2 receptor occupancy due to tight binding to the dopamine D2 receptor (Kapur and Seeman, 2001). According to the rapid dissociation model, tight-binding atypical agents are hypothesized to have antipsychotic action when they cause other effects of dopamine blockade, including raised prolactin levels or extrapyramidal adverse effects (Kapur and Seeman, 2001). The present study had several limitations. First, the incidence of adverse effects related to hyperprolactinemia was not evaluated. In large clinical trials, the risperidone-associated increase in serum prolactin levels was not significantly correlated with the emergence of possible prolactin-related adverse effects (Kleinberg et al., 1999). This may result from the considerable number of patients who had no adverse effects despite having high prolactin levels. Nevertheless, prolactin monitoring during risperidone treatment should be conducted or physicians should ask about the possible prolactin-related adverse effects, especially to premenopausal women who may suffer from potential adverse effects associated with hyperprolactinemia. Second, the small number of patients in this study greatly limited secondary comparisons because the prolactin response to antipsychotics varies, particularly in females. Third, since the study was not designed to assess the hormone levels associated with menstrual cycle phases in premenopausal females, blood sampling failed to capture the anticipated normalization of reproductive hormone levels with the return to euprolactinemia. Blood sampling throughout the menstrual cycle would have allowed more definitive conclusions about the effects of risperidone and olanzapine on gonadal hormone levels. Further studies are required to clarify the relationship of prolactin kinetics to plasma drug concentrations. Fourth, the dosages in this study were relatively higher than the typical dosages and were administered at night; the dosage should be 4 mg for risperidone. As a result, prolactin concentrations in this study might not be the same as those in the usual clinical situation. Finally, only four weeks of testing may be insufficient for some of the patients in the present study. The period of testing in further studies should be much longer than four weeks. 5. Conclusion The present results indicate that smoking status is associated with prolactin concentration during risperidone treatment in female schizophrenia patients. Further studies will be valuable in determining whether smoking status is clinically relevant in treatment with antipsychotics. Acknowledgement All authors indicate no conflict of interest that might serve to bias this work. This study was supported by a grant from the Hirosaki Research Institute for Neurosciences, and Health and Labour Sciences Research Grants (Research on Psychiatric and Neurological Diseases and Mental Health) (H22-Seishin-Ippan-011). References Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999;37(3):177–93 Sep.
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