a Flügelman s (Mazra) Mental Health Medical Center, Acre, b Rappaport Faculty *Michael Segal and Avi Avital have contributed equally.

Transcription

1 192 Original article Prolactin serum levels in paranoid versus nonparanoid male schizophrenia patients treated with risperidone Michael Segal a,b,*, Avi Avital c,d,*, Andrei Derevenski a, Severina Berstein e, Sergio Sandbank a and Abraham Weizman f,g The frequently seen side effect of hyperprolactinemia thought to be the price paid for the antipsychotic treatment of schizophrenia. Various reports have linked the use of risperidone, an atypical antipsychotic drug, with the significant rise of prolactin levels. Thus, we set to assess possible difference between prolactin levels among schizophrenia subtypes in 45 male patients treated with stable doses (2 6 mg/day) of risperidone as antipsychotic monotherapy. All patients showed increased prolactin levels beyond the normal range, with a significant difference between the paranoid and all other groups (P < ). Specifically, the paranoid patients prolactin levels were higher than those of the schizoaffective and the disorganized ones. These results suggest that the blockade of higher dopamine activity in the paranoid schizophrenia corresponds to the prolactin increase, more than in the schizoaffective and disorganized subtypes. These findings are opposite of what was observed in the previous study of unmedicated patients. Int Clin Psychopharmacol 22: c 200 Lippincott Williams & Wilkins. International Clinical Psychopharmacology 200, 22: Keywords: dopamine, nonparanoid schizophrenia, paranoid, prolactin a Flügelman s (Mazra) Mental Health Medical Center, Acre, b Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, c Department of Neurobiology, Weizmann Institute of Science, Rehovot, d Department of Behavioral Sciences, The Max Stern Academic College of Yezreel valley, e Rebeca Sieff Health Medical Center, Safed, f Research Unit, Gehah Psychiatric Hospital, Petach Tiqva and g Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Dr Michael Segal, MD, Flügelman s (Mazra) Mental Health Medical Center, Acre, Israel Tel: ; fax: ; s: mdsegalpsy@gmail.com; Avi.Avital@Weizmann.ac.il *Michael Segal and Avi Avital have contributed equally. Received 24 March 2006 Accepted 2 January 200 Introduction In schizophrenia, increase of serum prolactin (PRL) (i.e. hyperprolactinemia) most commonly results from treatment with antipsychotic agents (Montgomery et al., 2004) Hyperprolactinemia is thought to be a cost of traditional neuroleptic therapy (Volavka et al., 2004). All atypical antipsychotics avoid extrapyramidal side effects; yet, differ in their susceptibility to induce PRL elevation (Markianos et al., 2001; Kapur et al., 2002). A low affinity and fast dissociation from the dopamine D 2 receptor, along with administration of the drug in doses that lead to appropriate levels of dopamine D 2 receptor blockade, have been proposed as most important requirements for atypicality (Kapur and Remington, 2001). Risperidone, a potent antagonist of both serotonergic (5HT 2A ) and dopaminergic D 2 receptors is associated with hyperprolactinemia in adults (Kaneda, 2001; Zhang et al., 2002). Elevation of PRL with risperidone is common and may be higher than with conventional agents (Henderson et al., 2001; Melkersson, 2005), but the frequency of clinical manifestations may be as low as 10%, and the relationship of symptoms to serum concentrations is considered unclear (Kleinberg et al., 1999). Various studies assessed the possibility that stimulated or basal PRL concentrations might differentiate schizophrenia patients or at least clinically meaningful subgroups of schizophrenic patients from normal individuals (Meltzer et al., 1983; Davis et al., 1985; Van Putten et al., 1991). Nothing much has come of past attempts to find correlations between the clinical response to antipsychotics and the rise in plasma PRL (Petty, 1999). Some data, however, suggest that patients with schizophrenia show a smaller and slower PRL response to a single dose of intravenous haloperidol than healthy controls (Keks et al., 198). This would imply that schizophrenia involves some abnormality in relationship between dopamine and PRL (Haddad and Wieck, 2004). Irrespective of this, both healthy individuals (Keks et al., 198) and patients with schizophrenia (Meltzer and Fang, 196; Keks et al., 198) show PRL elevation within minutes to hours of starting treatment with conventional antipsychotics. Prospective studies with an open-label or double-blind design indicate that medium-term treatment (3 9 weeks) with therapeutic doses of antipsychotics can increase mean baseline PRL levels by up to 10-fold. Whether patients develop a partial tolerance to the pituitary effect of antipsychotics after several months of treatment is unclear (Haddad and Wieck, 2004). Other study (Kakihara et al., 2005) found a positive correlation between plasma levels of risperidone plus 9-hydroxyrisperidone (active moiety) and extrapyramidal scores, but not the Positive and Negative Syndrome Scale. Knegtering c 200 Lippincott Williams & Wilkins

2 Prolactin levels in treated paranoid males Segal et al. 193 et al. (2005) showed that the oral dose of risperidone correlated significantly with plasma concentrations of risperidone, 9-hydroxyrisperidone, active moiety and PRL. A multicenter prospective assessment of 402 inpatients and outpatients suffering from various forms of schizophrenia and treated with antipsychotic drugs (Kinon et al., 2003) reported a high prevalence of hyperprolactinemia among males (42.4%). This rate is considerably higher than those in the general population (Halbreich and Kahn, 2003). Previously, we found a significant association between PRL serum levels and schizophrenia subtypes in unmedicated patients with low-normal rates for the paranoid subtype, intermediate for the schizoaffective subtype and high-normal for the disorganized ones (Segal et al., 2004). In this study, we have focused on male schizophrenia patients treated by risperidone because women have significantly greater PRL elevation than men during chronic antipsychotic treatment with equivalent doses (Kuruvilla et al., 1992; Smith et al., 2002). We assessed the dopaminergic blockade by risperidone illustrated as serum PRL values in schizophrenic male patients and evaluated possible differences in PRL levels between schizophrenia subtypes. Method The Ethical Local Board Committee of Flügelman s (Mazra) Mental Health Center Acre approved the study protocol. The individuals are 45 male patients years old meeting the Diagnostic and statistical manual of mental disorders-iv criteria for schizophrenia (American Psychiatric Association, 1994), hospitalized in Mazra Hospital, Acre, who received risperidone treatment at a stable dose of 2 6 mg/day for at least 1 month with no other antipsychotic, mood stabilizer or antidepressant as simultaneous treatment. The patients had received no other oral antipsychotic treatment for at least 1 month and no depot antipsychotics for at least 3 months. Exclusion criteria were physical illness including any cerebral or endocrine pathology, alcohol or drug abuse. After complete description of the study to the patients, written informed consent was obtained from all participants. The diagnosis of schizophrenia and of its subtypes was made by an investigator who was blind to the PRL serum levels. The severity of paranoid symptoms was evaluated by the MAINE paranoid versus nonparanoid scale (Magaro et al., 1981). The Positive and Negative Syndrome Scale (Kay et al., 198) was used to assess the severity of symptoms. Blood samples for serum PRL determination were collected between 8.00 and 9.00 h, before any medication and evaluated using the IMx Prolactin assay (Abbott Laboratories) a microparticle enzyme immunoassay for the quantitative measurement of PRL in human serum and plasma. Statistical analysis One-way analysis of variance followed by Scheffe posthoc multiple comparison test were used as indicated. To characterize the relationships between different measures, a Spearman correlation was calculated. All tests were two-tailed. The results are presented as means ± standard error of the means. Results The diagnosis of schizophrenia subtypes yielded the following: paranoid (n = 15), schizoaffective (n = 11) and disorganized (n = 19). No significant differences were Fig. 1 Prolactin serum level (mlu/l) Prolactin serum levels of three schizophrenia subtypes show higher level in the paranoid patients compared with both the schizoaffective and disorganized ones (***P < ).

3 194 International Clinical Psychopharmacology 200, Vol 22 No 4 Fig. 2 (a) 19 1 'MAINE' nonparanoid score (5 25) (b) 19 1 'MAINE' paranoid score (5 25) MAINE paranoid (a) and nonparanoid (b) subscale score indicate individuality of clinical diagnosis of the different forms of the disease (***P < ; **P < 0.026; *P < 0.045). present in ages between the subtypes [F(2,42) = 3.132; P > 0.131]. All patients showed an abnormal level of PRL ( > 450 miu/l). One-way analysis of variance revealed a significant difference in PRL serum level between the three schizophrenia subgroups [F(2,42) = 24.5; P < ]. Post-hoc Scheffe test revealed a significant difference between the paranoid, the schizoaffective (P < ) and the disorganized (P < ) groups. No significant difference, however, exists between the schizoaffective and the disorganized subtypes (Fig. 1). These differences were not a function of whether the patients were at their first admission or readmission. No significant difference was seen between the three schizophrenia subgroups (paranoid: 4 ± 0.6; schizoaffective: 3.54 ± 0.69; disorganized: 4 ± 0.5 mg) with regard to the dose of risperidone treatment [w 2 (8) = 5.12; P > 0.44]. A significant difference was present in MAINE paranoid subscale score between the three schizophrenia subgroups [F(2,42) = 46.15; P < ]. Post-hoc Scheffe test revealed a significant difference between the paranoid, the schizoaffective (P < ) and the disorganized (P < ) groups. Moreover, a significant difference was seen between the schizoaffective and the disorganized (P < 0.045) (Fig. 2a). In accordance, there was a significant difference in MAINE nonparanoid subscale score between the three schizophrenia subgroups [F(2,42) = 13.25; P < ]. Post-hoc Scheffe test revealed a significant difference between the paranoid and the disorganized (P < ) groups. Moreover, a significant difference was seen between the schizoaffective and the disorganized (P < 0.026) (Fig. 2b). A Spearman correlation was calculated to relate the difference in PRL serum level of the paranoid, schizoaffective and disorganized patients with their doses of risperidone treatment. A significantly positive correlation was found between the PRL serum level and risperidone doses only in the disorganized subgroup (r = 0.581, P < 0.009) (Fig. 3). No significant correlations, however,

4 Prolactin levels in treated paranoid males Segal et al. 195 Fig. 3 Prolactin serum level (mlu/l) Risperidone (mg/day) A correlation between the prolactin serum level and doses of risperidone treatment (r = 0.581, P < 0.009). were found in the paranoid (r = 0.15, P > 0.595) or the schizoaffective (r = 0.298, P > 0.33) subgroups. Discussion This study shows a significant difference in PRL levels between the paranoid and nonparanoid schizophrenia male patients treated by risperidone: the paranoid patients had higher PRL levels than the schizoaffective and the disorganized ones. These changes were observed even though all the 45 investigated schizophrenia male patients showed increased PRL levels with risperidone beyond the normal levels. The results seem to indicate a different pattern of PRL secretion in the various subtypes of the disease. These findings are complementary to our previous study (Segal et al., 2004), in which we observed opposite results in unmedicated patients: the paranoid schizophrenia patients showed significantly lower normal PRL levels than the schizoaffective and the disorganized ones, suggesting enhanced dopamine activity in the paranoid forms of the disease. The opposite results in the treated versus unmedicated patients can be related to the therapeutic action of antipsychotic drug, which is due to the blockade of D 2 receptors specifically in the mesolimbic dopamine pathway. This has the effect of reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of psychosis (Stahl, 2005). This overactivity of the dopaminergic system was recently proposed to lead to enhanced pituitary-adrenal responses in males with paranoid schizophrenia (Walsh et al., 2005). Moreover, Davis et al. (1991) suggested that the negative symptoms of schizophrenia also reflect a low dopaminergic tone. Taken together, these findings support the alleged intrinsic tone of dopaminergic activity as specific for the various forms of the disease. De Haan et al. (2004) suggested that higher striatal D 2 receptor occupancy by atypical antipsychotics is related to more severe negative symptoms. Therefore, we postulate that risperidone treatment probably raises the PRL level to a plateau imposed by specific dopamine bioactivity. We also found no differences in PRL levels between the first admissions and readmissions in the various subtypes of the disease. Kinon et al. (2003) suggested that the number of years on treatment was not related to hyperprolactinemia and that the effects of elevating PRL by antipsychotics may be detected shortly following initiation of treatment and may persist for a long time with prolonged effects on patients. Our results suggest that the evaluation of treatment with risperidone can be accompanied by a routine serum PRL examination in the different forms of schizophrenia, before and after the treatment. References American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington District of Columbia: American Psychiatric Association. Davis BM, Davis KL, Mohs RC, Mathe AA, Rothpearl AB, Johns CA, et al. (1985). Evaluating prolactin response to dopamine agonists in schizophrenia. Methodological problems. Arch Gen Psychiatry 42: Davis KL, Kahn RS, Ko G, Davidson M (1991). Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148: De Haan L, Lavalaye J, van Bruggen M, van Nimwegen L, Booij J, van Amelsvoort T, Linszen D (2004). Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications. Can J Psychiatry 49: Haddad PM, Wieck A (2004). Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64: Halbreich U, Kahn LS (2003). Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J Psychiatr Pract 9: Henderson DC, Goff DC, Connolly CE, Borba CP, Hayden D (2001). Risperidone added to clozapine: impact on serum prolactin levels. J Clin Psychiatry 62: Kakihara S, Yoshimura R, Shinkai K, Matsumoto C, Goto M, Kaji K, et al. (2005). Prediction of response to risperidone treatment with respect to plasma

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