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A Crossover Study of Prolactin Changes Associated With Risperidone and Olanzapine
Abstract
A crossover study on prolactin changes associated with risperidone and olanzapine
We read with interest the recent article by Melkersson to reveal the different effect on prolactin elevation in schizophrenic patients treated with clozapine (none of the patients), olanzapine (24% of the patients) and risperidone (89% of the patients).1 Previous head-to-head clinical trials have revealed the similar result.2-5 However, these comparison studies might be limited by the individual variation in endocrine profiles and the demographic variables, such as age, gender, and concomitant medication use.6;7 We designed a crossover study to compare the prolactin level changes in patients switching from olanzapine to risperidone or vice versa.
Method. This is an observational crossover study to compare the prolactin levels associated with olanzapine and risperidone treatment in patients with DSM-IV schizophrenia. The subjects were treated in the routine outpatient setting and had poor or partial response to risperidone or olanzapine for at least 3 months, defined by a Clinical Global Impression Severity Score (CGI-S) more than 4 (moderately ill). They were willing to change to the other medication (olanzapine or risperidone) and to give full informed consent. The patients with specific medical diseases, such as diabetes mellitus, dyslipidemia, cardiovascular diseases and hypertension, and the patients needing to be hospitalized for an acute exacerbation of the psychotic illness, were not included in this study. The institutional ethics review board approved this research.
For the switching, their previous antipsychotic agents were gradually tapered and discontinued in 2 weeks. The clinicians were free to titrate the dose of the second drug according to clinical condition. The concomitant agents, including anticholinergics (biperidine in two patients), β blocker (propranolol in two patients) and benzodiazepines (lorazepam in eight patients, estazolam in one patient and fludiazepam in one patient), were kept at the same dose in the study period. No other antipsychotics or hormonal treatments were co-administered during the pre-switch treatment of at least 3 months and then for the 3 months after the switch. The prolactin levels were assessed following an overnight (>12 hours) fasting before medication switch, and 3 months after crossover. The paired t test was used to compare prolactin levels for baseline and postbaseline differences by the Statistical Package for Social Sciences, Version 9.0 (SPSS Inc.). The difference was considered statistically significant if a P-value was equal to or smaller than 0.05.
Results: Seventeen patients (eight females and nine males) with schizophrenia completed this study. The mean age was 34.9 ± 7.5 (ranged 22-46) years. In the nine patients taking risperidone at the time of inclusion (risperidone-first group), there was a significant (p=0.004) decrease in prolactin level (59.9±38.5μg/L) after shift to olanzapine (13.6±9.7μg/L). In the other eight patients (olanzapine-first group), the prolactin level (26.1±19.7μg/L) was increased after shifting to risperidone (40.0±16.2μg/L), but the difference did not reach a significant level (p=0.106). When comparing all patients (n=17) after olanzapine and after risperidone treatment (irrespectively of the order), the mean prolactin level was significantly higher (p=0.001) in patients receiving risperidone (50.3±31.1μg/L) than receiving olanzapine (19.5±16.1μg/L).
There were no significant differences in the mean doses of olanzapine (10.0±4.3 for risperidone-first group vs. 8.1±2.6 for olanzapine-first group) or risperidone (3.7±1.8 for risperidone-first group vs. 2.6±0.7 for olanzapine-first group) taken as first or second drugs. The mean (±SD) durations of pharmacotherapy prior to the switch of risperidone and olanzapine were 17.3±6.9 weeks and 18.0±9.1 weeks, respectively. However, there is an imbalanced male-to-female distribution between risperidone-first group (3 to 6) and olanzapine-first group (6 to 2).
Discussion: To our knowledge this is first crossover comparison study on prolactin changes in the same patients, switching from olanzapine to risperidone or vice versa. This study confirms that elevated levels of serum prolactin could be associated with the use of risperidone as compared with olanzapine. This is consistent with the result of most previous head-to-head comparison studies. 2-5 When switching from risperidone to olanzapine, serum prolactin level decreased significantly. This is consistent with the result of Kim and colleagues’ study.8 However, their study included only female subjects switched from risperidone to olanzapine (not crossover) and covered only 2 weeks.
This study has some limitations. Firstly, probably due to the small sample size, the increase of prolactin level in patients switching from olanzapine to risperidone did not reach significant level. Secondarily, due to an observational fashion, the patients were not free from antipsychotic drugs at enrolment, the male-to-female distribution between risperidone-first group (3 to 6) and olanzapine-first group (6 to 2) was not balanced, the duration of risperidone or olanzapine treatments were not the same, and the assignment to risperidone or olanzapine as first treatment was not randomised. Finally, the dosage of both drugs was not controlled, although there are no significant differences between groups. Nevertheless, our study clearly showed that in the average clinical dosage, elevated level of prolactin are associated with the use of risperidone and improved with olanzapine. According to the result of our finding, we recommend that prolactin should be closely monitored in patients during treatment with atypical antipsychotic drugs, especially with risperidone.
Reference List
1. Melkersson K. Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry 2005;66: 761-767
2. Volavka J, Czobor P, Cooper TB, et al. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry 2004;65: 57-61
3. Kinon BJ, Gilmore JA, Liu H, et al. Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials. Psychoneuroendocrinology 2003;28 Suppl 2: 69-82
4. Ahl J, Kinon BJ, Liu-Seifert H. Sexual dysfunction associated with neuroleptic-induced hyperprolactinemia improves with reduction in prolactin levels. Ann N Y Acad Sci 2004;1032: 289-290
5. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17: 407-418
6. Su KP, Wu PL, Pariante CM. A crossover study on lipid and weight changes associated with olanzapine and risperidone. Psychopharmacology (Berl) 2005; 1-4
7. Su KP, Shen WW, Chuang CL, et al. A pilot cross-over design study on QTc interval prolongation associated with sulpiride and haloperidol. Schizophr Res 2003;59: 93-94
8. Kim KS, Pae CU, Chae JH, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002;63: 408-413
... Studies involving changing to olanzapine have reported beneficial effects both in the reduction of PRL and the associated clinical symptoms in both sexes (LE: Ib-III) (Kim et al., 2002;Kaneda et al., 2004;Kinon et al., 2006;Lin et al., 2006). ...
... 72,104 Open label studies 98 reported improved sexual functioning for adjunctive therapy with aripiprazole, 104-106 vardenafil, 108 peony-glycyrrhiza-decoction, 109 carbegoline, 110 amantadine, 111,112 shakuyaku-kanzo-to 113 , and imipramine. 114 Open label studies described improvement in sexual performance when switching from antipsychotics that are strong dopamine antagonists (which often lead to elevated prolactin levels) to aripiprazole, 105,115-117 ziprasidone, 118,119 olanzapine [120][121][122][123] , and quetiapine 124,125 (prolactin sparing antipsychotics); the switch to aripiprazole was the most studied strategy. 98 In summary, strategies to treat antipsychotic-induced sexual dysfunction include lowering the dose, switching to a prolactin sparing antipsychotic, adding a dopamine agonist, aripiprazole, or a PDE-5-inhibitor. ...
A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce.
... The study showed a higher serum prolactin level and a greater impairment of sexual functioning in male outpatients who were treated with risperidone but not with quetiapine (Nakonezny et al., 2007). The open-label studies that described the switch to antipsychotic with a better profile involved the switch to aripiprazole (Byerly et al., 2009; Lee, Kim, & Park, 2006; Lu, Shen, & Chen, 2008; Mir et al., 2008), ziprasidone (Montejo & Rico-Villademoros, 2008; Weiden, Daniel, Simpson, & Steven, 2003), olanzapine (Kaneda, Kawamura, Fujii, & Ohmori, 2004; Kim et al., 2002; Kinon, Ahl, Liu-Seifert, & Maguire, 2006; Lin, Wu, Pariante, & Su, 2006), and quetiapine (Byerly et al., 2004; Nakajima, Terao, Iwata, & Nakamura, 2005 ). All of them showed improvement in sexual function and/or prolactin levels, but few had adequate sample sizes. ...
There is limited evidence for the management of sexual dysfunction and/or hyperprolactinemia resulting from use of antipsychotics in patients with schizophrenia and spectrum. The aim of this study was to review and describe the strategies for the treatment of antipsychotic-induced sexual dysfunctions and/or hyperprolactinemia. The research was carried out through Medline/PubMed, Cochrane, Lilacs, Embase, and PsycINFO, and it included open labels or randomized clinical trials. The authors found 31 studies: 25 open-label noncontrolled studies and 6 randomized controlled clinical trials. The randomized, double-blind controlled studies that were conducted with adjunctive treatment that showed improvement of sexual dysfunction and/or decrease of prolactin levels were sildenafil and aripiprazole. The medication selegiline and cyproheptadine did not improve sexual function. The switch to quetiapine was demonstrated in 2 randomized controlled studies: 1 showed improvement in the primary outcome and the other did not. This reviewed data have suggested that further well-designed randomized controlled trials are needed to provide evidence for the effects of different strategies to manage sexual dysfunction and/or hyperprolactinaemia resulting from antipsychotics. These trials are necessary in order to have a better compliance and reduce the distress among patients with schizophrenia.
The results from case-control and retrospective studies revealed that olanzapine might be associated with more increased risks of metabolic dysfunction than risperidone. The crossover design can minimize the influence of individual variation in metabolic profiles and demographic variables, such as age, sex, concomitant medication use and personal life styles.
We design a crossover study to evaluate the metabolic effect of olanzapine and risperidone.
Fifteen schizophrenic patients were shifted from olanzapine and risperidone or from risperidone and olanzapine due to poor treatment response. The body weights, lipid profiles and fasting glucose levels were assessed before medication switch and 3 months after crossover.
In the seven patients taking risperidone at the time of inclusion (risperidone-first group), after shifting to olanzapine, there was a significant increase in triglyceride level (p=0.048) and body weight (p=0.008). In the other eight patients (olanzapine-first group), after shift to risperidone, there was a decrease in triglyceride level (p=0.009), body weight (p=0.049) and body mass index (BMI; p=0.04). When comparing the metabolic profiles in all patients after olanzapine and after risperidone (irrespective of the order of treatment), the mean triglyceride level (p=0.001), body weight (p=0.001) and BMI (p=0.015) were significantly higher in patients receiving olanzapine than in those receiving risperidone. Furthermore, there was a small increase in total cholesterol level (p=0.091) and a small decrease in high-density lipoprotein (HDL) level (p=0.061) in olanzapine group, but the differences did not reach a significant level. There was no significant difference between olanzapine and risperidone in fasting glucose and low-density lipoprotein (LDL).
This study confirms that elevated levels of triglyceride and body weight could be associated with the use of olanzapine as compared with risperidone. The changes in body weights and lipid profiles should be closely monitored in patients during treatment with atypical antipsychotic drugs.
Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.
Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.
Atypical antipsychotic drugs for the treatment of schizophrenia provide effective treatment of psychotic symptoms with a safety profile superior to conventional antipsychotic medications. Neuroendocrine abnormalities in patients with schizophrenia, such as chronic hyperprolactinemia, may now potentially be minimized by the use of newer prolactin-sparing antipsychotic drugs. A discrimination of prolactin-sparing versus prolactin-elevating antipsychotic drugs may provide the clinician with treatment choices in order to avoid or mitigate hyperprolactinemia-associated morbidity.
Results from five clinical trials were used to characterize factors that may influence antipsychotic drug effects on levels of serum prolactin. Factors investigated included drug treatment, gender, time course, potential for reduction or reversibility, and age.
Factors that influenced the risk of hyperprolactinemia included gender, with females appearing to be more sensitive than males, and drug treatment, with risperidone and conventional antipsychotic agents increasing prolactin more than olanzapine. Patients of all ages demonstrated sensitivity to increased prolactin. Furthermore, patients with hyperprolactinemia sustained the effect over time. Hyperprolactinemia reversed when patients were switched to a prolactin-sparing antipsychotic medication.
Effects of antipsychotic medications on serum prolactin are multi-factorial. Evidence for sexual, reproductive, and general medical consequences of antipsychotic-induced hyperprolactinemia is developing, and identifying antipsychotic drugs with a favorable prolactin profile would be important in mitigating these consequences. Most notably for women, atypical or novel antipsychotic drugs with a prolactin-sparing profile may offer effective clinical treatment with preservation of physiological hormonal function.
Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level.
Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999.
Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects.
Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect.
We attempt to demonstrate the association between neuroleptic-induced hyperprolactinemia and sexual dysfunction in schizophrenic patients treated with prolactin-elevating antipsychotics. Our findings indicate that sexual function improved with euprolactinemia in patients switched from treatment with prolactin-elevating antipsychotics to olanzapine.
The aim of this cross-sectional study was to investigate the degree and frequency of prolactin (PRL) elevation and related symptoms in patients treated with 3 different atypical antipsychotics: clozapine, olanzapine, and risperidone.
Twenty-eight patients receiving clozapine, 29 patients receiving olanzapine, and 18 patients receiving risperidone (all meeting DSM-IV criteria for schizophrenia, schizophreni-form disorder, or schizoaffective disorder) were studied. The median daily dose was 400 mg of clozapine, 10 mg of olanzapine, and 3 mg of risperidone. Fasting morning blood samples were analyzed for PRL, and the occurrence of hyper-prolactinemic symptoms in the patients was evaluated.
Elevated PRL levels were found in 16 (89%) of the patients receiving risperidone and in 7 (24%) of the patients receiving olanzapine, but in none of the patients receiving clozapine. In addition, there was a significant difference in median PRL level among the treatment groups (p < .0001), in that the PRL level was higher both in the patients treated with risperidone and in the patients treated with olanzapine, compared to those treated with clozapine. Moreover, hyperpro-lactinemic symptoms-menstrual disturbances, galactorrhea, impotence, oligospermia, and decreased libido-were reported in 8 (44%) of the risperidone-treated patients and in 1 (3%) of the olanzapine-treated patients, but in none of the clozapine-treated patients.
Treatment with risperidone was frequently associated with hyperprolactinemia and related symptoms, whereas the occurrence of PRL elevation and related symptoms was modest in patients receiving olanzapine and nonexistent in those receiving clozapine. Thus, atypical anti-psychotics in therapeutic doses differ with regard to effect on PRL secretion.