Antipsychotic medications are the most common pharmacological cause of hyperprolactinemia,1 and patients taking antipsychotics have higher prevalence rates of hyperprolactinemia than the general population.2 Sustained elevation of prolactin can cause amenorrhea, galactorrhea, hirsutism, gynecomastia, impotence, loss of libido, and infertility.3 Long-term hypogonadism due to hyperprolactinemia has been associated with osteoporosis4 and hip fracture.5 Preclinical animal models indicate that prolonged high levels of prolactin may predispose to breast cancer; however, clinical data are limited and inconclusive.6
Antipsychotic drugs differ in their propensity to cause hyperprolactinemia.3,7 Most first-generation antipsychotics have been associated with pronounced elevation of prolactin levels.8 Second-generation antipsychotics are less likely to induce sustained hyperprolactinemia with the exception of risperidone and amisulpride.9–13 Several mechanisms have been proposed to account for the different antipsychotic propensity to induce hyperprolactinemia: (1) D2 receptor–binding affinity,14 (2) differential penetrability across the blood-brain barrier,15 and (3) central mechanisms modulated by monoamines other than dopamine.16
Apart from the aforementioned pharmacokinetic and pharmacodynamic properties, dosage and duration of treatment may have an effect on prolactin levels and might explain a significant amount of variability. A key factor to a better understanding of the long-term consequences of antipsychotic-induced hyperprolactinemia is to establish whether prolactin response is transient and tolerance is developed over time or if elevated prolactin levels are sustained.
Long-term longitudinal studies of prolactin response to antipsychotics are scarce. In 1976, Kolakowska et al17 observed that patients on chronic chlorpromazine treatment had lower prolactin levels than patients on acute treatment, suggesting that there was tolerance to its hyperprolactinemic effects. Other prolactin naturalistic studies on first-generation antipsychotics described prolactin decrease over time.18,19 The existing evidence shows that most second-generation antispsychotics induce temporary elevations.20–22 Data available on risperidone are contradictory. Some studies indicate that there is a tendency toward normal levels,23–25 and others have found persistent elevated prolactin concentrations after months or years of treatment.26,27
In this study, we investigated the long-term (up to 1 year) effect on prolactin levels of olanzapine, risperidone, and haloperidol in a naturalistically treated first-episode psychosis population. By using longitudinal design with repeated measures, which allows us to control for individual differences, we will be able to detect relatively small effects.
MATERIALS AND METHODS
Patients included in this study were drawn from a prospective, randomized, open-label clinical trial. The study population comprised a consecutive sample of psychotic patients enrolled in the first-episode psychosis program of Cantabria. A detailed description of the program has been published elsewhere.28 The patients had to meet the following criteria: (a) experiencing their first episode of psychosis, (b) age 15 to 60 years, (c) living in the catchment area, and (d) never treated with antipsychotic medication. All patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for schizophrenia spectrum disorders.
The patients were randomly assigned to receive haloperidol, olanzapine, or risperidone. Concomitant medications were permitted if clinically needed. Those patients who did not respond after 6 weeks of treatment or who had significant adverse effects were changed to a different antipsychotic. All subjects gave written informed consent to the protocol approved by The Ethics Committee of Marques de Valdecilla University Hospital.
Fasting venous blood samples were collected between 8:00 and 10:00 AM (10–12 hours after the bedtime antipsychotic dose) at baseline, 3 months, and 1 year follow-up. Prolactin levels were measured by chemiluminescent automated assay in an Advia Centaur Chemistry System from Siemens (SIEMENS Health Care Diagnostics, Newark, Del) using the reagents supplied by Siemens. The reference range for the laboratory was 2.80 to 29.2 ng/mL for women and 2.10 to 17.7 ng/mL for men.
Adverse Drug Reactions
To evaluate adverse drug reactions (ADRs) associated to antipsychotic treatment, the Udvalg for Kliniske Undersogelser scale was used.
Differences over time in prolactin plasma levels were evaluated with a repeated-measures analysis of variance that included the time by treatment interaction. Sex and age were used as covariates. Bonferroni post hoc tests were conducted to assess differences between the treatment groups. The Statistical Package for Social Science version 16.0 was used for statistical analyses.
Characteristics of Study Population
One hundred forty-one subjects were included in the first episode program of Cantabria between February 2002 and February 2005. Of these, 16 subjects were lost before 1-year follow-up and 15 subjects did not have any of the 3 prolactin measurements. This resulted in 110 subjects who were included in the final analysis. Sixty-one percent (67/110) had a diagnosis of schizophrenia. The mean ± SD age was 27.7 ± 7.3 years. The prevalence of the male sex was 61% (67/110).
Thirty-five percent (39) of the 110 subjects were initially treated with haloperidol, 31% (34/110) were initially treated with olanzapine, and 34% (37/110) were initially treated with risperidone. Median doses and prolactin levels at baseline, 3 months, and 1 year are described in Figure 1. At the end of the first year, 66% (73) of the 110 patients continued with the same treatment (51% of the haloperidol group, 74% of the olanzapine group, and 76% of the risperidone group). Adverse drug reactions were the main reason for antipsychotic change (21/37 [57%]).
Differences Between Treatments in Inducing Hyperprolactinemia
A repeated-measures analysis of covariance revealed on both, per intention-to-treat analysis (n = 110; F = 21.63, df = 2.105; P < 0.001; partial eta square = 0.29) and per protocol analysis (n = 73; F = 17.28, df = 2.68; P < 0.001; partial eta square = 0.34), a significant difference between treatments. Post hoc tests showed that the difference was significant between risperidone and olanzapine (P < 0.001) and between risperidone and haloperidol (P < 0.001).
The drug-by-time interaction analysis showed a statistically significant effect (intention-to-treat analysis: F = 8.21, df = 4; P < 0.001; partial eta square = 0.14 and per protocol analysis: F = 8.45, df = 4; P < 0.001; partial eta square = 0.20). The post hoc analyses indicated that risperidone, but not olanzapine or haloperidol, caused a significant increased in prolactin levels at 3 months and at 1 year compared with baseline values.
The percentage of patients with pathological values was calculated according to the reference ranges used by the laboratory of our hospital. A significantly higher percentage of patients had abnormal prolactin levels in the risperidone group (32/36 [89%]) compared with olanzapine (15/33 [45%]) and haloperidol (17/37 [46%]) treatment groups at 3 months (men: χ2 = 11.3; P = 0.004; women: χ2 = 7.4; P = 0.025). The prolactin levels persisted elevated in patients treated with risperidone (20/28 [71%]) compared with those treated with olanzapine (4/25 [16%]) and haloperidol (4/20 [20%]) at 1-year follow-up (men: χ2 = 12.9; P = 0.002; women: χ2 = 8.4; P = 0.015).
Hyperprolactinemia and ADRs
At 1-year assessment, the prevalence of sexual ADRs with any level of severity at the Udvalg for Kliniske Undersogelser scale was 39% (11/28) in the risperidone group, 24% (6/25) in the olanzapine group, and 20% (4/20) in the haloperidol group. This difference did not reach statistical significance (P = 0.28).
Eleven patients (6 patients from the risperidone group, 4 patients from the haloperidol group, and 1 patient from the olanzapine group) with high prolactin levels associated with sexual ADRs required treatment change before the end of the year. The initial antipsychotic treatment was changed to another antipsychotic less prone to cause hyperprolactinemia. All patients except one responded with a normalization of prolactin levels and improvement or disappearance of sexual ADRs.
These results revealed that long-term treatment with olanzapine and haloperidol does not significantly affect prolactin plasma levels. At the end of the first year, elevated prolactin levels persisted in most of the patients treated with risperidone, although they showed a tendency to decrease.
Several factors could contribute to the decrease of plasma prolactin levels over time. First, prolactin is known to exert a negative feedback effect on its own secretion.29 Such a negative feedback may be in part responsible for the fall in prolactin levels at long term. Second, maintenance treatment required lower doses of antipsychotics, and the lower prolactin levels at one year might reflect in part a dose-dependent effect.15 Third, the population of patients who continue with the same antipsychotic drug at the end of the follow-up represent a subgroup of patients who tolerate the treatment better. Finally, we cannot ignore that over time, the patients’ adherence to treatment decreased.
A high percentage of patients in the 3 groups of treatments showed prolactin levels above the reference range at baseline. Prolactin-secretory response has been observed in different stressful situations.30 The high level of stress secondary to the acute psychotic symptoms at the moment of admission may play a role in the prolactin levels observed at the beginning of the study. Another factor that could explain in part the increased prolactin values is that a small proportion of patients had received their first dose of antipsychotic the night before or a rapid tranquilization including an antipsychotic drug. Similarly, the European First Episode Schizophrenia Trial,31 which included patients with first-episode psychosis with no or minimal exposure to antipsychotic medications, reported high rates of hyperprolactinemia at baseline with all the treatments (from 59% to 78%).
The results showed a significant difference between treatments in the long-term prolactin response. At 1-year follow-up, most of the patients in the haloperidol and olanzapine arms had prolactin values that fell within the reference range. These findings are in agreement with most previous studies that have reported no significant or transient elevations with olanzapine treatment.12,21,22 The existing evidence for haloperidol seems contradictory. Most studies showed a significant prolactin increase,21,22,32 but some authors have reported no significant changes with haloperidol treatment.12 In first-episode psychosis studies, Schooler et al33 found hyperprolactinemia in 49.8% of patients treated with haloperidol at the end of the first year. Green et al34 did not find differences between haloperidol and olanzapine treatments. In the European First Episode Schizophrenia Trial study,31 abnormal prolactin values were observed in 44% of patients at 1-year follow-up in patients treated with haloperidol.
Patients treated with risperidone experienced a substantial increase at 3 months resulting in prolactin levels above the reference range in 90% of men and 87% of women. The levels decreased at 1 year, although still more than 70% of the patients remained above the normative range. In the same way, previous studies have reported the highest liability to elevate plasma prolactin levels with risperidone treatment.10–12,33,35 There are few studies on long-term prolactin response to risperidone. In a double-blind clinical trial in patients with a first episode of psychosis, Schooler et al33 described similar results with a prevalence of hyperprolactinemia of 73.8% at 1 year.
Some previous investigations have described ADRs such as osteopenia36 and sexual dysfunction37 associated with prolactin elevation induced by antipsychotics. In contrast, several other studies have failed to find an association between hyperprolactinemia and sexual ADRs.10,38 We found a higher proportion of patients with sexual dysfunction in the risperidone group, but the difference was not significant. In most studies, sexual ADRs are presumably underreported owing to patients possibly finding it difficult to discuss them or because the physician does not systematically inquire about them. Despite sexual dysfunction having been found as the most severe and distressful of all ADRs,39 it is the least studied of the ADRs associated with antipsychotic therapy.40 Sexual dysfunction not only may negatively affect adherence to medication but also prevent patients reaching functional recovery, which ultimately should be the goal in patients with first-episode psychosis.
In conclusion, treatment with some antipsychotic drugs like risperidone requires long-term monitoring of prolactin levels, and patients should be queried about possible symptoms related to hyperprolactinemia. Change to another treatment should be considered in those patients more sensitive to prolactin-releasing effect.
Several limitations should be mentioned. First, the main limitation of this study is the relatively small sample size, particularly relating to the ability to compare the sexual ADRs related to hyperprolactinemia. More frequent prolactin measurements and more frequent and specific questionnaires to measure sexual ADRs could provide more accurate data to evaluate the relationship between hyperprolactinemia and sexual dysfunction. Second, the number of patients who required treatment change was higher in the haloperidol group than in the other 2 groups. The patients who remain with the same medication are the ones who tolerate the treatment better, and this may partially explain the reduced prolactin levels of the haloperidol group at the end of the first year. Third, we did not find a correlation between risperidone dose and prolactin levels (data not shown), but a dose-dependent effect could not be ruled out by this study owing to the narrow dose range used in this population. Finally, longer follow-ups are needed to investigate if the prolactin plasma levels continue decreasing after the first year in patients treated with risperidone. Plasma medication levels could contribute to discard the possibility that the reduced prolactin levels detected at 1 year is a consequence of poor compliance at long term.
AUTHOR DISCLOSURE INFORMATION
In the past 3 years, Dr Garcia-Unzueta, Dr Amado, and Dr Martínez-Garcia had no conflicts of interest. In the past 3 years, Dr Perez-Iglesias has received support to attend scientific conferences from Lilly; Dr Mata has received honoraria for his participation as a speaker at educational events from Lilly and Johnson & Johnson; and Prof Vazquez-Barquero and Prof Crespo-Facorro have received unrestricted research funding from AstraZeneca, Pfizer, Bristol-Myers Squibb, and Johnson & Johnson, which was deposited to the research accounts at the University of Cantabria, Spain. Prof Vazquez-Barquero has received honoraria for his participation as a speaker at educational events from Johnson & Johnson. Prof Crespo-Facorro has received honoraria for his participation as a speaker at educational events from Pfizer, Bristol-Myers Squibb, and Johnson & Johnson, and consultant fees from Pfizer. Dr Valdizan has received honoraria for research activity for FAES SA.
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