Prolactin-sparing Antipsychotics Research Articles

Antipsychotic-induced prolactin elevation in premenopausal women with schizophrenia: associations with estrogen, disease severity and cognition.

Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17β-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17β-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. In women receiving prolactin-raising antipsychotics, 17β-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17β-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17β-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17β-estradiol and prolactin together explained 29% of the variation in processing speed (β17β-estradiol = 0.24, βprolactin=-0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17β-estradiol correlated negatively with depression/anxiety (r=-0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (β17β-estradiol=-0.41, βprolactin = 0.32, F(2,18) = 4.44, p = 0.027). In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.

Antipsychotic Use and Risk of Breast Cancer in Women With Severe Mental Illness: Replication of a Nationwide Nested Case-Control Database Study.

Breast cancer is more prevalent in women with severe mental illness than in the general population, and use of prolactin-increasing antipsychotics may be a contributing factor. A nested case-control study was conducted using the Swedish nationwide registers (inpatient/outpatient care, sickness absence, disability pension, prescribed drugs, cancers). All women aged 18-85 years with schizophrenia/schizoaffective/other nonaffective psychotic disorder/bipolar disorder and breast cancer (cases) were matched for age, primary psychiatric diagnosis, and disease duration with five women without cancer (controls). The association between cumulative exposure to prolactin-increasing/prolactin-sparing antipsychotics and breast cancer was analyzed using conditional logistic regression, adjusted for comorbidities and co-medications. Among 132 061 women, 1642 (1.24%) developed breast cancer between 2010 and 2021, at a mean age of 63.3 ± 11.8 years. Compared with 8173 matched controls, the odds of breast cancer increased in women with prior exposure to prolactin-increasing antipsychotics for 1-4 years (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI] = 1.03-1.41), and for ≥ 5 years (aOR = 1.47, 95%CI = 1.26-1.71). There were no increased or decreased odds of breast cancer with exposure to prolactin-sparing antipsychotics of either 1-4 years (aOR = 1.17, 95%CI = 0.98-1.40) or ≥5 years (aOR = 0.99, 95%CI = 0.78-1.26). The results were consistent across all sensitivity analyses (ie, according to different age groups, cancer types, and primary psychiatric diagnosis). Although causality remains uncertain, exposure to prolactin-elevating antipsychotics for ≥ 1 year was associated with increased odds of breast cancer in women with severe mental illness. When prescribing antipsychotics, a shared decision-making process should consider individual risk factors for breast cancer.

Association between long-term use of prolactin-elevating antipsychotics in women and the risk of breast cancer: What are the clinical implications?

Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

Prolactin-Raising and Prolactin-Sparing Antipsychotic Drugs and the Risk of Fracture and Fragility Fracture in Patients With Schizophrenia, Dementia, and Other Disorders

Patients who require antipsychotic drug treatment are at increased risk of fractures, including osteoporosis-related fragility fractures, for reasons related to demographics, illness-related factors, and treatment-related factors. As examples, patients with dementia may be vulnerable to falls due to cognitive and psychomotor impairment, patients with schizophrenia may be vulnerable to injury related to physical restlessness or physical aggression, and patients receiving antipsychotics may suffer falls related to sedation, psychomotor impairment, bradykinesia, or postural hypotension. Antipsychotics may also increase the risk of fracture through long-term hyperprolactinemia and resultant osteoporosis. A meta-analysis of 36 observational studies conducted in mostly elderly samples found that antipsychotic exposure was associated with an increased risk of hip fracture as well as increased risk of any fracture; the findings were consistent in almost all subgroup analyses. An observational study that controlled for confounding by indication and illness severity found that fragility fractures in patients with schizophrenia were associated with higher daily doses, higher cumulative doses, longer duration of treatment, and prolactin-raising rather than prolactin-sparing antipsychotics; in patients receiving prolactin-raising antipsychotics, the concurrent use of aripiprazole appeared protective. The absolute risks of fracture are unknown and could vary depending on patient age, patient sex, indication for antipsychotic use, nature of the antipsychotic (and associated risk of sedation, psychomotor impairment, bradykinesia, and postural hypotension), daily dose prescribed, duration of antipsychotic exposure, baseline risk of fracture, and other risk factors. Patients should therefore be individually evaluated for risk factors for falls and fractures related to sociodemographic, clinical, and treatment-related risk factors. Patients identified to be at risk should be advised about risk-mitigating strategies. If prolactin-raising antipsychotics are required in the long term, prolactin levels should be monitored and prolactin-lowering strategies should be considered. Osteoporosis should be investigated and managed, if identified, to prevent fragility fractures.

Antipsychotic Use and Risk of Low-Energy Fractures in People With Schizophrenia: A Nationwide Nested Case-Control Study in Finland.

Low-energy fractures (LEF) are more frequent in people with schizophrenia than the general population, and the role of prolactin-increasing antipsychotics is unknown. We conducted a nested case-control study using Finnish nationwide registers (inpatient, specialized outpatient care, prescription drug purchases). We matched each person with schizophrenia aged 16-85 years and incident LEF (cases) with 5 age/sex/illness duration-matched controls with schizophrenia, but no LEF. We investigated the association between cumulative exposure (duration, and Defined Daily Doses, DDDs) to prolactin-increasing/sparing antipsychotics and LEF. Adjusted conditional logistic regression analyses were performed. Sensitivity analyses were conducted. Out of 61 889 persons with schizophrenia between 1972 and 2014, we included 4960 cases. Compared with 24 451 controls, 4 years or more of exposure to prolactin-increasing antipsychotics was associated with increased risk of LEF (adjusted odds ratio (aOR) from aOR = 1.22, 95%CI = 1.09-1.37 to aOR = 1.38, 95%CI = 1.22-1.57, for 4-< 7 />13 years of exposure, respectively), without a significant association for prolactin-sparing antipsychotics. All cumulative doses higher than 1000 DDDs of prolactin-increasing antipsychotics were associated with LEF (from aOR = 1.21, 95%CI = 1.11-1.33, 1000-<3000 DDDs, to aOR = 1.64, 95%CI = 1.44-1.88, >9000 DDDs). Only higher doses of prolactin-sparing antipsychotics reached statistical significance (aOR = 1.24, 95%CI = 1.01-1.52, 6000-<9000 DDDs, aOR = 1.45, 95%CI = 1.13-1.85, >9000 DDDs). Sensitivity analyses confirmed the main analyses for prolactin-increasing antipsychotics. For prolactin-sparing antipsychotics, significant associations were limited to extreme exposure, major LEF, older age group, and males. Long-term exposure to prolactin-increasing antipsychotics at any dose, and high cumulative doses of prolactin-sparing antipsychotics is associated with significantly increased odds of LEF. Monitoring and addressing hyperprolactinemia is paramount in people with schizophrenia receiving prolactin-increasing antipsychotics.

Understanding the Limitations of the Odds Ratio in a Case-Control Study of the Association Between Breast Cancer and Exposure to Antipsychotic Drugs

Evidence suggests that women with schizophrenia are less likely to be screened for breast cancer, more likely to suffer from breast cancer, and more likely to die of breast cancer than women without schizophrenia or general population controls. Antipsychotic drugs, and especially prolactin-raising antipsychotic drugs, have been suggested to increase the breast cancer risk, but the evidence has so far been inconclusive. Against this background, a recent, large, nationwide, case-control study in Finland examined the odds of previous prolonged exposure to prolactin-raising and prolactin-sparing antipsychotic drugs in women with schizophrenia who were (cases) versus were not (controls) diagnosed with breast cancer. The study found that, relative to < 1 year of antipsychotic exposure, breast cancer was associated with significantly increased odds of previous, prolonged (> 5 years) exposure to prolactin-raising antipsychotics. The associations were not statistically significant for prolactin-sparing antipsychotics. The study is critically examined from the perspective of interpretation of the odds ratio and its limitations in order to help readers understand how to better evaluate and generalize findings in case-control studies. This is necessary because results in case-control studies are often incorrectly interpreted, and the limitations of the odds ratios derived in such studies are often not recognized. It is concluded that the design and findings of the reviewed study could not allow readers to judge whether or not prolactin-sparing antipsychotics are associated with lower breast cancer risk than prolactin-raising antipsychotics. In contexts other than breast cancer risk, adverse consequences associated with prolactin elevation are well known, and avoidance or management of hyperprolactinemia is therefore desirable.

Antipsychotic use and risk of breast cancer in women with schizophrenia: a nationwide nested case-control study in Finland

Breast cancer is more common in female patients with schizophrenia than in the general population. It is not known whether treatment with prolactin-increasing antipsychotics contributes to increased odds of breast cancer. We used Finnish nationwide registers of hospital treatment, prescription drug purchases, and cancer diagnoses to do a nested case-control study. Of women with schizophrenia, those with breast cancer (cases) were matched by age and duration of illness with five women without cancer (controls). Cases and controls were aged 18-85 years and exclusion criteria were any previous cancer diagnoses, receipt of organ transplant, mastectomy, or diagnosis of HIV. The main analysis was the association between cumulative exposure to prolactin-increasing drugs and breast cancer. The analyses were done with conditional logistic regression, by adjusting for comorbid conditions and concomitant medications. Ethnicity data were not available. Of 30 785 women diagnosed with schizophrenia between 1972 and 2014, 1069 were diagnosed with breast cancer between Jan 1, 2000, and Dec 31, 2017. Compared with 5339 matched controls, 1-4 years cumulative exposure (adjusted odds ratio [OR] 0·95, 95% CI 0·73-1·25) or 5 or more years exposure (adjusted OR 1·19, 0·90-1·58) to prolactin-sparing antipsychotics (including clozapine, quetiapine, or aripiprazole) was not associated with an increased risk of breast cancer in comparison with minimal exposure (<1 year). When compared with less than 1 year of exposure to prolactin-increasing antipsychotics (all other antipsychotics), 1-4 years of exposure was not associated with an increased risk, but exposure for 5 or more years was associated with an increased risk (adjusted OR 1·56 [1·27-1·92], p<0·001). The risk for developing lobular adenocarcinoma associated with long-term use of prolactin-increasing antipsychotics (adjusted OR 2·36 [95% CI 1·46-3·82]) was higher than that of developing ductal adenocarcinoma (adjusted OR 1·42 [95% CI 1·12-1·80]). Long-term exposure to prolactin-increasing, but not to prolactin-sparing, antipsychotics is significantly associated with increased odds of breast cancer. Monitoring prolactinemia and addressing hyperprolactinemia is paramount in women with schizophrenia being treated with prolactin-increasing antipsychotics. Finnish Ministry of Social Affairs and Health.

Estrogens in schizophrenia: progress, current challenges and opportunities.

Purpose of reviewSchizophrenia is a heterogeneous psychiatric disorder with a different, but not necessarily milder clinical presentation in women as compared to men. These sex differences have largely been attributed to the protective role of estrogens. This article reviews the current state of estrogen research in schizophrenia.Recent findingsEstrogens regulate important pathophysiological pathways in schizophrenia, including dopamine activity, mitochondrial function, and the stress system. Estrogen deficiency is common in both sexes and is associated with increases in psychotic symptoms. Hyperprolactinemia causes secondary estrogen deficiency and can be a reaction to stress, or secondary to prolactin-raising antipsychotics. Therefore, prolactin-sparing antipsychotics should be preferred especially in premenopausal women, who are more prone to hyperprolactinemia. Premenopausal women furthermore require lower doses of antipsychotics than men, since estrogens raise the availability and efficacy of antipsychotics.SummaryThe past years have established the importance of estrogens in the pathophysiology of schizophrenia and have shown its relevance to clinical practice through its influence on antipsychotic drug efficacy. Future research should focus on the neurobiological and clinical effect of contraceptives in premenopausal women with schizophrenia. Furthermore, the potential of estrogen-like augmentation with raloxifene and phytoestrogens in schizophrenia should be established in the coming years.

Women With Schizophrenia Only Half as Likely to Receive Mammograms

Women With Schizophrenia Only Half as Likely to Receive Mammograms

Sexual dysfunctions in schizophrenia: Beyond antipsychotics. A systematic review

BackgroundSexual dysfunctions (SD) in schizophrenia are frequent with strong impact on adherence and quality of life. Current recommendations stipulate to switch to prolactin-sparing antipsychotic in case of SD. ObjectivesTo synthetize in a systematic review data on the SD prevalence and the associated risk factors in schizophrenia (SZ). MethodsMedline, Google Scholar, PsychInfo, and Cochrane were explored, without any year or language restriction. ResultsOverall, 89 studies and 25,490 participants were included in the present review. SZ subjects aged 18–70 reported high SD frequency [30%–82%] (men [33%- 85%]; women [25%- 85%]). For SZ men erectile dysfunction [31%–95%] was the most frequent SD vs. loss of libido for women [31%–100%]. The following risk factors were associated with increased SD: 1. Illness severity (including psychotic symptomatology, early age at SZ onset, negative symptomatology, and continuous illness course), 2. Depressive symptomatology 3. Antipsychotics (especially first generation antipsychotics, risperidone and antipsychotic polytherapy). Switching to prolactin-sparing antipsychotics has shown effectiveness in some studies (especially aripiprazole). Antidepressants were not found to be associated with SD in SZ subjects. ConclusionThe prevalence of SD is high in SZ subjects. In addition to the current guidelines, the present review suggests that treating depressive symptoms may be a major intervention to improve SD in SZ subjects. Sociodemographic variables, physical illnesses, metabolic syndrome and peripheral inflammation have been poorly or never explored and should be included in future studies.

Efficacy and acceptability of three prolactin-sparing antipsychotics in patient with schizophrenia: a network meta-analysis

Background: The present study aimed to systematically evaluate three prolactin-sparing antipsychotics for treating schizophrenia.Methods: We performed a meta-analysis of three prolactin-sparing ant...

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.

Prolactin-Elevating Antipsychotics and the Risk of Endometrial Cancer.

The use of antipsychotics may increase the risk of endometrial cancer through elevation of prolactin levels. We investigated the association between antipsychotics that are known to cause prolactin elevation and the risk of endometrial cancer. In data from the United Kingdom Clinical Practice Research Datalink, all women who were newly treated with antipsychotics from 1990-2013 were identified and followed until 2014. Within this cohort of antipsychotic users, a nested case-control analysis was conducted. Main exposure was nonsporadic use of prolactin-elevating antipsychotics, and the active comparator was prolactin-sparing antipsychotics. Cases were women newly diagnosed with endometrial cancer (ICD-10) matched with up to 20 controls on age, calendar year of cohort entry, linkability to the Hospital Episode Statistics repository, and duration of follow-up. Conditional logistic regression models were used to determine the association of prolactin-elevating antipsychotics and endometrial cancer compared with prolactin-sparing antipsychotics. All analyses were adjusted for relevant potential confounders, including smoking, obesity, and diabetes mellitus. The cohort included 65,930 women. During 366,112 person-years of follow-up, there were 139 cases of endometrial cancer (incidence rate: 38/100,000 person-years), which were matched to 1,603 controls. Compared with the use of prolactin-sparing antipsychotics, the use of prolactin-elevating antipsychotics was not associated with an increased risk of endometrial cancer (adjusted odds ratio [aOR] = 1.00; 95% CI, 0.68-1.48). These findings remained similar with different durations of use (≤ 1 year, aOR = 1.07; 95% CI, 0.64-1.78, and > 1 year, aOR = 0.95; 95% CI, 0.58-1.54) and were robust to various sensitivity analyses. Prolactin-elevating antipsychotics were not associated with an increased risk of endometrial cancer.

Effects of aripiprazole, quetiapine and ziprasidone on plasma prolactin levels in individuals with first episode nonaffective psychosis: Analysis of a randomized open-label 1 year study

RationaleHyperprolactinemia is considered a troubling adverse effect of antipsychotics. Direct comparisons among second generation antipsychotics are scant in clinical practice. We hypothesize prolactin-sparing second-generation antipsychotics may have differential effects on prolactin levels and that they may be influenced by sex. ObjectivesTo explore the differential effect of three widely used prolactin-sparing antipsychotics, aripiprazole, quetiapine and ziprasidone, on prolactin plasma levels in first episode non-affective psychosis during a 1year of treatment. MethodFrom October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. 141 patients who were randomly allocated to aripiprazole (N=56), quetiapine (N=36) or ziprasidone (N=49) were analyzed. The main outcome was differences in prolactin plasma levels over 1year follow-up among the three antipsychotics. Prolactin levels had a skewed distribution and therefore they were log-transformed before statistical analyses. ResultsMale patients on aripiprazole had a lower risk of suffering an increase on prolactin plasma levels (N=71; F=12.645; p<0.001). There was a gender effect with smaller changes in mean prolactin values only in males. Aripiprazole had a reduced risk of hyperprolactinemia (aripiprazole 19.6%) compared to quetiapine (44.4%) and ziprasidone (32.7%) (p=0.038); and quite similar findings were found when investigating males (p=0.040). No significant differences were found in females. The percentages of mild prolactin excess were: 14.3% on aripiprazole, 36.1% on quetiapine and 18.4% on ziprasidone (χ2=6.611 p=0.037). ConclusionsOur findings provide additional evidence of differential effects of three sparing-prolactin antipsychotics on prolactin release and may help clinicians to decide among therapeutic options.

Effects of Antipsychotics on Bone Mineral Density in Patients with Schizophrenia: Gender Differences.

Low bone mineral density (BMD) and osteoporosis are common in patients with schizophrenia and detrimental to illness prognosis and life quality. Although the pathogenesis is not fully clear, series of studies have revealed factors related to low BMD such as life style, psychotic symptoms, medication use and the activity of bone absorption markers. It has been known that antipsychotic-induced hyperprolactinemia plays a critical role on decreased BMD. However, it remains uncertain whether the risk factors differ between men and women. According to the effect on prolactin, antipsychotics can be classified into two groups: prolactin-sparing (PS) and prolactin-raising (PR). Our previous study has demonstrated that clozapine which is among the PS antipsychotics is beneficial for BMD when compared with PR antipsychotics in women with chronic schizophrenia. We have also found that risks factors associated with low BMD are different between men and women, suggesting that gender-specific risk factors should be considered for intervention of bone loss in patients with schizophrenia. This article reviews the effects of antipsychotics use on BMD with particular discussion for the differences on gender and age, which implicate the alterations of sex and other related hormones. In addition, currently reported protective and risk factors, as well as the effects of medication use on BMD including the combination of antipsychotics and other psychotropic agents and other potential medications are also reviewed.

Antipsychotic Drugs and Risk of Hip Fracture in People Aged 60 and Older in Norway.

To examine associations between exposure to various subgroups of antipsychotic drugs and risk of hip fracture in older adults. Nationwide cohort study. Norway, 2005-2010. Everyone living in Norway born before 1945 (N=906,422). Information was obtained on all prescriptions of antipsychotic drugs dispensed from 2004 to 2010 (Norwegian Prescription Database) and data on all primary hip fractures from 2005 to 2010 (Norwegian Hip Fracture Registry). Incidence rates of hip fracture during person-time exposed and unexposed to antipsychotic drugs were compared by calculating the standardized incidence ratio (SIR). Thirty-nine thousand nine hundred thirty-eight (4.4%) participants experienced a primary hip fracture. Greater risk of hip fracture was associated with exposure to any antipsychotic (SIR=2.1, 95% confidence interval (CI)=1.9-2.1), first-generation antipsychotics (SIR=2.0, 95% CI=1.8-2.2), second-generation antipsychotics (SIR=2.2, 95% CI=1.9-2.4), prolactin-sparing antipsychotics (SIR=2.4, 95% CI=1.8-3.1) and prolactin-elevating antipsychotics (SIR=2.0, 95% CI=1.9-2.2). In people aged 60 and older in Norway, those who took an antipsychotic drug had twice the risk of sustaining a hip fracture during exposure than during nonexposure. Although confounding by indication, comorbidity, or other drugs used cannot be excluded, this association is relevant for clinical practice because hip fracture and antipsychotic drug use are prevalent in vulnerable older individuals. Clinical studies examining mechanisms or causality of the observed association between antipsychotic drug use and excess risk of hip fracture are needed.

The Effects of Prolactin-Raising and Prolactin-Sparing Antipsychotics on Prolactin Levels and Bone Mineral Density in Schizophrenic Patients.

We aimed to investigate the effects of antipsychotics on prolactin levels in patients diagnosed with schizophrenia and the effects of hyperprolactinemia on bone mineral density (BMD) in patients on long-term antipsychotics. In this study, we included eighty consecutive patients who were diagnosed with schizophrenia according to DSM-IV, had been using the same antipsychotic for the last ten months, and fulfilled the inclusion criteria. Data on sociodemographic characteristics of the patients were collected through an information sheet. The Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) were used to rate positive and negative symptoms of the patients. In addition, their body mass indices (BMI) were calculated. Prolactin levels were measured through luminescence immune assay and BMD measurements were made at lumbar and femoral sites using dual-energy x-ray absorbtiometry. Haloperidol (n=20) and risperidone (n=20) were assigned to prolactin-raising antipsychotic group, and olanzapine (n=20) and quetiapine (n=20) were assigned to prolactin-sparing antipsychotic group for this study. The effects of antipsychotics on BMD were compared among these groups. Hyperprolactinemia was determined in 60% of haloperidol using patients, 90% of risperidone using patients, 25% of olanzapine using patients and 10% of quetiapine using patients. Mean prolactin levels were found to be significantly higher in prolactin-raising antipsychotic using group (p<0.001). There were no statistically significant differences in BMD values between the two groups, for the sites where the measurement was done. Lumbar spine and femoral neck T-scores and Z-scores in the prolactin-raising group significantly negatively correlated with the treatment durations and chlorpromazineequivalent doses (p<0.05). BMI and BMD values of both groups also displayed statistically significant positive correlations (p<0.05). The statistically significant differences in mean prolactin levels and numbers of patients with hyperprolactinemia between the treatment groups support the validity of classifying the antipsychotics as prolactin-raising and prolactin-sparing". The relationship of BMD with the treatment duration and doses in the prolactin-raising antipsychotic using group was deemed to be important, since it indicated that a decrease in BMD was to be expected in long-term antipsychotic treatment.

Hyperprolactinémies induites par les antipsychotiques : physiopathologie, clinique et surveillance

Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it. Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don't mention them spontaneously and clinicians underestimate their prevalence. In the long-term, hypogonadism involves a premature bone loss in men and women. Klibanski and colleagues showed that this loss is significant only in women with hyperprolactinemia associated with amenorrhea. That suggests that prolactin is not directly responsible for this clinical feature. Nevertheless, prolactin seems to be involved in the development of breast cancer, but its role is unclear for prostate cancer. Our review promotes a check-up before beginning a treatment with antipsychotic agents. First, a baseline prolactin level should be measured. It should also include the research on previous treatment with antipsychotic-drugs and the assessment of adverse effects suggestive of hyperprolactinemia. Questioning should finally look for any contra-indication to antipsychotics. Monitoring during antipsychotic treatment has been studied by a group of international experts in psychiatry, medicine, toxicology and pharmacy who made a critical review of clinical guidance on hyperprolactinemia. Experts notify that it is important to check whether patients have any sexual dysfunction, such as loss of libido or menstrual irregularity, and galactorrhoea. Prolactin level should also be controlled after three months of stable dose treatment, or if any clinical feature of hyperprolactinemia appears. If a patient prescribed antipsychotic-drugs has a confirmed prolactin level above the normal range, it is necessary to exclude other causes of hyperprolactinemia. If antipsychotics are really involved, the management should be adapted with the prolactin level and the patient him/herself. To summarize, clinicians can decrease the dose of the antipsychotic or switch to a prolactin-sparing drug. Oral contraceptives can be added whether to prevent pregnancy or to prevent bone loss and osteoporosis. Finally, experts recommend reserving dopamine agonists to treat antipsychotic-induced hyperprolactinemia in very exceptional circumstances as it can worsen the mental illness.

Hiperprolactinémia em doentes psiquiátricos.

Hyperprolactinemia is a common, but neglected, adverse effect of conventional antipschycotics and of some of the atypical antipshycotics. It occurs in almost 42% of men and in 75% of women with schizophrenia who are treated with prolactin-raising antipshycotics, even though it has aroused minimal interest within the scientific community when compared with extra-pyramidal effects. Conventional antipsychotics and some of the atypical antipsychotics, such as risperidone, paliperidone, amisulpride and zotepine, are frequently associated with the raise in prolactin plasma levels. Because of this increment in prolactin secretion, they are usually known as prolactin-raising antipshycotics. On the contrary, some of the atypical antipsychotics, such as clozapine, quetiapine, olanzapine, aripiprazole and ziprazidone, have a minimal or no significant effect in prolactin levels, being known as prolactin-sparing antipsychotics. Hyperprolactinemia clinical symptoms include gynaecomastia, galactorrhoea, menstrual irregularities, infertility, sexual dysfunction, acne and hirsutism. Some of these symptoms are due to the prolactin direct action in body tissues, while a couple of them can be due to a hypothalamic-pituitary-gonadal axis dysregulation mediated by the elevation of prolactin. Some studies seem to point the evidence of an association between hyperprolactinemia and long-term consequences, such as bone mineral density decrement and breast cancer. However, these results must be confirmed through further studies. Antipsychotic treatment is the most common cause of hyperprolactinemia in psychiatric patients. However, the evidence of a prolactin increased plasma level demands the differential diagnosis with other pathologies, such as hyphotalamic and pituitary neoplasic disease. The management of a patient with antipsychotic-induced hyperprolactinemia must be adapted to each patient and it may include a reduction in the dosage of the offending antipsychotic, switching to a prolactin-sparing antipsychotic or the use of a dopamine receptor agonist, such as bromocriptine, cabergoline and amantadine. Given the osteopenic and osteoporosis risk, combined oral contraceptives must be considered in female patients in fertile age which have amenorrhoea for at least a one year period. With the exception of the Maudsley Prescribing Guidelines and the National Collaborating Centre for Mental Health, none of the current international psychiatric guidelines recommend a routine baseline prolactin determination, neither periodic prolactin levels without the presence of any hyperprolactinemia symptoms.

A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics

The aim of this meta-analysis was to quantify sexual dysfunction (SD) in patients treated with antipsychotics on the basis of selected papers that specifically investigated this type of adverse events by means of adequate instruments. A literature research was conducted using three electronic databases. Studies providing measures of SD in patients taking antipsychotics and providing separate data on single drugs were considered for inclusion. Our primary outcome measure was the rate of total SD, and our secondary outcome measures were the rates of desire, arousal, and orgasm dysfunction. We found that significant differences exist across different antipsychotics in terms of total SD, such that, partially consistent with the traditional dichotomy between prolactin-raising and prolactin-sparing antipsychotics, quetiapine, ziprasidone, perphenazine, and aripiprazole were associated with relatively low SD rates (16-27%), whereas olanzapine, risperidone, haloperidol, clozapine, and thioridazine were associated with higher SD rates (40-60%). Apart from a few exceptions, secondary analyses substantially confirmed the primary outcome measure. However, sensitivity analyses showed a significant impact of several variables on SD rates. In addition, taking into account several limitations, including the difficulty to disentangle SD related to drugs from SD related to illness itself, further studies are needed to determine more thorough evidence concerning antipsychotic-induced SD.