Prolactin-raising 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.

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.

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.

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.

The use of clozapine is protective for low bone mineral density induced by prolactin-raising antipsychotics in inpatients with schizophrenia.

This retrospective study aimed to evaluate the effects of prolactin-raising (PR) antipsychotics vs. clozapine combined with PR antipsychotics on BMD of patients with schizophrenia and analyzed clinically related factors that may affect BMD. A total of 125 participants (males/females = 62/63) were included. Patients were treated with PR antipsychotics vs. clozapine combined with PR antipsychotics. They were similar in demographic and clinical characteristics. BMD was examined in their lumbar spine and proximal femur by a dual-energy X-ray (DEXA) absorption measurement device. Laboratory variables (including blood levels of prolactin, estradiol, testosterone, and cortisol) were collected. Among 125 inpatients with schizophrenia, the prevalence of osteoporosis and low BMD (including osteoporosis and osteopenia) was 26.4% and 64%. The average BMD T value in patients receiving clozapine combined with PR antipsychotics was significantly higher than in patients receiving PR antipsychotics (p< 0.05). Patients in the clozapine combined with PR antipsychotic group had higher testosterone levels than the PR antipsychotic group (Z = - 2.77, p= 0.006). Linear logistic regression analysis indicated that clozapine combined with PR antipsychotic treatment (p< 0.05) and higher estradiol level (p< 0.05) may be significantly associated with higher BMD. Our results suggest that the use of clozapine may be a protective factor for low BMD induced by PR antipsychotics in inpatients with schizophrenia. The possible mechanism is that clozapine may protect BMD by regulating estrogen and testosterone levels, but the mechanism by which clozapine regulates these two sex hormones needs further investigation.

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.

The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: Findings from a longitudinal observational cohort

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ≥2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean±SD age: 58.5±11.0years; duration of treatment: 26.7±13.8years). Patients were divided into a prolactin-raising antipsychotic (n=141) or prolactin-sparing (n=23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4±1.6years, a significant antipsychotic-class vs. time interaction was found (p=0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings.

Clozapine protects bone mineral density in female patients with schizophrenia

Decreased bone mineral density (BMD) is common in patients with schizophrenia; however, the pathogenesis is unclear. Different classes of antipsychotic agents may affect BMD. This study systemically examined the effects of clozapine vs. other antipsychotics, and several hormonal and metabolic factors that may contribute to BMD in female patients with schizophrenia, who are more vulnerable than males. Forty-eight women with schizophrenia, treated with long-term antipsychotics of the prototype prolactin-sparing (PS) antipsychotic agent clozapine vs. prolactin-raising (PR) antipsychotics were enrolled. They were matched for demographic and clinical characteristics. Various factors, including blood levels of prolactin and sex hormones, psychopathological symptoms, global assessment of functioning, physical activity, and menopausal status, were determined to explore their contribution to low BMD (LBMD), defined as a dual-energy X-ray absorptiometer (DEXA) T score <-1. Overall, women receiving clozapine have better bone density than women receiving PR antipsychotics. Compared to PR antipsychotics, PS clozapine therapy is a protective factor (odds ratio 28.2, 95% confidence interval 2.37-336.10, p=0.008) for LBMD. Predictors for higher bone density in the clozapine group included higher clozapine dose (p<0.001), younger age (p<0.001), and higher thyroid-stimulating hormone level (p<0.001); in the PR group, higher body mass index (p=0.003) and lower alkaline phosphatase level (p=0.007) were associated with LBMD. This study suggests that clozapine treatment is beneficial for BMD compared to PR antipsychotic treatment in women with chronic schizophrenia, and clozapine's bone-density protecting effect is dose-related.

Bone Remodeling, Bone Mass and Weight Gain in Patients with Stabilized Schizophrenia in Real-Life Conditions Treated with Long-Acting Injectable Risperidone

Background: Prolactin-raising antipsychotics, risperidone (antidopaminergic activity), may be associated with low bone mass. On the other hand, risperidone may cause an increase in body weight thought to be favorable for bone. Objectives: (1) To determine bone remodeling parameters and bone mass in patients with schizophrenia on long-term treatment with long-acting injectable risperidone (LAIR) in naturalistic settings, and (2) to evaluate the change in body weight, metabolic profile and neuroendocrine status in these patients. Design: This was a prospective, cross-sectional study. Patients: Patients included 26 outpatients with controlled schizophrenia in real-life conditions (age 31.3 ± 1.3 years, BMI 28.1 ± 1.0) on long-term maintenance therapy with LAIR for a mean of 18.0 ± 1.6 months (range 6–36) with a mean dose of 38 ± 2 mg. 35 subjects matched for sex, age, BMI and education served as healthy controls. Methods: Serum osteocalcin, C-terminal telopeptide of type I collagen (CTx), vitamin D, leptin, prolactin, sex steroids, and parathyroid hormone were assessed. Indices of insulin sensitivity and resistance were determined following an oral glucose tolerance test (OGTT). Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN). Results: Mild to moderate hyperprolactinemia (1,000–2,000 mU/l) was associated with asymptomatic hypogonadism. Prolactin values >2,000 mU/l occurred in a few female patients. Hypogonadism leads to a slight increase (upper limit of normal) in bone resorption marker (CTx) in patients with schizophrenia (p = 0.023). As for bone mass, although lower at the spine than in healthy subjects, it did not reach statistical significance (p = 0.094), while at the FN, BMD was not different from healthy subjects. Body weight increased on average 8.7 ± 1.6 kg in more than 50% of patients. Leptin levels adjusted for BMI in females were significantly higher in patients than in healthy female subjects (p = 0.018), while in males there was no difference between the groups (p = 0.833). A high prevalence of low vitamin D levels and more current smokers were found in patients with schizophrenia. As for the metabolic profile during treatment with risperidone, the low Matsuda index of insulin sensitivity (p = 0.039) confirmed insulin resistance in these patients. Conclusion: A potential long-term consequence of asymptomatic hypogonadism due to risperidone-induced hyperprolactinemia might cause a slight rise in bone resorption marker (CTx). On the other hand, by increasing body weight, risperidone could have a protective effect on the bone and thus no change in bone mass was recorded when compared with healthy controls.

Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole

Hyperprolactinemia is an important but neglected adverse effect of antipsychotic medication. All first generation antipsychotics and the second generation antipsychotics amisulpride and risperidone have been shown to cause marked elevation in serum prolactin levels, whereas most other second generation antipsychotics and aripiprazole appear to have little or no effect on serum prolactin levels. This study was aimed to assess the time course of changes in antipsychotic-induced hyperprolactinemia during the process of antipsychotic switching to aripiprazole. Twenty-three female schizophrenic subjects with risperidone- or sulpiride-induced symptomatic hyperprolactinemia were recruited into the study and 20 of them completed the trial. We added aripiprazole to the therapeutic dose first, then overlapped the preexisting antipsychotic treatment and aripiprazole, and finally tapered the preexisting antipsychotic treatment. Clinical status was assessed by using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity Scale (CGI-S). Assessment scales and serum prolactin levels were measured at baseline, during the combination treatment period, and four weeks after having completed discontinuation of the preexisting antipsychotic treatment. Switching antipsychotic drugs to aripiprazole was effective in reducing serum prolactin levels and restoring menstruation in schizophrenic patients who received prolactin-raising antipsychotics. Mean serum prolactin levels at baseline, during combination period, and after the switch were 97.0 ± 69.0 ng/ml, 27.2 ± 10.6 ng/ml ( p < 0.001, vs. baseline), and 12.2 ± 5.3 ng/ml ( p < 0.001, vs. baseline), respectively. None of the study subjects experienced any serious adverse effects during the switching process. No significant changes were noted in the PANSS and CGI-S scores during the switching process. The prolactin-normalizing effects of aripiprazole are likely caused by the unique characteristics of the dopamine partial agonist with its high affinity for dopamine D 2 receptors.

Are sexual side effects of prolactin-raising antipsychotics reducible to serum prolactin?

To assess the degree to which sexual side effects (SSE) are associated with prolactin-raising antipsychotics, and to what degree such SSE are reducible to serum prolactin levels. A large sample (n=264) of patients treated for 6 weeks with prolactin-raising and prolactin-sparing antipsychotics was assessed for changes in sexual performance in terms of libido, arousal and orgasm using the Antipsychotics and Sexual Functioning Questionnaire. For men also erection and ejaculation were evaluated. At 6 weeks, prolactin levels were assessed and analyzed in relation to sexual performance. Men and women reported SSE (libido and orgasm) with about the same frequency. Prolactin-raising medication induced significantly more SSE than prolactin-sparing medication (adjusted OR=3.4, 95% CI: 1.8, 6.5) with 43% of emerging SSE attributable to prolactin-raising medication. When adjusted for serum prolactin, the association between prolactin-raising medication and SSE was reduced but remained significant (OR=2.1, 95% CI: 1.0, 4.5); 27% of emerging SSE remained attributable to prolactin-raising medication. For erectile and ejaculatory dysfunction in men, the attributable fraction due to prolactin-raising medication was 32% before, and 11% after adjustment for serum prolactin. Around 40% of emerging SSE in schizophrenia are attributable to the prolactin-raising properties of antipsychotic medication. Of this attributable fraction, around one-third to two-thirds is directly reducible to the effects of serum prolactin.

Bone mineral density changes over a year in young females with schizophrenia: Relationship to medication and endocrine variables

Introduction Hyperprolactinaemia is associated with the use of potent dopamine-2 receptor blocking anti-psychotic agents in schizophrenia and with bone loss in the general population. Significantly higher rates of reduced bone mineral density (BMD) have been identified in young pre-menopausal females with schizophrenia receiving prolactin-raising anti-psychotics compared to those receiving prolactin-sparing anti-psychotics. This prospective study compared BMD alterations over a period of 1 year in patients maintained on either prolactin-raising (e.g. risperidone, amisulpride or depot anti-psychotics) or prolactin-sparing (olanzapine) anti-psychotics. The effects of specific interventions to improve BMD were also examined in the context of whether patients were receiving either prolactin-raising or anti-psychotics or Olanzapine. Methods Pre-menopausal females ( n = 38) with a diagnosis of schizophrenia, who had received exclusively either prolactin-raising ( n = 25) or prolactin-sparing ( n = 13) anti-psychotics during their treatment history, had clinical, endocrine and bone marker assessments performed at baseline and every 3 months for a period of 1 year. BMD was measured by DEXA scan at baseline and at 1-year follow-up. Patients from both groups either received specific interventions ( n = 16) or no interventions ( n = 16) to improve bone density. Results There was an overall gain in lumbar BMD values in the prolactin-sparing subgroup, compared to an overall loss in the prolactin-raising subgroup ( p = 0.02), for the groups that received no specific interventions to improve BMD. Within the group that received specific interventions, the subgroup receiving prolactin-sparing anti-psychotics had a significant increase in lumbar ( p = 0.01) and hip ( p = 0.01) BMD over time, whereas alterations in the prolactin-raising subgroup were not significant. Discussion Women taking prolactin-raising anti-psychotics and not receiving specific interventions to improve bone density had evidence of ongoing bone demineralisation over a year; whereas women taking prolactin-sparing anti-psychotics had a modest overall increase in BMD. Most clinical interventions appeared to be helpful, but were significantly more effective in those taking prolactin-sparing anti-psychotics.

Risk of hip fracture in patients with a history of schizophrenia

There is evidence of an association between decreased bone mineral density, schizophrenia, and prolactin-raising antipsychotic medication. However, it is not known whether this is clinically significant. To investigate whether patients with a history of schizophrenia are at increased risk of hip fracture. In a case-control study, we compared cases of 'hip fracture' on the General Practice Research Database (n=16,341) with matched controls (n=29,889). Hip fracture was associated with schizophrenia (OR=1.73; 95% CI 1.32-2.28), and prolactin-raising antipsychotics (OR=2.6; 95% CI 2.43-2.78), in the univariate analysis. In the multivariate analysis, prolactin-raising antipsychotics were independently associated with hip fracture but schizophrenia was not. A significant interaction between gender and antipsychotics was foundinthe association with hip fracture (P=0.042); OR=2.12 (95% CI1.73-2.59) for men, OR=1.93 (95% CI1.78-2.10) for women. The association between prolactin-raising antipsychotic medication and hip fracture may have serious implications for public health. Mental health service patients may require preventive measures including dietary and lifestyle advice.

0281 HIGH RATES OF MEDICATION ADHERENCE REQUIRED TO ACHIEVE THERAPEUTIC BENEFIT IN FIRST EPISODE PSYCHOSIS

Hyperprolactinaemia is associated with the use of potent dopamine-2 receptor blocking anti-psychotic agents in schizophrenia and with bone loss in the general population. Significantly higher rates of reduced bone mineral density (BMD) have been identified in young pre-menopausal females with schizophrenia receiving prolactin-raising anti-psychotics compared to those receiving prolactin-sparing anti-psychotics. This prospective study compared BMD alterations over a period of 1 year in patients maintained on either prolactin-raising (e.g. risperidone, amisulpride or depot anti-psychotics) or prolactin-sparing (olanzapine) anti-psychotics. The effects of specific interventions to improve BMD were also examined in the context of whether patients were receiving either prolactin-raising or anti-psychotics or Olanzapine.Pre-menopausal females (n = 38) with a diagnosis of schizophrenia, who had received exclusively either prolactin-raising (n = 25) or prolactin-sparing (n = 13) anti-psychotics during their treatment history, had clinical, endocrine and bone marker assessments performed at baseline and every 3 months for a period of 1 year. BMD was measured by DEXA scan at baseline and at 1-year follow-up. Patients from both groups either received specific interventions (n = 16) or no interventions (n = 16) to improve bone density.There was an overall gain in lumbar BMD values in the prolactin-sparing subgroup, compared to an overall loss in the prolactin-raising subgroup (p = 0.02), for the groups that received no specific interventions to improve BMD. Within the group that received specific interventions, the subgroup receiving prolactin-sparing anti-psychotics had a significant increase in lumbar (p = 0.01) and hip (p = 0.01) BMD over time, whereas alterations in the prolactin-raising subgroup were not significant.Women taking prolactin-raising anti-psychotics and not receiving specific interventions to improve bone density had evidence of ongoing bone demineralisation over a year; whereas women taking prolactin-sparing anti-psychotics had a modest overall increase in BMD. Most clinical interventions appeared to be helpful, but were significantly more effective in those taking prolactin-sparing anti-psychotics.