Prolactin-related Adverse Events Research Articles

Guideline Adherence of Monitoring Antipsychotic Use for Nonpsychotic Indications in Children and Adolescents: A Patient Record Review.

Antipsychotics are frequently prescribed to children and adolescents for nonpsychotic indications. Guidelines recommend regularly assessing treatment response and adverse effects and the ongoing need for their use. We aimed to assess adherence to recommendations of available guidelines regarding monitoring antipsychotic use and to test the influence of children's age, sex, intelligence quotient, and diagnosis on adherence. We reviewed 426 medical records from 26 centers within 3 large Dutch child and adolescent psychiatry organizations, excluding children with schizophrenia, psychosis, mania, or an intelligence quotient below 70. We investigated whether there was regular assessment of treatment response, adverse events (physical and laboratory), and at least annual discussion of the need of continued use. On average, treatment response was assessed in 69.3% of the recommended treatment periods, height in 25.6%, weight in 30.6%, blood pressure in 20.6%, evaluation of adverse events in 19.4%, and cardiometabolic measures in 13.7%; discontinuation and/or continued need was discussed at least annually in 36.2%. Extrapyramidal and prolactin-related adverse effects, waist circumference, glucose, and lipids were rarely investigated. Higher age was associated with lower rates of assessment of treatment response. Most antipsychotics were prescribed long-term. In those children with sufficient documentation of the course of treatment, 57.7% was still using an antipsychotic 3 years after initiation. Our findings indicate insufficient adherence to guideline recommendations for monitoring antipsychotic use in children and adolescents, as well as long duration of use in the majority of children. Especially, older children are at higher risk of receiving suboptimal care.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Real-world data on paliperidone palmitate for the treatment of schizophrenia and other psychotic disorders: a systematic review of randomized and nonrandomized studies.

The aim of this study was to perform a systematic review of the effects of 1-month paliperidone palmitate (PP1M) for the treatment of schizophrenia and related psychotic disorders in terms of outcomes reported in real-world evidence studies. A systematic review of real-world randomized and nonrandomized studies with PP1M was performed and is reported according to PRISMA guidelines. Comparative effectiveness data with oral antipsychotics indicate that PP1M has a lower likelihood of relapse-related events, including rehospitalization, and these differences are clinically relevant. A randomized, double-blind study showed that PP1M has no advantage over haloperidol decanoate in the time to treatment failure. Although there was a marked variability across studies, PP1M was not superior to other antipsychotics in terms of study completion rates. Pharmacoeconomic data show that, during a follow-up period of 12 months, the mean total healthcare cost was not significantly different in patients treated with PP1M compared with those receiving oral antipsychotics. The mean maximum prolactin levels were significantly higher with PP1M than with haloperidol decanoate; however, neither drug differs in the frequency of prolactin-related adverse events. Results on prolactin-related adverse events were inconsistent in two randomized comparisons with oral antipsychotics and were not reported in a randomized comparison with aripiprazole. There were no significant differences between haloperidol decanoate and PP1M in the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia; however, patients treated with haloperidol decanoate showed greater worsening of akathisia and required treatment for parkinsonism and akathisia significantly more frequently than patients who received PP1M. In conclusion, real-world data that originate from both pragmatic randomized clinical trials and observational studies indicate that PP1M is superior to oral antipsychotics in delaying the time to relapse or treatment failure. Furthermore, the pharmacoeconomic data reviewed for this article suggest that the advantages of PP1M compared with oral antipsychotics are not associated with an increased total cost for healthcare providers.

Change in Prolactin Levels in Pediatric Patients Given Antipsychotics for Schizophrenia and Schizophrenia Spectrum Disorders: A Network Meta-Analysis.

Background Treatment of schizophrenia with first- and second-generation antipsychotics has been associated with elevated prolactin levels, which may increase the risk for prolactin-related adverse events. Methods Randomized controlled trials (RCTs) included in a recent systematic review were considered for this analysis. A Bayesian network meta-analysis was used to compare changes in prolactin levels in pediatric patients diagnosed with schizophrenia or schizophrenia spectrum disorders treated with second-generation antipsychotics (SGAs). Results Five RCTs, including 989 patients combined, have evaluated the changes in prolactin for pediatric patients after 6 weeks of treatment with risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone. In the overall study population, treatment with risperidone was associated with the highest increase in mean prolactin levels compared to other SGAs. Patients treated with risperidone 4–6 mg/day were found to experience the greatest increases (55.06 ng/ml [95% CrI: 40.53–69.58]) in prolactin levels, followed by risperidone 1–3 mg/day, paliperidone 3–6 mg/day, and paliperidone 6–12 mg/day. Conclusions This study shows that there are differences in SGAs ability to cause hyperprolactinemia. Further, there is clear evidence of safety concerns with risperidone and paliperidone treatment in adolescent schizophrenia patients. Registration PROSPERO CRD42014009506.

Evaluation of Potentially Prolactin-Related Adverse Events and Sexual Maturation in Adolescents with Schizophrenia Treated with Paliperidone Extended-Release (ER) for 2 Years: A Post Hoc Analysis of an Open-Label Multicenter Study.

Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty. This study assessed potentially prolactin-related treatment-emergent adverse events (PPRL-TEAEs) and sexual maturation during long-term treatment of adolescents with paliperidone extended-release (ER). This post hoc analysis of a 2-year open-label multicenter study (NCT00488319) included patients of either sex aged 12-17 years at study enrollment, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for ≥1 year, who had received one or more adequate antipsychotic treatment prior to enrollment but had not responded sufficiently. Patients were initially treated with 6mg/day paliperidone ER and further titrated between 1.5 and 12mg/day based on clinical response and tolerability. The primary objective was to determine the relationship between characteristics (including sex, age at study entry, ethnicity, geographic region, age at diagnosis, duration of illness, number of prior hospitalizations, serum prolactin, and baseline Tanner stages) and onset or risk of PPRL-TEAEs. The secondary objective was to assess sexual maturation during long-term treatment with paliperidone ER. In total, 400 patients were enrolled in the study and 184 patients completed the 2-year study; the majority were boys (61%), White (66%), and aged >14 years at study enrolment (73%) with mean (standard deviation [SD]) body mass index (BMI) of 21.96 (4.375) kg/m2 at baseline. Girls (18.5%) had a higher incidence of PPRL-TEAEs than did boys (3.3%). Most of these events were mild to moderate in severity, and none were serious; four patients discontinued the study due to PPRL-TEAEs. Mean prolactin levels in the total population of boys and girls increased early during treatment then stabilized with time. Mean ± SD maximum changes in prolactin levels from baseline were higher in girls and boys with PPRL-TEAEs than in those without (Girls: 74.7±32.3ng/ml [n=28] vs. 50.5±44.9 ng/ml [n=114]; p=0.008. Boys: 33.6±23.7 ng/ml [n=8] vs. 31.0±24.5ng/ml [n=205]; p=0.77). No clinically significant mean changes from baseline in growth-adjusted z-score for weight, height, or BMI were observed. Overall, ~90% of the patients who completed the 2-year study achieved Tanner stages 4-5 by study endpoint. Female sex, age at diagnosis (13-14 years), girls of Hispanic ethnicity, and region (EU and North America) were associated with a greater risk for PPRL-TEAEs; higher baseline Tanner stages for pubic hair (boys and girls) and breast development (stage 3 vs. 4 or 5) also seemed to be associated with a higher incidence of PPRL-TEAEs. Female sex appeared to be associated with an increased risk for PPRL-TEAEs. Other potential predictors, such as ethnicity, region, age at diagnosis, and Tanner stage 4 or 5, all seemed to be related to sex. Evidence from this study was insufficient to definitively conclude that prolactin values at baseline and change during treatment were predictive of PPRL-TEAEs, although there is a signal that this may be the case in girls. These results are exploratory in nature, and confirmatory studies are needed to confirm these observations. ClinicalTrials.gov identifier: NCT00488319.

Reduced sexual dysfunction with aripiprazole once-monthly versus paliperidone palmitate: results from QUALIFY.

Sexual dysfunction, a common side effect of antipsychotic medications, may be partly caused by dopamine antagonism and elevation of prolactin. In QUALIFY, a randomized study, aripiprazole once-monthly 400 mg (AOM 400), a dopamine D2 receptor partial agonist, showed noninferiority and subsequent superiority versus paliperidone palmitate (PP), a dopamine D2 receptor antagonist, on the Heinrichs-Carpenter Quality-of-Life Scale (QLS) in patients with schizophrenia aged 18-60 years. Sexual dysfunction (Arizona Sexual Experience Scale) and serum prolactin levels were also assessed. Odds for sexual dysfunction were lower with AOM 400 versus PP [week 28 adjusted odds ratio (95% confidence interval), 0.29 (0.14-0.61); P=0.0012] in men [0.33 (0.13-0.86); P=0.023], women [0.14 (0.03-0.62); P=0.0099], and patients aged 18-35 years [0.04 (<0.01-0.34); P=0.003]. Among patients shifting from sexual dysfunction at baseline to none at week 28, there was a trend toward greater improvement in the QLS total score. The mean (SD) prolactin concentrations decreased with AOM 400 [-150.6 (274.4) mIU/l] and increased with PP [464.7 (867.5) mIU/l] in both men and women. Six PP-treated patients experienced prolactin-related adverse events. In addition to greater improvement on QLS, patients had a lower risk for sexual dysfunction and prolactin elevation with AOM 400 versus PP in QUALIFY.

Prolactin-related adverse events and change in prolactin levels in pediatric patients given antipsychotics for schizophrenia and schizophrenia spectrum disorders: A systematic review.

BackgroundSecond-generation antipsychotics are commonly prescribed for pediatric patients with schizophrenia and schizophrenia spectrum disorders despite their lack of approval for use in children. Although considered a safer alternative to first-generation antipsychotics, there is evidence to suggest that second-generation antipsychotics may be associated with some adverse events as well as an increase in prolactin levels. The purpose of this review is to examine the risk of prolactin-related adverse events in pediatric patients using antipsychotics and to quantify changes in prolactin for this population.MethodsLiterature searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO databases, supplemented with review of select gray literature to identify both randomized controlled trials and observational studies on pediatric patients prescribed antipsychotic medications for schizophrenia or schizophrenia spectrum disorders. Using a narrative approach, data on adverse events were recorded and changes from baseline in prolactin were pooled, where possible, from the randomized trials. Change from baseline in prolactin was evaluated for each treatment, as well as in comparison to placebo and to other treatments. Where data was available, these changes were evaluated separately for male and female patients.ResultsSix randomized controlled trials and five observational studies, all examining the effects of second-generation antipsychotics, were selected. Literature reporting the effects of risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone was identified, with varying doses. Prolactin-related adverse events were sparsely reported across studies. In evidence gathered from randomized controlled trials, risperidone, olanzapine, and two doses of paliperidone (3–5 mg/day and 6–12 mg/day) were associated with increased prolactin levels compared to baseline. With the exception of paliperidone, similar trends were observed in males and females, separately. The findings of the observational evidence served to both complement and run contrary to the randomized trials, with discrepancies attributed to differences in patient and treatment characteristics.ConclusionsNo definitive conclusions between second-generation antipsychotic use and prolactin-related adverse events can be made based on the available literature. While some trends in prolactin level changes emerged, this was based on few trials with small sample sizes. Future investigations should emphasize reporting on treatment safety.Trial registrationPROSPERO CRD42014009506.Electronic supplementary materialThe online version of this article (doi:10.1186/s12887-016-0710-y) contains supplementary material, which is available to authorized users.

A randomized trial of aripiprazole vs blonanserin for the treatment of acute schizophrenia and related disorders.

ObjectiveThere has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6−30 mg/d) vs blonanserin (4−24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194).MethodsThe primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events.ResultsForty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups.ConclusionOur results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia.

Long-Acting Injectable Antipsychotics for Prevention of Relapse in Bipolar Disorder: A Systematic Review and Meta-Analyses of Randomized Controlled Trials.

Background:This meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder.Methods:Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications.Results:We identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials)=449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio=0.63, P<.0001), relapse of manic symptoms (risk ratio=0.42, P<.00001), and all-cause discontinuation (risk ratio=0.75, P=.007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio=4.82, P=.001) and weight gain (risk ratio=3.80, P<.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I2=0%, RR=0.58, P=.0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR=2.66, P=.03).Conclusions:Long-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.

Risperidone (depot) for schizophrenia.

This is a copy of an article published in the Cochrane Database of Systematic Reviews © 2016 Cochrane Collaboration Publications. © The Author(s). http://www.cochranelibrary.com/

Paliperidone extended-release tablets in Chinese patients with schizophrenia: meta-analysis of randomized controlled trials.

BackgroundPrevious meta-analyses have compared paliperidone extended-release (ER) tablets with other antipsychotics, but none have involved Chinese patients or studies from People’s Republic of China. Further, the results of these meta-analyses may not be applicable to Chinese patients. In the present study, we evaluated the efficacy, safety, and acceptability of paliperidone ER compared with other second-generation antipsychotics (SGAs) for Chinese patients with schizophrenia.MethodsRandomized controlled studies of paliperidone ER and other SGAs as oral monotherapy in the acute phase treatment of schizophrenia were retrieved from Medline, Embase, and the Cochrane Library (CENTRAL), as well as from Chinese databases including the China National Knowledge Infrastructure, Wanfang, and VIP Information/Chinese Scientific Journals Database. We pooled data on response rates, chance of withdrawal due to adverse events, probability of adverse events, and odds of withdrawal for any reason.ResultsFifty randomized controlled trials were identified. The response rate for paliperidone ER was significantly higher than that of other pooled SGAs (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.72–0.96) and ziprasidone (RR 0.57, 95% CI 0.39–0.82). Paliperidone ER significantly reduced the chance of withdrawal due to adverse events and the chance of any adverse events compared with other pooled SGAs (RR 0.32, 95% CI 0.17–0.58 and RR 0.88, 95% CI 0.79–0.97) and risperidone (RR 0.31, 95% CI 0.14–0.67 and RR 0.70, 95% CI 0.57–0.86). The incidence of extrapyramidal symptoms on paliperidone ER was comparable with other pooled SGAs (RR 0.94, 95% CI 0.66–1.35) and significantly lower than that of risperidone (RR 0.56, 0.41–0.77) but higher than that of olanzapine (RR 1.88, 95% CI 1.05–3.36). Paliperidone ER was superior to other pooled SGAs (RR 0.32, 95% CI 0.21–0.49 and RR 0.50, 95% CI 0.35–0.72) and olanzapine (RR 0.23, 95% CI 0.15–0.33 and RR 0.33, 95% CI 0.23–0.47) as far as weight gain and somnolence were concerned. Further, prolactin-related adverse events caused by paliperidone ER were comparable with other pooled SGAs (RR 1.30, 95% CI 0.73–2.33), but outnumbered those caused by olanzapine (RR 7.53, 95% CI 2.05–27.71).ConclusionPaliperidone ER is efficacious, safe, and well accepted when compared with other pooled SGAs for the treatment of Chinese patients with schizophrenia.

Paliperidone palmitate versus oral risperidone and risperidone long-acting injection in patients with recently diagnosed schizophrenia

Early in the course of illness, patients with schizophrenia may be particularly susceptible to adverse events (AEs). In this post-hoc, subgroup analysis of a 13-week, double-blind, double-dummy, multicenter study, patients recently diagnosed with schizophrenia (≤ 5 years) were administered once-monthly flexible-dose paliperidone palmitate (PP) (n=161; initiation doses, 150 mg eq day 1 and 100 mg eq day 8) [PP doses can be expressed as milligram equivalents (mg eq) of paliperidone or as milligrams (mg) of PP. 150 mg eq paliperidone=234 mg PP; 100 mg eq paliperidone=156 mg PP. In the USA, dosing tends to be expressed in mg] or oral risperidone [during initiation of risperidone long-acting injection (RLAI) days 1-28] and biweekly flexible-dose RLAI (n=173; initial injection day 8). Assessments were performed at baseline and days 4, 15, 22, 36, 64, and 92. Because of RLAI's release profile, data through day 22 correspond to oral risperidone in the RLAI arm. During this period, the AE profile and onset of efficacy of PP and oral risperidone were similar. The overall AE rates at week 13 for PP and RLAI were 54.7 and 50.3%, respectively, for any AE; 11.2 and 8.1% for extrapyramidal symptom-related AEs; and 2.5 and 2.3% for prolactin-related AEs. No significant differences in the mean weight change, most metabolic parameters, or mean efficacy measures were observed at end point. In patients with recently diagnosed schizophrenia, the tolerability and efficacy of PP and RLAI were generally similar over 13 weeks.

The effect of the Taq1A variant in the dopamine D2 receptor gene and common CYP2D6 alleles on prolactin levels in risperidone-treated boys

To investigate the effect of the Taq1A variant in the Dopamine D2 receptor gene (DRD2) and common functional genetic variants in the cytochrome P450 2D6 gene (CYP2D6) on prolactin levels in risperidone-treated boys with autism spectrum disorders and disruptive behavior disorders. Forty-seven physically healthy 10-year-old to 19-year-old boys with autism spectrum disorders and/or disruptive behavior disorders, chronically treated (mean 52 months, range 16-126 months) with an antipsychotic, were recruited into this observational study. Prolactin levels, hyperprolactinemia, risperidone levels, and 9-hydroxyrisperidone levels were assessed and the participants were genotyped for common CYP2D6 polymorphisms and the Taq1A allele of the dopamine D2 receptor gene. Group differences were tested using Student's t-test, χ², and logistic regression analysis. Prolactin levels were associated positively and significantly with risperidone levels (P=0.05), 9-hydroxyrisperidone levels (P≤0.0001), and with the oral risperidone dose in milligrams per kilogram (P≤0.0001). Furthermore, multiple regression analysis showed no correlations between prolactin level and the presence of at least one Taq1A A1 allele of the DRD2 gene (P=0.12). Although CYP2D6 might have an effect, the presence of at least one Taq1A A1 allele of the D2DR gene did not contribute toward susceptibility to risperidone-induced hyperprolactinemia, and as a result, toward prolactin-related adverse events such as amenorrhea, galactorrhea, and sexual dysfunctioning.

An Analysis of Potentially Prolactin-Related Adverse Events and Abnormal Prolactin Values in Randomized Clinical Trials with Paliperidone Palmitate

Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinemia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs were obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90.3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, there was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

Paliperidone ER versus risperidone for neurocognitive function in patients with schizophrenia

This study aims to determine the effectiveness of paliperidone extended release (ER) on cognitive function in patients with schizophrenia in comparison with risperidone. This was a 12-week, randomized, open-label study on schizophrenia patients who were receiving risperidone. The patients were randomized to a risperidone-continuation group or a paliperidone-switch group. The primary outcome measure was neurocognitive function, which was measured using a computerized battery. Secondary efficacy measures included the Positive and Negative Syndrome Scale, Social and Occupational Functioning Scale, and Calgary Depression Scale for Schizophrenia. In total, 58 patients participated in this trial. Improvements in recall after an interference phase in the verbal learning test were significantly greater in the paliperidone-switch than in the risperidone-continuation group. No significant differences in changes were observed in the other six neurocognitive domains measured. Improvements in the Social and Occupational Functioning Scale were significantly greater in the paliperidone ER-switch group than in the risperidone-continuation group. In other efficacy outcome measures, no significant differences were observed between the two drugs. Paliperidone ER had a side-effect profile similar to that of risperidone, including metabolic problems and prolactin-related adverse events. In conclusion, switching from risperidone to paliperidone ER may lead to additional cognitive and social functional improvements.

Risk factors for suicide behaviors in the observational schizophrenia outpatient health outcomes (SOHO) study.

BackgroundTo identify risk factors for suicide using data from a large, 3-year, multinational follow-up study of schizophrenia (SOHO study).MethodsBaseline characteristics of 8,871 adult patients with schizophrenia were included in a logistic regression post-hoc analysis comparing patients who attempted and/or committed suicide during the study with those who did not.Results384 (4.3%) patients attempted or committed suicide. Completed suicides were 27 (0.3%). The significant risk factors for suicide behaviors were previous suicidality, depressive symptoms, prolactin-related adverse events, male gender and history of hospitalization for schizophrenia.ConclusionsIn view of the observational design of the study and the post-hoc nature of the analysis, the identified risk factors should be confirmed by ad-hoc specifically designed studies.

A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia

The safety and tolerability of paliperidone palmitate, an injectable atypical antipsychotic agent, were assessed in a 1-year open-label extension of a double-blind study in patients with schizophrenia. Patients from the double-blind study who experienced a recurrence, remained recurrence free until study end, or who were in the transition, maintenance or double-blind phases and had received at least one injection of paliperidone palmitate when enrollment was stopped, were eligible for the open-label extension. Patients received gluteal injections of paliperidone palmitate once every 4 weeks: starting dose 50 mg eq. followed by 25, 50, 75, or 100 mg eq. flexible dosing. Of the 388 patients enrolled, 288 completed the open-label extension. During the open-label extension, the median (range) duration of exposure to paliperidone palmitate was 338 days (10; 390), and 74% of patients received all 12 open-label injections of paliperidone palmitate. The most frequent (≥ 5% in total group) adverse events were insomnia (7%); worsening of schizophrenia; nasopharyngitis; headache; and weight increase (6% each). Potentially prolactin-related adverse events occurred in 13 (3%) patients, mostly women, and none resulted in study discontinuation. Extrapyramidal treatment-emergent adverse events were reported in 25 (6%) patients; tremor was the most frequently reported (n = 8, 2%). At open-label extension endpoint, investigator-rated redness at the injection site was observed in ≤ 4% of patients in each group. Injection-site pain was rated by investigators as absent in 82-87% of patients. Schizophrenia symptoms measured by Positive and Negative Syndrome Scale and personal and social performance changes improved during the open-label extension.

A 12-week, naturalistic switch study of the efficacy and tolerability of aripiprazole in stable outpatients with schizophrenia or schizoaffective disorder

The objectives of this 12-week multicenter open-label switching study were to evaluate the overall clinical efficacy, safety, and tolerability of aripiprazole in stable patients with schizophrenia or schizoaffective disorder, and to assess, in a naturalistic setting, whether such patients experience symptom worsening when switched from D2 receptor antagonists to aripiprazole (a D2 receptor partial agonist). Patients with schizophrenia or schizoaffective disorder in a symptomatically stable state were randomized to aripiprazole or standard-of-care antipsychotics. The Clinical Global Impression (CGI), Positive and Negative Syndrome Scale, and Investigator's Assessment Questionnaire were used monthly. The Udvalg for Kliniske Undersogelser side-effect rating scale scores and treatment emergent adverse events were recorded to assess the safety and tolerability of switching to aripiprazole from other antipsychotics. A total of 292 patients were randomly assigned to receive aripiprazole (N = 245) or non-aripiprazole antipsychotics (N = 47). Mean CGI-Improvement score at 12 weeks was 3.56+/-1.29 (95% confidence interval: 3.39-3.73) in the aripiprazole group, indicating that aripiprazole was effective in treating schizophrenic patients. Aripiprazole treatment resulted in improvement from baseline on all efficacy outcome measures, including Positive and Negative Syndrome Scale total, positive, negative, and general subscale, and CGI-Severity scores. In addition, after aripiprazole treatment, the remission rate was increased from 43.9% at baseline to 51.7% at 12 weeks. The proportion of patients with symptom worsening at 12 weeks was low (12.4%). Both Investigator's Assessment Questionnaire and Udvalg for Kliniske Undersogelser scores showed that there were fewer prolactin-related adverse events in the aripiprazole group than in the standard-of-care antipsychotics group (P<0.05). There were no significant between-group differences in time to failure to maintain remission and time to dropout. In the naturalistic setting, symptomatically stable outpatients with schizophrenia who were switched to aripiprazole showed clinically meaningful treatment benefits. The majority of patients was successfully switched from other antipsychotics without serious symptom exacerbation or adverse events over a course of 12 weeks.

Bipolar disorder and dopamine dysfunction: an indirect approach focusing on tardive movement syndromes in a naturalistic setting

BackgroundIt has been suggested that dopamine dysfunction may play a role in bipolar disorder (BD). An indirect approach to examine this issue was developed, focusing on associations between dopamine proxy measures observed in BD (dopamine-related clinical traits using tardive movement syndromes as dopamine proxy measure of reference).Methods3459 eligible bipolar patients were enrolled in an observational study. Incidence rates of tardive movement syndromes (tardive dyskinesia and tardive dystonia; TDD) were examined. A priori hypothesized associations between incident TDD and other dopamine proxies (e.g. prolactin-related adverse effects, bipolar symptoms) were tested over a 2 year follow-up period.ResultsThe incidence rate of tardive syndromes was 4.1 %. Incident TDD was independently associated not only with use of antipsychotics, but also with more severe bipolar symptoms, other extrapyramidal symptoms and prolactin-related adverse effects of medication.ConclusionApart from the well-known association with antipsychotics, development of TDD was associated with various other dopamine proxy measures, indirectly supporting the notion of generalised dopamine dysregulation in BD.

Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: a claims-based study

BackgroundA reporting association of risperidone with pituitary tumors has been observed. Because such tumors are highly prevalent, there may be other reasons why they were revealed in association with risperidone treatment. We assessed two potential explanations: disproportionately more prolactin assessment and head/brain imaging in risperidone-treated patients vs patients treated with other antipsychotics.MethodsTreatment episodes with risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole, haloperidol, perphenazine and 'other typical' antipsychotics were identified in two databases (large commercial, Medicaid). Comparisons used proportional hazards regression to determine whether prolactin testing was disproportionate with risperidone, regardless of prior potentially prolactin-related adverse events (PPAEs). Logistic regression determined whether magnetic resonance imaging (MRI)/computed tomography (CT) were disproportionate in risperidone-treated patients vs other patients, regardless of hyperprolactinemia or PPAEs. In each regression, the 'other typical' antipsychotic category served as the comparator. Regression models controlled for age, gender, and other factors.ResultsAltogether, 197,926 treatment episodes were analyzed (63,878 risperidone). Among patients with or without preceding PPAEs, risperidone treatment was associated with a significantly greater likelihood of prolactin assessment (hazard ratio (HR) 1.34, 95% confidence interval (CI) = 1.09 to 1.66, p = 0.007). Among patients with hyperprolactinemia or PPAEs, those treated with risperidone (odds ratio (OR) 1.66, 95% CI 1.23 to 2.23, p = 0.001) or ziprasidone (OR 1.66, 95% CI 1.06 to 2.62, p = 0.028) had a higher likelihood of MRI/CT.ConclusionRisperidone-treated patients are more likely to undergo prolactin assessment regardless of prior PPAEs, and more likely to undergo MRI/CT in association with hyperprolactinemia or PPAEs. Thus, a predisposition for more evaluations in risperidone-treated patients may contribute to disproportionate identification and reporting of prevalent pituitary adenoma.