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RISPERDAL® (risperidone)

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Adverse Event of RISPERDAL - Elevated Prolactin Levels in Adults

Last Updated: 04/03/2023

Summary

As with other drugs that antagonize dopamine D₂ receptors, RISPERDAL elevates prolactin (PRL) levels and the elevation persists during chronic administration.¹ Serum prolactin elevations occur with the use of RISPERDAL in both male and female patients.
RISPERDAL is associated with higher levels of PRL elevation than other antipsychotic agents. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.¹
There are conflicting clinical trial data in regard to an association between RISPERDAL-induced hyperprolactinemia and osteoporosis.²^-⁹
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving PRL-elevating compounds.¹
While most schizophrenia patients on RISPERDAL have elevated PRL levels, the majority of patients do not exhibit short-term PRL-related adverse events.¹⁰
There is conflicting data on whether PRL increases with RISPERDAL in adults are dose-dependent.²^,¹⁰^-¹⁵
Atypical Antipsychotics - Comparative Data: In double-blind trials significantly higher PRL levels were observed in patients receiving RISPERDAL compared to quetiapine,¹⁶^,¹⁷ clozapine,¹⁸^,¹⁹ olanzapine,¹⁸ or haloperidol.¹⁸ However, in an 8-week, double-blind, comparative trial, the incidence of potentially PRL-related adverse events was similar between RISPERDAL- and olanzapine-treated patients²⁰ and mean plasma PRL levels were not correlated with PRL-related adverse events.²¹
For information regarding PRL-related effects in children and adolescents, specific adverse events related to elevated PRL levels, or the management of hyperprolactinemia related to treatment with RISPERDAL, please contact Janssen Medical Information at 1-800-JANSSEN (1-800-526-7736).

BACKGROUND

PRL elevation is frequent in patients treated with antipsychotics which increase PRL secretion by blocking the inhibitory actions of dopamine on lactotrophic cells in the anterior pituitary.²² The increase in PRL level may vary depending on the extent of dopamine blockade.

RISPERDAL is associated with higher levels of PRL elevation than other antipsychotic agents. Hyperprolactinemia, may suppress hypothalamic gonadotropin releasing hormone, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.¹ Prolactin-related adverse events include amenorrhea, galactorrhea, gynecomastia, and decreased libido in female patients, and erectile and/or ejaculatory dysfunction, gynecomastia, and decreased libido in male patients. An association between PRL levels and sexual dysfunction in patients treated with RISPERDAL has not been definitively established.²³

Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male subjects.¹ In the absence of hypogonadism, there is a lack of consistent evidence to establish whether antipsychotic-induced hyperprolactinemia is an independent risk factor for bone loss and osteoporosis.²⁴ While individuals with schizophrenia are known to have an increased risk for low bone mineral density and osteoporosis, prospective clinical trials to differentiate between etiological mechanisms and effects of disease and treatment have not been conducted.

clinical data

Double-Blind Trials

Effects of RISPERDAL on PRL Levels in Double-Blind Trials

Study Design	Summary
Double-Blind Pivotal Trials – Bipolar I Disorder
Khanna et al (2005)²⁵ conducted a 3-week, DB, randomized, PBO-controlled trial in India evaluating the efficacy and safety of RIS monotherapy for the treatment of patients with acute manic or mixed episodes of bipolar I disorder, with or without psychotic features: *RIS* (n=146); *PBO* (n=144) *Mean Modal Dose*: 5.6 mg/day - Dose range was 1-6 mg/day.	*Outcomes*: Concomitant medications used during the trial included lorazepam (allowed during the washout period and the first 10 days of treatment, but not within 8 hours of assessments), β-blockers, and antiparkinsonian drugs. At endpoint, mean PRL levels increased to 86 ng/mL in the RIS group compared to baseline of 19 ng/mL. Neither treatment group reported PRL-related adverse events.
Hirschfeld et al (2004)²⁶ conducted a 3-week, DB, randomized, PBO-controlled multicenter trial evaluating the efficacy and safety of RIS monotherapy for acute mania associated with bipolar I disorder: *RIS* (n=134): PBO (n=125): *RIS Mean Modal Dose*: 4.1 mg/day; dose range was 1- 6 mg/day.	Outcomes: At endpoint, PRL levels increased for both males and females in the RIS group: Males: Baseline: 13.7±9.8 ng/mL vs Endpoint: 43.5±23.0 ng/mL Females: Baseline: 19.4±26.6 ng/mL vs Endpoint: 96.1±51.4 ng/mL In the PBO group, baseline PRL levels of 14.1±17.7 ng/ml for males decreased to 12.5±8.7 ng/ml at endpoint. For females, baseline PRL levels of 14.5±11.8 ng/ml increased to 14.6±11.2 ng/ml at endpoint.
Double-Blind Trials – Schizophrenia
Kumar et al (2016)²⁷ conducted a DB, randomized, 1-year study in 71 patients with schizophrenia and compared RIS with OLA. Mean Modal Doses: *RIS* (n=35): 5.8 mg/day *OLA* (n=36): 14.4 mg/day	Approximately 74% of patients in each treatment arm completed the study. PRL levels at baseline and mean change from baseline to endpoint: RIS: 11.7±11.2; 44.3±31.9 OLA: 18.7±31.9; 20.8±27.1 Mean change from baseline to endpoint in PRL was significantly higher in the RIS group than the OLA group (P=0.03).
Li et al (2016)²⁸ conducted a DB, randomized, 8-week study in 264 Chinese patients with schizophrenia and compared RIS with blonanserin. *RIS Dose* (n=135): 2-6 mg/day *Blonanserin Dose* (n=129): 8-24 mg/day	The most common drug-related AE was increased PRL, which occurred in 67.16% of patients treated with RIS and 52.31% of patients treated with blonanserin. Patients in the RIS group also experienced galactorrhea. Mean PRL levels at baseline vs end of study: RIS: 32.21 ng/mL vs 94.83 ng/mL (mean change from baseline: 62.17 ng/mL) Blonanserin: 40.75 ng/mL vs 53.09 ng/mL (mean change from baseline: 12.24 ng/mL)
Berwaerts et al (2010)²⁹ conducted a phase 1, 6-day, DB, randomized, study in patients with stable schizophrenia comparing serum PRL concentrations following PAL ER and RIS administration; patients were previously treated with oral RIS for at least 1 month prior to screening. Patients were randomized to 1 of 3 treatment groups: (1) *PBO* on day 1 and 12 mg *PAL ER* Days 2-6; (Note: Group 1 excluded from analysis; delay in exposure to PAL by 1 day may differentially affect the serum PRL concentration-time profiles 5 days after initiation of DB study drug.) (2) 12 mg *PAL ER* Days 1-6 (n=38); (3) *RIS* 2 mg on Day 1 and 4 mg on Days 2–6 (n=38).	*Outcomes*: There was a mean increase in PRL levels with both PAL ER and RIS between days and 1 and 6. However, the peak-trough variation of PRL levels was lower in the PAL ER groups vs RIS. Day 1: The C_max (ng/ml) for PRL in serum samples was 71.8 for PAL and 89.7 for RIS. Day 6: The AUC _0-24h for PAL ER was 1,389 ng·h/ml and 1,306 ng·h/ml for RIS. The C_max (ng/mL) for PRL in serum samples was 68.5 for PAL ER and 71.4 for RIS. The mean t_max (hrs) was 16.6 for PAL ER and 8.9 for RIS. No potentially PRL-related adverse events were reported. The results suggest that the administration of PAL ER 12 mg/day and RIS 4 mg/day over 6 days results in similar increases in PRL concentration based on the AUC_0-24h.
Zhang et al (2005)³⁰ conducted a 12-week, DB, randomized trial evaluating the effects of RIS vs HAL on serum PRL levels in 78 Chinese inpatients diagnosed with schizophrenia. Mean Age: *RIS* (n=41, 30 males): 43.8 years *HAL* (n=37, 30 males): 43.7 years Sex- and age-matched healthy control group (n=30, 22 males): 40.4 years *RIS Dose: titrated up to 6 mg/day HAL Dose*: titrated up to 20 mg/day	*Outcomes: Analyses comparing the control group and treatment group (RIS + HAL) were only carried out in males due to the small number of females. There was a significant difference between PRL levels in health controls (11.5±6.9 ng/ml) vs the treatment group baseline levels (5.2±7.1 ng/mL, P=0.009) and vs the treatment group posttreatment (25.4±17.8 ng/mL, P=0.006). Serum PRL levels by treatment group: RIS: Baseline: 4.8±4.8 ng/mL vs Week 12: 29.8±19.2 ng/mL, P<0.001 HAL*: Baseline: 5.6±7.2 ng/mL vs Week 12: 22.4±14.9 ng/mL, P<0.001 Week 12 PRL levels were marginally higher in the RIS group compared to HAL (P=0.07) When the PRL levels were dose-adjusted, (RIS 1 mg=HAL 2 mg), RIS produced a significant increase in serum PRL compared to HAL (2.5±1.6 ng/mL/mg vs 1.1±0.75 ng/mL/mg, respectively; P<0.001). Females experienced significantly higher endpoint PRL levels (P=0.003) and greater mean changes in PRL (P<0.01) compared to males, even after adjusting for significantly higher baseline PRL levels in females.
Volavka et al (2004)¹⁸ conducted a 14-week, DB trial in 157 patients with treatment-resistant schizophrenia or schizoaffective disorder assessing the differential effects of antipsychotics on PRL levels and the relationship between clinical effects and PRL levels.	*Outcomes*: RIS (mean dose: 11.6 mg/day), HAL (mean dose: 25.7 mg/day), CLZ (mean dose: 526.6 mg/day), or OLA (mean dose: 30.4 mg/day) Analyses on PRL were limited to 75 male patients in the trial. RIS was associated with significantly greater PRL elevations than each of the other antipsychotics (P<0.002). Changes in PRL level did not correlate with improvement on the PANSS scale or changes in parkinsonism.
Breier et al (1999)¹⁹ conducted a 6-week DB study comparing the efficacy of CLZ and indexes of neuroendocrine function in patients with schizophrenia who had responded previously to traditional antipsychotic agents (n=14; mean dose: 403.6 mg/day) and *RIS* (n=15; mean dose 5.9 mg/day, 3 of 15 patients received doses >16 mg/day).	Serum PRL levels by treatment group: RIS: Baseline: 38.9 ng/mL vs Week 6: 50.7 ng/mL CLZ: Baseline: 53.3 ng/mL vs Week 6: 12.2 ng/mL Treatment with CLZ and RIS had a significantly different effect on the PRL level. CLZ and RIS did not have a significant difference in effect on growth hormone and cortisol. The efficacy and safety associated with a lower RIS dose in this population needs to be examined, as 20% of the RIS-treated patients in this study received doses greater than 6 mg/day.
Abbreviations: AE(s), adverse event(s); AUC, area under the curve; CLZ, clozapine; C_max, maximum plasma concentration; DB, double-blind; HAL, haloperidol; OLA, olanzapine; PANSS, Positive and Negative Syndrome Scale; PAL ER, paliperidone extended-release; PBO, placebo; PRL, prolactin; RIS, RISPERDAL; SD, standard deviation; tmax, time to maximum plasma concentration.

Open-Label Studies (N>50)

Open Label Studies

Study Design	Summary
Jiang et al (2018)³¹ conducted a comparative study of RIS monotherapy and the effects of adjunctive ARI therapy on serum PRL, testosterone and estradiol levels in adult Chinese female patients with schizophrenia receiving stable doses of RIS monotherapy (4 mg/day). Data were retrospectively collected from 30 female patients on RIS for 6 months while another 30 female patients were enrolled in a prospective 6-week open-label study. In the OL study, patients receiving RIS 4 mg/day were randomly assigned RIS (2-4-mg/day) or adjunctive ARI treatment (5-10 mg/day) at a 1:2 ratio. Hyperprolactinemia was defined as a serum PRL levels above 636 mIU/L (30 μg/L^-1).	Retrospective Study: Following 6 months of treatment, serum levels of testosterone, estradiol and PRL were lower than baseline however serum PRL levels remained high. Before and after serum levels: PRL (mIU/L; Testosterone (nmol/L); Esatradiol (pmol/L, respectively Before Tx: 1946.38±119.29;1.87±1.13;78.1±69.65 After 6 months of Tx: 1690.3±951.31;1.53±1.1^a;54.3±29.74^a ^aCompared with before treatment; P<0.05 Prospective Study: Serum testosterone and estradiol levels of patients treated with RIS or adjunctive ARI were significantly lower at week 6 vs baseline. There was no significant difference between RIS and adjunctive ARI treatment. PRL levels at week 1, 2 and 6 were significantly lower than at baseline (P < 0.05) in the adjunctive ARI treatment group. At the end of treatment, doses of adjunctive ARI 5 mg and 10 mg achieved the same efficacy. Prolactin (mIU/L) at Baseline, Weeks 1,2, and 6, respectively RIS: 1652.7±931; 1567.4 ±1009.8; 1317.3±835.8; 1556.9±882.2 Adjunct ARI: 1925.6±1285.1; 914.5±744^b; 749.5±705.2^b; 657.9±589.6^b ^bP<0.05
Bo et al (2016)³² conducted a study in 374 patients with clinically stable schizophrenia who were treated with *RIS* 4-8 mg/day. Patients were randomized to 1 of 3 groups: no-dose-reduction, 50% dose reduction beginning at 4 weeks, or 50% dose reduction beginning at 26 weeks. The dose reductions occurred over an 8week period, and all patients were followed for 1 year. PRL-related AEs were assessed for 16 items including menstrual cycle irregularities, breast symptoms, sexual dysfunction, and acne.	PRL-related AEs at baseline (n=374) and 1 year (n=237): No dose reduction group: 14% vs 7.6% 4-week dose reduction group: 18.4% vs 9.6% 26-week dose reduction group: 15% vs 11.1% Factors associated with development of PRL-related AEs include female gender, younger age of onset of schizophrenia, higher PANSS total scores at baseline.
Kim et al (2015)³³ reported the results of an open-label study comparing once monthly PP (78-234 mg) to oral atypical antipsychotics. Specific oral antipsychotics could be deselected prior to randomization based on the patient's past history. Mean Dose: PP (n=168): 179.0 mg/month *RIS* (n=37): 3.6 mg/day	Among the 90 patients who deselected RIS prior to randomization, 2.7% had experienced PRL elevation/sexual AEs PRL-related AEs for PP vs RIS: All PRL-related AEs - 23.2% vs 5.4% Decreased libido - 6.5% vs 2.7% Erectile dysfunction - 6.0% vs 0 Retrograde ejaculation - 1.8% vs 5.4%
Yasui-Furukori et al (2010)³⁴ conducted a 4-week, open-label study examining gender differences in PRL effects during RIS and OLA treatment in 94 Japanese patients (46 male; 48 female) diagnosed with acutely exacerbated schizophrenia. *Exclusions: Concomitant use of dopamine antagonists or other antipsychotics for ≥4 weeks; use of depot antipsychotics; female patients receiving hormonal therapy. Dose: RIS: 3 mg twice daily x 4 weeks (22 male, mean age: 41.7 years; 22 female, mean age: 43.6 years) OLA: 10 mg twice daily x 4 weeks (24 male, mean age: 42.1 years; 26 female, mean age: 42.2 years) Concomitant Meds: biperiden (n=40): 4-6 mg; flunitrazepam (n=68): 1-4 mg; sennoside (n=32): 12-48 mg Endpoints: PRL* levels (prior to 8AM dose); plasma drug concentrations (RIS: LC-MS/MS, limit of quantification: 0.3 ng/mL; OLA: HPLC, limit of quantification: 2.5 ng/mL)	*Outcomes: PRL levels were significantly elevated for RIS and OLA patients (male + female) at 1, 2, 3, and 4 weeks compared to baseline (P<0.001). At all sampling points, female patients receiving RIS or OLA had significantly higher PRL levels compared to male patients (P<0.001). In addition, male and female RIS patients experienced significantly higher increases in PRL levels compared to male and female OLA patients. Baseline and Week 4 Levels: RIS: Male (10.6 ng/mL and 53.6 ng/mL, respectively); Female (14.3 ng/mL and 170.4 ng/mL, respectively) OLA*: Male (11.3 ng/mL and 34.1 ng/mL, respectively); Female (13.8 ng/mL and 68.8 ng/mL, respectively) In males receiving OLA a significant negative correlation was observed between delta PRL levels (week 4 - baseline) and plasma OLA concentration concentrations at week 4 (r=-0.518, P<0.01). Multiple regression analysis (without medication and with plasma drug concentration) revealed that delta PRL during RIS was significantly correlated with gender (β=1.002, P<0.001) and age (β=-0.269, P<0.05) while delta PRL during OLA was significantly correlated with gender (β=0.623, P<0.001) and plasma drug concentration (β=-0.323, P<0.01).
Yasui-Furukori et al (2010)³⁵ evaluated the patterns of PRL fluctuation in schizophrenic patients receiving *RIS* 3 mg twice daily (13 male; 17 female), *OLA* 10 mg twice daily (6 male; 7 female) and *PER* (perospirone) 16 mg daily (6 male; 7 female) for ≥4 weeks compared to 12 healthy controls. *Concomitant Meds: biperiden (n=25): 46 mg; flunitrazepam (n=28): 14 mg; sennoside (n=17): 12-48 mg Endpoints: Predose and 2, 4, 6, 8 and 12 hour post-8AM dose blood samples for quantification of drug and PRL levels (RIS: LC-MS/MS, limit of quantification: 0.3 ng/mL; OLA: HPLC, limit of quantification: 2.5 ng/mL; PER*: HPLC, limit of quantification: 1 ng/mL)	*Outcomes*: Throughout the dosing interval plasma concentrations of RIS active moiety (RIS + 9-OH-RIS), OLA and PER fluctuated. In females, AUCs for RIS active moiety only were significantly greater than in males (P<0.05). While the C₀, C_max and AUC of PRL for treatment groups and controls were significantly higher in females compared to males, females receiving RIS had a significantly higher PRL C₀ compared to healthy control females and females receiving OLA or PER. However, males receiving RIS had a significantly higher PRL C₀ compared to PER only (P<0.05). Patients receiving RIS had the greatest PRL AUC magnitude followed by PER then OLA. The C_max magnitude was greatest for PER followed by RIS then OLA.
Konarzewska et al (2009)¹¹ conducted an open-label study evaluating the effects of RIS vs OLA on the hypothalamo-pituitary-gonadal axis in 89 adult male patients with DSM-IV schizophrenia. Mean Doses Week 8 (Final Evaluation): *RIS* (n=32): 4.4 mg/day *OLA* (n=27): 15.7 mg/day Prior to study initiation, patients were free from oral (≥3 weeks) and depot (≥3 months) antipsychotic medications. Concomitant medications included as needed diazepam (≤20 orally mg/day) and biperiden (≤10 mg/day). *Endpoints*: At weeks 3 and 8, following treatment initiation, fasting blood samples were drawn prior to the morning dose of medication for analysis of PRL, FSH (follicle-stimulating hormone), LH (luteinizing hormone), estradiol, testosterone, and inhibin B plasma levels.	*Final Evaluation* (Week 8 Following Drug Initiation) ANCOVA results revealed a statistically significant drug effect on FSH (P=0.01) and PRL (P=0.01). Compared to OLA, mean PRL levels were significantly higher in RIS patients (13.76 ng/mL vs 31.78 ng/mL, respectively) whereas FSH levels were lower (5.78 mIU/mL vs 2.8 mIU/mL, respectively). PRL levels were slightly affected by the dose of OLA but not RIS (Multiple regression analyses with dose, body mass and age as independent variables, P=0.04) Inhibin B levels<80 pg/mL were detected in 1 RIS patient and 3 OLA patients, indicating Sertoli's cell dysfunction. Testosterone levels were below the lower limit of normal (<241 ng/mL) in 2 out of 32 RIS patients, reflecting Leydig's cell impairment. The prevalence of hyperprolactinemia (mean PRL >17.7 ng/mL) was 78% for RIS patients (n=25/32) and 25.9% for patients receiving OLA (n=7/27). In all cases, mean LH, FSH, testosterone and estradiol levels were with the normal reference range. Correlations Inhibin B levels were negatively correlated with FSH in all investigated groups with the exception of the RIS hyperprolactinemic group.
Stroup et al (2009)³⁶ -Phase 3 of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia trial (n=270; mean age: 40.5 years; 70% male) which included patients who had discontinued treatment in DB phases 1 and 2, were eligible to select from 9 antipsychotic treatment regimens, with the help of their study doctor, allowing them to complete the entire 18 months of treatment. To allow for gradual transition to the new medication regimen, overlap of the previous antipsychotic was permitted for the first 4 weeks of phase 3. Mean Modal Dose: *ARI* (n=30): 16.1 mg/day *CLO* (n=32): 317.2 mg/day *COMBO* (n=40): N/A *FLU-D* (n=7): 41.1 mg *OLA* (n=39): 21.8 mg/day *PER* (n=4): 30.0 mg/day *QUE* (n=33): 500 mg/day *RIS* (n=32): 3.9 mg/day *ZIP* (n=33): 132.1 mg/day	*Outcomes: Mean change in PRL (Phase 3 baseline to Average of 2 Largest Values): ARI* (n=33): -6.6 ng/mL CLO (n=37): -9.8 ng/mL COMBO (n=40): -1.6 ng/mL FLU-D (n=9): 6.8 ng/mL OLA (n=41): -4.7 ng/mL PER (n=4): 9.2 ng/mL QUE (n=33): -1.3 ng/mL RIS (n=36): 24.2 ng/mL ZIP (n=37): -5.6 ng/mL Percent of patients reporting sexual dysfunction (sex drive, sexual arousal, sexual orgasm) as moderate or severe AEs by systematic inquiry: ARI (n=33): 9% CLO (n=37): 27% COMBO (n=40): 30% FLU-D (n=9): 11% OLA (n=41): 10% PER (n=4): 25% QUE (n=33): 30% RIS (n=36): 17% ZIP (n=37): 14%
Bushe et al (2008)³⁷ conducted an open-label study evaluating the prevalence and severity of hyperprolactinemia in 178 patients with severe mental illnesses participating in the London and Leeds Wellbeing Support Programme. Mean Age: Leeds (n=108): 45.7 years (male); 47.9 years (female) London (n=70): 41.8 years (male); 43.4 years (female) *Endpoints*: PRL levels were assessed from nonfasting blood samples obtained between 0900 and 1700 hours without regard to medication timing. The PRL ULN (upper limit normal) in Leeds was <550 mIU/L for males and <600 mIU/L for females. In London, the ULN was <500 mIU/L for both males and females.	*Outcomes: For the combined cohort, hyperprolactinemia was found in 33.1% of patients (47.3% females vs 17.6% males). Prolactin levels >1,000 mIU/L and >2,000 mIU/L were found in 16% and 6.2% of the combined cohort, respectively. Hyperprolactinemia severity was greater in females than males with only one male having PRL levels >1,000 mIU/L and no males having levels >2,000 mIU/L. The percentages of patients with hyperprolactinemia, according to individual antipsychotic (combined cohort), are as follows: >AMI* (n=20): 89% >RIS IM (n=6): 67% >RIS oral (n=30): 55% >Typical Antipsychotics (n=56): 35% >QUE (n=8): 29% >OLA(n=57): 8% Limitations included: 1) naturalistic study design, 2) small cohorts, and 3) timing of PRL sampling.
Švestka et al (2007)¹² conducted a 6- week, prospective, open-label, single-center study evaluating the effect of AMI (amisulpride), OLA, QUE, RIS and ZOT (zotepine) on PRL levels in 433 female in-patients (mean age: 40.58 years) primarily diagnosed with schizophrenia. Median Doses: *AMI* (n=93): 800 mg/day *OLA* (n=125): 20 mg/day *QUE* (n=84): 700 mg/day *RIS* (n=93): 5 mg/day *ZOT* (n=38): 150 mg/day-Dosing was flexible and based upon the patient's clinical condition. *Percentage of Patients Receiving Concomitant Medications: benzodiazepines (41%); promethazine (38%); anticholinergics (29%); zolpidem (11%); mood-stabilizers (continued in 4.8%); antidepressants (continued in 2.5%) Endpoints*: PRL levels were determined from weekly blood samples drawn in the morning under fasting conditions. Additional efficacy and safety parameters assessed at baseline and endpoint (6 weeks) included the CGI-S, CGI-I, and TSH (thyroid-stimulating hormone), T4, cholesterol, triglyceride and blood glucose levels.	*PRL Level Analysis: At baseline, 104 patients were antipsychotic naïve, 145 were treated with a typical antipsychotic, 165 with a second-generation antipsychotic, and 19 with an antidepressant only. After 6 weeks of therapy, the whole group experienced significant increases in mean PRL levels (baseline: 1,015 mIU/L vs endpoint: 1,777 mIU/L; P<0.002). From baseline to endpoint, PRL levels decreased in patients receiving QUE (828 mIU/L vs 304 mIU/L, respectively; P<0.002) and ZOT (1,213 mIU/L vs 913 mIU/L, respectively; P<0.05), were mildly elevated in OLA (1,095 mIU/L vs 1,247 mIU/L, respectively; P<0.05) patients and markedly elevated in patients receiving RIS (986 mIU/L vs 7,758 mIU/L, respectively; P<0.002) and AMI (1025 mIU/L vs 3,193 mIU/L, respectively; P<0.002). Both AMI and RIS increased PRL significantly more than OLA, ZOT and QUE. In addition, AMI and OLA increased PRL significantly more than QUE. Over the 6-week period patients treated with AMI and RIS had PRL levels ≥620 mIU/L. PRL Levels and Parameter Correlations*: Correlations between PRL levels and other parameters (age, weight, lipids, T4, TSH and blood glucose) were carried out using simple and multidimensional linear regression and multidimensional correlation analysis. Overall, no correlation was found between endpoint PRL levels and age, menopausal condition, therapeutic efficacy, total cholesterol, triglycerides, and blood glucose. A significant positive correlation between PRL levels and daily dose was found for OLA only (P<0.00002). A significant negative correlation was observed between patients' endpoint weight and prolactinemia (t=-3.2700, P=0.00022). Prolactinemia was also positively associated with first episode psychosis vs more psychotic episodes (t=46.55, P<0.0005), EPS vs no EPS (t=8783, P<0.005), and T4 (t=4.5250, P=0.0) and TSH (t=2.2636, P=0.0241) levels.
Eberhard et al (2007)³⁸ conducted a 5-year, open-label, longitudinal, multicenter, trial assessing the effects of RIS on PRL levels, and associated side effects, in 218 patients. Prolactin ULN reference values were 300 nmol/L for males and 500 nmol/L for females. The UKU scale was utilized for evaluation of side effects. Diagnoses: Mean Age Schizophrenia (n=151): 38.1 years Bipolar/Schizoaffective (n=30): 43.5 years Delusional (n=9): 39.2 years Psychosis NOS (n=15): 31.7 years Other (n=13): 38.3 years Treatment *RIS Monotherapy* (n=181) *RIS plus Atypical* (n=7) *RIS plus ≥1 Conventional* (n=30)	*Outcomes*: Significantly higher mean PRL levels were initially observed in females vs males (2387 nmol/L vs. 967 nmol/L, respectively; P<0.001). Prolactin levels were unaffected by diagnosis if adjusted for gender, current age, and age at onset of illness. No significant correlations were observed between PRL levels and PANSS total or subscale scores. Of the 59 patients with complete data over the 5 year period, mean PRL levels decreased significantly from baseline to year 5 (1,192 nmol/L vs. 412 nmol/L, respectively). A significant linear and quadratic trend was observed (P<0.001). For patients receiving continuous RIS monotherapy (n=20) over the 5-year period, a highly significant linear reduction of PRL was observed (P<0.001). Concomitantly used drugs, other than RIS, were not associated with PRL increases. Prolactin increases during RIS administration appeared to be associated with plasma levels of its main metabolite 9-OH-RIS. According to the UKU scale the following sexual side effects were observed during RIS use. No correlation between PRL levels and sexual side effects was observed.
Wang et al (2007)³⁹ conducted an 8-week, open-label study assessing the relationship between plasma concentrations, serum PRL levels, and clinical efficacy of first-time RIS treatment in 118 Chinese patients (mean age: 35.92 years; 40 male:78 female) diagnosed with schizophrenia. The relationship between CYP2D610 alleles, determined through genotyping, and plasma concentrations of RIS and 9-OH-RIS was also assessed. Mean RIS Dose: 4 mg/day Endpoints*: The BPRS was utilized to assess psychopathology at baseline and week 8 (endpoint). At endpoint, blood samples were collected in the morning, approximately 12 hours following the prior evening's dose, for determination of RIS and 9-OH-RIS concentrations via HPLC (detection limits: 2 ng/mL and 1 ng/mL, respectively). Measured concentrations were corrected for dose (ng/mL per mg).	*Outcomes: At endpoint, the total plasma concentrations for RIS and 9-OH-RIS were 7.57±6.3 ng/mL per mg and 21.95±12.98 ng/mL per mg, respectively. There was a significant correlation between plasma levels of RIS and 9OHRIS (r=0.404; P<0.001). However, no correlation was observed between plasma levels of active moiety (RIS + 9OHRIS) and clinical response (improvement in BPRS). In addition, no correlation was found between age or gender and plasma levels of RIS, 9-OH-RIS or active moiety. While the mean serum PRL concentration significantly increased from baseline to endpoint (775.19 MIU/L vs 2,212.19 MIU/L, respectively; P<0.001), this change was not correlated to the improvement in BPRS scores. Plasma levels of RIS, 9-OH-RIS and active moiety were not correlated with plasma PRL levels. No statistical differences were observed in the concentration of 9-OH-RIS, active moiety and clinical response among the 3 identified genotypes (CYP2D61/1, 1/10, 10/10) although the metabolic ratio of RIS/9-OH-RIS was significantly different among them. Results suggested that the metabolism of RIS is dependent upon CYP2D6 and neither changes in plasma concentration of active moiety or serum PRL appeared to be significantly correlated to clinical efficacy.
Gorobets (2005)⁴⁰ conducted an open-label trial comparing the effects of RIS, OLA, QUE, and HAL on PRL levels in 231 patients (average age: 31.1 years; 82 males:149 females) diagnosed with schizophrenia, schizotypical, or schizoaffective disorders. Following a 7-10-day washout period of previously prescribed antipsychotic medications, the *Average Monotherapy Doses* of study medications were: *RIS* (n=83): 3.83 mg/day *OLA* (n=56): 13.58 mg/day *QUE* (n=37): 358.11 mg/day *HAL* (n=55): 17.27 mg/day Prolactin concentrations were measured in 3 stages: Stage 1: Baseline (before treatment) Stage 2: 3-4 weeks following treatment initiation Stage 3: 6–8 weeks following treatment initiation	*Outcomes: PRL results (mU/L) were reported separately for male (normal PRL 50–500 mU/L) and female (normal PRL 70700 mU/L) patients. RIS (male, n=45; female, n=38): Stage 1: 883.0 (male); 1998.0 (female) Stage 2: 1149.0 (male); 2543.0* (female) Stage 3: 1090.0 (male); 2490.0 (female) OLA (male, n=10; female, n=46): Stage 1: 560.0 (male): 1132.0 (female) Stage 2: 399.0 (male); 799.0* (female) Stage 3: 350.0^† (male); 696.0^† (female) QUE (male, n=5; female, n=31): Stage 1: 658.0 (male); 1676.8 (female) Stage 2: 381.0 (male); 648.9* (female) Stage 3: 301.0* (male); 525.3 (female) HAL (male, n=22; female, n=33): Stage 1: 731.6 (male); 1564.6 (female) Stage 2: 1203.7* (male); 1892.0* (female) Stage 3: 1032.0^† (male); 1843.0 (female)(*P<0.05 compared to stage 1; ^†P<0.05 compared to stage 2) Mean baseline PRL levels exceeded normal values in both males and females.
Melkersson et al (2005)⁴¹ evaluated the degree and frequency of PRL elevation and associated symptoms in patients receiving RIS (n=18; mean age: 41 years), CLZ (n=28; mean age: 40 years), or OLA (n=29; mean age: 39 years) for DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder. In addition, the effects on LH, FSH, estradiol, testosterone, growth hormone (GH), and insulin-like growth factor were also analyzed. Median daily doses received for ≥2.5 months: *RIS: 3 mg (range 1-8 mg) CLZ: 400 mg (range 25-600 mg) OLA*: 10 mg (range 5-20 mg)	*Outcomes*: Eighty-nine percent of RIS patients, compared to 24% of patients receiving OLA and 0% of patients receiving CLZ, were found to have elevated PRL levels (≥10 μg/L in males & menopausal females; ≥20 μg/L in premenopausal females). Median PRL levels were significantly higher in the RIS (27.5 μg/L; P=0.00001) and OLA (7.1 μg/L; P=0.001) groups compared to patients receiving CLZ (4.5 μg/L). When evaluating gender groups, significantly (P=0.04) more females (n=14/33; 42%) than males (n=9/42; 21%) experienced hyperprolactinemia. Increased PRL levels, induced by the atypical antipsychotics, did not markedly affect the secretion of LH, FSH, or sexual steroid hormones. In addition, no GH deficiency was observed during treatment with RIS, CLZ, or OLA.
Kearns et al (2000)⁴² conducted an open-label study comparing the effects of RIS, CLZ, and typical antipsychotics (TAP) on serum PRL and TSH in 68 outpatients diagnosed with DSM-IV schizophrenia. Mean Age: *RIS: Male* (n=18): 41 years; Female (n=12): 44 years (RIS group included patients concomitantly receiving RIS and CLZ [n=10]) *CLZ: Male* (n=17): 37 years; Female (n=4): 35 years *TAP: Male* (n=11): 43 years; Female (n=6): 45 years *Endpoints*: Blood samples for PRL and TSH analysis were drawn between 9-11 am.	*Outcomes*: Normal PRL range for men in this study was 015 ng/mL in males and 0-20 ng/mL in females. A higher percentage of females receiving RIS (100%, n=12/12) had elevated PRL levels compared to females receiving CLZ (25%, n=1/4; P=0.0071 clinically significant) or TAP (83%, n=5/6; P=0.333). Significantly more males receiving RIS (94%, n=17/18) experienced elevated PRL levels compared to males receiving CLZ (18%, n=3/17; P<0.0001) or TAP (27%, n=3/11; P=0.0003). Mean PRL concentrations (ng/mL) were also significantly higher in the RIS group (males 37.3±23.9; females 125±56.6) compared to both the CLZ (males 13.3±22.4, P<0.0001; females 22±25.9, P=0.0004) and TAP (males 13.3±9.1, P=0.0003; females 69±59.8, P=0.036) treatment groups. Females receiving RIS experienced significantly higher PRL levels compared to males receiving RIS. PRL levels within the RIS group were also inversely dependent on age while duration of treatment had no effect. TSH levels did not differ between treatment groups.
Abbreviations: AE(s), adverse event(s); AMI, amisulpride; ARI, aripiprazole; AUC, area under the curve; BPRS, Brief Psychiatric Rating Scale; C_0,concentration at time zero; C_max,maximum plasma concentration; CGII, Clinical Global Impression - Improvement; CGI-S, Clinical Global Impression - Severity; CLZ, clozapine; EPS, extrapyramidal; symptoms; FSH, follicle stimulating hormone; GH, growth hormone; HAL, haloperidol; NOS, not otherwise specified; OLA, olanzapine; PANSS, Positive and Negative Syndrome Scale; PER, perospirone; PP, paliperidone palmitate; PRL, prolactin; QUE, quetiapine; RIS, RISPERDAL; 9-OH-RIS, 9-hydroxy risperidone; SOC, standard of care; TAP, typical antipsychotics; TSH, thyroid stimulating hormone; ULN, upper limit of normal; ZOT, zotepine.

Other Relevant Literature

Additional articles discussing RISPERDAL-induced PRL-related adverse events have been referenced.¹⁵^,⁴³^-⁵⁶

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to double-blind and openlabel (N>50) studies in adults with schizophrenia and bipolar I disorder in which elevated PRL levels were reported was conducted on 21 March 2023.

References

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