INVEGA SUSTENNA®

(paliperidone palmitate)

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INVEGA SUSTENNA® (paliperidone palmitate)

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INVEGA SUSTENNA - Adverse Event - Prolactin Effects

Last Updated: 09/09/2026

SUMMARY

Prolactin (PRL) regulation is complex, involving many different neurochemicals and receptors. The two primary receptors involved in the release of PRL are the dopamine D2 and serotonin (5-HT)_2Areceptors. D2 receptor blockade by paliperidone increases the release of PRL.¹ Paliperidone has a PRL-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of PRL than other antipsychotic drugs.²
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving PRL-elevating compounds.¹ Long-standing hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male subjects.³
Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.⁴
In a long-term maintenance trial of INVEGA SUSTENNA in schizophrenia patients, mean serum PRL levels increased during the transition and maintenance phase by 25.3 ng/mL in women and 9.8 ng/mL in men. In the double-blind phase, levels increased by 12.7 ng/mL in women and 3.7 ng/mL in men receiving INVEGA SUSTENNA and decreased by 16.6 ng/mL in women and 9.2 ng/mL in men receiving placebo (PBO). Potentially PRL-related adverse events (AEs) were reported in 1% and 2% of the PBO and INVEGA SUSTENNA group, respectively.⁵
In a long-term maintenance trial of INVEGA SUSTENNA in patients with schizoaffective disorder, PRL related treatment-emergent adverse events (TEAEs) were reported in 13.9% of women and 7.1% of men receiving INVEGA SUSTENNA compared to 5.8% and 1.2% in the PBO group, respectively. The most common TEAEs with INVEGA SUSTENNA and PBO in women were hyperprolactinemia/blood PRL increase (8.9%, 3.5%), amenorrhea (3.8%, 2.3%), and galactorrhea (3.8%, 1.2%). The most common TEAE with INVEGA SUSTENNA and PBO in men was hyperprolactinemia/blood PRL increase (4.7%, 0%).⁶
During a 15-month, prospective, randomized, open-label, event monitoring board-blinded, multicenter United States (US) study designed to reflect real-world schizophrenia patients, treatments and outcomes, treatment-emergent PRL-related AEs were reported in 23.5% (n=53) and 4.1% (n=9) of INVEGA SUSTENNA and oral antipsychotic patients, respectively.⁷
In a pooled analysis of 10 randomized, double-blind and open-label, PBO and active-controlled trials of INVEGA SUSTENNA in patients with schizophrenia⁵^,⁸^-¹⁷, the incidence of potentially PRL-related AEs in the INVEGA SUSTENNA group was 3.4%, which was significantly higher than that in the PBO group; 2.0% of patients experienced symptomatic PRL-related AEs.¹
PRL levels were also evaluated in a noninferiority trial comparing paliperidone palmitate 3-month (PP3M) to INVEGA SUSTENNA.¹⁸ The overall incidence of PRL-related TEAEs was comparable between the PP3M and INVEGA SUSTENNA groups.
A prospective cohort study of 28 patients with schizophrenia treated with INVEGA SUSTENNA for ≥3 months reported a significant increase in PRL levels from baseline (median, 18.1 to 52.1 ng/mL; P=0.0185), with elevations in 42.86% of patients, mainly in females. Baseline ANXA11 and DIABLO elevations and reduced CLEC5A plasma protein levels were associated with hyperprolactinemia risk.¹⁹
Numerous observational and retrospective real-world studies evaluated changes in prolactin levels and clinical manifestations of hyperprolactinemia with INVEGA SUSTENNA²⁰^-²⁷
Case reports examining the effects of aripiprazole on paliperidone or INVEGA SUSTENNA-induced hyperprolactinemia have been identified.²⁸^-³¹

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents (mg eq.) of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths available in the United States. The conversion factor from mg eq. to mg is 1.56.

INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq. of paliperidone, respectively.

BACKGROUND

PRL is a 199-amino acid polypeptide hormone that is secreted by the lactotroph cells in the anterior pituitary under the inhibitory control of D₂ receptors. Many antipsychotics, conventional and atypical, which block dopamine receptors in the tuberoinfundibular pathway of the hypothalamus, can increase PRL secretion.³²^,³³

Paliperidone has a PRL-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of PRL than other antipsychotic drugs.²

Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male subjects.³ 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.³ 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.

Management of Hyperprolactinemia

Asymptomatic hyperprolactinemia

Most guidelines recommend against treating asymptomatic hyperprolactinemia induced by antipsychotics.³²

Symptomatic hyperprolactinemia

The recommendations for the management of symptomatic hyperprolactinemia may include, reducing the dose of the PRL raising agent, switching to a low potency or PRL sparing agent, adding a full or partial dopamine agonist, or discontinuing the PRL elevating agent. Treatments noted with various degrees of support include aripiprazole, cabergoline, bromocriptine, amantadine, estrogen or testosterone, and metformin.³²^-³⁴

Two separate algorithms, specific to male and female patients for the management of hyperprolactinemia, are also described in the publication.³²

Concomitant use with aripiprazole

Aripiprazole as a substitute or in combination with the primary antipsychotic if aripiprazole monotherapy is not achievable may be considered; however, caution should be exercised when combination therapy is utilized as the primary antipsychotic’s efficacy might be reduced due to partial agonism by aripiprazole at D₂ receptors, leading to competitive receptor occupancy.³²

CLINICAL STUDIES

Clinical Studies

Trial Design	PRL Changes
SCHIZOPHRENIA
Double-Blind Trials including Open-Label Extensions
Hough et al (2010)⁵ conducted a longer-term, DB, randomized, multicenter, PBO-controlled, parallel group study examining the efficacy and safety of INVEGA SUSTENNA in delaying time to relapse in schizophrenic patients following an initial 9-week, OL transition phase and 24-week, OL maintenance phase (n=849, transition and maintenance population; n=408, DB safety analysis set). Dosing Schedule (All doses administered IM via gluteal muscle): 9-week OL transition phase INVEGA SUSTENNA 78 mg on day 1 and day 8 followed by adjustable INVEGA SUSTENNA doses (39, 78, or 156 mg) administered every 4 weeks for the rest of the transition period. 24-week OL maintenance phase Adjustable INVEGA SUSTENNA doses (39, 78, or 156 mg) administered every 4 weeks for the first 12 weeks followed by fixed INVEGA SUSTENNA doses of 39, 78, or 156 mg every 4 weeks for the last 12 weeks. DB phase Fixed INVEGA SUSTENNA doses of 39, 78, or 156 mg (n=205) or PBO (n=203) every 4 weeks.	PRL Changes During the OL transition and maintenance phases, mean PRL levels increased by 9.8 ng/mL in males and by 25.3 ng/mL in females. Mean Change in PRL Levels from DB Baseline to Endpoint: PBO: males, -9.2 ng/mL; females, -16.6 ng/mL INVEGA SUSTENNA: males, 3.7 ng/mL; females, 12.7 ng/mL PRL-Related TEAEs PRL-related TEAEs during the transition and maintenance phases occurred in 3% of patients. PRL-related TEAEs during the DB phase occurred in 2% of INVEGA SUSTENNA-treated patients and in 1% of PBO-treated patients.
Gopal et al (2011)¹³ conducted a 52-week, OLE study assessing the long-term safety and efficacy of INVEGA SUSTENNA in 388 patients with schizophrenia (Hough 2010).⁵ Study Treatment All patients received gluteal injections of INVEGA SUSTENNA beginning with a 78 mg dose followed by flexible dosing (39, 78, 117, or 156 mg) once every 4 weeks for 12 injections. PBO/INVEGA SUSTENNA (n=153): PBO during DB phase; INVEGA SUSTENNA during OLE phase. INVEGA SUSTENNA/INVEGA SUSTENNA (n=161): INVEGA SUSTENNA during DB and OLE phases. No DB/INVEGA SUSTENNA (n=74): Patients in transition or maintenance phases entering directly to OLE phase upon DB termination.	Mean Changes in PRL Levels from OLE Baseline to Endpoint PBO/INVEGA SUSTENNA: males, 7.2 ng/mL; females, 17.0 ng/mL INVEGA SUSTENNA/INVEGA SUSTENNA: males, -2.6 ng/mL; females, -3.1 ng/mL No DB/INVEGA SUSTENNA: males, -0.7 ng/mL; females, 6.6 ng/mL Incidence of PRL Levels >2 Times ULN at Any Time During OLE PBO/INVEGA SUSTENNA: males, 30%; females, 63% INVEGA SUSTENNA/INVEGA SUSTENNA: males, 29%; females, 73% No DB/INVEGA SUSTENNA: males, 25%; females, 76% PRL-Related TEAEs PRL elevations, occurred in 13 patients (primarily females); however, no patient discontinued treatment because of these TEAEs. Most common were amenorrhea (n=6) and galactorrhea (n=3).
Pandina et al (2011)¹⁷ conducted a 13-week, randomized, DB, double-dummy, active-controlled, parallel-group, multicenter study assessing non-inferiority of INVEGA SUSTENNA to RLAI in the treatment of patients with schizophrenia (n=1214, safety analysis set). INVEGA SUSTENNA (n=606): Deltoid injection of INVEGA SUSTENNA 234 mg on day 1 followed by a 156-mg deltoid injection on day 8; thereafter, patients received flexibly dosed INVEGA SUSTENNA injections on days 36 (78 or 156 mg) and 64 (78, 156, or 234 mg) in either the deltoid or gluteal muscle. RLAI (n=608): RLAI 25 mg on days 8 and 22, followed by 25 or 37.5 mg on days 36 and 50; thereafter, patients received flexible doses of 25, 37.5, or 50 mg on days 64 and 78, all in the gluteal muscle. Oral supplementation with RIS (1-6 mg) was administered for the first 28 days. Optional supplementation with RIS was permitted under certain circumstances.	PRL Changes Mean increase in PRL levels (ng/mL) from baseline to endpoint: INVEGA SUSTENNA: females: 21.8; males: 9.38 RLAI: females: 15.6; males: 6.0 PRL-Related TEAEs The most common potentially PRL-related TEAEs were erectile dysfunction (4 males in the INVEGA SUSTENNA group and 3 males in the RLAI group) and amenorrhea (4 females in the INVEGA SUSTENNA group and 4 females in the RLAI group).
Gopal et al (2010)¹² conducted a 13-week, multicenter, randomized, DB, PBO-controlled, dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA (78, 156, or 234 mg), administered via gluteal injection on days 1, 8, 36 and 64, in patients with schizophrenia (n=388, safety analysis set).	PRL Changes PBO: males, 1.2 ng/mL; females, -11.21 ng/mL INVEGA SUSTENNA 78 mg: males, 7.13 ng/mL; females, 32.04 ng/mL INVEGA SUSTENNA 156 mg: males, 15.10 ng/mL; females, 40.17 ng/mL INVEGA SUSTENNA 234 mg: males, 15.21 ng/mL; females, 62.33 ng/mL Potential PRL-Related TEAEs occurred in 1 patient who received INVEGA SUSTENNA 78 mg (breast hypertrophy), in 1 patient who received INVEGA SUSTENNA 156 mg (erectile dysfunction), and in 2 patients who received PBO (erectile dysfunction, galactorrhea).
Kramer et al (2010)¹⁰ conducted a 9-week, DB, randomized, international study comparing the safety and efficacy between INVEGA SUSTENNA (2 fixed doses) and PBO in the treatment of adults with schizophrenia (n=247). Following a 5-day screening/washout phase and a 7-day oral run-in period, patients were randomized to receive gluteal IM injections of INVEGA SUSTENNA 78 mg (n=79), INVEGA SUSTENNA 156 mg (n=84), or PBO (n=84), without oral supplementation, on days 1, 8, and 36.	PRL Changes Median PRL levels increased during the oral paliperidone run-in period. Although PRL levels decreased from baseline to endpoint of DB treatment period, they remained above pre-dose levels in INVEGA SUSTENNA-treated patients. PRL levels decreased to pre-dose values in PBO-treated patients. Potential PRL-Related TEAEs occurred in 3 INVEGA SUSTENNA-treated patients (erectile dysfunction, galactorrhea, and amenorrhea) and 1 PBO-treated patient (amenorrhea).
Pandina et al (2010)¹⁶ and Haskins et al (2009)³⁵ conducted a 13-week, phase 3, randomized, DB, PBO-controlled, international dose response INVEGA SUSTENNA study in patients experiencing an acute exacerbation of established schizophrenia (n=652). *Initiation Dose: Day 1 (Deltoid IM Inj) INVEGA SUSTENNA 234* mg (n=488) PBO (n=164) *Fixed Dose: Day 8, 36, and 64 (Deltoid or Gluteal IM Inj) INVEGA SUSTENNA 234* mg (n=163) INVEGA SUSTENNA 156 mg (n=165) INVEGA SUSTENNA 39 mg (n=160) PBO (n=164)	PRL Changes Mean PRL levels increased in all INVEGA SUSTENNA groups from baseline to endpoint, with larger increases in females (4.72 ng/mL to 37.24 ng/mL) than in males (3.73 ng/mL to 13.15 ng/mL). The highest increases were observed for each sex in the 234-mg dose group. Mean PRL levels decreased in the PBO-treated group. PRL-Related TEAEs occurred in 3 INVEGA SUSTENNA-treated patients (ejaculation disorder, loss of libido, and galactorrhea) and 1 PBO-treated patient (ejaculation disorder).
Nasrallah et al (2010)⁸ conducted a 13-week, phase 3, multicenter, randomized, DB, PBO-controlled, parallel group, international dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA (39, 78, or 156 mg), administered by gluteal IM injection on days 1, 8, 36, and 64, in patients with schizophrenia (n=517, safety analysis set).	PRL Changes Patients receiving INVEGA SUSTENNA had higher frequencies of and greater dose-related increases in PRL levels from baseline to endpoint than those receiving PBO. Mean Changes in PRL Levels from Baseline to Endpoint PBO: males, -2.1 ng/mL; females, -8.8 ng/mL INVEGA SUSTENNA 39 mg: males, 4 ng/mL; females, 9.3 ng/mL INVEGA SUSTENNA 78 mg: males, 6.8 ng/mL; females, 35.1 ng/mL INVEGA SUSTENNA 156 mg: males, 10.4 ng/mL; females, 43.6 ng/mL PRL-Related TEAEs INVEGA SUSTENNA: 1-2%; PBO: 1% Included erectile dysfunction (PBO, 1%; INVEGA SUSTENNA 156 mg, 1%); galactorrhea (INVEGA SUSTENNA 156 mg, 1%); decreased libido (PBO, 1%); and sexual dysfunction (INVEGA SUSTENNA 78 mg, 1%; INVEGA SUSTENNA 156 mg, 2%).
Hough et al (2009)¹⁵ conducted a 25-week, randomized, DB, multicenter, cross-over study assessing the safety and tolerability of INVEGA SUSTENNA administered via a deltoid or gluteal IM injection in adults with stable schizophrenia (n=252, safety analysis set). Patients were randomized to receive one of two injection-site sequences (Period 1: Doses administered on days 1, 8, 36, and 64 followed by Period 2: Doses administered on days 92, 120, and 148). 1) GD (Gluteal IM inj during period 1 followed by Deltoid IM Inj during period 2) 2) DG (Deltoid IM Inj during period 1 followed by Gluteal IM Inj during period 2)	INVEGA SUSTENNA doses: 78 mg: GD (n=40); DG (n=42); 117 mg: GD (n=44); DG (n=40); 156 mg: GD (n=40); DG (n=46) PRL Changes Mean PRL levels increased in all INVEGA SUSTENNA groups, from baseline to endpoint, with larger increases occurring in females (0 ng/mL to 43.1 ng/mL, respectively) compared to males (5.8 ng/mL to 16.7 ng/mL, respectively). Larger increases in PRL were observed in the 117 and 156 mg dosing groups, compared to the 78 mg dose. PRL-Related TEAEs Only 2 TEAEs, potentially related to increased PRL levels, were observed (galactorrhea and decreased libido). Both occurred during period 1.
Additional Double-Blind Trials
Savitz et al (2016)¹⁸ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of PP3M and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase. The study consisted of 4 phases: A 3-week screening phase, a 17-week, OL stabilization phase, a 48-week DB phase, and a follow-up phase. During the OL phase, 1429 patients received INVEGA SUSTENNA at the following doses: Day 1/Day 8: 234 mg/156 mg (deltoid administration); Weeks 5 and 9: flexible dosing between 78-234 mg (deltoid or gluteal administration). The week 13 dose was the same as week 9. Based on pre-defined criteria, patients who were clinically stable after completing the OL phase were randomized (1:1) into the DB phase. Patients in the DB phase received fixed doses of INVEGA SUSTENNA (78, 117, 156 or 234 mg; n=512) or PP3M (273, 410, 546, 819 mg; n=504) in the deltoid or gluteal muscle. In the INVEGA SUSTENNA group, injections occurred every 4 weeks and in the PP3M group PBO injections were given monthly when active therapy was not administered.	Mean Change in Serum PRL Levels (µg/L): OL Baseline to OL Endpoint: INVEGA SUSTENNA: males, 7.65; females, 18.56 DB Baseline to DB Endpoint: PP3M: males, -1.28; females, -3.37 DB Baseline to DB Endpoint: INVEGA SUSTENNA: males, 0.45; females, 0.69 Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (N=1429), PP3M (n=504) and INVEGA SUSTENNA (n=512) patients, respectively: galactorrhea (1.2; 0.6; 1.0); sexual dysfunction (0.3; 0.4; 0); libido decreased (0.2; 0.2; 0); anorgasmia (0.1; 0.2; 0.2); breast enlargement (0.1; 0.2; 0); breast pain (0.1; 0.2; 0) Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (n=782), PP3M (n=258) and INVEGA SUSTENNA (N=281) Male patients, respectively: gynecomastia (0.4; 0.8; 0); erectile dysfunction (0.1; 0.4; 0.4) Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (n=647), PP3M (n=246) and INVEGA SUSTENNA (n=231) Female patients, respectively: amenorrhea (2.6; 3.3.; 1.7); irregular menstruation (1.4; 2.0; 1.3) Males in the INVEGA SUSTENNA group experienced treatment-emergent abnormally high PRL levels at a greater rate than males in the PP3M group (45% vs. 39%; OL baseline to DB). Females in both the INVEGA SUSTENNA and PP3M groups experienced a similar percentage of high PRL levels (32% vs. 33%; OL baseline to DB).
McEvoy et al (2014)³⁶ conducted the ACLAIMS trial, a DB, randomized, multisite, parallel-group US clinical trial comparing the effectiveness of INVEGA SUSTENNA vs HAL decanoate for the maintenance treatment of schizophrenia or schizoaffective disorder. LAI treatment (≤24 months): INVEGA SUSTENNA (n=147): Initiation doses, IM deltoid (234 mg on day 1; 156 mg on day 8); Maintenance doses, IM deltoid or gluteal (117 mg monthly) HAL decanoate (n=147): Initiation doses, IM deltoid (50 mg on day 1; 50 mg on day 8); Maintenance doses, IM deltoid or gluteal (75 mg on days 28 and 56, then 50 mg monthly)	Mean monthly doses of INVEGA SUSTENNA and HAL decanoate ranged from 129-169 mg and 67-83 mg, respectively. Patients were followed for a median of 488 days. Highest mean PRL levels (SI unit conversion factor, multiply by 43.478 for pmol/L) were significantly higher for INVEGA SUSTENNA vs HAL decanoate patients: Males: INVEGA SUSTENNA (34.56 μg/L); HAL decanoate (15.41 μg/L); P<0.001 Females: INVEGA SUSTENNA (75.19 μg/L); HAL decanoate (26.84 μg/L); P<0.001
Takahashi et al (2013)³⁷ conducted a 13-week, randomized, DB, PBO-controlled trial assessing the safety and efficacy of INVEGA SUSTENNA in Asian patients with schizophrenia (N=323; mean age: 45 years; 57% male). INVEGA SUSTENNA (n=159): 234 mg on day 1 (deltoid IM); 156 mg on day 8 (deltoid IM); once-monthly injections of 117 mg (deltoid IM or gluteal IM) on days 36 and 64. PBO (n=164)	Mean duration of INVEGA SUSTENNA and PBO exposure was 87 and 50 days, respectively. INVEGA SUSTENNA: Mean PRL levels (ng/mL) remained stable at baseline and endpoint for males (30.57 vs 30.72, respectively) and slightly increased at endpoint for females (68.73 vs 79.36, respectively). PBO: Irrespective of gender, an overall decrease in mean PRL level was observed. One patient in the PBO group experienced a PRL-related TEAE (irregular menstruation).
Open-label Rater-Blinded Studies
Wang et al (2024)³⁸ conducted a 49-week, prospective, randomized, active-controlled, OL, rater-blinded, multicenter study in China between November 2017 and June 2020 to evaluate the impact of INVEGA SUSTENNA vs OAPs on violent behavior in patients with schizophrenia and aggressive tendencies. A total of 134 patients (mean age, 39.1 years; male, 52.2%) were randomized to receive either OAPs (n=67; RIS, aripiprazole, ziprasidone, OLA, quetiapine, and amisulpride) or INVEGA SUSTENNA (n=67; on-label initiation followed by once-monthly injections of flexible dosing range of 117 to 234 mg [deltoid IM or gluteal IM]).	Of the 134 patients, 104 (77.6%) completed the study (INVEGA SUSTENNA group, n=59; OAP group, n=45). The duration of maintenance treatment was significantly different between the groups: INVEGA SUSTENNA group, 44.9 (95% CI, 42.2-47.6) weeks; OAP group, 37.1 (95% CI, 38.5-43.6) weeks; P=0.002 PRL-related TEAEs In the INVEGA SUSTENNA group, 45 patients (70.3%) experienced hyperprolactinemia; 9 patients (14.1%) experienced amenorrhea. In the OAP group, 42 patients (62.7%) experienced hyperprolactinemia; 7 patients (11.0%) experienced amenorrhea. There was no significant difference in PRL-related TEAEs between the groups (P>0.05).
Alphs et al (2015)⁷ conducted a 15-month, prospective, randomized, OL, EMB-blinded, multicenter US study (PRIDE) designed to reflect real-world schizophrenia patients, treatments and outcomes. The clinician and patient reviewed the list of available OAPs (aripiprazole, HAL, OLA, paliperidone, perphenazine, quetiapine and RIS) before randomization and could preselect up to 6 from the list based on prior experience. Patients were stratified on the basis of their selection of OAP treatments and randomly assigned to flexibly dosed INVEGA SUSTENNA (78-234 mg) or flexibly dosed OAP therapy.	A treatment-emergent PRL-related AE was reported in 23.5% (n=53) and 4.1% (n=9) of INVEGA SUSTENNA and OAP patients, respectively. The most common (>5%) PRL-related AEs in males receiving INVEGA SUSTENNA (n=193) or OAPs (n=190), respectively were: erectile dysfunction (8.8%; 0%) and decreased libido (6.7%; 1.6%). The most common (>5%) PRL-related AEs in females receiving INVEGA SUSTENNA (n=33) or OAPs (n=28), respectively were: amenorrhea (15.2%; 3.6%), galactorrhea (15.2%; 0%), irregular menstruation (6.1%; 3.6%), hyperprolactinemia (6.1%; 3.6%) and increased blood PRL (6.1%; 0%).
Huang (2017)³⁹ conducted a randomized, 13-week, rater-blinded study evaluating the metabolic effects and efficacy of INVEGA SUSTENNA and oral OLA in Han Chinese patients with first-episode schizophrenia. INVEGA SUSTENNA (n=28): Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by deltoid or gluteal injection on days 36 (78 or 156 mg) and 64 (78 to 234 mg). OLA (n=29): Fixed 5 mg daily x 1 week followed by flexible dosing according to efficacy and tolerability.	Mean doses of INVEGA SUSTENNA and OLA at endpoint were 201.0 mg and 17.8 mg, respectively. PRL Changes Significant increases in PRL occurred in both treatment groups with greater increases observed in the INVEGA SUSTENNA vs OLA group from baseline to endpoint (P=0.025). PRL (µg/L) baseline/endpoint: INVEGA SUSTENNA (n=26): 26.76/58.15 (P=0.002) OLA (n=25): 23.80/27.65 (P<0.001) PRL-Related TEAEs: No significant between group differences (INVEGA SUSTENNA n=4; OLA n=1; P=0.148)
Li (2011)⁹ conducted a 13-week, phase 3, randomized, active-controlled, parallel-group, multicenter, OL, rater-blinded study assessing non-inferiority of INVEGA SUSTENNA to RLAI in Chinese patients with acute schizophrenia (n=452, safety analysis set). INVEGA SUSTENNA (n=229): Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) with the optional injection site of the gluteal muscle for days 36 (78 or 156 mg) and 64 (78 to 234 mg). RLAI (n=223): Gluteal IM injection on days 8 and 22 (25 mg); flexible doses of 25 or 37.5 mg on days 36 and 50; and flexible doses of 25 to 50 mg every 2 weeks thereafter beginning on day 64. Daily oral RIS supplementation occurred during the first 4 weeks (2 mg on day 1 and flexible doses of 1 to 6 mg on days 2 through 28). Additional oral RIS 1 to 2 mg was allowed during the 3-week period after each dosage increase.	PRL Changes Mean changes in PRL levels were greater in females than in males for INVEGA SUSTENNA (37.7 ng/mL vs 9.8 ng/mL) and RLAI (31.1 ng/mL vs 8.2 ng/mL). PRL-Related TEAEs INVEGA SUSTENNA: 8.3%; RLAI: 9.0% Most common event was increase in blood PRL levels (>5%).
Open-Label Studies (≥6 Months)
Zhang et al (2015)⁴⁰ conducted a phase 3b, OL, multicenter study evaluating the safety, tolerability, and efficacy of INVEGA SUSTENNA in Asian/Australian patients with recent-onset schizophrenia who previously failed treatment with OAPs (n=521 ITT/safety population). Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections of 78-234 mg (deltoid IM or gluteal IM).	Mean duration of exposure: 382.6 days; Mean maintenance dose after day 8: 157.2 mg PRL-Related TEAEs occurred in 11.9% (n=62) of patients and occurred more frequently in females than males (25.6% vs. 4.7%, respectively). Most common potential PRL-related TEAEs (≥2%): Females: amenorrhea (11.1%); menstrual disorder (5.6%); increased blood PRL (4.4%) Males: sexual dysfunction (2.1%)
PALMFlex is an international, prospective, 6-month, OL study assessing the efficacy and safety of treatment with flexibly dosed INVEGA SUSTENNA in adult patients with acute or nonacute schizophrenia who previously failed treatment with other antipsychotics.⁴¹^,⁴² Dosing Regimens: Transition from OAPs After tapering off OAPs over ≤4 weeks, INVEGA SUSTENNA was initiated at 234 mg on day 1 and 156 mg on day 8 (±2 days), both administered IM in the deltoid muscle. Patients receiving CLOZ within 3 months of trial initiation were not eligible to participate. Transition from LAI Antipsychotics For patients receiving LAIs, the first INVEGA SUSTENNA dose (78-234 mg) was administered in place of the next scheduled depot injection. Maintenance Flexible INVEGA SUSTENNA doses of 78-234 mg were administered monthly thereafter (±7 days).	Acute Schizophrenia switched from OAPs (n=212)⁴¹ Potentially PRL-related TEAEs occurred in 5.7% of the total patient population; reported as: amenorrhea (2.4%), amenorrhea, galactorrhea (0.5%), erectile dysfunction (1.4%), galactorrhea (0.5%), gynecomastia (0.5%) and sexual dysfunction (1.4%). Nonacute Schizophrenia switched from OAPs (n=593)⁴² While protocol-based laboratory tests were not conducted during the study, 18 patients (3.0%) reported at least one potentially PRL-related TEAE, 4 patients (0.7%) reported hyperprolactinemia and 7 patients (1.2%) reported a potentially PRL-related TEAE as well as hyperprolactinemia.
Wakamatsu et al (2013)⁴³ conducted a 57-week, OL, flexible-dose study evaluating the long-term safety and efficacy of INVEGA SUSTENNA in Japanese patients with schizophrenia (N=201; n=184, safety analysis set). Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections (deltoid IM or gluteal IM).	Patients received a mean INVEGA SUSTENNA dose of 166.8 mg for a mean duration of 238.7 days. PRL-Related TEAEs occurred in 32.8% of patients, occurring more frequently in females (41%) vs males (25%), and primarily increased blood PRL (29.9%), No patient required discontinuation of therapy. Additional potentially PRL-related TEAEs: menstrual irregularity (2.0%); amenorrhea (1.5%); galactorrhea (1.5%)
Coppola et al (2012)¹¹ conducted a 53-week, OL, multidose, multicenter study evaluating the pharmacokinetics and long-term safety and tolerability of INVEGA SUSTENNA 234 mg in adults with stable schizophrenia (n=212, safety analysis set). Following a screening and washout phase of ≤21 days, each patient received a deltoid IM injection of INVEGA SUSTENNA 234 mg on day 1. Each patient who tolerated the dose (Group A, n=186) received a second deltoid IM injection of INVEGA SUSTENNA 234 mg on day 8 and 12 once-monthly injections (deltoid or gluteal muscle) starting on day 36. Patients who were unable to tolerate the 234-mg dose or unwilling to participate in intensive pharmacokinetic sampling (Group B, n=26) received a second IM injection of INVEGA SUSTENNA 78-234 mg (flexible dose) on day 8 (deltoid or gluteal muscle) and 12 once-monthly injections starting on day 36 (deltoid or gluteal muscle).	PRL-Related AEs Potentially PRL-related AEs occurred in 19% of patients (n=41). Incidences were higher in females (32.8%) than in males (14.3%). Majority of events were laboratory abnormalities without reported symptoms. Potentially PRL-related AEs with clinical signs and symptoms which occurred in more than one patient were libido decreased (n=4), erectile dysfunction (n=2), and amenorrhea (n=2). Three patients discontinued treatment because of PRL-related AEs. Treatment-emergent abnormal PRL levels were reported in 78% of patients.
Pooled Analysis
Einarson et al (2012)¹ pooled analysis of 10 short- and long-term clinical trials⁵^,⁸^-¹⁰^,¹²^-¹⁷^,⁴⁴ (included randomized, DB, OL, and cross-over studies; and PBO- and active-controlled studies) of INVEGA SUSTENNA (N=3173; males, 61.4%) to evaluate the frequency of symptomatic, potentially PRL-related AEs. Serum PRL levels at baseline and ≥1 post-baseline assessment were available for 89% of patients (n=2831). Doses of INVEGA SUSTENNA ranged from 39 to 234 mg, including flexible-dose trials (weighted average dose in trials with flexible dosing was 108.5 mg monthly). INVEGA SUSTENNA vs PBO, 5 studies⁵^,⁸^,¹⁰^,¹²^,¹³^,¹⁶ INVEGA SUSTENNA vs RLAI, 3 studies⁹^,¹⁴^,¹⁷ Cross-over comparison of INVEGA SUSTENNA between gluteal and deltoid injection, 1 study¹⁵ Long-term, OL, safety study⁴⁴	Elevated PRL Levels In the INVEGA SUSTENNA group, 38.8% of patients had elevated PRL levels, with no difference between males and females (incidence was similar to that in the RLAI group, 35.4%). Hyperprolactinemia did not correlate with monthly dose of INVEGA SUSTENNA (P=0.109). PRL-Related TEAEs In the INVEGA SUSTENNA group, 3.4% of patients experienced potentially PRL-related AEs (significantly higher than in the PBO group, 1.1%; P=0.002); 44% of these AEs were associated with abnormal laboratory values, most of which were asymptomatic. Incidence of potentially PRL-related AEs that were symptomatic was 2% (exposed patients), and only 0.4% of patients required treatment. Higher INVEGA SUSTENNA doses were significantly correlated with potentially PRL-related AEs (P=0.004).
Post Hoc Analyses
Serretti et al (2026)²⁰ conducted analysis on population of the ACLAIMS trial to evaluate sexual function and its association with PRL levels in patients (N=175) with schizophrenia or schizoaffective disorder treated with INVEGA SUSTENNA or HAL decanoate for up to 24 months. Sexual function was assessed using the ASEX and PRL levels were measured from screening through month 24. INVEGA SUSTENNA (n=84): Patients from the ACLAIMS trial who had ≥1 ASEX assessment and received monthly INVEGA SUSTENNA. HAL decanoate (n=87): Patients from the ACLAIMS trial who had ≥1 ASEX assessment and received monthly HAL decanoate.	Sexual Dysfunction At baseline, sexual dysfunction was reported in 48.8% and 48.3% of patients receiving INVEGA SUSTENNA and HAL decanoate, respectively. Longitudinal ASEX total score trajectories did not differ significantly between treatment groups over 24 months. Mean (±SD) ASEX total scores at month 24 were 14.1 (±6.2) and 17.9 (±7.2) in the INVEGA SUSTENNA and HAL decanoate groups, respectively (P=0.019). However, the treatment-x-time interaction at month 24 was not significant in the repeated measures mixed-effects model (P=0.274). PRL Changes Before randomization, PRL levels did not differ between the groups. INVEGA SUSTENNA was associated with markedly and persistently higher prolactin levels than HAL decanoate throughout the 24-month follow-up in both sexes (all P<0.001). Mean PRL levels (at 24 months): Males: INVEGA SUSTENNA, 26.2 μg/L; HAL decanoate, 9.3 μg/L (P<0.01) Females: INVEGA SUSTENNA, 33.6 μg/L; HAL decanoate, 9.0 ug/L (P<0.001). Association Between PRL and Sexual Function At 12 months, greater increases in PRL levels from baseline were associated with greater worsening sexual function (r=0.21; P=0.013; n=139). However, this was non-significant at the 18 month and 24 month visits.
Li et al (2025)²² conducted a post hoc analysis of 3 phase IV studies to evaluate the efficacy and safety of INVEGA SUSTENNA in Chinese patients with early-, mid-, and late-phase schizophrenia. A total of 1053 patients received INVEGA SUSTENNA (maintenance doses of 117-234 mg monthly).	TEAEs of Special Interest Among patients included in the safety population (early-phase, n=388; mid-phase, n=297; late-phase, n=382), clinical symptoms associated with hyperprolactinemia were reported in 13 (3.4%), 6 (2.0%), and 16 (4.2%) patients in the early-, mid-, and late-phase cohorts, respectively.
Schizoaffective Disorder
Fu et al (2013 and 2015)⁶^,⁴⁵ conducted an international, long-term, DB, PBO-controlled, randomized-withdrawal study of INVEGA SUSTENNA in patients with schizoaffective disorder. During the 15-month, DB phase, stable patients were randomized to PBO (n=170) or a fixed dose of INVEGA SUSTENNA (n=164) INVEGA SUSTENNA dose distribution during DB phase: 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%) or 234 mg (38.4%) doses.	During the DB phase, PRL-related TEAEs occurred in 13.9% of females and 7.1% of males receiving INVEGA SUSTENNA and 5.8% of females and 1.2% of males receiving PBO. Most common (INVEGA SUSTENNA vs PBO, respectively): Females: hyperprolactinemia/blood PRL increase (8.9% vs 3.5%); amenorrhea (3.8% vs 2.3%); galactorrhea (3.8% vs 1.2%) Males: hyperprolactinemia/blood PRL increase (4.7% vs 0%)
Abbreviations: AE, adverse event; ASEX, Arizona Sexual Experience Scale; CI, confidence interval; CLOZ, clozapine; DB, double-blind; EMB, event monitoring board; HAL, haloperidol; IM, intramuscular; Inj, injection; ITT, intent-to-treat; LAI, long-acting injectable; OAP, oral antipsychotic; OL, open-label; OLA, olanzapine; OLE, open-label extension; PBO, placebo; PP3M, paliperidone palmitate 3-month; PRIDE, Paliperidone Palmitate Research In Demonstrating Effectiveness; PRL, prolactin; RIS, risperidone; RLAI, risperidone long-acting injection; SI, International System of Units; TEAE, treatment-emergent adverse event; ULN, upper limit of normal; US, United States.

Real-World Observational Studies

Aly El-Gabry et al (2026)²³ conducted a retrospective, observational, cross-sectional study to evaluate demographic and pharmacologic predictors of risperidone- and paliperidone-induced hyperprolactinemia in routine clinical practice in the United Arab Emirates. Electronic medical records collected between 2017 and 2023 were reviewed for adults with schizophrenia receiving oral or LAI risperidone or paliperidone for ≥6 weeks before serum PRL assessment.

A total of 835 patients were included in the final analysis and stratified into 4 groups by antipsychotic exposure: Oral paliperidone (n=235), intramuscular paliperidone (n=28), oral risperidone (n=512), and intramuscular risperidone (n=60). The mean (±SD) age was 40.2 (±14) years, and 53.8% of patients were males. The overall mean (±SD) serum PRL level was 1126 (±1334) mIU/L, and prevalence of hyperprolactinemia among patients with available prolactin measurements was reported in 61.9% (517/835) of patients. PRL levels differed significantly among treatment groups (P=0.005), with the highest mean level observed in patients receiving oral paliperidone (1369 mIU/L). Post hoc analysis demonstrated significantly higher PRL levels with oral paliperidone than with oral risperidone (P=0.003).

Rate of hyperprolactinemia in each drug occurred in 69.8% (155/222) of patients receiving oral paliperidone, 68.3% (28/41) receiving intramuscular paliperidone, 57.7% (303/525) receiving oral risperidone, and 66.0% (31/47) receiving intramuscular risperidone. For hyperprolactinemia distribution of cases across groups, pairwise analysis demonstrated a significant difference between oral paliperidone and oral risperidone (P=0.002). Also, significant differences observed among treatment groups (P=0.013) for the rate of hyperprolactinemia.

Documented sexual side effects were reported in 9.2% of patients and included amenorrhea (6.2%), erectile dysfunction (1.3%), sexual dysfunction (0.7%), mastalgia/myalgia (0.4%), gynecomastia (0.2%), galactorrhea (0.2%), and decreased libido (0.1%).

Labad et al (2026)²⁴ conducted a retrospective, cross-sectional, observational study to compare PRL levels and rates of sexual dysfunction in patients with schizophrenia or related psychotic disorders receiving risperidone ISM or INVEGA SUSTENNA. The study included
59 patients receiving stable monotherapy with either risperidone ISM (n=27) or INVEGA SUSTENNA (n=32) for at least 2 months. Sexual functioning was assessed using the Arizona Sexual Experience Scale (ASEX), and hormonal assessments included PRL, follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol measurements.

There were no significant differences between treatment groups in ASEX total scores (P=0.841) or rates of clinically significant sexual dysfunction (P=0.465). The prevalence of clinically significant hyperprolactinemia (defined as PRL above sex-specific thresholds with along with either clinically significant sexual dysfunction or hypogonadism) was reported in 55.6% and 68.8% of patients receiving risperidone ISM and INVEGA SUSTENNA, respectively (P=0.296). Sexual dysfunction was highly prevalent overall (67.8%), with no statistically significant differences across treatment groups. Multiple linear regression analysis demonstrated a significant interaction between female sex x INVEGA SUSTENNA treatment interaction (P=0.002), with women who received INVEGA SUSTENNA exhibiting higher PRL levels than those receiving risperidone ISM. Concomitant treatment with aripiprazole was associated with lower PRL concentrations (P=0.028).

Kuru et al (2026)²⁵ conducted a naturalistic, within-patient observational study comparing AEs following treatment with INVEGA SUSTENNA among patients who were then switched to INVEGA TRINZA. 43 patients who received a stable dose of INVEGA SUSTENNA for at least 4 months before being transitioned to INVEGA TRINZA were included in the final analysis. Data on UKU side effects showed that amongst patients receiving monotherapy, diminished sexual desire was reported in 41.9% (18/43) and 37.2% (16/43) of patients receiving INVEGA SUSTENNA and then after transitioning to INVEGA TRINZA, respectively, with no significant differences observed following conversion (P=0.500).

Zeng et al (2025)¹⁹ conducted a prospective cohort study to investigate the correlation between individual variability in response to INVEGA SUSTENNA and changes in plasma protein abundance using proteomic analysis in patients with schizophrenia undergoing treatment. The study included 28 patients with schizophrenia (mean age, 37 years; female, 71.4%), with assessments conducted at baseline (prior to INVEGA SUSTENNA initiation) and after at least 3 months of treatment.

After 3 months of treatment, serum PRL levels significantly increased from baseline (median, 18.1 ng/mL) to follow-up (median, 52.1 ng/mL; mean change, 13.7±45.6 ng/mL; P=0.0185). Elevated PRL levels were observed in 42.9% of patients at endpoint, with a higher prevalence among females (n=10). Menstrual disturbances were reported in 21.4% of female patients (n=6).

Subgroup analysis revealed two distinct trajectories among patients with abnormal PRL levels (n=24):

New-onset hyperprolactinemia (n=12): Patients with normal baseline prolactin who developed elevated levels of PRL post-treatment.
Normalization group (n=12): Patients with elevated baseline PRL who showed reduced levels after treatment.

In the new-onset group, at baseline, there were significant increases in 12 different proteins, with significant decreases in ARG1, ROR1, and LRP11. After treatment with INVEGA SUSTENNA, there was a significant increase in CLEC5A, with decreases in SNAP23, GRAP2, SERPINB6, PPP1R2, CRKL, ANXA11, CA13, and DIABLO. Patients with higher levels of ANXA11 and DIABLO, and lower levels of CLEC5A expression at baseline, were associated with increased susceptibility to INVEGA SUSTENNA-induced hyperprolactinemia.

Zipursky et al (2025)²¹ conducted an exploratory study to evaluate the association between plasma paliperidone levels and well-being, AEs, and attitude towards medication in outpatients with schizophrenia who received INVEGA SUSTENNA. Twenty-one patients (mean age, 41 years; female, 52.4%) were assessed at two visits aligned with consecutive INVEGA SUSTENNA injections dosed from 78 mg to 234 mg, spaced 3 or 4 weeks apart based on individual schedules.

Mean plasma paliperidone levels were 34.9 ng/mL at visit 1 (n=21) and 35.1 ng/mL at visit 2 (n=18) with a strong correlation between the two timepoints (ρ=0.8; P<0.001). Plasma paliperidone and PRL levels were also significantly correlated (ρ=0.59, P<0.01, n=21) and were more pronounced in female patients (P<0.05).

Sexual dysfunction was evaluated using the CSFQ-14. The study found that patients with higher paliperidone and PRL levels reported lower sexual desire. Specifically, as paliperidone levels increased, scores reflecting sexual desire/frequency and sexual desire decreased (ρ=−0.60; P<0.01 and ρ=−0.58; P<0.01 respectively). Similarly, higher PRL levels were associated with lower scores on the pleasure scale (ρ=−0.52, P<0.05), the Desire/Interest scale (ρ=−0.51, P<0.05), and desire scales (ρ=−0.49; P<0.05).

Tost et al (2024)²⁶ conducted a single-center, prospective, pragmatic observational study in Spain to evaluate the impact on sexual function and PRL levels in patients with schizophrenia after switching from risperidone LAI to INVEGA SUSTENNA. Sexual functioning was measured using the Arizona Sexual Experience Scale (ASEX; a 5-item scale that obtains a total score between 5 and 30, with high scores indicating sexual dysfunction). Plasma PRL and sex hormone levels were determined by immunoassays. Clinical assessments and laboratory measurements were taken at baseline, 3, and 6 months post-switch.

The analysis included 27 patients (mean age, 35 years; male, 81.5%), with a mean (standard deviation) disease duration of 8.9 (2.1) months and age of disease onset at 26.1 years. Men were younger than women (33.1 years vs 43.8 years), with no significant difference in baseline antipsychotic doses. At 6 months post-switch, PRL levels in women significantly decreased from the baseline (119.9 ± 65.5 to 83.0 ± 40.7 ng/mL; P<0.001), with no significant changes in men over the same period. Additionally, higher antipsychotic doses (measured in risperidone equivalents) were associated with higher PRL levels (P=0.006). No significant differences in ASEX total scores were observed 6 months post-switch, and clinical sexual dysfunction rates decreased from 51.9% at baseline to 37.0% at 3 months and 36.4% at 6 months, but this change was not statistically significant (P=0.125).

Pappa et al (2023)²⁷ conducted a real-world, 10-year, mirror-image, observational study between 2011 and 2021 in the United Kingdom to evaluate the long-term effect of INVEGA SUSTENNA on hospitalization rate and treatment discontinuation.

Of 167 patients who were initiated on INVEGA SUSTENNA, 70% (n=117) were primarily diagnosed with schizophrenia and the remaining 30% (n=50) with schizoaffective disorder, bipolar affective disorder, or other diagnoses. Overall, the continuation rates of INVEGA SUSTENNA in the first, second, third, fourth, and fifth years were 76%, 64.7%, 53.3%, 50.3%, and 46.1%, respectively, in the total cohort. Treatment with INVEGA SUSTENNA was discontinued due to poor tolerability, ineffectiveness, or poor adherence. Of the 33 patients who discontinued treatment due to poor tolerability, 9% (n=3) were due to hyperprolactinemia.

Case Reports

There currently are no systematically collected data to support the use of INVEGA SUSTENNA concomitantly with another antipsychotic; however, case reports examining the effects of aripiprazole on paliperidone- and INVEGA SUSTENNA-induced hyperprolactinemia have been identified.

A 25-year-old female patient, hospitalized for schizoaffective disorder, developed hyperprolactinemia (PRL level: 94 ng/mL) and amenorrhea following treatment with quetiapine 600 mg/day plus paliperidone 12 mg/day. Treatment was switched to INVEGA SUSTENNA (initiation: 234 mg day 1, 156 mg day 8 [both in the deltoid muscle]; maintenance: 156 mg monthly). Following the first two injections of INVEGA SUSTENNA, PRL levels increased to 125 ng/mL with continued amenorrhea. At discharge, 30 days after INVEGA SUSTENNA initiation, amenorrhea continued (PRL level: 105 ng/mL). Two months following discharge, the patient continued to experience amenorrhea. PRL levels remained elevated at 74 ng/mL. Aripiprazole 5 mg/day was added to her treatment. One month later, the patient's PRL level decreased to 38 ng/mL. One month after the decrease in PRL levels, amenorrhea resolved. Following 6 months of treatment with INVEGA SUSTENNA plus aripiprazole, PRL levels remained within normal limits at 31 ng/mL.²⁸
A 30-year-old female patient diagnosed with paranoid schizophrenia experienced amenorrhea and hyperprolactinemia (141 ng/mL; reference: 3-30 ng/mL) following treatment with paliperidone 12 mg/day and lorazepam 3 mg/day. Paliperidone was decreased to 9 mg/day but the patient experienced an exacerbation of positive symptoms. Paliperidone was then increased to 12 mg/day and combined with aripiprazole 5 mg/day. Four weeks later, the PRL level dropped to 37 ng/mL.²⁹
A 38-year-old patient with paranoid schizophrenia was resistant to treatment with several typical and atypical antipsychotics. During a course of risperidone (4 mg/day) and clomipramine (225 mg/day) she experienced menstrual irregularities and a PRL level of 307 ng/mL. Risperidone was switched to paliperidone 9 mg/day; however, the patient’s PRL levels still fluctuated between 228-289 ng/mL. Aripiprazole 15 mg/day was added to the patient’s treatment regimen. One month later PRL levels dropped from 253 ng/mL to 47.1 ng/mL.³⁰
A 16-year-old-male patient developed persistent aggressive and impulsive behaviors following a severe traumatic brain injury at 9 years of age. The patient had received multiple oral antipsychotic treatments; however, treatment was limited by nonadherence and adverse effects. Treatment was switched to INVEGA SUSTENNA 100 mg monthly, which was subsequently increased to 150 mg monthly. Following initiation of INVEGA SUSTENNA, the patient demonstrated significant reductions in aggression and improved behavioral control. Family members reported fewer aggressive outbursts and improved social interactions. Mild weight gain and increased PRL levels were reported but were generally well tolerated.³¹

Recent review articles discussing the effects of antipsychotics on serum PRL levels⁴⁶^,⁴⁷ and the clinical management of antipsychotic-induced hyperprolactinemia³²^,⁴⁸^,⁴⁹ have been referenced for your convenience.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 July 2026.

References

Show

1	Einarson TR, Hemels ME, Nuamah I, et al. An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate. Ann Pharmacother. 2012;46(10):1322-1330.
2	Berwaerts J, Cleton A, Rossenu S, et al. A comparison of serum prolactin concentrations after administration of paliperidone extended-release and risperidone tablets in patients with schizophrenia. J Psychopharmacol. 2010;24(7):1011-1018.
3	De Hert M, Detraux J, Stubbs B. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: a critical literature review. Expert Opin Drug Saf. 2016;15(6):809-823.
4	INVEGA SUSTENNA (paliperidone palmitate) extended-release injectable suspension [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/INVEGA+SUSTENNA-pi.pdf
5	Hough D, Gopal S, Vijapurkar U, et al. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2010;116(2-3):107-117.
6	Fu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. J Clin Psychiatry. 2015;76(3):253-262.
7	Alphs L, Benson C, Cheshire-Kinney K, et al. Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study. J Clin Psychiatry. 2015;76(5):554-561.
8	Nasrallah HA, Gopal S, Gassmann-Mayer C, et al. A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology. 2010;35(10):2072-2082.
9	Li H, Rui Q, Ning X, et al. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1002-1008.
10	Kramer M, Litman R, Hough D, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol. 2010;13(5):635-647.
11	Coppola D, Liu Y, Gopal S, et al. A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry. 2012;12:26.
12	Gopal S, Hough DW, Xu H, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. Int Clin Psychopharmacol. 2010;25(5):247-256.
13	Gopal S, Vijapurkar U, Lim P, et al. A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol. 2011;25(5):685-697.
14	Fleischhacker WW, Gopal S, Lane R, et al. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol. 2012;15(1):107-118.
15	Hough D, Lindenmayer JP, Gopal S, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(6):1022-1031.
16	Pandina GJ, Lindenmayer JP, Lull J, et al. A randomized placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010;30(3):235-244.
17	Pandina G, Lane R, Gopal S, et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):218-226.
18	Savitz AJ, Xu H, Gopal S, et al. Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol. 2016;19(7):pyw018.
19	Zeng W, Liang F, Lin X, et al. Plasma protein patterns associated with paliperidone palmitate maintenance therapy in schizophrenia: a prospective cohort study. CNS Drugs. 2025;39 (12):1297-1315.
20	Serretti A. Sexual function despite hyperprolactinemia: a 24-month analysis of paliperidone palmitate versus haloperidol decanoate. World J Biol Psychiatry. 2026;(published online July 13, 2026):doi: 10.1080/15622975.2026.2697979.
21	Zipursky RB, Agid O, Kiang M, et al. Clinical correlates of antipsychotic plasma levels with long-acting paliperidone. Can J Psychiatry. 2025;70(3):209-216.
22	Li Q, Li Y, Yang Y, et al. Efficacy and safety of once-monthly paliperidone palmitate long-acting injections in Chinese patients with early-, mid-, and late-phase schizophrenia: a post-hoc analysis of three phase 4 studies. CNS Drugs. 2025;39(8):795-805.
23	El-Gabry DA, Ahmed HM, G Andrade, et al. Risperidone- and paliperidone-induced hyperprolactinemia in routine clinical practice: demographic and pharmacological determinants from the UAE. Int Clin Psychopharmacol. 2026;41(4):232-243.
24	Labad J, Gálvez V, Gregorio M, et al. Assessment of prolactin levels and sexual dysfunction in patients on long-acting risperidone ISM vs monthly paliperidone palmitate. Span J Psychiatry Ment Heal. 2026;19(2):84-88.
25	Kuru E, Ozdemir I, Yucens B, et al. Comparison of side effects between 3-monthly and 1-monthly paliperidone palmitate formulations in patients with schizophrenia. Hum Psychopharmacol. 2026;41(1):e70033.
26	Tost M, Barbero JD, Montalvo I, et al. Sex differences in changes in prolactin levels and sexual function after switching from risperidone to paliperidone palmitate in schizophrenia. Eur J Psychiatry. 2024;38(3):100259.
27	Pappa S, Barnett J, Mason K. A 10-year observational study of the use, acceptability and effectiveness of long-acting paliperidone palmitate: implications for clinical decision making. CNS Drugs. 2023;37(1):107-116.
28	Alpak G, Unal A, Bulbul F, et al. Hyperprolactinemia due to paliperidone palmitate and treatment with aripiprazole. Psychiatry Clin Psychopharmacol. 2014;24(3):253-256.
29	Basterreche N, Zumárraga M, Arrue A, et al. Aripiprazole reverses paliperidone-induced hyperprolactinemia. Actas Esp Psiquiatr. 2012;40(5):290-292.
30	Rocha FL, Hara C, Ramos MG. Using aripiprazole to attenuate paliperidone-induced hyperprolactinemia. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(6):1153-1154.
31	Ghailani AYA, Mirza H, Adawi SA. Long-acting paliperidone in the management of severe behavioral disturbances post-traumatic brain injury: a case report. Eur Psychiatry. 2025;68 (Suppl 1):S533.
32	Grigg J, Worsley R, Thew C, et al. Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology (Berl). 2017;234(22):3279-3297.
33	Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872.
34	Labad J, Montalvo I, González-Rodríguez A, et al. Pharmacological treatment strategies for lowering prolactin in people with a psychotic disorder and hyperprolactinaemia: a systematic review and meta-analysis. Schizophr Res. 2020;222:88-96.
35	Haskins JT, Sliwa JK, Ma Y-W, et al. Efficacy and safety of 234 mg initiation dose and 3-fixed maintenance doses of paliperidone palmitate-a once-monthly injectable atypical antipsychotic. Poster presented at: the US Psychiatric and Mental Health Congress; November 2-5, 2009; Las Vegas, NV.
36	McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014;311(19):1978-1987.
37	Takahashi N, Takahashi M, Saito T, et al. Randomized, placebo-controlled, double-blind study assessing the efficacy and safety of paliperidone palmitate in Asian patients with schizophrenia. Neuropsychiatr Dis Treat. 2013;9:1889-1898.
38	Wang G, Huang H, Wang Y, et al. A randomized, prospective, active-controlled study comparing intramuscular long-acting paliperidone palmitate versus oral antipsychotics in patients with schizophrenia at risk of violent behavior. Prog Neuropsychopharmacol Biol Psychiatry. 2024;129:110897.
39	Huang M, Yu L, Pan F, et al. A randomized, 13-week study assessing the efficacy and metabolic effects of paliperidone palmitate injection and olanzapine in first-episode schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:122-130.
40	Zhang F, Si T, Chiou CF, et al. Efficacy, safety, and impact on hospitalizations of paliperidone palmitate in recent-onset schizophrenia. Neuropsychiatr Dis Treat. 2015;11:657-668.
41	Hargarter L, Cherubin P, Bergmans P, et al. Intramuscular long-acting paliperidone palmitate in acute patients with schizophrenia unsuccessfully treated with oral antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:1-7.
42	Schreiner A, Bergmans P, Cherubin P, et al. A prospective flexible-dose study of paliperidone palmitate in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents. Clin Ther. 2014;36(10):1372-1388.
43	Wakamatsu A, Takahashi N, Takahashi M. A 57-week, open-label evaluation of paliperidone palmitate flexible doses in Japanese patients with schizophrenia. Poster presented at: 26th European College of Neuropsychopharmacology (ECNP) Congress; October 5-9, 2013; Barcelona, Spain.
44	Coppola D, Liu Y, Gopal S, et al. Long-term safety, tolerability and pharmacokinetics of paliperidone palmitate: a one-year open-label study in patients with schizophrenia. Poster presented at: the 163rd Annual Meeting of the American Psychiatric Association; May 22-26, 2010; New Orleans, LA.
45	Fu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate long-acting injectable in acute exacerbation of schizoaffective disorder. Poster presented at: the 14th International Congress on Schizophrenia Research; April 21-25, 2013; Orlando, FL.
46	M De Hert, Detraux J, Peuskens J. Second-generation and newly approved antipsychotics, serum prolactin levels and sexual dysfunctions: a critical literature review. Expert Opin Drug Saf. 2014;13(5):605-624.
47	Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs. 2014;28(5):421-453.
48	Milano W, Colletti C, Capasso A. Hyperprolactinemia induced by antipsychotics: from diagnosis to treatment approach. Endocr Metab Immune Disord Drug Targets. 2017;17(1):38-55.
49	Montejo ÁL, Arango C, Bernardo M, et al. Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics. Front Neuroendocrinol. 2017;45:25-34.

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