Summary

• INVEGA SUSTENNA has not been studied in controlled clinical trials and is not approved for use in patients with Bipolar Disorder.
• An open-label, multicenter, real-world, observational study by Martiadis et al (2023) evaluated the efficacy and safety of adjunctive therapy with INVEGA SUSTENNA or aripiprazole once-monthly (AOM) in patients with bipolar I disorder (BD-1) and comorbid Obsessive Compulsive Disorder (OCD).¹
• A prospective, open-label, observational trial by Li et al (2021) evaluated the efficacy, safety, and compliance associated with INVEGA SUSTENNA in patients with BD-1.²
• A retrospective mirror-image study by Caliskan et al (2020) evaluated the number of relapses and rehospitalizations occurring 1 year before and after treatment with INVEGA SUSTENNA in patients with BD-1.³
• Several case reports described the use of INVEGA SUSTENNA in patients with BD-1.^4,5
• A case series by Buoli et al (2015) described the use of INVEGA SUSTENNA in 3 patients with BD-1 with psychotic features and a history of noncompliance to medication.⁶

PUBLISHED LITERATURE

Observational Studies

Martiadis et al (2023)¹ conducted an open-label, multicenter, real-world, observational study to evaluate the efficacy and safety of adjunctive therapy with INVEGA SUSTENNA or AOM in patients with BD-1 and comorbid OCD.

Study Design/Methods

Patients with BD-1 and comorbid OCD who received either adjunctive treatment with INVEGA SUSTENNA or AOM in addition to the stabilizing therapy were observed over 24 weeks. Psychopathological assessment was conducted by Yale-Brown Obsessive Compulsive Scale (YBOCS), Hamilton Depression Rating Scale (HDRS), Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), and Hamilton Anxiety Rating Scale (HARS).

Results

A total of 24 patients were included in this analysis. The mean INVEGA SUSTENNA dosage administered was 117.8 mg/month, and the mean AOM dosage was 400 mg/month.

At the end of the observation period, a reduction in obsessive symptoms and maintenance of effective mood stability with no reported signs of hypomanic/manic change was observed in all patients who completed the study (YBOCS mean reduction 24.5 to 16.2, generalized linear model repeated measures [GLM rm] P<0.001; HDRS mean reduction 19 to 10, GLM rm P<0.001; YMRS mean reduction from 23.2 to 6.3, GLM rm P<0.001). Overall, the study reported that INVEGA SUSTENNA and AOM were well tolerated, and the outcomes were in line with the safety profiles of both drugs; however, due to the small study size, significant differences in the efficacy of the 2 long-acting injectables (LAIs) were not determined.

Li et al (2021)² conducted an open-label, one-arm, prospective, observational study to evaluate the efficacy, safety, and compliance of INVEGA SUSTENNA in patients with BD-1.

Study Design/Methods

Patients (aged 16-65 years) were required to fulfill the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria for bipolar disorder, tolerate and respond well to oral risperidone or paliperidone ER, and have a history of noncompliance. Patients were treated with INVEGA SUSTENNA as either monotherapy or adjunctive therapy with oral antipsychotics, mood stabilizers, anxiolytics, or modified electroconvulsive therapy. Efficacy was evaluated by assessing compliance, symptomatic improvement, prevention of relapse or switch to another polarized affective episode, and prevention of hospitalization. Symptomatic remission was evaluated by comparing the differences in the 17-item Hamilton Depression Rating Scale (HAMD-17), Clinical Global Impression – Bipolar Disorder – Severity of Illness Scale (CGI-BP), and YMRS scores from baseline to endpoint. Safety was evaluated using the Treatment Emergent Symptom Scale (TESS).

All patients received fixed initiation doses of INVEGA SUSTENNA (234 mg on day 1 and 156 mg on day 8), followed by flexible doses of INVEGA SUSTENNA.

Results

• A total of 11 patients were included in the study (median age, 33 years; 45.4% female). At the study endpoint, 6 (54.5%) patients were on INVEGA SUSTENNA monotherapy, and the remaining patients received INVEGA SUSTENNA and concomitant lithium, alprazolam, or fluoxetine.
• From baseline to study endpoint, a decrease in mean (SD) HAMD-17 (16.1 [10.3] vs 7.4 [5.7]), CGI-BP (5.3 [0.7] vs 2.3 [0.7]), and YMRS (30.9 [12.6] vs 3.7 [3.2]) scores was reported. No new hospitalizations or hypomanic episodes occurred during the treatment period; however, 3 cases of mild to moderate depressive episodes were reported.
• At follow-up endpoint, 6 (54.5%) patients discontinued treatment with INVEGA SUSTENNA due to efficacy reasons (36.4%) or for personal reasons (18.2%) unrelated to the medication. The median duration of treatment was 14 months. The most common treatment-emergent adverse events were sedation (63.6%), weight gain (54.5%), prolactin-related adverse events (45.5%), insomnia (45.5%), and decreased energy (45.5%).

Caliskan et al (2020)³ conducted a retrospective, mirror-image study to evaluate the effect of INVEGA SUSTENNA on relapse and rehospitalization in patients with BD-1.

Study Design/Methods

Patients included in the study were required to have a BD-1 diagnosis, must have initiated treatment with INVEGA SUSTENNA (50, 75, 100, or 150 mg eq.), continued to take INVEGA SUSTENNA for at least 1 year, and had 1-year data before and after INVEGA SUSTENNA initiation. Outcomes included the number and types of relapses and hospitalizations, days of hospitalization, and analysis of metabolic and prolactin levels a year before and after initiation of INVEGA SUSTENNA.

Results

Thirty-six patients (mean age, 38.86 years; age range, 21 to 63 years; male, n=27) were included, in which 27.8% had somatic comorbidities, 8.3% had substance abuse or dependence, 22.2% had alcohol use disorder, and 83.3% had tobacco use disorder. All patients were hospitalized for manic episodes at the initiation of INVEGA SUSTENNA.

At the time of initiation with INVEGA SUSTENNA, the total duration (±SD) of illness was 15.88 (±7.07) years, and the mean age (±SD) of disease onset was 22.97 (±7.21) years. Before starting INVEGA SUSTENNA, the mean number (±SD) of total hospitalizations was 7.97 (±4.88); the mean number (±SD) of mood episodes, 11.97 (±6.58); number (±SD) of manic episodes, 8.97 (±5.04); number (±SD) of depressive episodes, 2.08 (±2.99); number (±SD) of mixed episodes, 0.61 (±2.00); and number (±SD) of hypomanic episodes, 0.38 (±0.99). Before initiating INVEGA SUSTENNA, 18 patients underwent electroconvulsive therapy, and none after initiation. Similarly, 10 patients had a history of suicidal attempts before initiating INVEGA SUSTENNA and none after initiation.

The mean (SD) dose of INVEGA SUSTENNA was 108.56 ± 23.50 mg (range: 75-150 mg/28 days). Concomitant treatments in the year following INVEGA SUSTENNA initiation included lithium carbonate (41.6%), valproic acid (63.8%), and oral antipsychotics (16.6%).

The number of relapses and number and duration of hospitalizations before and after initiation of INVEGA SUSTENNA are summarized in the Table: Comparison of Relapses and the Number and Duration of Hospitalizations Before and After Initiation of INVEGA SUSTENNA.

No statistically significant differences in the metabolic analyses were detected before and after initiation of INVEGA SUSTENNA (fasting blood glucose [P=0.302], total cholesterol [P=0.169], triglyceride [P=0.172], high-density lipoprotein [P=0.441], low-density lipoprotein [P=0.071], and prolactin [P=0.626]).

Case Report

Olguner Eker et al (2024)⁴ described the case of a 48-year-old male patient with bipolar affective disorder who presented with feelings of disorientation, speech incoherence, sleepiness, and day-night confusion. In medication history, he was initiated on INVEGA SUSTENNA and concomitant lithium (900 mg/day) and had received the second dose of INVEGA SUSTENNA 234 mg 20 days before the current presentation. It was recorded that he experienced symptoms of trembling, rigidity, weakness, and drowsiness ~2 days after receiving the second dose of INVEGA SUSTENNA but was discharged with those symptoms. He also discontinued taking lithium at home and experienced a few additional symptoms, including slurred speech and difficulties in walking and talking, and he slept for 18-20 hours/day. The patient’s vital status, blood, and renal and liver function tests were normal. A diagnosis of postinjection delirium sedation syndrome (PDSS) was made. Four days later, the patient’s sedation and delirium symptoms and rigidity declined, and he was treated with biperiden 2 mg/day and diazepam 5 mg/day. Later, the biperiden dose was increased to 6 mg/day and diazepam to 10 mg/day, leading to a reduction in muscle contractions and complete resolution of delirium symptoms. The patient was discharged on a reduced dose of biperiden, and diazepam was discontinued.

Zhang et al (2024)⁵ described the case of a Black female patient in her early 20s with BD-1 who, at the time of the presentation to the outpatient clinic, was treated with INVEGA SUSTENNA 156 mg for the last 4 months and had been considered to switch to INVEGA TRINZA (the 3-month formulation) due to complete resolution of symptoms after treatment with INVEGA SUSTENNA. However, involuntary orofacial movements of the jaw were noted, including clenching, chewing, and retraction of the corners of the mouth, indicating possible paliperidone-induced tardive dyskinesia. The patient’s Abnormal Involuntary Movement Scale (AIMS) score was 11, and it was decided to reduce her INVEGA SUSTENNA dose (100 mg eq. to 75 mg eq. monthly) and not proceed with the switch to INVEGA TRINZA. Two months later, the patient's AIMS score had reduced to 4.

Case Series

Buoli et al (2015)⁶ described the utilization of INVEGA SUSTENNA in 3 patients with BD-1 with psychotic features and a history of noncompliance to medication. All patients received the recommended INVEGA SUSTENNA initiation dosing (234 mg on day 1 and 156 mg 1 week later). Case details can be found below:

• A 31-year-old female receiving haloperidol decanoate 50 mg every 4 weeks presented with a manic psychotic episode complicated by alcohol abuse (YMRS=34). Her past medical history was positive for a major depressive episode with psychotic features, suicidal ideation, and poor insight. Upon current hospitalization, treatment was changed to oral paliperidone 9 mg/day, and then switched to and maintained on INVEGA SUSTENNA 234 mg monthly due to a history of noncompliance. In the following days, the patient experienced an improvement of symptoms with complete remission (YMRS=8) observed 3 weeks from hospital admission. The patient remained relapse-free for approximately 1 year and did not report any adverse effects.
• A 27-year-old female presented with a third recurrence of bipolar disorder with psychotic features. Oral paliperidone 9 mg/day was initiated upon hospitalization. A reduction in psychotic and mood symptoms was observed within a few weeks (YMRS=14). Three weeks following admission, the patient was discharged on INVEGA SUSTENNA 234 mg monthly. The treatment was well tolerated, and the patient remained relapse-free during the 1 year follow-up period.
• A 60-year-old male presented with a manic episode combined with mixed jealousy and grandiosity delusions (YMRS=33). He had a 30-year history of illness with a predominant manic polarity. He refused oral medications but has discontinued previous depot medications due to extrapyramidal symptoms and sedation (zuclopenthixol 200 mg monthly; risperidone LAI 37.5 mg every 2 weeks). He was maintained on INVEGA SUSTENNA 156 mg monthly. One month after initiation, he showed a response to treatment (YMRS=15) and reached complete remission after 2 months (YMRS=8). The treatment was well tolerated, and the patient remained relapse-free for approximately 2 years.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 22 August 2024.