Summary

• Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.¹

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate can be expressed in milligram equivalents 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 TRINZA doses expressed as 175, 263, 350, and 525 mg eq. are equal to 273, 410, 546, and 819 mg of paliperidone palmitate, respectively.

BACKGROUND

The use of second-generation antipsychotics (SGAs) has been associated with weight gain and metabolic abnormalities, including increased levels of low-density lipoprotein (LDL) cholesterol and triglycerides and decreased levels of high-density lipoprotein (HDL) cholesterol.² These metabolic side effects are common and generally observed in the initial months of treatment but can also occur later in treatment. It is unclear whether triglyceridemia is a direct result of antipsychotic medications or an indirect result of increased triglycerides in the blood with concomitant diabetes. The American Psychiatric Association guidelines for the treatment of patients with schizophrenia highlight the importance of assessing for other contributors to metabolic syndrome and to ensure appropriate treatment with a lipid-lowering agent, as clinically indicated.³ The guidelines recommend an initial baseline lipid panel followed by another lipid panel at 4 months after initiating a new antipsychotic agent and at least annually thereafter.³

The European Psychiatric Association, supported by the European Association for the Study of Diabetes and the European Society of Cardiology, recommends cholesterol measurements for all patients with severe mental illness be taken at the initial presentation and before the first prescription of antipsychotic medication.⁴ For patients with normal baseline tests, it is recommended that measurements are repeated at 6 weeks and 12 weeks after initiation of treatment and at least annually thereafter. Testing frequency will then depend on the patient's medical history and the prevalence of baseline risk factors.⁴

SCHIZOPHRENIA CLINICAL STUDIES

Berwaerts et al (2015)⁵ conducted a double-blind (DB), placebo (PBO)-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA formulation in delaying time-to-relapse of schizophrenia symptoms in patients previously treated with paliperidone palmitate 1-month (PP1M) formulation for at least 4 months.

Study Design/Methods

The study included 4 phases: a screening and oral tolerability testing phase of up to 3 weeks, a 17-week open-label (OL) transition phase, a 12-week OL maintenance phase, and a DB phase of variable length. During the transition phase, all patients except those who were receiving other long-acting injectable (LAI) antipsychotics or those who were receiving PP1M before entering the study received 4 months of PP1M treatment. Dosing included the following: Day 1: PP1M 234 mg (deltoid intramuscular [IM] administration); Day 8: PP1M 156 mg (deltoid IM administration); Days 36 and 64: PP1M 78, 117, 156, or 234 mg flexible doses (deltoid IM or gluteal IM administration); and Day 92: the same dose of PP1M as was administered on Day 64. During the maintenance phase, patients received a single dose of INVEGA TRINZA (273, 410, 546, or 819 mg; a 3.5-fold multiple of the final PP1M dose administered on Day 92) in either the deltoid or gluteal muscle. During the DB phase, stabilized patients were randomized 1:1 to receive a fixed dose of INVEGA TRINZA (the same dose as during the maintenance phase) or PBO. In addition to efficacy, safety and laboratory parameters were measured, which included lipids.

Results

Changes in fasting lipids and the proportion of patients with abnormal shifts in lipids from the long-term maintenance trial with INVEGA TRINZA are reported in Table: Change in Fasting Lipids and Proportion of Subjects with Shifts.^5,6

Savitz et al (2016)⁷ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and PP1M.  The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase.

Study Design/Methods

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.  

The study included patients between the ages of 18-70 years with a PANSS score between 70-120 who had worsening schizophrenia symptoms and discontinued other antipsychotics due to insufficient efficacy, safety or tolerability issues with current treatment, or those with a preference for injectable medications.

During the open label phase, 1429 patients received PP1M in the following doses:

• Day 1: 234 mg (deltoid administration)
• Day 8: 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 PP1M (78, 117, 156 or 234 mg; n=512) or INVEGA TRINZA (273, 410, 546, 819 mg; n=504) in the deltoid or gluteal muscle. In the PP1M group, injections occurred every 4 weeks, and in the INVEGA TRINZA group, active drug was administered every 3 months along with placebo injections given monthly when active therapy was not administered.

Results

Changes in fasting lipids are reported in Table: Mean Changes in Fasting Lipids from Double-blind Baseline to Double-blind Endpoint.

LITERATURE SEARCH

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