Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available as a long-acting injection. Paliperidone (9-hydroxyrisperidone) is the active metabolite of risperidone, introduced initially as an extended release oral (ORal Osmotic System, OROS®, Alza Corporation) formulation (Invega®, Janssen). Paliperidone long-acting injection (PLAI) has now been developed as a suspension of paliperidone palmitate nanocrystals in an aqueous formulation (Invega Sustenna®, Xeplion®), administered monthly by intramuscular injection (deltoid or gluteal). Doses of PLAI can be expressed either in milligram equivalents (mg eq) of paliperidone palmitate or in milligrams of the active fraction of paliperidone. The recommended initiation regimen of 150 mg eq (234 mg) on day 1 and 100 mg eq (156 mg) on day 8 (both administered in the deltoid) achieves therapeutic blood levels rapidly and without the necessity of oral supplementation. No refrigeration or reconstitution prior to administration is required. PLAI has been shown in to be effective in controlling the acute symptoms of schizophrenia as well as delaying time to relapse. Safety and tolerability are comparable to RLAI with no new safety signals. Thus, PLAI may represent the rational development of RLAI with greater ease of use.

Paliperidone, or 9-hydroxyrisperidone (Invega(®), Janssen, Antwerp, Belgium) is the major active metabolite of the atypical antipsychotic risperidone (Risperdal(®), Janssen). It possesses a similar, though not identical, receptor pharmacology to the parent molecule. There are additional differences in terms of its predominant renal metabolism, lower protein binding and decreased inhibition of P-glycoprotein leading to decreased potential for drug-drug interactions. Paliperidone is approved as an extended release (ER) tablet based on an osmotic-controlled release oral Push-Pull™ delivery system (Oral Osmotic System, OROS(®), Alza Corporation) for the treatment of schizophrenia. The ER formulation results in decreased fluctuations in plasma drug levels and allows for once-daily administration with initial tolerability that permits treatment initiation at a clinically effective dose without the need for titration. This achieves therapeutic levels rapidly and simplifies dosing regimens, leading to potentially better adherence and improved outcome. The present review focuses on the clinical implications of the pharmacology and formulation of paliperidone ER.

Schizophrenia is an extremely costly disease for families and society owing to the age of onset, chronicity and severity of impact in social, academic and vocational domains. Relapse and often consequent hospitalizations are the most significant healthcare cost drivers, and are closely related to partial- and non-adherence to treatment. Long-acting injections of first-generation antipsychotics or depots were initially developed to attempt to address the adherence problems that are inherent in the treatment of a disorder characterized by difficulties in therapeutic engagement and alliance, as well as impaired insight. Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available in a long-acting formulation. Determining the pharmacoeconomic benefit of a long-acting injection compared with other treatments is challenging, as there are many different factors and costs involved. Data from pharmacoeconomic modeling, hospitalization, mirror image and other studies suggest that, in general, the greater initial acquisition cost of RLAI is offset by reductions in other domains including hospitalization. However, most of the published studies are open label and are subject to significant selection and sponsor bias. While overall cost-effectiveness in a wide array of different healthcare systems and diverse patient populations has been demonstrated with RLAI, not all studies show a clear benefit. Furthermore, there are unique challenges with RLAI in terms of storage and administration that add to the costs of this treatment.

Efficacy has been demonstrated in the short term and maintenance treatment of schizophrenia with OLAI at doses of 150 - 300 mg every two weeks or 405 mg every four weeks. The overall side effect profile is similar to oral olanzapine. While injection site complications are mild, there is an incidence rate per injection of 0.07 % (incidence rate per patient of 1.4%) of post-injection delirium sedation syndrome (PDSS). This manifests as overdose-like symptoms which necessitates mandatory administration and continuous monitoring of OLAI by health care professionals for the first three hours in a suitable clinical facility. As a consequence, final regulatory approval was delayed and market release and clinical use have been limited.

Up to 20% of depressed patients demonstrate treatment resistance to one or more adequate antidepressant trials, resulting in a disproportionately high burden of illness. Ketamine is a non-barbiturate, rapid-acting general anesthetic that has been increasingly studied in treatment resistant depression (TRD), typically at sub-anesthetic doses (0.5 mg/kg over 40 min by intravenous infusion). More recent data suggest that ketamine may improve response rates to electroconvulsive therapy (ECT) when used as an adjunct, but also as a sole agent. In the ECT setting, a dose of 0.8 mg/kg or greater of ketamine demonstrates improved reduction in depressive symptoms than lower doses; however, inconsistency and significant heterogeneity among studies exists. Clinical predictors of responses to ketamine have been suggested in terms of non-ECT settings. Ketamine does increase seizure duration in ECT, which is attenuated when concomitant barbiturate anesthetics are used. However, most studies are small, with considerable heterogeneity of the sample population and variance in dosing strategies of ketamine, ECT, and concomitant medications, and lack a placebo control, which limits interpretation. Psychotomimetic and cardiovascular adverse effects are reported with ketamine. Cardiovascular adverse effects are particularly relevant when ketamine is used in an ECT setting. Adverse effects may be mitigated with concurrent propofol; however, this adds complexity and cost compared to standard anesthesia. Long-term adverse effects are still unknown, but relevant, given recent class concerns for anesthetic and sedative agents.