Association of malignant hyperthermia and exertional heat illness in young athletes: An analysis of awareness among clinical and athletic first responders.

Background: Malignant hyperthermia (MH), a rare inherited condition seen almost exclusively in the perioperative setting, is triggered by volatile anesthetics or an intravenous paralytic drug, succinylcholine. It can, however, occur without any exposure to anesthetic drugs, being associated with heat illness and rhabdomyolysis, thus presenting a little-known risk to young athletes exercising in hot environments. Objective: This study aimed to determine the first responder awareness of MH and its association with heat illness in young athletes within athletic and clinical environments. Methods: Awareness within the clinical milieu was assessed by an institutional chart review of 3296 charts. The identified heat illness cases were examined for treatment consistent with the management of a suspected episode of MH. Awareness among first responders in an athletic setting was examined by a survey administered to a total of 1,500 coaches and athletic trainers at the high school level along with emergency medical services providers across the United States. Results: No treatment consistent with the suspicion of MH was noted among clinical first responders, suggesting a lack of awareness. Survey administration also revealed a limited amount of knowledge of MH and its potential role in heat illness. Conclusion: The results point to lack of awareness among pre-hospital and hospital-based first responders of the relationship between MH and heat illness in young athletes. An effort to educate these members of the healthcare community can contribute to an expeditious and life-saving intervention. Clinical Relevance: First responders who may interact with a young athlete have low knowledge of MH and its relationship to heat illness. Similar lack of awareness exists among hospital personnel who care for young individuals with heat illness. Educating the first responders about this condition can speed up the time to intervene and save lives.

A review of ketamine's role in ECT and non-ECT settings.

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.

A critical appraisal of paliperidone long-acting injection in the treatment of schizoaffective disorder.

Schizoaffective disorder (SCA) is a chronic and disabling mental illness that presents with mixed symptoms of schizophrenia and affective disorders. SCA is recognized as a discrete disorder, but with greater heterogeneity and symptom overlap, leading to difficulty and delay in diagnosis. Although the overall prognosis is intermediate between schizophrenia and mood disorders, SCA is associated with higher rates of suicide and hospitalization than schizophrenia. No treatment guidelines exist for SCA, and treatment is frequently complex, involving off-label use and polypharmacy (typically combinations of antipsychotics, mood stabilizers, and antidepressants). Oral paliperidone extended-release was the first agent to be approved for the treatment of SCA. As in schizophrenia and bipolar disorder, adherence to oral medications is poor, further contributing to suboptimal outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses adherence issues, thus potentially reducing relapse. Paliperidone palmitate represents the LAI formulation of paliperidone. In a long-term, double-blind, randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55-3.99; P<0.001). This study demonstrated the efficacy and safety of PLAI when used as either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The results are consistent with a similarly designed study conducted in patients with schizophrenia, which suggests a benefit in the long-term control of not only psychotic but also affective symptoms. No new safety signals were observed. When used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy and obviating the necessity for daily oral medications. PLAI is the second agent, and the first LAI, to be approved for the treatment of SCA; as an LAI formulation, there is the advantage of improved adherence and simplified treatment in the long-term management of SCA.

A review of aripiprazole long-acting injection.

OBJECTIVES: To review the published literature on aripiprazole once monthly, a second generation antipsychotic (SGA) recently developed as a long-acting injection (LAI), in the form of a suspension of lyophilized aripiprazole reconstituted with an aqueous diluent, for intramuscular administration. METHODS: An electronic database search was conducted using the key words; relevant articles were then hand searched and websites (FDA, EMA, Otsuka, Lundbeck, NIH) reviewed. RESULTS: Efficacy has been demonstrated in preventing relapse in a 52 week study versus placebo, and non-inferiority to oral aripiprazole in a 38 week study, as well as in the treatment of hospitalized adult patients with acutely relapsed schizophrenia. Aripiprazole LAI appears cost-effective versus other SGA-LAIs, with improved health-related quality of life and functioning in a head-to-head study with paliperidone LAI. A 6 month (pre and post), mirror-image switch study demonstrated a reduction in hospitalization and associated costs compared with previous antipsychotic treatment. Safety and tolerability are comparable to oral aripiprazole with no new safety signals. CONCLUSIONS: Experience with oral aripiprazole and the current availability of the long-acting formulation suggest a potential benefit in a variety of clinical scenarios and therefore consideration as a treatment option in the treatment of schizophrenia.

A review of paliperidone palmitate.

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.

The pharmacology and formulation of paliperidone extended release.

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.

A review of olanzapine pamoate.

INTRODUCTION: Olanzapine long-acting injection (OLAI), or olanzapine pamoate , is one of three second generation (SGA) antipsychotics now available in a long-acting formulation. OLAI is a microcrystalline salt of pamoic acid and olanzapine suspended in an aqueous solution that slowly dissociates into the separate components once injected intramuscularly (im) into gluteal muscle. AREAS COVERED: A systematic search of databases including PubMed, PsychInfo, and Embase was conducted using the keywords. Relevant articles were then hand searched and relevant websites (FDA, EMA, Eli Lilly, and NIH) were also reviewed. EXPERT OPINION: 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.

The cost-effectiveness of risperidone long-acting injection in the treatment of schizophrenia.

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.