Long-acting Intramuscular Injections Research Articles

Population Pharmacokinetic Modeling and Simulation for Dose Optimization of GB-5001, a Long-Acting Intramuscular Injection of Donepezil, in Healthy Participants.

GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer's disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation. A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280mg, and the oral formulation at 10mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation. The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210-215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE. The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials. ClinicalTrials.gov identifier, NCT05525780.

Long-acting intramuscular injections of ELQ-331, an antimalarial agent

The overarching premise of this investigation is that injectable, long-acting antimalarial medication would encourage adherence to a dosage regimen for populations at risk of contracting the disease. To advance support for this goal, we have developed oil-based formulations of ELQ-331 (a prodrug of ELQ-300) that perform as long-acting, injectable chemoprophylactics with drug loading as high as 160 mg/ml of ELQ-331. In a pharmacokinetic study performed with rats, a single intramuscular injection of 12.14 mg/kg maintained higher plasma levels than the previously established minimum fully protective plasma concentration (33.25 ng/ml) of ELQ-300 for more than 4 weeks. The formulations were well tolerated by the rats and the tested dose produced no adverse reactions. We believe that by extending the length of time between subsequent injections, these injectable oil-based solutions of ELQ-331 can offer a more accessible, low-cost option for long-acting disease prevention and reduced transmission in malaria-endemic regions and may also be of use to travelers.

Predicting lung exposure of intramuscular niclosamide as an antiviral agent: Power-law based pharmacokinetic modeling.

Niclosamide, a potent anthelmintic agent, has emerged as a candidate against COVID-19 in recent studies. Its formulation has been investigated extensively to address challenges related to systemic exposure. In this study, niclosamide was formulated as a long-acting intramuscular injection to achieve systemic exposure in the lungs for combating the virus. To establish the dose-exposure relationship, a hamster model was selected, given its utility in previous COVID-19 infection studies. Pharmacokinetic (PK) analysis was performed using NONMEM and PsN. Hamsters were administered doses of 55, 96, 128, and 240 mg/kg with each group comprising five animals. Two types of PK models were developed, linear models incorporating partition coefficients and power-law distributed models, to characterize the relationship between drug concentrations in the plasma and lungs of the hamsters. Numerical and visual diagnostics, including basic goodness-of-fit and visual predictive checks, were employed to assess the models. The power-law-based PK model not only demonstrated superior numerical performance compared with the linear model but also exhibited better agreement in visual diagnostic evaluations. This phenomenon was attributed to the nonlinear relationship between drug concentrations in the plasma and lungs, reflecting kinetic heterogeneity. Dose optimization, based on predicting lung exposure, was conducted iteratively across different drug doses, with the minimum effective dose estimated to be ~1115 mg/kg. The development of a power-law-based PK model proved successful and effectively captured the nonlinearities observed in this study. This method is expected to be applicable for investigating the drug disposition of specific formulations in the lungs.

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.

Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants.

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m2. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.

Supporting the Safe Use of the Dorsogluteal Intramuscular Injection Site: An Evidence-Based Quality Improvement Project.

Administering intramuscular (IM) injections is common in the adult mental health patient care setting, using the deltoid, vastus lateralis, ventrogluteal, or dorsogluteal site. Mental health nurses frequently use the dorsogluteal site to administer short and long-acting IM injections as specified in the drug package insert or because of patient agitation. However, the site is often not recommended due to the potential risk of nerve injury. Aims of this evidence-based quality improvement project were to (1) determine the best evidence for supporting the safe use of the dorsogluteal site for short and long-acting IM injections and (2) implement this evidence through nurse education. This project had two phases: Determining best evidence through an integrative literature review and implementing the recommendations to use the dorsogluteal site when directed by the drug package insert, clinical need, nursing judgment, or patient preference. Implementation followed the Plan-Do-Study-Act quality improvement process and involved written resources and simulation. Evidence supported the use of the dorsogluteal site in four instances and the importance of education. Nurses were highly satisfied with the education and opportunity to practice their skills with feedback during return demonstration. After studying nurses' follow-up survey results, a refresher simulation and medical center guideline were completed. There were no reports of IM injection patient injuries after 2 years and approximately 768 dorsogluteal and ventrogluteal IM injections in the academic medical center. Pursuing recent and possibly overlooked evidence provided guidance in supporting the safe use of the dorsogluteal site for IM injections.

A population pharmacokinetic model based on HPTN 077 of long-acting injectable cabotegravir for HIV PrEP.

Cabotegravir delivered as a long-acting intramuscular injection has shown superior efficacy to oral tenofovir-emtricitabine as pre-exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long-acting depot preparations, exhibit variability between individuals and between injection occasions. The aim of this study is to describe the population pharmacokinetics of long-acting cabotegravir (CAB-LA). Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analysed CAB-LA PK data using nonlinear mixed-effects modelling to develop a population PK model. A two-compartment model with first order absorption best described the CAB-LA PK. The analysis identified between-occasion variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate, with an estimated contribution of BOV to PK variability on the absorption rate (ka ) of 38.5%. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB-LA after intramuscular injection at various doses and frequencies. Male participants had 67% higher ka than female participants. Serially adding to the model body weight on clearance, sex on ka , and BOV on ka led to a decrease in the objective function value (OFV) of 24.4, 36 and 321.4, respectively. The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB-LA.

Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study.

Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways. This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520. Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons. After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile. ViiV Healthcare and Janssen Research & Development.

Aripiprazole Lauroxil, a Novel Injectable Long-Acting Antipsychotic Treatment for Adults with Schizophrenia: A Comprehensive Review.

Purpose of Review. This is a comprehensive review of the literature regarding the use of Aripiprazole lauroxil for schizophrenia. This review presents the background, evidence, and indications for using aripiprazole lauroxil to treat schizophrenia in the context of current theories on the development of schizophrenia. Recent Findings. Schizophrenia is a chronic mental health disorder that currently affects approximately 3.3 million people in the United States. Its symptoms, which must be present for more than six months, are comprised of disorganized behavior and speech, a diminished capacity to comprehend reality, hearing voices unheard by others, seeing things unseen by others, delusions, decreased social commitment, and decreased motivation. The majority of these symptoms can be managed with antipsychotic medication. Aripiprazole lauroxil is a long-acting intramuscular injection that works as a combination of partial agonist activity at D2 and 5-HT1A receptors combined with antagonist activity at 5-HT2A receptors. It can be dosed as a 4-, 6-, or 8-week injection, depending on oral dosage. Aripiprazole lauroxil was FDA approved in October of 2015. Summary. Schizophrenia is a severe psychiatric disorder if left untreated. There are multiple medications to help treat schizophrenia. One antipsychotic agent, aripiprazole lauroxil, offers long duration injections that optimize and improve compliance. Known side effects include weight gain, akathisia, neuroleptic malignant syndrome, tardive dyskinesia, and orthostatic hypotension. Aripiprazole lauroxil is an FDA-approved drug that can be administered monthly, every six weeks, or every two months and has been shown to be both safe and effective.

Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long Term Follow up Study on Prevalence, Determinants, and the Effect of Years of Exposure

Background: Erythrocytosis is a known side effect of testosterone therapy in hypogonadal men and can increase the risk of thromboembolic events. Erythrocytosis is also seen in trans men (birth-assigned female, male gender identity) receiving testosterone therapy. Currently there are no clinical guidelines for the management of this problem in trans men. Specific aims: 1. To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone. 2. To study the association between duration of testosterone treatment and hematocrit levels. Methods: A 20 year follow-up study in adult trans men who started testosterone, and had monitoring of hematocrit levels at our center (n=1073). Results: Erythrocytosis (defined as hematocrit levels of >0.50 l/l twice) occurred in 11% of trans men. Multilevel analyses showed former or current smoking (OR 2.2, 95%CI 1.6-3.3), testosterone administration as long-acting intramuscular injection (OR 2.9, 95% CI 1.7-5.0), a higher age at initiation of hormone therapy (up to OR 5.9, 95% CI 2.8-12.3) for people above 40 compared to <18), higher BMI (>30 g/m2 compared to 18.5-25 kg/m2) (OR 3.7, 95% CI 2.2-6.2) and a medical history for chronic pulmonary diseases, sleep apnea or polycythemia vera (OR 2.5, 95% CI 1.4-4.4) as determinants that increased the risk of high hematocrit levels. In the first year of testosterone therapy hematocrit levels increased most: from 0.39 l/l at baseline to 0.45 l/l after 1 year. Although there was only a slight continuation of this increase in the following 20 years (0.45 at 1 year and 0.46 at 20 years), the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 20 years). Conclusion: Erythrocytosis frequently occurs in trans men using testosterone. The biggest increase in hematocrit was seen in the first year, but also after the first years there is a substantial number of people that present with hematocrit >0.50. Because smoking, obesity and use of injection as dosage form are associated with a higher risk for erythrocytosis, a reasonable first step in the care for transmen with erythrocytosis while on testosterone is to advise them to quit smoking and to switch to a transdermal administration type and if BMI is high, to lose weight.

Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depots: case study with paliperidone palmitate suspension

Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance.The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work.Sparse sampling composite study was used in rats, (Wistar/Sprague–Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography–mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis.Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (Tmax) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0–28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8–10 days).Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).

An evaluation of long-acting intramuscular injection administration training

The safe administration of oil-based depot, and other long-acting intramuscular antipsychotic injections, is an integral and distinct aspect of the role of registered nurse practitioners within mental health nursing. This article provides an evaluation of education and training workshops for inpatient and community nurses at West London Mental Health NHS Trust. There was a significant (p &gt; 0.05) difference in pre- and post-training self-ratings for knowledge, confidence and attitude observed.

Ethical issues experienced by mental health nurses in the administration of antipsychotic depot and long-acting intramuscular injections: a qualitative study.

The ethical issues experienced by mental health nurses in administering antipsychotic depot and long-acting intramuscular injections (LAI) were explored in the present study. Mental health nurses face ethically-difficult situations when administering these medications. A phenomenological research method guided by Max van Manen's human science approach describes and interprets the ethical issues involved in performing the procedure. Purposive and snowball sampling was used to select eight participants from two mental health hospitals. Semistructured interviews were carried out to collect data. A thematic analysis was conducted on the data. The four main themes that emerged from the analyses were: (i) lack of alternatives; (ii) safety; (iii) feeling uncomfortable; and (iv) difficulty maintaining the therapeutic relationship. The findings suggest that mental health nurses face ethical challenges in administering LAI. The findings raise much needed awareness of the need for mental health nurses and nurse educators to consider the ethical issues experienced while performing the procedure. There is a need for nurse education providers and organizations to provide opportunities for mental health nurses to address their 'lived experiences'. Educational courses are needed to equip mental health nurses with the technical and critical thinking skills to administer safe and effective antipsychotic depot and LAI.

Administering long-acting antipsychotic injections

This is the first of two articles. It introduces the background to a workshop to update mental health nurses toward competently administering long-acting intramuscular injections. The art and science of administering intramuscular injections is a complex activity for the nurse to perform, thus key issues in doing so are discussed.

1493 LOWER URINARY TRACT SYMPTOMS IMPROVE WITH TESTOSTERONE REPLACEMENT THERAPY IN MEN WITH LATE ONSET HYPOGONADISM

INTRODUCTION AND OBJECTIVES: We studied the effect of Testosterone Undecanoate long acting intramuscular injections on lower urinary tract symptoms (LUTS) in men with late onset hypogonadism (LOH). In addition we sought to determine whether this therapy has a direct effect on the improvement of LUTS irrespective of its effect on body weight or use of the PDE5 inhibitor Vardenafil. METHODS: As of November 2004 130 patients with LOH (diagnosis criteria: total testosterone 3.5ng/dl and documented erectile dysfunction (ED)by SHIM 21) were included in a prospective cohort study to investigate the effect of long-actingTestosterone Undecanoate (TU) 1000mg intramuscular injection. Treatment was initiated at day 1 (T1) then the second dose was administered 6 weeks after (T2). TU was injected at 3 months intervals thereafter. LUTS was measured with the International Prostate Symptom Score (IPSS) recorded at treatment visits. Linear regression was used to assess the change in the mean IPSS of the entire cohort over time. The subgroup was subsequently divided to weight losers (L) and Non-Losers (NL). L-patients were the patients who had at least a 5% weight loss at the last visit from baseline. T-test analysis was used to compare the IPSS means of L and NL subgroups. A similar statistical procedure was also used to investigate the confounding effect of using or not using the PDE5 inhibitor Vardenafil. RESULTS: Mean IPSS showed a linear decrease with time after the initiation of therapy with statistical significance by ANOVA (p 0.00). T-tests analysis showed a higher mean IPSS for NL when compared to L with no statistical significance (p 0.5). Additionally, the scatter plot shows similar linearity between L and NL. There was no difference between those who used Vardenafil and those who did not. CONCLUSIONS: Testosterone replacement therapy with Testosterone Undecanoate long-acting intramuscular injections is associated with improvement of LUTS. This association is not confounded by weight loss or use of PDE5 inhibitors. The exact physiological mechanism of this association deserves further research.

Categorical prevalence and severity of hyperprolactinaemia in two UK cohorts of patients with severe mental illness during treatment with antipsychotics

Hyperprolactinaemia may be associated with hidden longer-term consequences, such as osteoporosis, bone fractures, pituitary tumours and breast cancer. Prolactin data from clinical trials is not always reported in a categorical manner and does not always allow the risk of hyperprolactinaemia to be evaluated for specific patient cohorts. Patients participating in a physical health management programme in the UK for severe mental illness patients--the Well-being Support Programme--had prolactin measurements made regardless of symptoms. Prolactin data from the complete cohort of 178 patients receiving antipsychotics in Leeds and London are reported. Hyperprolactinaemia was measured in 33.1% but more commonly in females than males (47.3% and 17.6%) and was associated with all antipsychotics except clozapine. The highest prevalence rates were found in amisulpride (n=20) 89%, risperidone long-acting intramuscular injection (LAIM) 67% (n=6) and risperidone (n=30) 55% used as antipsychotic monotherapy. Clinically Significant hyperprolactinaemia (>1000 mIU/L approximately 47 ng/ml) was measured in 15.8% of patients, predominantly in females. Levels >2000 mIU/L approximately 95 ng/ml in 6.2% of the complete cohort. Clinicians may wish to add prolactin measurement to the routine laboratory parameters currently measured for some antipsychotics and should be advised of the potential longer-term consequences of hidden hyperprolactinaemia.

Reversal of Symptomatic Hyperprolactinemia by Aripiprazole

Back to table of contents Previous article Next article Letter to the EditorFull AccessReversal of Symptomatic Hyperprolactinemia by AripiprazoleREBECCA WAHL, M.D., and ROBERT OSTROFF, M.D., REBECCA WAHLSearch for more papers by this author, M.D., and ROBERT OSTROFFSearch for more papers by this author, M.D., New Haven, Conn.Published Online:1 Aug 2005https://doi.org/10.1176/appi.ajp.162.8.1542-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Hyperprolactinemia is a well-recognized complication of treatment with antipsychotics, causing multiple endocrine and sexual side effects, including the risk for osteoporosis and possibly breast cancer (1). We report a case of successful treatment of risperidone-induced hyperprolactinemia by the partial dopamine agonist aripiprazole.Anne was a 17-year-old adolescent diagnosed with schizophrenia complicated by medication noncompliance. She was admitted to the inpatient service while acutely psychotic. She had mild asthma but no other medical problems. Her periods had been normal since menarche. Her maternal grandfather also has schizophrenia but had been asymptomatic for many years while taking haloperidol.Risperidone was started because of the option for a long-acting formulation. Anne accepted the idea of an intramuscular injection because of her grandfather’s history. Her oral dose was titrated up to 4 mg/day over 2 weeks, after which she received her first injection of 25 mg. She reported a decrease in psychotic symptoms but began to complain of bilateral breast pain, swelling, and galactorrhea. Serum prolactin was drawn and found to be elevated, at 119 μg/ml (normal range 0–25 μg/ml). Aripiprazole (15 mg/day) was added to her drug regimen because of its partial agonism at the dopamine receptor (2), making it a theoretically useful tool in lowering prolactin. Anne remained taking oral risperidone, 4 mg/day, and had a gradual resolution of her breast pain and galactorrhea. Another prolactin level taken 12 days later was 18 μg/ml. Anne was discharged from the hospital much improved while taking a combination of a long-acting intramuscular injection of risperidone, 25 mg every 2 weeks, and aripiprazole, 15 mg/day.Aripiprazole lowers serum prolactin below placebo when it is used as a single agent (3). To our knowledge, this is the first case report of aripiprazole used in combination with another antipsychotic expressly to treat symptomatic hyperprolactinemia. Risperidone causes more marked elevations in prolactin than other atypical antipsychotics because it does not fully cross the blood-brain barrier (4). Dopamine D2 receptor occupancy is therefore higher at the level of the pituitary than in the striatum. Aripiprazole has a greater affinity for the D2 receptor than risperidone, with central D2 receptor occupancy around 90% at a dose of 15 mg/day (5). The partial agonist property of this compound means that in the presence of dopamine hypoactivity, as induced by risperidone, aripiprazole will function as a dopamine agonist with roughly 30% intrinsic activity at postsynaptic receptors (5), restoring tonic inhibition to anterior pituitary lactotrophs. Spontaneous prolactin decline in this case would be unlikely because the time since risperidone exposure was short. However, normalization after longer-term treatment (1 year) has been reported (6).It may be advantageous to avoid the use of directly acting dopaminergic agents in psychotic patients because of the risk for worsening psychosis. Whether this risk is really any lower for aripiprazole when combined with a direct D2 receptor antagonist is not clear and would need to be answered in a controlled trial.

The use of Medroxyprogesterone Acetate to assist in the treatment of sexual offenders

Within a population of 5132 sexual offenders referred to an outpatient sexual abuse clinic, the first 100 cases receiving Medroxyprogesterone Acetate (MPA) as a long-acting intramuscular injection were retrospectively reviewed and compared to a matching cohort which did not receive the drug. MPA appeared to be a safe and effective short-term supplement to an ongoing treatment program emphasizing behavioral, cognitive, group, and family therapy approaches. Data indicate no interference with concurrent treatment approaches and no irreversible side-effects, although caution is advised regarding prolonged use of this medicine, as long term effects of MPA were not examined. These findings also help in defining the characteristics of sexual offenders who are most likely to need, and to benefit from, MPA. Those with histories of hypersexuality, poor sexual impulse control, developmental disabilities, aggressive sexuality, homosexual pedophilia, multiple paraphilias, and predatory patterns of inappropriate sexual behavior merit consideration for MPA. However, the drug should be employed as an aid, particularly early in therapy, rather than as a treatment by itself. Findings are offered with the caution that data collection and statistical analyses were relatively unsophisticated. Recommendations for further investigation are offered.