Human immunodeficiency virus infection challenges: Current therapeutic limitations and strategies for improved management through long-acting injectable formulation.

HIV infection has been a severe global health burden, with millions living with the virus and continuing new infections each year. Antiretroviral therapy can effectively suppress HIV replication but requires strict lifelong adherence to daily oral medication regimens, which presents a significant challenge. Long-acting formulations of antiretroviral drugs administered infrequently have emerged as a promising strategy to improve treatment outcomes and adherence to HIV therapy and prevention. Long-acting injectable (LAI) formulations are designed to gradually release drugs over extended periods of weeks or months following a single injection. Critical advantages of LAIs over conventional oral dosage forms include less frequent dosing requirements, enhanced patient privacy, reduced stigma associated with daily pill regimens, and optimised pharmacokinetic/pharmacodynamic profiles. Several LAI antiretroviral products have recently gained regulatory approval, such as the integrase strand transfer inhibitor cabotegravir for HIV preexposure prophylaxis and the Cabotegravir/Rilpivirine combination for HIV treatment. A leading approach for developing long-acting antiretroviral depots involves encapsulating drug compounds in polymeric microspheres composed of biocompatible, biodegradable materials like poly (lactic-co-glycolic acid). These injectable depot formulations enable high drug loading with customisable extended-release kinetics controlled by the polymeric matrix. Compared to daily oral therapies, LAI antiretroviral formulations leveraging biodegradable polymeric microspheres offer notable benefits, including prolonged therapeutic effects, reduced dosing frequency for improved adherence, and the potential to kerb the initial HIV transmission event. The present manuscript aims to review the pathogenesis of the virus and its progression and propose therapeutic targets and long-acting drug delivery strategies that hold substantial promise for enhancing outcomes in HIV treatment and prevention.

Predictors of the Availability of Long-Acting Injectable Antipsychotics in US Mental Health Facilities Serving Older Adults.

INTRODUCTION:  Older adults are at increased risk of psychotic symptoms and even more at risk of medication nonadherence due to various factors specific to their age including memory impairment. This study aimed to examine the availability of long-acting injectable antipsychotics (LAIs) in US mental health (MH) facilities that serve older adults. METHODS: This study includes 1,216 MH facilities, using the 2022 National Substance Use and Mental Health Services Survey (N-SUMHSS) data from the Substance Abuse and Mental Health Services Administration (SAMHSA). Descriptive statistics were used to evaluate the availability of LAIs in US MHs that provide services to older adults while logistic regression was used to compare facilities that offer the services compared to those that do not. RESULTS: Of the total facilities included, 420 (35%) and 58 (4.8%) offered at least one LAI and all LAIs, respectively. Hospital-based facilities compared to community-based facilities, facilities that provided only MH services compared to those providing SU and MH services, facilities that offer special Alzheimer's programs compared to those that do not, and facilities in Midwest states compared to those in East South Central, New England, and Mountain regions of the US were more likely to offer at least one LAI. Facilities that offer special services for veterans were less likely to have all LAIs examined. Only 43% of the facilities were certified by the Joint Commission. CONCLUSION: Less than half of US MH facilities that serve older adults have at least one LAI service despite the usefulness of these medications in the studied population.

Attitude and influencing factors of patients with schizophrenia toward long-acting injections: A community-based cross-sectional investigation in China.

Background: Low prescription rates of antipsychotic long-acting injections (LAIs) may be a major challenge in the prevention and treatment of schizophrenia. However, there are few studies on the usage and attitude toward LAIs among community-based patients with schizophrenia. Methods: A large community-based cross-sectional investigation was conducted among 6,336 patients with schizophrenia from Shanghai, China from March 1 to June 30, 2021. The structured Attitude and Status toward Treatment of Community Patients with Schizophrenia Questionnaire (AST-CSQ) was used to investigate the attitude and influencing factors of community-dwelling patients with schizophrenia toward LAIs. Results: Among the 6,336 participants, the average age was 49.28 ± 11.23. The rate of agreement to LAI antipsychotics among participants was 3.16% (n = 200). The family financial resources, care ability, and disease course of the LAIs group were less than those of the non-LAIs group. However, the LAIs group had higher immediate family guardianship, social activity, previous hospitalization, number of hospitalization, outpatient adherence, previous antipsychotic use, antipsychotic adherence, and attitude toward oral antipsychotics than the non-LAIs group, with significant differences between the two groups (p < 0.05). Furthermore, age (ß = -0.036, OR 0.964, 95% CI 0.947-0.982), marital status (ß = 0.237, OR 1.267, 95% CI 1.002-1.602), care ability (ß = 0.709, OR 2.032, 95% CI 1.437-2.875), outpatient adherence (ß = -0.674, OR 0.510, 95% CI 0.358-0.725), antipsychotic adherence (ß = 0.920, OR 2.509, 95% CI 1.092-5.764), and attitude toward oral antipsychotics (ß = -1.357, OR 0.258, 95% CI 0.103-0.646) were significant predictors of attitude toward LAI antipsychotics (p < 0.05). Conclusions: The community-dwelling patients with schizophrenia in China had a low willingness to use LAIs. Patients of a younger age, more hospitalizations, and a shorter course of disease were prone to be more willing to accept LAIs. The patients' age, marital status, care ability, outpatient adherence, antipsychotic adherence, and attitude toward oral antipsychotics were important predictor of patients' attitudes toward LAIs. Under the global deinstitutionalized management model of mental disorders, these results highlight an urgent problems for public mental health service providers and policy-makers and provide more solutions for them.

Testosterone in men with hypogonadism and transgender males: a systematic review comparing three different preparations.

Testosterone therapy is the cornerstone in the care of men with hypogonadism and transgender males. Gel and intramuscular injections are most frequently used and are registered and included in the international guidelines. The specific preparation should be selected according to the patient's preference, cost, availability, and formulation-specific properties. As the majority of men with hypogonadism and transgender males require lifelong treatment with testosterone, it is important to utilize a regimen that is effective, safe, inexpensive, and convenient to use with optimal mimicking of the physiological situation. This systematic review reviews current literature on differences between the three most used testosterone preparations in adult men with hypogonadism and transgender males. Although it appeared hardly any comparative studies have been carried out, there are indications of differences between the preparations, for example, on the stability of testosterone levels, hematocrit, bone mineral density, and patient satisfaction. However, there are no studies on the effects of testosterone replacement on endpoints such as cardiovascular disease in relation to hematocrit or osteoporotic fractures in relation to bone mineral density. The effect of testosterone therapy on health-related quality of life is strongly underexposed in the reviewed studies, while this is a highly relevant outcome measure from a patient perspective. In conclusion, current recommendations on testosterone treatment appear to be based on data primarily from non-randomized clinical studies and observational studies. The availability of reliable comparative data between the different preparations will assist in the process of individual decision-making to choose the most suitable formula.

Effectiveness and Quality of Life with Paliperidone Palmitate 3-Monthly in Comparison with Other Long-Acting Drugs.

Purpose: Antipsychotic long-acting injections (AP-LAIs) are indicated for patients affected by schizophrenia especially those with poor treatment adherence. Patients and Methods: To compare paliperidone palmitate 3-monthly (PP3M), paliperidone palmitate one-monthly (PP1M) and haloperidol decanoate (HAL-D) treatment, we enrolled 90 patients with schizophrenia treated in Mental Health Center with one of the three AP-LAIs for at least six months and followed them for another 6 months. At 6 and 12 months of treatment we administered Clinical Global Impression-Severity, Global Assessment of Functioning and World Health Organization Quality of Life-26 items (WHOQOL-BREF). At 1-year treatment, we evaluated relapses (psychiatric hospitalizations and urgent consultations), side effects and drop-outs. Results: We did not highlight any statistically significant difference among the three treatments in relapses and scale scores. Weight increase was significantly higher in PP1M and PP3M groups. Twelve patients (13.3%) discontinued AP-LAI. At 1-year AP-LAI treatment, 69% of patients rated quality of life as "good" or "very good" and 71% declared themselves to be "satisfied" or "very satisfied". Conclusion: HAL-D, PP1M and PP3M 1-year treatments were similarly effective in preventing relapses and improving quality of life and health satisfaction. All discontinuations in the new 3-monthly antipsychotic treatment were caused by patient refusal to continue it.

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.

Study on the Slow-Release Mometasone Furoate Injection of PLGA for the Treatment of Knee Arthritis.

PURPOSE: The purpose of this study is to develop a new PLGA based formulation for microspheres, which aims to release mometasone furoate for one month, so as to improve compliance. METHODS: The microspheres containing mometasone furoate were prepared by oil in water emulsion and solvent evaporation. The microspheres were characterized by surface morphology, shape, size and encapsulation efficiency. The release in vitro was studied in 37°C phosphate buffer, and in vivo, pharmacodynamics and preliminary safety evaluation were conducted in male Sprague Dawley rats. RESULTS: The morphology results showed that the microspheres have a smooth surface, spherical shape and an average diameter of 2.320-5.679µm. The encapsulation efficiency of the microspheres loaded with mometasone furoate was in the range of 53.1% to 95.2%, and the encapsulation efficiency of the microspheres could be greatly affected by the proportion of oil phase to the water phase and other formulation parameters. In vitro release kinetics revealed that drug release from microspheres was through non-Fick's diffusion and PLGA polymer erosion. Pharmacokinetic data showed that the initial release of microspheres was small and then sustained. The results of the pharmacodynamics study fully proved the long-term effectiveness of mometasone furoate microspheres. The results of in vivo safety evaluation showed that the preparation system possessed good in vivo safety. CONCLUSION: This study shows that the microspheres prepared in this study have sufficient ability to stable drug release at least for 35 days, with good efficacy and high safety. In addition, mometasone furoate can be used as a potential candidate drug for 35 days long-term injection.

From QAAPAPLE 1 to QAAPAPLE 2: how do we move from one algorithm to another one with Long Acting Antipsychotics (LAIs).

BACKGROUND: In 2011, the authors published an algorithm summarizing practice guidelines related to the use of long-acting antipsychotics (LAIs) called the Québec Algorithme Antipsychotique à Action Prolongée (QAAPAPLE), and proposed that it be revised every 5-10 years to update it according to most recent scientific knowledge. Therefore, a re-evaluation of the algorithm was conducted to determine which recommendations were still relevant and which needed modification. METHODS: The authors conducted a two-fold approach: a review of the literature to include new evidence since 2011 (controlled trials, meta-analyses, and practice guidelines); and a participatory component involving electronic surveys, conferences, encounters with opinion leadres, and patients' representatives. RESULTS: Overall, prescribers tended to make decisions based on personal experience and conversations with colleagues rather than consulting evidence-based guidelines. To test if the algorithm was useful worldwide, it was presented in the United Arab Emirates, where the feedback was in agreement with the algorithm and its limitations. CONCLUSIONS: Since its initial publication, the QAAPAPLE algorithm has been updated to guide clinicians on the use of LAIs. The new algorithm has also been assessed outside Canada to test its generalizability worldwide, and indicated its flexibility, efficiency, and user-friendliness in order to guide clinicians on the use of LAIs.

Sociodemographic Factors and Medication Administration Factors Affecting Re - Hospitalization in Patients with Schizophrenia - Spectrum Disorders.

Schizophrenia - spectrum disorders have been shown to have large economic costs for the society due to hospitalizations. Long Acting Injections (LAIs) have been shown to promote adherence and reduce hospitalizations. However, socio-demographic and environmental variables have been shown to be associated with relapses. The present study attempted to explore relationships between rehospitalisation and such variables by analysing data from the Attitudes Study. Our findings validate previous literature on LAIs showing a larger effect of route of drug administration on hospitalizations. However, our study also highlights the importance of living circumstances and ethnicity that were shown to have an effect on hospitalizations and explained a larger part of the variance when it came to furthers hospitalisations. Furthermore, associations of variables relating to disease history with variables like gender, education and employment are presented highlighting the importance of a multi-approach model when it comes to preventing future hospitalizations.

Oral Antipsychotic Versus Long-Acting Injections Antipsychotic in Schizophrenia Spectrum Disorder: a Mirror Analysis in a Real-World Clinical Setting.

Despite mixed results found in literature, long-acting injectable antipsychotics (LAIs) should offer better efficacy and tolerability, compared to oral antipsychotics due to improved adherence and more stable pharmacokinetics. From this perspective, authors evaluated 153 patients, diagnosed with Schizophrenia Spectrum Disorder and residing in the province of Varese (Italy), in order to compare oral antipsychotics' and LAIs' efficacy in terms of accesses to emergency room, number and length of hospitalizations. Data analysis showed a substantial reduction in all considered variables after the introduction of long-acting therapy, especially for those who received LAI treatment from disease's onset. Authors emphasised the use of long-acting antipsychotic as first-line treatment in the early stage of disease, since available data seem to confirm the hypothesis of a better prognosis for patients who received antipsychotic depot from illness's onset.

The modern perspective for long-acting injectables antipsychotics in the patient-centered care of schizophrenia.

Schizophrenia is a chronic syndrome involving different clinical dimensions, and causes significant disability with a negative impact on the quality of life of patients and their caregivers. Current guidelines for the treatment of schizophrenia focus on maximizing a patient's adaptive functioning and quality of life in a recovery-oriented approach that encourages active collaboration among patients, caregivers, and mental health professionals to design and manage a customized and comprehensive care plan. In the present study, a panel of experts (psychiatrists, psychologists, nurse, and social worker) gathered to review and explore the need for contemporary use of second-generation antipsychotic long-acting injectables (SGA LAIs) in "recovery-oriented" and "patient-centered" care of schizophrenia. Starting from the available data and from sharing personal attitudes and experiences, the panel selected three clinical dimensions considered useful in characterizing each patient: phase of disease, adherence to treatment, and level of functioning. For each clinical dimension, perspectives of patients and caregivers with regard to needs, expectations, and personal experiences were reviewed and the role of SGA LAIs in achieving shared goals examined. The experts concluded that from today's modern perspectives, SGA-LAIs may play an important role in breaking the spiral of desocialization and functional decline in schizophrenia, thus favoring the recovery process.

Development and Characterization of Olanzapine Loaded Poly(lactide-coglycolide) Microspheres for Depot Injection: In vitro and In vivo Release Profiles.

PURPOSE: The purpose of this study was to develop a new PLGA based microsphere formulation aimed to release the olanzapine for the period of one month which will result in increased compliance. METHODS: Microspheres loaded with olanzapine were prepared using oil in water emulsion and solvent evaporation technique. The microspheres were characterized by surface morphology, shape, size, bulk density, encapsulation efficiency, and Fourier transform infrared spectrometry. In vitro release studies were performed in phosphate buffer at 37°C and in vivo studies were conducted on male Sprague- Dawley rats. RESULTS: The morphological results indicated that microspheres produced were having a smooth surface, spherical shape and the size in the range from 9.71 to 19.90 µm mean diameter. Encapsulation efficiency of olanzapine loaded microspheres was in the range of 78.53 to 96.12% and was affected by changing the ratio of lactic to glycolic acid in copolymer PLGA. The properties of PLGA and other formulation parameters had a significant impact on in vitro and in vivo release of drug from microspheres. In vitro release kinetics revealed that release of drug from microspheres is by both non-Fickian diffusion and erosion of PLGA polymer. In vivo data indicated an initial burst release and then sustained release depending on properties of PLGA, microsphere size, and bulk density. CONCLUSION: This study indicates that microsphere formulations developed with PLGA (75:25) and PLGA (85:15) have provided a sufficient steady release of drug for at least 30 days and can be potential candidates for 30-day depot injection drug delivery of olanzapine.

Once-Monthly Subcutaneously Administered Risperidone in the Treatment of Schizophrenia: Patient Considerations.

Adherence to antipsychotic medications is a major challenge in schizophrenia. Long-acting injectable antipsychotics have been shown to offer advantages over oral formulations. A new extended release formulation of risperidone for subcutaneous injection was developed to address issues of non-adherence. The aim of this manuscript was to compare the new subcutaneous formulation to currently available formulations of injectable risperidone and paliperidone to determine whether the novel delivery by subcutaneous injection may provide substantial benefits. A literature search was conducted using PubMed, OVID, and Cochrane Library electronic databases to assess the advantages and disadvantages of long-acting formulations of risperidone. Potential advantages of risperidone for subcutaneous injection include a simplified dosing and ease of administration. Potential disadvantages include injection site pain and medication cost.

The Long-Acting Injectable Antipsychotics in Clinical Practice / 신경정신의학

Symptomatic relapse is observed frequently and often associated with social and/or occupational decline that can be difficult to reverse in patients with schizophrenia. Several atypical antipsychotics, including risperidone, olanzapine, paliperidone, and aripiprazole, have become available as long-acting injectable antipsychotics (LAIs), and new evidence has been accumulating. LAIs appear to have a significant role in at least a group of schizophrenia patients. Improving the adherence, continuous availability, managing changes in receptor sensitivity, and lowering the requirement of cumulative doses are some of the major advantages of LAIs. Patients with first episode psychosis, dopamine super-sensitivity syndromes, and comorbid substance abuse might particularly benefit. Delaying the initiation of LAI until the establishment of non-adherence is not recommended. The results of clinical trials comparing LAIs with oral antipsychotics (OAPs) are inconsistent because they are influenced considerably by the study design. On the other hand, several barriers to LAIs use in current practice include clinical lack of knowledge, and negative attitudes about LAIs. This article tries to help clinicians better characterize the role of LAIs in the treatment of schizophrenia.

Reducing the stigma of long acting injectable antipsychotics - current concepts and future developments.

BACKGROUND: Long acting injectable antipsychotics (LAI-APs) are considered a major advance in psychiatric treatment concerning treatment adherence and outcomes. Yet, both, doctors and patients remain sceptical. AIM: To explain the rationale for using LAI-APs, review their effectiveness and explore barriers to use. METHOD: Clinical overview of LAI-APs from the patient and doctor's perspective. RESULTS: LAI-APs were developed to increase adherence to treatment, thereby improving treatment outcomes. LAI-APs may reduce the risk of relapse and hospitalisation. Yet, the evidence from the few meta-analyses available remains weak. Both patients and doctors may associate LAI-APs with stigma and coercion. Current means of improving adherence include more focus on the therapeutic relationship, better information, adverse effects minimisation and half-life extension of LAI-APs. Future means of improving adherence include novel administration techniques that abolish the need for injection. CONCLUSIONS: For both, clinicians and drug developers, drug adherence remains a major target for improving treatment outcomes.

Ethnic and Age Disparities in Patients Taking Long-acting Injectable Atypical Antipsychotics.

Introduction This study will determine whether different ethnicities and different age groups receive equal amounts of long-acting atypical antipsychotics in comparison to their oral equivalents. Methods Secondary analyses of data from the Los Angeles County Department of Health Services Electronic Health Record (total N=63,134 inpatient visits) were performed. Chi-squared statistics were used to compare ethnicity and age with the use of either risperidone injectable or paliperidone palmitate (r-LAIs) versus risperidone oral. Results Among the 63,134 total inpatient visits, there were 3,011 patient visits that included the use of an atypical antipsychotic. Of these 3,011 visits, 452 (15.0%) were on r-LAIs and 2,559 (85.0%) were on risperidone oral. No statistically significant disparities were identified with the use of r-LAIs as compared to oral risperidone amongst ethnic groups (chi-square = 0.88, df = 3, p = 0.831). However, there was a statistically significant difference with the use of r-LAIs as compared to oral Risperidone amongst age groups, favoring younger patients (chi-square = 13.46, df = 3, p < 0.004). Conclusion Our data indicate a lack of ethnic disparities in prescribing long-acting atypical antipsychotics and an increased percentage of younger patients being treated with atypical depot antipsychotics over their oral equivalents.

A critical appraisal of long acting injectable antipsychotics: Translating research to clinics.

Long acting injections (LAI) are an effective alternative mode of administration of antipsychotics, less commonly used in clinical practice. Gap in knowledge base is an important source of attitudinal bias. Current article is focused on reviewing the literature for the principles underlying the choice, initiation, maintenance, switch and termination of an LAI; historical, pharmacological and clinical factors implicating the rationale of using LAI against oral agents and older against newer LAIs. Evidences available in clinical and basic psychopharmacological researches are critically appraised, highlighting the lacunae in our understanding. It is endeavored to open the window for the studies to be carried forward in the future answering critical questions which could lay a stronger base for clinical utility of different LAIs. Thus, this article tries to acquaint clinicians with the translatable knowledge imparted from the research and riposte queries for the researchers to explore in relation to LAI.

Effect of paliperidone palmitate on hospitalisation in a naturalistic cohort - a four-year mirror image study.

BACKGROUND: Clinical trial outcomes are heavily influenced by the non-naturalistic clinical trial process. Observations of outcomes in clinical practice are a valuable adjunct to clinical trial results. HYPOTHESIS: Our null hypothesis was that clinically indicated switching to paliperidone palmitate had no effect on hospital admissions or hospital bed days. METHOD: This was a part-prospective mirror image study examining outcomes 2years before starting paliperidone palmitate and 2years after. Sensitivity analyses examined the effect of different placings of the mirror in the mirror image design. RESULTS: We prospectively followed-up 225 patients prescribed paliperidone palmitate in clinical practice. At 2years, 41.8% of patients were still receiving paliperidone palmitate. In the primary analysis, the mean number of admissions fell from 1.80 in the two years before starting paliperidone palmitate to 0.81 in two years following the drug's initiation (outpatients) or two years following hospital discharge (inpatients) (P<0.001). More than half of patients were not admitted to hospital during two years follow-up. Mean total bed days was reduced from 79.6 in the two years before to 46.2 in the two years after paliperidone palmitate initiation or discharge (P<0.001). Sensitivity analyses gave broadly similar outcomes. Continuers demonstrated better outcomes than discontinuers in sensitivity analyses but not in the primary analysis. CONCLUSION: Paliperidone palmitate initiation is associated with a substantial reduction in hospital admissions and days spent in hospital. The reduction in costs associated with reduced use of health care facilities is likely to exceed the purchase and administration costs of the drug.

Treatment of early episode in patients with schizophrenia: the role of long acting antipsychotics.

The use of long-acting injectable antipsychotics (LAIs) in schizophrenia is usually restricted to patients in long-term treatment, who prefer them to oral antipsychotics, and to patients with multiple relapses who have a history of non-adherence. However, preliminary evidence from patients in the early phases of the disease suggest that second generation LAIs may be superior to second generation oral medications with regard to the control of negative symptoms and psychosocial functioning. Moreover, several studies have found that psychiatrists are generally reluctant to prescribe LAI antipsychotics and under-estimate their acceptability by patients. Key elements to take into account when offering a LAI in the early course of schizophrenia should include their potential superiority in allowing early detection of non-adherence and in reducing the number of rehospitalisations and relapses.

The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal.

Despite their widespread use, long-acting injectable (LAI) antipsychotics (APs) are often regarded with some negativity because of the assumption of punishment, control and insufficient evolution towards psychosocial development of patients. However, LAI APs have proved effective in schizophrenia and other severe psychotic disorders because they assure stable blood levels, leading to a reduction of the risk of relapse. Therapeutic opportunities have also arisen after introduction of newer, second-generation LAI APs in recent years. Newer LAI APs are more readily dosed optimally, may be better tolerated and are better suited to integrated rehabilitation programmes. This review outlines the older and newer LAI APs available for the treatment of schizophrenia, with considerations of past and present pharmacological and therapeutic issues. Traditional, evidence-based approaches to systematic reviews and randomized clinical trials are of limited utility in this area so this paper's blending of experimental trials with observational research is particularly appropriate and effective.