First-generation Antipsychotic Long-acting Injections Research Articles

Outcomes of long-acting injectable antipsychotics use in pregnancy: A literature review.

Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy. Long-acting injectable (LAI) antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders, but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy. To summarize relevant data on maternal, pregnancy, neonatal, and developmental outcomes from published cases of LAI antipsychotic use in pregnancy. A literature search was performed through November 11, 2023, using three online databases: PubMed/MEDLINE, Scopus, and Web of Science. Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy, with available full texts, were included. Descriptive statistics, narrative summation, and tabulation of the extracted data were performed. A total of 19 publications satisfied the inclusion criteria: 3 case series, 15 case reports, and 1 conference abstract. They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies. The use of second-generation LAI antipsychotics was reported in the majority (n = 47; 61.0%) of pregnancies. First-generation LAI antipsychotics were administered during 30 pregnancies (39.0%). Most of the women (approximately 64%) had either satisfactory control of symptoms or no information about relapse, while approximately 12% of them had developed gestational diabetes mellitus. A minority of cases reported adverse outcomes such as stillbirth, spontaneous abortion, preterm birth, low birth weight, congenital anomalies, and neurological manifestations in newborns. However, there were no reports of negative long-term developmental outcomes. Currently available data seem reassuring, but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.

Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders

This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015–December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18–34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = −0.19, −0.26 and −0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = −0.20, −0.24, −0.21, respectively) and ED admissions (SMD = −0.15, −0.13, −0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.

How can we improve the care of patients with schizophrenia in the real-world? A population-based cohort study of 456,003 patients

An important step to improve outcomes for patients with schizophrenia is to understand treatment patterns in routine practice. The aim of the current study was to describe the long-term management of patients with schizophrenia treated with antipsychotics (APs) in real-world practice. This population-based study included adults with schizophrenia and who had received ≥3 deliveries of an AP from 2012–2017, identified using a National Health Data System. Primary endpoints were real-life prescription patterns, patient characteristics, healthcare utilization, comorbidities and mortality. Of the 456,003 patients included, 96% received oral APs, 17.5% first-generation long-acting injectable APs (LAIs), and 16.1% second generation LAIs. Persistence rates at 24 months after treatment initiation were 23.9% (oral APs), 11.5% (first-generation LAIs) and 20.8% (second-generation LAIs). Median persistence of oral APs, first-generation LAIs and second-generation LAIs was 5.0, 3.3, and 6.1 months, respectively. Overall, 62.1% of patients were administered anxiolytics, 45.7% antidepressants and 28.5% anticonvulsants, these treatments being more frequently prescribed in women and patients aged ≥50 years. Dyslipidemia was the most frequent metabolic comorbidity (16.2%) but lipid monitoring was insufficient (median of one occasion). Metabolic comorbidities were more frequent in women. Standardized patient mortality remained consistently high between 2013 and 2015 (3.3–3.7 times higher than the general French population) with a loss of life expectancy of 17 years for men and 8 years for women. Cancer (20.2%) and cardiovascular diseases (17.2%) were the main causes of mortality, and suicide was responsible for 25.4% of deaths among 18–34-year-olds. These results highlight future priorities for care of schizophrenia patients. The global persistence of APs used in this population was low, whereas rates of psychiatric hospitalization remain high. More focus on specific populations is needed, such as patients aged >50 years to prevent metabolic disturbances and 18–34-year-olds to reduce suicide rates.

Cardiovascular risk factors and metabolic syndrome in patients treated with long-acting injectables antipsychotics: a retrospective study.

The present cross-sectional, retrospective study aimed to assess the prevalence of cardiovascular disease (CVD) risk factors and metabolic syndrome in a sample of psychiatric patients treated with long-acting injectable antipsychotics (LAIs). The clinical charts of 120 patients, mainly diagnosed with schizophrenia (30.0%), schizoaffective disorder (15.0%), and bipolar disorder (13.3%) on LAIs therapy - initiated in the period from 2013 to 2019 and lasting at least one year - were retrospectively reviewed and related socio-demographic, clinical and laboratory variables were collected. The 70.8% of patients were treated with first-generation LAIs, and the remaining 29.2% with second-generation LAIs. The overall sample showed low compliance in performing the required exams and evaluations related to CVD risk factors. The prevalence of metabolic syndrome was 30.8%, and, considering specific CVD risk factors, 55% of the total sample reported abdominal obesity, 43.3% arterial hypertension, 41.7% low HDL-cholesterol, 25.8% hypertriglyceridemia, and 20.8% fasting hyperglycemia. Lastly, 6.7% showed prolonged corrected QT (QTc) interval at the ECG. Patients treated with LAIs should be regularly monitored for metabolic changes and CVD risk factors. Metabolic changes rapidly develop after initiating an antipsychotic therapy and these often involve parameters, that can be easily recorded in an outpatient setting (e.g. abdominal obesity and hypertension).

Use of Long-Acting Injectable Antipsychotics in Inpatients with Schizophrenia Spectrum Disorder in an Academic Psychiatric Hospital in Switzerland.

Long-acting injectable antipsychotics (LAIs) offer many benefits to patients with schizophrenia spectrum disorder (SSD). They are used with very different frequencies due to questions of eligibility or patients and prescribers’ attitudes towards LAI use. We assessed the prescribing rates of LAIs in a large academic psychiatric hospital with a public service mandate in Switzerland and compared them with other countries and health care systems. To our knowledge, this study is the first to investigate inpatient LAI use in Europe. Medical records of all patients diagnosed with SSD discharged from the Clinic of Adult Psychiatry of the University Hospital of Psychiatry Zurich over a 12 month period from January to December 2019 were evaluated regarding the prescribed antipsychotics at the time of discharge. The rates of use of LAIs among all patients and among patients receiving LAI-eligible antipsychotic substances were assessed retrospectively. We assessed records of 885 patients with SSD. Among all cases, 13.9% received an LAI. Among patients who received antipsychotic medication that was eligible for LAI use (n = 434), 28.1% received an agent as an LAI. LAI use included paliperidone palmitate (69.9%), aripiprazole monohydrate (14.6%), risperidone (4.9%) and first-generation LAIs (9.8%). Compared to international frequencies of LAI administration, the prescription rate of LAIs in SSD patients was low. Further studies will evaluate patient- and prescriber-related reasons for this low rate.

Clinical pharmacokinetics and pharmaceutical forms of long-acting injectable antipsychotics

Long-acting injectable antipsychotics (LAIs) hold an important place in the therapeutic management of patients with schizophrenia and other psychoses. They offer advantages, such as knowledge of whether patients follow the medical advice that is given, stable pharmacokinetics and better correlation between the administered dose and the plasma levels of the drug, regular follow-up and reduced risk of overdose. Knowledge of the best way to administer LAIs is important in clinical practice because it maximizes the efficacy of the drug and minimizes the side-effects. This knowledge is facilitated through understanding both the pharmacokinetics and the pharmaceutical forms of these drugs because it provides necessary information concerning their mode of action. Currently in Greece, two first-generation (haloperidol and zuclopenthixol) and four newer LAIs (risperidone, olanzapine, paliperidone and aripiprazole) are in circulation. Their pharmaceutical form facilitates the delayed delivery of the drug during a period of weeks, thus increasing the time interval needed for the drug administration in order to maintain plasma therapeutic concentrations under stable state conditions. This is achieved by creating an extravascular drug reservoir (depot) in the skeletal muscles from which the drug is slowly released into the systemic circulation. The rate of removal of LAIs is regulated by the slow rate of absorption in the site of injection and the phenomenon of their increased half-life is called flip-flop pharmacokinetics. Their rate of absorption from skeletal muscles depends on factors, such as the injection technique, the pharmaceutical form of the drug, the distribution of fat tissue and the blood supply of the muscle. First-generation LAIs are characterized chemically by an esterified drug molecule that is dissolved in oil vehicle. The esterified drug is then hydrolyzed rapidly by plasma esterases allowing the entrance of the drug into the brain. On the contrary, newer LAIs are aqueous- based formulations characterized by various pharmaceutical forms: microspheres (risperidone), pamoic acid crystal (olanzapine), nanocrystals (paliperidone), dry drug- suspension with water (aripiprazole). Among newer drugs, risperidone and aripiprazole must be administered orally concurrently with the LAI for an initial time period. Furthermore, risperidone is the only LAI administered every 2 weeks and 3-monthly paliperidone is the only one administered every 3 months. All the other LAIs (1st generation and atypical) are usually administered every 4 weeks. This paper reviews the pharmacokinetic and pharmaceutical characteristics of these drugs. It also provides information concerning basic elements of LAI pharmacokinetics in order to understand these characteristics better.

Trends in the Use of Long-Acting Injectable Antipsychotics in the Province of Manitoba, Canada.

Long-acting injectable antipsychotics (LAIAs) have advantages over oral antipsychotics but are not widely used. We aimed to evaluate the impact of market entry of second-generation LAIAs on prescribing trends. We used administrative health databases to describe trends in LAIA use from 1995 to 2015 in the Canadian province of Manitoba. Age- and sex-specific incident and prevalent use were determined using prescription dispensation records for the entire population. We used interrupted time series analysis with Poisson regression to estimate change in LAIA use attributable to the market entry of the second-generation LAIA risperidone. We observed 3380 prevalent LAIA users and 2375 incident users in our cohort. Long-acting injectable antipsychotic use was higher in males. Incidence proportions declined from 21.5 users per 100,000 in 1996 to 4.8 in 2004 and then climbed to 14.7 by 2015. First-generation LAIA use peaked at 94.6 prevalent users per 100,000 in 1998 but fell to 40.9 in 2015. Long-acting injectable antipsychotic use increased 1.4% per quarter after the market entry of risperidone long-acting injectable. Risperidone risperidone long-acting injectable market entry had a positive impact on LAIA prescribing.

A Comparison of Long-Acting Injectable Antipsychotics With Oral Antipsychotics on Time to Rehospitalization Within 1 Year of Discharge in Elderly Patients With Schizophrenia

ObjectiveThe effectiveness of long-acting injectable antipsychotics (LAIs) in elderly patients with schizophrenia remains unclear. This study aimed to compare the effect of LAIs with oral antipsychotics (OAPs) on time to rehospitalization within 1 year of discharge in this population. Other factors potentially associated with time to rehospitalization and trends in LAI prescription rates during the study period were also investigated. MethodsPatients over 60 years of age with schizophrenia discharged between 2006 and 2017 were followed for 1 year under naturalistic conditions. Survival analysis was used in the comparison between LAIs and OAPs regarding time to rehospitalization. Covariates thought to affect time to rehospitalization were also analyzed. The Cochran-Armitage trend test was used to evaluate whether a time trend existed for LAI prescription rates. ResultsThe LAIs group had a significantly lower rehospitalization rate and a significantly longer time to rehospitalization within 1 year of discharge than the OAPs group. Other factors that were associated with a longer time to rehospitalization included a shorter index hospitalization during the time of the study and fewer previous hospitalizations. No significant time trend was found for LAI prescription rates during the study period. However, the prescription rate of second-generation LAIs grew significantly. ConclusionLAIs were found superior to OAPs in preventing rehospitalization. A continuous increase in second-generation LAI prescription rate may be due to the better side-effect profile of second-generation LAIs compared to first-generation LAIs. More studies investigating the effectiveness of LAIs in elderly patients with schizophrenia are needed in the future.

"Impact of drug-reimbursement policies on prescribing: A case-study of a newly marketed long-acting injectable antipsychotic among relapsed schizophrenia patients".

To quantify and explain variation in use of long-acting injectable antipsychotics (LAIs) in the United States, and understand the relationship between patient characteristics, drug reimbursement policies, and LAI prescribing after relapse. A cohort of recently relapsed patients with schizophrenia ages 18 to 64, were identified immediately after discharge from a related inpatient hospitalization, partial hospitalization, or emergency room visit, drawn from 2004 to 2006 Medicaid claims, and followed for 90days until LAI initiation. Data on state-level Medicaid prior authorization (PA) policies for LAIs were collected. Sequential longitudinal Poisson regression models were developed to understand the relationship between patient and PA policy variables and LAI prescribing, including prior adherence to oral antipsychotics, demographics, clinical variables, and presence of PA policy for LAI. Among 36282 patients, 3.1% received risperidone LAI, and 3.8% received a first-generation (FGA) LAI with wide variation across states. Prior adherence ranged from 29% to 89% but was marginally associated with initiation and did not explain variation for LAI prescribing. FGA initiation was associated with geography and race/ethnicity but not PA policy. For risperidone LAI initiation, demographics and clinical factors explained, respectively, 5.0% and 3.0% of the variation; PA policy had a large negative association with initiation (RR=0.41; 95%CI 0.20-0.87) and explained 8.4% of the variation. PA policies may represent a major treatment barrier for risperidone LAI among relapsed patients. Non-adherence plays a little role in predicting which patients receive LAIs. Policy makers and health insurers will need to consider these findings when guiding the use of LAIs. KEY POINTS Among a nationwide cohort of relapsed schizophrenia patients enrolled in US Medicaid, 3.1% received Risperdal Consta, a long-acting injectable antipsychotic (LAI), and 3.8% initiated a first-generation first-generation LAI within 90days after discharge. During 2004 to 2006, there was marked variation in 90day post-relapse initiation of Risperdal-Consta-a newly marketed medication during this period-and also marked variation in 90day post-relapse initiation of any first-generation LAI, which appeared to be associated with race/ethnicity and geography. Prior authorization policies were associated with substantially lower initiation of Risperdal Consta in this cohort of relapsed patients even after accounting for clinical indication (non-adherence), relapse history, demographics, adjunctive medication, and mental health service use.

Cross-sectional comparison of first-generation antipsychotic long-acting injections vs risperidone long-acting injection: patient-rated attitudes, satisfaction and tolerability.

The objective of this study was to compare patients' attitudes and satisfaction with medication and patient-rated tolerability between those prescribed a first-generation antipsychotic long-acting injection (FGA-LAI) and those prescribed risperidone long-acting injection (RLAI). A cross-sectional study of a representative sample of outpatients prescribed an FGA-LAI or RLAI for a minimum of 6 months and attending a depot clinic. Attitudes to medication were assessed by the Drug Attitude Inventory (DAI-30), tolerability was measured by the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and satisfaction with antipsychotic medication was assessed by the Satisfaction with Antipsychotic Medication (SWAM) scale. The RLAI (n = 28) and FGA-LAI (n = 39) groups did not differ in terms of mean age, sex, diagnosis and ethnicity. All individual LAIs were prescribed within British National Formulary limits. The most commonly prescribed FGA-LAI was flupentixol decanoate (n = 22). There was no significant difference between the RLAI and FGA-LAI groups in terms of mean total scores on the DAI-30, LUNSERS and SWAM or the tolerability subscales of the LUNSERS or the two subscales (treatment acceptability and medication insight) of the SWAM. In both LAI groups there was a low level of side effects (LUNSERS) and a generally positive attitude (DAI-30) and reasonable satisfaction (SWAM) with medication. Patients treated with FGA-LAI and RLAI for at least 6 months did not differ in terms of patient-rated tolerability, attitudes and satisfaction with medication. The current design cannot determine whether differences would have been evident earlier on during treatment. These results should be regarded as preliminary and are subject to prescribing bias. Randomized studies avoid prescribing bias and are a superior way to compare specific LAIs. Ideally randomized studies should include patient-rated outcome measures including medication tolerability; assessment of side effects, efficacy and quality of life made by blinded raters; and additional objective side-effect data including changes in weight and key blood parameters.

Factors Associated With Antipsychotic Polypharmacy and High-Dose Antipsychotics Among Individuals Receiving Compulsory Treatment in the Community

Community treatment orders (CTOs) are a form of compulsory treatment of individuals with a mental illness in the community. The objectives of this study were to determine the demographic, clinical, and treatment plan factors associated with antipsychotic polypharmacy and high-dose antipsychotics among individuals issued with a CTO. This was a secondary analysis of all 377 individuals who were prescribed an antipsychotic, extracted from a retrospective study of 378 individuals issued with a CTO by the New South Wales Mental Health Review Tribunal in Australia in 2009. Deidentified information relating to individuals' treatment plans, demographic, and clinical details were systematically extracted. Of the 377 individuals, 121 (32%) were prescribed antipsychotic polypharmacy and 101 (27%) high-dose antipsychotics. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for factors associated with antipsychotic polypharmacy and high-dose antipsychotics were computed using binary logistic regression. There was a strong association between the use of antipsychotic polypharmacy and high-dose antipsychotics (P < 0.001). Only treatment plan factors were associated with antipsychotic polypharmacy and high-dose antipsychotics in adjusted models. Although first-generation long-acting injectable antipsychotics and clozapine were associated with antipsychotic polypharmacy (adjusted OR, 9.12; 95% CI, 4.21-19.74; adjusted OR, 7.97; 95% CI, 2.93-21.72), oral second-generation antipsychotics and risperidone long-acting injection were associated with high-dose antipsychotics (adjusted OR, 5.67; 95% CI, 2.89-11.12; adjusted OR, 8.14; 95% CI, 3.22-20.53). Therefore, the use of antipsychotic polypharmacy and high-dose antipsychotics among individuals issued with CTOs is associated only with the drugs prescribed in their treatment plans and not their individual demographic and clinical characteristics.

P-1112 - Attitudes of french psychiatrists toward antipsychotic depot medication in schizophrenia

Despite a favorable pharmacological rational, the prescription of antipsychotics depot formulation in patients with schizophrenia is low. The goal of our study was to assess the attitudes of French psychiatrists toward the use of depot antipsychotics in patients with schizophrenia. 113 french psychiatrists were interviewed at a congress of psychiatry, using a questionnaire to identify psychiatrists attitudes influencing the use of long-acting injectable antipsychotics (LAI) in schizophrenia. Multidimensional and cluster analyses were used to detect correlations. According to data compiled by the german team of S. Heres (2008), two clusters of factors specific to the patient for the prescription of antipsychotic depot, have been identified: the cluster “high level of therapeutic alliance and high level of insight” on the one hand and the cluster “poor compliance to oral therapy and high number of relapses in the past” on the other. The most important factor against the use of LAI antipsychotics is a sufficient estimated compliance with the oral formulation. For first-generation LAI, the main factor is the risk of extra pyramidal symptoms and for second-generation LAI, it is the unavailability of the equivalent of oral formulation. Among the reasons influencing the prescription of LAI antipsychotic, history of poor adherence to oral therapy is important. In contrast, the highlighting of a profile of patients with a high level of insight and a high level of therapeutic alliance, confirms the value of these forms beyond the traditional profile of non-adherent.

First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: Systematic review of randomised controlled trials and observational studies

Antipsychotic long-acting injections (LAIs) are often used in an attempt to improve medication adherence in people with schizophrenia. To compare first-generation antipsychotic long-acting injections (FGA-LAIs) with first- and second-generation oral antipsychotics in terms of clinical outcome. Systematic literature review. A meta-analysis of randomised controlled trials (RCTs) showed no difference in relapse or tolerability between oral antipsychotics and FGA-LAIs but global improvement was twice as likely with FGA-LAIs. Four prospective observational studies were identified; two studies reported lower discontinuation rates for FGA-LAIs compared with oral medication and two found that outcome was either no different or better with oral antipsychotics. Mirror-image studies consistently showed reduced in-patient days and admissions following a switch from oral antipsychotics to FGA-LAIs. The results are variable and inconclusive. Some evidence suggests that FGA-LAIs may improve outcome compared with oral antipsychotics. Methodological issues may partly explain the variable results. Selective recruitment in RCTs and lack of randomisation in observational studies are biases against LAIs, whereas regression to the mean in mirror-image studies favours LAIs. In terms of future research, a long-term pragmatic RCT of an FGA-LAI against an oral antipsychotic, in patients with problematic adherence, would be of value.

Second-generation antipsychotic long-acting injections: Systematic review

Second-generation antipsychotics (SGAs) represent an advance in the long-term management of schizophrenia. To review the available evidence concerning SGA long-acting injections (LAIs). A systematic review of the literature was conducted using PubMed. Risperidone long-acting injection was the first licensed SGA-LAI compound and is effective in the long-term management of schizophrenia, with a safety profile similar to that of oral risperidone. Olanzapine pamoate has recently been approved in Europe. In terms of efficacy, at injection intervals of up to 4 weeks it appears comparable to oral olanzapine, although the potential for ;post-injection syndrome' (delirium) calls for additional safety considerations. Paliperidone palmitate is currently under review with the licensing authorities. It also affords the potential advantage of monthly dosing. More long-term comparisons of SGA-LAIs with oral SGAs as well as with first-generation antipsychotic LAIs are needed. These studies should include cost-effectiveness data.