Expanding Therapeutic Options and Developing Novel Long-Acting Injectables in Schizophrenia

The 2023 Schizophrenia International Research Society (SIRS) symposium opened on May 11, 2023 with a satellite symposium, “Expanding therapeutic options for schizophrenia: considering patient preferences when developing novel long-acting injectable treatments.”


Consider patient preferences to improve medication adherence

Prof. Eric Achytes (Western Michigan University, USA) opened the symposium by discussing what can be learned from patient preferences to improve medication adherence in the treatment of schizophrenia.

Over 50% of patients are non-compliant with their antipsychotic regimen

Prof. Achytes shared research which identified that >50% of patients are non-compliant with their antipsychotic regimen;1 lack of adherence to antipsychotic treatment significantly raises the risk of relapse and rehospitalization. It is more common to see interruptions to antipsychotic medication compliance in the early phase of illness;2 the incidence of treatment discontinuation tends to decrease over the course of illness.2 Prof. Achytes shared a US study which identified the following predictors of nonadherence:3 newly starting treatment, younger age, substance abuse, use of a mood stabilizer, antidepressant, anxiolytic or anticholinergic, and receiving first-generation long-acting injectable (LAI) antipsychotics.

Lack of adherence to antipsychotic medication significantly raises the risk of relapse

In contrast, the introduction of LAI formulations of traditional oral antipsychotics has emerged as a strategy to improve patient compliance.4

Patients tend to report an increased sense of self-empowerment, health related quality of life, and symptom improvement with LAIs over oral formulations.5 Furthermore, there is a general preference for LAIs with a longer dosing interval over LAIs administered monthly. Reasons given by patients for this preference include: less frequent injections, a feeling of receiving less medicine, a reduced need for planning to receive treatment, and increased stability and less focus on their illness.6 All of these perceptions combine to have a positive impact on patients’ everyday lives and social relations, thus improving their health related quality of life and allowing them to pursue their own goals.6

Patients show greater adherence to long-acting injectables and report increased self-empowerment and illness stability with these formulations

Ultimately, Prof. Achytes stressed that a greater emphasis on integrating patient preferences when planning treatment regimens may ultimately lead to greater adherence, treatment satisfaction, and better treatment outcomes in schizophrenia.


Bridging pharmacokinetic data

Prof. Ric Procyshyn (University of British Columbia, Canada) outlined a new approach to developing novel treatment formulations for schizophrenia. He pointed out that traditionally, clinical trials of LAI formulations have used time to impending relapse or symptom deterioration as endpoints. This approach poses a risk to patients that it can allow for relapse, facilitate illness progression, reduce treatment response and increase the risk for suicide, substance abuse and violence.7 Relapse of schizophrenia is associated with increased levels of homelessness and unemployment and an overall reduced health related quality of life.8

Studying a drug’s pharmacokinetics is an integral and essential component of the drug development and approval process

Studying a drug’s pharmacokinetics (PK) is an integral and essential component of the drug development and approval process. Pharmacokinetic data can be derived from traditional approaches, i.e., using several blood samples from a small number of participants who typically do not have the condition of interest being studied, or a population-based approach can be used, which requires fewer blood samples from a larger number of participants who are from the patient population of interest.9 This approach requires the building of a model to collect and analyze data; simultaneously, it allows for the quantification of covariates which can impact PK (for instance, age, sex, BMI etc.)9

PK bridging is a process in which PK data is leveraged to support the efficacy of a new version of an already approved drug. This allows for expedition of the drug approval process by bypassing Phase 2 and 3 trials. The process involves data collection, the development of a model followed by its validation, and simulations. This process has been used successfully in the development of novel LAI antipsychotic agents with extended dosing intervals.

Pharmacokinetics bridging is a process in which PK data is leveraged to support the efficacy of a new version of an already approved drug

Leveraging the strategy of PK bridging may reduce costs, facilitate streamlined drug development, and help to reduce the risk of relapse for patients when compared to the traditional approach using time to impending relapse or symptom deterioration as endpoints in clinical trials.7 


Translating PK data to clinical efficacy

Prof. Christoph Correll (The Donald and Barbara Zucker School of Medicine, USA) went on to provide some real world applications of PK data bridging. PK modelling developed during Phase 1, 2 and 3 testing for an LAI was adapted to inform dose selection and validation during the development of the longer acting version of the same LAI.10 Similarly, the development of another LAI was achieved by using an exposure-matching, PK‑bridging strategy using data derived from a Phase 1 trial that compared plasma concentrations.11

The more stable plasma concentration associated with more slowly absorbed LAIs can help to improve tolerability and patient adherence

The more stable plasma concentration associated with more slowly absorbed LAIs can help to improve tolerability and patient adherence.12 Fewer relapses translate to improved patient adherence.

Improved patient adherence leads to stability of illness; this stability can be used to help patients to achieve their own goals in between injections. Psychosocial interventions can now be applied, said Prof. Correll.  Allowing the patient to focus on their own treatment goals allows the switch from “schizophrenic patients” to “a patient with schizophrenia.”


Educational financial support for this Satellite symposium was provided by Otsuka Pharmaceutical Development and Commercialization Inc., and Lundbeck A/S.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. Tiihonen J, Haukka J, Taylor M et al. A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia. Am J Psychiatry. 2011;168(6):603–609.
  2. Rubio JM, Taipale H, Tanskanen A et al. Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study. Schizophr Bull. 2021;47(6):1611–1620.
  3. Lang K, Meyers JL, Korn JR et al. Medication adherence and hospitalization among patients with schizophrenia treated with antipsychotics. Lang et al. Psychiatr Serv. 2010;61(12):1239–1247.
  4. Weiser M, Davis JM, Brown CH et al. Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs. Am J Psychiatry. 2021;178(10):932–940.
  5. Blackwood C, Sanga P, Nuamah I et al. Patients' Preference for Long-Acting Injectable versus Oral Antipsychotics in Schizophrenia: Results from the Patient-Reported Medication Preference Questionnaire. Patient Prefer Adherence. 2020;14:1093–1102.
  6. Rise MB, Stølan LO, Erdner A et al. Patients' perspectives on three-monthly administration of antipsychotic treatment with paliperidone palmitate - a qualitative interview study. Nord J Psychiatry. 2021;75(4):257-265.
  7. Lawrence RE, Appelbaum PS & Lieberman JA. Are Placebo-Controlled, Relapse Prevention Trials in Schizophrenia Research Still Necessary or Ethical? JAMA Psychiatry. 2019;76(7):673–674.
  8. Lin D, Joshi K, Keenan A et al. Associations Between Relapses and Psychosocial Outcomes in Patients With Schizophrenia in Real-World Settings in the United States. Front Psychiatry. 2021;12:695672.
  9. Charles B. Population pharmacokinetics: an overview. Aust Prescr. 2014;37(6):210-210.
  10. Samtani MN, Nandy P, Ravenstijn P et al. Prospective dose selection and acceleration of paliperidone palmitate 3-month formulation development using a pharmacometric bridging strategy. Br J Clin Pharmacol. 2016;82:1364-1370.
  11. Harlin M, Yildirim M, Such P et al. A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2‑Month Long‑Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder. CNS Drugs. 2023;37:337-350.
  12. Correll C, Kim E, Sliwa JK et al. Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview. CNS Drugs. 2021;35:39-59.
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