The Use of Long-Acting Injectables for People with Schizophrenia: Consensus Panel Recommendations for Overcoming Barriers and Implementing Treatment

Abstract

Introduction

Antipsychotic medications are effective for people living with schizophrenia, but long-term treatment adherence remains challenging, leading to relapses and poor outcomes. Long-acting injectable antipsychotics (LAIs) may improve adherence and reduce relapses compared with oral antipsychotics. Barriers to the use of LAIs exist, yet practical recommendations to overcome them are lacking. Therefore, an expert consensus panel was formed to develop key recommendations using a modified Delphi panel method.

Methods

The panel chair and Interactive Forums, Inc., conducted a narrative literature review of English-language articles published in the 10 years before 02/02/2024. Panelists rated, discussed, and re-rated proposed statements during 2 online premeetings and 2 virtual group meetings in 2024. Consensus was defined as ≥ 75% agreement.

Results

The consensus panel initially included 9 experts and was expanded to 12, representing 6 countries and diverse psychiatric and lived experiences. In the first round, 31 recommendations were developed, with a high level of agreement; these were refined to 26 statements in the second round. Recommendations covered: (1) overcoming barriers to LAI initiation and use for the treatment of people with schizophrenia, and (2) procedures for initiation and switching, monitoring, and maintenance of LAIs for people with schizophrenia. The panel recommended that healthcare professionals (HCPs) consider LAIs proactively and initiate them early after a confirmed schizophrenia diagnosis. The importance of continued treatment with LAIs and their role in assessing nonadherence and treatment resistance were also highlighted. Further, the panel recommended that HCPs evaluate any personal biases about LAIs and engage in training/education to support goal setting and shared decision-making with patients and caregivers. Guidance on switching between antipsychotic formulations and maintaining treatment was also provided.

Conclusions

This expert consensus panel provided recommendations to guide HCPs on how to overcome barriers to LAI use and to implement, monitor, and maintain LAIs as routine schizophrenia treatment.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00838-3.

Plain Language Summary

Antipsychotic medicines can work well for people living with schizophrenia, but some struggle to take their pills every day. Antipsychotic medicines that are injected and can be given once every 2 weeks or once every 2-, 3-, or 6-months work for a long time and can help these people; however, there are some problems that prevent patients from getting these injectable antipsychotics. A group of experienced doctors came together to give suggestions that other doctors can use to successfully offer injectable antipsychotics to their patients. The group had 2 meetings to work on the suggestions. The experts advised that the injectable antipsychotics should be given to patients as early as possible. Once people living with schizophrenia start taking the injectable antipsychotics, they should take them for as long as possible to stay healthy. These medicines are given by a healthcare professional, which makes them easier to use because doctors and caregivers know when patients miss an injection and can help them remember to get the injection. Injectable antipsychotics can also help doctors know if the medicines do not work for some patients. Doctors, nurses, patients, and caregivers all need good training to help them decide which long-acting injectable antipsychotic to use. The suggestions from the expert doctors will teach other doctors how to switch patients from antipsychotic pills to an injectable antipsychotic or from one injectable antipsychotic to another. They will also help doctors learn how to keep patients who are taking these medicines healthy for longer.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00838-3.

Key Summary Points

Why carry out this study?

Antipsychotic medications are effective for people living with schizophrenia, but long-term treatment adherence remains challenging, leading to relapses and poor outcomes

Long-acting injectable antipsychotics (LAIs) may address some of the challenges of treatment non-adherence and of the related negative downstream effects; however, despite their documented advantages, LAIs remain underused in clinical practice

An expert consensus panel was formed to describe key recommendations to overcome existing barriers to the use of LAIs and provide practical implementation guidelines by using a modified Delphi panel method

The panel recommended that healthcare professionals examine the potential for using LAIs proactively rather than reactively, evaluate any limiting opinions they might have regarding the use of LAIs, and consider whether, when, and how LAIs might facilitate enhanced care for people living with schizophrenia

What has been learned from the study?

LAIs provide an opportunity to address the long-standing needs of people with schizophrenia by facilitating improved adherence and decreasing the burden of the disease through improved symptom stability and personalized goal attainment

These advantages of LAIs can only manifest when healthcare providers examine preconceived notions about them and proactively offer LAIs to people with schizophrenia, linking their advantages to goals that people living with schizophrenia want to achieve, and thereby facilitating informed decisions, which ideally are made in a shared decision paradigm

Introduction

Schizophrenia is a complex and chronic mental disorder, with a global prevalence of 23 million people in 2021 [1]. This serious disorder can affect all aspects of life, and a longer duration of untreated psychosis is associated with poorer prognosis [2–5]. Antipsychotic treatment is effective; however, relapses are common and are associated with significant burdens, including personal and family suffering, societal costs, and delayed or decreased treatment response [6–9]. Moreover, while approximately 20% of people with a first episode have treatment-resistant schizophrenia, this number doubles to approximately 40% among those with multiple episodes [10], and is likely related to the negative effects of relapses [7, 11, 12]. Thus, long-term antipsychotic treatment is the mainstay of therapy, with the goals of treating symptoms of psychosis and preventing relapse [2, 9, 13].

Antipsychotic treatment formulations used in ongoing treatment include oral antipsychotics (OAs), short-duration transdermal preparations, and long-acting injectable antipsychotics (LAIs) [14]. While antipsychotic treatment is effective, long-term treatment adherence has been low [15–17] or intermittent, which can lead to relapse, rehospitalization, and subsequent poor outcomes [18, 19]. In comparison with OAs, LAIs have the potential to improve adherence because administration is less frequent and generally occurs in healthcare settings, where patients have support [20]. Although not observed in all studies [21–23], in part due to the selection of highly adherent patients who participate in randomized and blinded clinical trials (as opposed to real-world patients who may be less adherent [24]), LAIs have been associated with greater adherence, improved functional outcomes, lower rates of relapse and rehospitalization, decreased mortality and suicidal behavior, and fewer inpatient and emergency department visits compared with OAs [15, 25–31]. Further, use of LAIs ensures that nonadherence is detected as soon as a scheduled injection is missed and therefore does not rely on guesswork or personal patient/caregiver reports of adherence [32], which can be unreliable and may often overstate adherence [33]. In general, comparing LAIs and OAs for patients with schizophrenia is methodologically complex. Different methodologies can yield varying results; however, studies using more rigorous methods generally demonstrate that LAIs are more effective than OAs in preventing relapse [34].

While the role of LAIs as a treatment option for people with a history of poor or uncertain adherence has been recognized, LAIs remain underused in people with other strong indications for the use of LAIs, such as a history of hospitalization related to nonadherence [35]. Moreover, studies have shown that preventive use of LAIs is more beneficial than reactive use after manifest nonadherence or relapse [7, 11, 29, 36, 37]. Thus, the importance of offering LAIs early in the disease course is being recognized, and guidelines and expert recommendations are increasingly identifying the utility of LAIs as a routine treatment for people with schizophrenia regardless of a documented history of nonadherence [2, 38–43]. However, there are many barriers to the use of LAIs. While such barriers have been described, practical recommendations are needed to specifically address these challenges and to facilitate healthcare professional (HCP) implementation of LAIs. An expert consensus panel was formed to describe key recommendations regarding the use of LAIs for the treatment of people living with schizophrenia for whom ≥ 6 months of ongoing antipsychotic treatment is indicated.

Methods

Consensus Panel Design and Members

A modified Delphi panel method was used to systematically and quantitatively combine expert opinion and evidence into key recommendations regarding the use of LAIs for the treatment of people with schizophrenia (Fig. 1). During 2 rounds of premeetings and 2 virtual meetings, panelists rated, commented on, discussed, and re-rated proposed statements. The panel chair (JMK) was invited by the panel sponsor, Teva Branded Pharmaceutical Products R&D LLC, based on his extensive research and clinical experience, past participation in other expert consensus panels, and reputation as an internationally recognized expert in the field of schizophrenia. Initial meeting objectives and potential topics were developed by the panel sponsor and Interactive Forums, Inc. (IFI), and the panel chair provided additional direction on the objectives. Under centralized oversight by IFI, potential panelists were identified, and those approved by the panel chair were invited by email to participate in the panel. Panelists were nominated based on previous and current experience in psychiatry clinical practice and research, with an emphasis on expertise in schizophrenia and the use of LAIs for the treatment of schizophrenia. Patient advocate panelists were nominated based on lived experience with schizophrenia and experience with advocacy activities. The panel size was determined based on the number of available and approved individuals with previous experience with similar virtual meetings, aimed at including panelists with a diversity of experience while maximizing interaction during the meetings, and was subsequently approved by Teva Compliance. The panel chair provided some of the nominations and feedback on nominations of panelists.

Fig. 1.

Flowchart of the expert consensus panel process

Preparation and Procedures

The panel chair provided direction and parameters for completion of a narrative literature review that was conducted by IFI. The literature search used the US National Library of Medicine PubMed.gov database to identify relevant English-language articles published in the 10 years before February 2, 2024. Overarching search terms were “long-acting injectable” and “schizophrenia.” Literature was filtered by article type (reviews, systematic reviews) to identify relevant review articles. Beyond review articles, other relevant publications were identified using search terms for expert statements (“expert,” “consensus,” “guideline,” and “statement”), overcoming barriers (“barriers,” “challenges,” “perspectives,” and “survey”), and procedures for the prescribing and use of LAIs (“initiation,” “switching,” “monitoring,” and “maintenance”). Additional relevant publications were identified in the reference lists of pertinent articles and by ad hoc PubMed searches; other data sources included published articles recommended by the program chair and relevant presentations from recent conference proceedings. A summary of the narrative literature review was created to guide the panel in providing recommendations.

Development of Recommendation Statements

The recommendation statements were made entirely by the panel. A medical writer from IFI assisted in revision of the statements, as directed by the panel. The panel sponsor was involved only in reviewing the statements to ensure that they could be substantiated by the existing literature. The panel sponsor and the medical writer from IFI did not participate in manuscript development except to clarify methods and to review the final draft of the manuscript for consistency with prescribing information for the antipsychotics included. Ethical approval was not required, as all the panelists were authors on the manuscript.

A list of key questions was developed with the panel chair, and the chair generated draft recommendation statements (n = 28) and prioritized questions (n = 23) for the first premeeting survey. Questions in the first premeeting survey were open-ended. Proposed recommendation statements were presented with a 5-point Likert response scale (0 = Do not agree to 4 = Very much agree) and included an area for comments under each statement to allow panelists to provide additional information.

Panel members completed the online survey and provided ratings for the draft recommendation statements, all of which were compiled by IFI. The panel chair reviewed the survey responses and revised the recommendation statements. The medical writer from IFI assisted the panel chair with revisions. In the first meeting, the panel members discussed the recommendation statements and responses provided in the first premeeting survey. Based on these discussions, the panel chair directed IFI to revise the recommendation statements, which were used in the second premeeting survey. As with the first survey, statements in the second premeeting survey were presented with a 5-point Likert response scale, with space available to include additional comments related to each statement. IFI compiled the survey responses, and the panel chair provided direction for revising the recommendation statements, as needed. In the second meeting, the panel members discussed the statements and provided final ratings. The panel chair made final revisions to the recommendation statements based on the meeting discussions.

Definition and Analysis of Consensus

Consensus was considered to be achieved with an average of 3.0 or higher on a 0–4 Likert scale. Descriptive statistics were used to summarize ratings from panel members at each stage of recommendation statement review. Discussion points of agreement and disagreement were collected from the panel meetings.

Results

Panelists and Meetings

In addition to the panel chair, 8 experts were initially invited, and they all accepted. These 9 panelists were from Australia, Canada, Germany, Italy, Japan, and the US. After the first meeting, 4 additional panelists were invited to increase the diversity of the panel; three accepted, all of whom were from the US. The final panel had 12 members, including 10 men and 2 women from the fields of psychiatry, psychology, and patient advocacy; 1 panelist had lived experience with schizophrenia. The first meeting was held on April 29, 2024, and the second meeting was held on July 2, 2024.

Overview

The recommendations were organized into 2 broad topics: (1) overcoming barriers to the initiation and use of LAIs for the treatment of people with schizophrenia and (2) procedures for initiation and switching, monitoring, and maintenance of LAIs for schizophrenia. Each topic had several subtopics (Table 1). In the first meeting, the panel (n = 9) reviewed and revised 31 recommendations, all of which had a high level of agreement (mean ≥ 3.3 for each statement on the premeeting survey) (Supplementary Tables 1 and 2). In the second meeting, the panel (n = 12) refined these recommendations into 26 statements and made final ratings. All statements had high levels of agreement (mean, ≥ 3.3 for each statement from ratings during the second meeting). In 2 cases, 2 recommendations from the first meeting were consolidated into a single recommendation in the second meeting. In addition, the panel removed 4 recommendations (statements C, F, I, and J) that had high levels of agreement in the first meeting (means shown in Supplementary Tables 1 and 2) because the group determined that they did not add value to the consensus recommendations. During each meeting, the panel also generated discussion points to support their recommendations.

Table 1.

Expert consensus panel topics

Topic 1. Overcoming barriers to the initiation and use of LAIs for treatment of patients with schizophrenia

Barriers

A. HCPs may undervalue the need for continued antipsychotic medication

B. HCPs do not consider all persons with schizophrenia to be appropriate candidates for LAIs

C. HCPs often find it challenging to identify appropriate timing in the course of illness and treatment setting for initiation of LAIs

D. HCPs often do not receive training or adequate education about LAIs

E. HCPs often feel they lack the time and support for adequate discussion and implementation of LAIs

F. HCPs often hesitate to offer and administer LAIs to their patients who may be reluctant to accept injections

G. HCPs often find it challenging to choose the most appropriate LAI for a given patient

H. HCPs often find it challenging to manage comorbidities associated with schizophrenia

I. HCPs often find it challenging to use LAIs in special populations

Topic 2. Procedures for initiation and switching, monitoring, and maintenance of LAIs for schizophrenia

Treatment stages

J. Initiation

K. Switching

L. Monitoring

M. Maintenance

HCP healthcare professional, LAI long-acting injectable antipsychotic

Overcoming Barriers to LAI Initiation and Use

The panel agreed upon 18 recommendations related to overcoming barriers, and these statements had mean levels of agreement of 3.6–4.0 (Table 2). One barrier is that HCPs may undervalue the need for continued antipsychotic treatment. However, the experts agreed that antipsychotics should be continued for individuals with a confirmed schizophrenia diagnosis to mitigate risks ranging from psychotic relapse to functional disability to all-cause mortality (statement A1), and LAI formulations are often preferable to OAs because of their ability to facilitate adherence and therefore effectiveness (A2). The panelists acknowledged the importance of shared decision-making with patients and available caregivers throughout their recommendations, including making sure that patients and caregivers are adequately informed regarding the need for continued antipsychotic treatment (A3) and providing information about LAI options (G2).

Table 2.

Key consensus recommendations for overcoming barriers to the initiation and use of LAIs for treatment of people with schizophrenia

Statement number	Statement	Final agreementa
Barrier: HCPs may undervalue the need for continued antipsychotic medication
A1	Continue the use of antipsychotic medication for individuals with confirmed schizophrenia to mitigate the risk of psychotic relapse, hospitalization, functional disability, and all-cause mortality	3.9
A2	LAI formulations are often preferable to oral medications due to their ability to facilitate adherence and therefore effectiveness	3.9
A3	HCPs should ensure that patients and available caregivers are provided with evidence supporting continued use of antipsychotic medication so that shared decision-making can be well informed	4.0
Barrier: HCPs do not consider all persons with schizophrenia to be appropriate candidates for LAIs
B1	Given the uncertainty and fluctuations in adherence over time, LAIs should be offered to all people with schizophrenia	3.9
Barrier: HCPs often find it challenging to identify appropriate timing in the course of illness and treatment setting for initiation of LAIs
C1	Consider an LAI as early as possible after a definitive diagnosis of schizophrenia, in a wide range of treatment settings, including outpatient, community mental health, inpatient, correctional or forensic, emergency medicine facilities, and other settings	4.0
C2	An adequate trial of an LAI may be considered to assess nonadherence as a possible reason for inadequate antipsychotic response before designating a patient as treatment resistant	3.9
Barrier: HCPs often do not receive training or adequate education about LAIs
D1	Provide education to HCPs early in training, as well as ongoing education once in practice, on how to discuss LAIs with patients and caregivers	4.0
D2	Education about the appropriate use of LAIs should focus on all key stakeholders (i.e., prescribers, other members of the care team, clinic/hospital administrators, and payers, among others)	3.9
Barrier: HCPs often feel they lack the time and support for adequate discussion and implementation of LAIs
E1	Support collaboration within the multidisciplinary treatment team to ensure that prescribers and other members of the care team are adequately informed about the potential advantages and disadvantages of LAIs	3.9
E2	HCPs can advise the leadership of their institutions to address system-related implementation barriers by ensuring appropriate infrastructure, staffing, protocols, training, and insurance reimbursement for administration of LAIs	3.9
E3	HCPs should initiate quality improvement strategies to support HCPs and healthcare systems in the evidence-based utilization of LAIs	3.9
Barrier: HCPs often hesitate to offer and administer LAIs to their patients who may be reluctant to accept injections
F1	HCPs should receive support, education, and training on how best to communicate the potential benefits and risks of LAIs and address misconceptions regarding injections with patients and available caregivers	3.6
F2	HCPs should be mindful of their personal biases associated with LAIs and foster well-informed, evidence-based, shared decision-making	3.7
Barrier: HCPs often find it challenging to choose the most appropriate LAI for a given patient
G1	HCPs should be adequately informed and educated about available LAI treatment formulations and data supporting their relative advantages and disadvantages	3.8
G2	In addition to providing general information about LAIs, HCPs should discuss specific information about available LAI options with patients and available caregivers so that shared decision-making can be well informed	3.9
Barrier: HCPs often find it challenging to manage comorbidities associated with schizophrenia
H1	As with any antipsychotic treatment choice, the choice of a specific LAI should be tailored to psychiatric and somatic comorbidities	4.0
H2	Consider LAI treatment for patients with comorbid substance use disorder	4.0
Barrier: HCPs often find it challenging to use LAIs in special populations
I1	As with all antipsychotics, with the appropriate treatment plan and dosing adjustments, LAIs can be considered in special populations such as adolescents, the elderly, pregnant women, and patients with renal or hepatic impairment	3.9

HCP healthcare professional, LAI long-acting injectable antipsychotic

^aMean score on a 5-point Likert response scale of 0 = Do not agree to 4 = Very much agree. Scores reflect final scores from the second expert consensus panel meeting

The panel agreed that LAIs should be offered to all people with schizophrenia (B1) and that they can be considered as early as possible after a definitive diagnosis of schizophrenia (C1). In addition, to assess nonadherence as a possible reason for an inadequate antipsychotic response, an adequate trial of an LAI may be considered before designating an individual as having treatment-resistant schizophrenia (C2). The panel noted that some challenges related to the use of LAIs are not unique to the LAI formulation. As with any antipsychotic treatment choice, the choice of a specific LAI should be tailored to comorbidities (H1), and LAIs can be considered for people with comorbid substance use disorder (H2) and special populations (such as adolescents, the elderly, pregnant women, and patients with renal or hepatic impairment) when used with an appropriate treatment plan and dosing adjustments (I1).

To address barriers that may arise from gaps in training and education, the panel recommended early and ongoing education for HCPs, including how to discuss LAIs with patients and caregivers (D1) and other key stakeholders, such as prescribers, other members of the care team, clinic/hospital administrators, and payers (D2). Recommendations for education and training were also provided to address barriers related to acceptance of injections (F1) and selection of appropriate LAIs based on available formulations and data supporting their relative advantages and disadvantages (G1). Panel recommendations related to overcoming system-level barriers included collaborating across multidisciplinary teams (E1), advocating for institutional leadership-related support (E2), and using quality improvement strategies to aid in overcoming barriers to LAI use (E3).

Procedures for LAI Initiation and Use

The panel agreed upon 8 recommendations related to procedures for the initiation and switching, monitoring, and maintenance of LAIs for the treatment of people with schizophrenia (Table 3). For treatment initiation, the panel advised considering multiple characteristics when choosing an LAI, including the specific agent, needle size, and initiation regimen (J1). The panel recommended that tolerability and safety of the oral agent should be established by history or a trial before switching to the corresponding LAI (K1). If switching from an oral agent to the corresponding LAI, tolerability will have been established during the course of treatment with the oral agent. If switching from an oral agent to an LAI formulation of a different medication, tolerability of the new antipsychotic should be established by a trial of the corresponding oral agent or by history (e.g., past receipt of the antipsychotic in an oral formulation) before making the switch. The panel recommended that, when switching from an oral agent to an LAI or from one LAI to another, particular attention should be paid to the pharmacokinetic and pharmacodynamic profiles, including the duration of overlap (K2).

Table 3.

Key consensus recommendations for procedures related to initiation and switching, monitoring, and maintenance of LAIs for schizophrenia

Statement number	Statement	Final agreementa
Treatment stage: Selection
J1	When choosing among LAIs, HCPs should consider their specific characteristics (i.e., specific agents/formulations, route of administration, needle size, injection volume, injection intervals, dosages, injection site options, and initiation regimens that may include oral supplementation/loading dose strategy/additional dosing)	3.8
Treatment stage: Switching
K1	When switching from an oral agent to an LAI, it is recommended that tolerability and/or safety of the oral agent should be established, either by history or a trial of the antipsychotic while observing if clinically relevant transient or lasting adverse effects occur	3.9
K2	When switching from an oral antipsychotic to an LAI or from one LAI to another, particular attention should be paid to the PK and PD profiles of the individual agents, including duration of overlap	3.8
Treatment stage: Monitoring
L1	As with other antipsychotics, HCPs should monitor the efficacy and safety of LAIs and assess and support the patient’s motivation to continue using the LAI	4.0
Treatment stage: Maintenance
M1	The clinically effective stabilization dose should be maintained unless dose-dependent tolerability issues emerge	3.4
M2	In cases where a given LAI proves ineffective or psychotic symptoms re-emerge, identify and address potential reasons, such as inappropriate dosing/idiosyncratic metabolism, late injections, end-of-dose failure, drug-drug interactions, psychosocial stressors, substance use, physical comorbidity, etc.	3.8
M3	If a patient does not respond to an LAI or relapses despite a trial with an adequate dose, duration, and adherence, consider switching to another LAI unless the patient has already experienced failure (lack of efficacy) with 2 antipsychotics	3.3

HCP healthcare professional, LAI long-acting injectable antipsychotic

^aMean score on a 5-point Likert response scale of 0 = Do not agree to 4 = Very much agree. Scores reflect final scores from the second expert consensus panel meeting

LAIs require ongoing monitoring to evaluate efficacy and safety, as with other antipsychotics; however, monitoring should include assessing and supporting the patient’s motivation to continue using the LAI (L1). In terms of maintenance, the panel advised that the clinically effective stabilization dose should be maintained unless dose-dependent tolerability issues emerge (M1). The panel also noted potential contributing causes to investigate if the LAI proves ineffective or psychotic symptoms re-emerge (M2). Causes can include inappropriate dosing/idiosyncratic metabolism, late injections, end-of-dose failure, drug–drug interactions, psychosocial stressors, substance use, and physical comorbidity. Finally, in cases of an inadequate response to an LAI or relapse despite a trial with an adequate dose, duration, and adherence, the panel recommended that a switch to another LAI could be considered unless the patient has already experienced failure (lack of efficacy) with 2 antipsychotics, in which case clozapine should be considered (M3). General principles for the use of LAIs when switching between antipsychotic treatments are presented in Table 4.

Table 4.

General principles related to the use of LAIs when switching between antipsychotic treatments [99]

Switching scenario	LAI initiation	Overlap	Baseline antipsychotic discontinuation
From OA to LAI of the same active agent	• Initiate LAI at the time of or shortly after the next scheduled dose of the OA	• An overlap with the OA may be required (i.e., 1 week from RIS to RIS-microspheres [120]; 2 weeks from ARI to ARI-monohydrate [79]; 3 weeks from ARI to ARI-lauroxil; 3 weeks from RIS to RIS-microspheres) [121] • A loading dose of the LAI may be required to quickly achieve therapeutic plasma levels (i.e., all FG-LAIs [79, 122–126], PALI 1-monthly loading doses on days 1 and 8 [127]; olanzapine pamoate loading dose regimen for 8 weeks with higher dose/shorter injection interval [128]) • Some formulations allow for a 2-injection start that can eliminate the need for prolonged oral co-treatment (i.e., co-initiation with two 400-mg ARI-monohydrate injections [79], co-initiation of ARI-lauroxil with ARI-lauroxil nanocrystal dispersion) [121] • For some extended-release formulations, there is no need for a loading dose or oral supplementation during transition (i.e., RIS sc ER RBP-7000 [129], RIS sc ER TV-46000 [81], RIS in situ microparticles [130]	• Immediate discontinuation possible, except for LAIs requiring oral overlap
Example Daily oral risperidone to risperidone long-acting subcutaneous antipsychotic [81]	• LAI should be administered on the same day as the last dose of oral risperidone	• Oral supplementation with risperidone is not needed during the transition	• Discontinue oral risperidone immediately without down-titration
From OA to LAI of a different active agent	• Initiate LAI at the time of the next scheduled dose of the previous OA, while also considering the PK properties of both agents • If the patient has not taken the active agent previously, establish tolerability by administering several oral doses of the new agent before starting the LAI	• An overlap with the OA may be required (see above) • A loading dose of the LAI may be required to achieve therapeutic plasma levels quickly (see above) • Additional oral co-treatment with the previous OA should be considered during the initial phase after starting the LAI, especially when switching from agents with more to less receptor antagonism (see next box)	• Half-life and time to peak plasma levels of both the OA and the LAI should be considered • For agents with strong binding to dopaminergic, noradrenergic, or serotonergic receptors, down-titrate the oral antipsychotic over 1–3 weeks to avoid risk of rebound effects
Example Daily oral risperidone to aripiprazole monohydrate LAI [79]	• If the patient has prior experience with aripiprazole, start the aripiprazole monohydrate on the day that the next risperidone dose would have been due	• Continue the oral risperidone or administer oral aripiprazole (instead of oral risperidone) for ≥ 2 weeks after initiating the aripiprazole LAI (unless co-initiation of two 400-mg ARI monohydrate injections is used)	• Oral risperidone can be discontinued 2 weeks after initiating aripiprazole LAI or can be discontinued immediately if LAI initiation will be supplemented with oral aripiprazole, or if co-initiation of two 400-mg ARI monohydrate injections is used
From an LAI to an LAI with a different active agent	• Initiate the new LAI on the day that the next scheduled injection of the current LAI would have been due • For LAIs that require 1–3 weeks of oral co-treatment after the first injection, one may consider LAI initiation 1, 2, or 3 weeks before the new scheduled injection of the pre-switch LAI • If switching from risperidone microspheres LAI, wait 2 weeks after next scheduled dose due to delayed release • If the patient has not taken the active agent previously, establish tolerability by administering several oral doses of the new agent before starting the LAI	• An overlap with the OA of the new LAI may be required (see above), unless the new LAI is initiated earlier than the pre-switch LAI injection was due • A loading dose of the new LAI may be necessary for the new LAI to quickly achieve therapeutic plasma levels (see above) • Oral co-treatment of the active ingredient of the previous LAI may be required during the transition period to ensure adequate coverage until the new LAI reaches effective concentrations, unless oral formulation of the new LAI is added instead, or the new LAI is initiated earlier than the pre-switch LAI injection was due	• Discontinue the previous LAI when initiating the new LAI on the day of the next scheduled injection • The speed of offset of the previous LAI depends on the half-life; those with longer half-lives will take more time to diminish in effect, allowing for a smoother transition
Example: risperidone microspheres LAI [131] to olanzapine LAI [128]	• Olanzapine LAI should be administered 2 weeks after the next scheduled injection of the risperidone microspheres	• Continue with oral risperidone for a short period (e.g., 1–2 weeks) after starting the olanzapine • Depending on the specific formulations and dose, a loading dose of olanzapine might also be administered	• Discontinue risperidone LAI immediately
From an LAI to an OA	• Delay the initiation of the OA until 1–2 weeks after the next scheduled injection of LAI	• Typically, there is no need for a loading dose when initiating the OA • Oral supplementation may be necessary if the patient experiences any resurgence of symptoms before the full dose/effect of the OA is achieved	• Discontinue the LAI on the day of the last scheduled injection and initiate OA at an interval before the next scheduled injection would have occurred that will provide sufficient time to titrate the OA and reach steady state of the target dose (e.g., approximately 1 week after 2-weekly injectable, 2 weeks after monthly injectable, 6 weeks after 2-monthly injectable, 10 weeks after 3-monthly injectable, and 5.5 months after 6-monthly injectable)
Example: paliperidone palmitate LAI to oral paliperidone [78, 127, 132]	• Start up-titration of oral paliperidone approximately 2 weeks after the last scheduled injection of paliperidone palmitate LAI	• No oral loading dose is needed	• Discontinue LAI immediately at the last scheduled injection

ARI aripiprazole, ER extended release, FG first generation, LAI long-acting injectable antipsychotic, OA oral antipsychotic, PALI paliperidone, PD pharmacodynamic, PD pharmacokinetic, RIS risperidone, sc subcutaneous

Discussion

This expert consensus panel provides key recommendations regarding the use of LAIs for the treatment of people with schizophrenia. Overall, among these experts with international representation and a range of professional psychiatric and lived experiences, there was broad agreement on recommendations to address barriers to the use of LAIs and regarding guidance on the initiation and use of LAIs. LAIs provide an opportunity to address long-standing needs of people with schizophrenia. Many HCPs face barriers to the implementation of LAIs; however, these challenges can be addressed [9]. With these recommendations, this expert consensus panel endeavors to encourage HCPs to examine the potential for using LAIs proactively rather than reactively, evaluate any limiting opinions they might have regarding the use of LAIs, and consider whether, when, and how LAIs might facilitate optimal care for people with schizophrenia.

Barriers to LAI Treatment

The Importance of Continued Antipsychotic Treatment

Schizophrenia is a heterogeneous disease with considerable variability in symptom presentation, clinical course, and treatment response [44, 45]. Regardless of this variability, most people who recover from a first episode of schizophrenia will experience a relapse within 5 years of discontinuing antipsychotic treatment, and clear predictors of who will not relapse have not been identified [46]. Considering the wide-reaching consequences of relapse, such as personal and family suffering, delayed and decreased response to subsequent treatments, and societal costs [6–9], a need exists for continuous antipsychotic treatment for most patients [47]. This need is supported by data from many studies. A systematic review and meta-analysis of 46 studies reported that continuous treatment remains the gold standard for good clinical practice, as patients on continuous treatment have a lower risk of relapse and remain relapse-free for longer compared with those receiving placebo or intermittent treatment [48]. A meta-analysis of 135 cohort studies found that use of any antipsychotic was associated with lower mortality compared with no antipsychotic treatment [25], and a 5-year, population-based Swedish cohort study found that patients with no antipsychotic exposure had the highest risk of mortality compared with those with low, moderate, or high antipsychotic exposure [49]. In addition, a 20-year, population-based, cohort study in Finland concluded that no safe time point for antipsychotic discontinuation could be defined, as the risk of treatment failure after first-episode schizophrenia was more pronounced after discontinuation for those with a longer continuous history of antipsychotic use [13]. Notably, antipsychotic treatment benefits people with first-episode and multi-episode schizophrenia and those who have been stable for up to 3–6 years [47, 50]. Thus, the panel agreed that antipsychotic medication should be continued in individuals with confirmed schizophrenia (statement A1).

Selection of LAI Versus OA Treatment

Disease management for people with schizophrenia should address short-term symptom reduction, long-term relapse prevention, maintenance of physical and mental well-being, improved quality of life, and full functional recovery [2, 38]. The advantages and disadvantages of LAIs versus OAs for achieving these goals have been investigated and deliberated [51–55]. Some meta-analyses and systematic reviews have reported some similar outcomes between the LAIs and OAs studied [21–23, 56–58]. Winter-van Rossum et al. [23] reported results from a randomized open-label trial in Europe and Israel and found that there was no substantial advantage between the use of LAIs and OAs regarding all-cause time to discontinuation in patients with early-phase schizophrenia over the 19-month study. However, methodological concerns have been highlighted [59]. In particular, several factors of the study design challenged the pragmatic character of the study population, procedures, and outcome measures [59]. Studies with a more pragmatic, real-world design are important to fully illustrate the benefits of LAIs over OAs [58, 60]. Indeed, LAIs have shown benefits over OAs in numerous reports with a variety of study designs, and, at this point, the cumulative evidence is robust and compelling [15, 25–31]. An 18-year, nationwide study in Finland in people with first-episode schizophrenia found that greater utilization of LAIs earlier in the course of illness may facilitate continuity of antipsychotic treatment [15]. Among 3343 participants, a median of 6 treatment interruptions occurred over a median of 8 years of follow-up; however, participants were 67% less likely to interrupt treatment with LAIs than with OAs. Another nationwide cohort study in Finland found 22% and 32% lower risks of rehospitalization associated with LAI treatment compared with equivalent oral formulations among cohorts of all patients with schizophrenia or newly diagnosed schizophrenia, respectively [17]. In a meta-analysis of studies comparing LAIs with OAs across 3 study designs (randomized trials, mirror image studies, and cohort studies), LAIs were consistently associated with significantly lower risks of hospitalization and relapses [31]. Additionally, the use of LAIs has been associated with clinically meaningful benefits in social function, work function, treatment satisfaction, and both symptomatic and functional remission [26, 57, 61, 62]. Importantly, symptomatic and functional remission are associated with improved quality of life [63].

The Impact of LAIs, Specifically Early Initiation, on Medication Adherence

Studies with pragmatic design features [60] allow visualization of a more complete picture of the impact of LAIs on adherence to antipsychotic treatment. Adherence to a daily oral medication regimen is challenging in many chronic diseases, including, for example, asthma and hypertension [64–66]. Rates of nonadherence are higher in schizophrenia than in most medical disorders because continuous medication adherence is further complicated by cognitive dysfunction, lack of illness insight, economic disadvantage, lack of social support, and stigma [16, 67]. Notably, 2 recent analyses in patients with a first episode of schizophrenia, 1 in Finland [68] and 1 in the UK [69], identified that women were more likely to discontinue antipsychotics than men, which should prompt particular attention to reasons why this may be the case and the consideration of LAIs early in women too. LAIs are commonly acknowledged for their potential to improve adherence [38]; however, it is also important to consider how difficult it is to accurately identify and assess nonadherence [51]. Self-reports of medication taking tend to be inflated, and clinicians often judge patients as having a higher level of adherence than is supported by objective measures [52, 53]. Nevertheless, even when an antipsychotic is discontinued, prevention of relapse seems to be greater and last for longer periods of time when an LAI is discontinued than when an OA is discontinued, even after 5 half-lives of each medication formulation have passed [70]. This difference, even after discontinuation of antipsychotic treatment, may be due to the much more gradual decrease in antipsychotic blood and brain levels after LAI discontinuation, which may be beneficial [71].

Considering the evidence supporting the benefits of LAIs in people with schizophrenia and the limitations of assessing adherence, recommendations from this expert consensus panel support the use of LAIs in a broad range of patients and clinical scenarios (statements A2, B1, G1, H2, and I1). This is consistent with evolving clinical practice guidelines and expert recommendations in which convenience and patient preferences are increasingly acknowledged as a consideration in the choice of antipsychotic [38]. Guidelines from the American Psychiatric Association recommend that LAIs be provided based on patient preference (e.g., convenience), not only because of nonadherence concerns [72]. Furthermore, the American Association of Community Psychiatrists note that LAIs may be extremely helpful to many individuals since they offer a more convenient way to take medications and better address a variety of clinical and social challenges [41]. Regional consensus statements and a panel focused on first-episode and early-phase schizophrenia provide similar recommendations for considering LAIs beyond the setting of apparent nonadherence or chronic disease [2, 39, 40]. Importantly, greater clinical benefits and lower healthcare resource utilization were observed with earlier initiation of LAIs [36, 37, 73]. In line with other expert opinions [2, 39, 40, 42, 74], the panel recommended that LAIs be considered as early as possible during the course of illness in individuals with confirmed schizophrenia (statement C2).

LAI Treatment in Special Populations

The panel also advised that, as with all antipsychotics, LAIs can be considered in special populations when used with an appropriate treatment plan and dosing adjustments (statement I1). While data are limited, support exists for use in pregnant women [75], elderly patients [76], and adolescents [77]. LAIs can be used in people with renal or hepatic impairment, with dosing adjustments made as needed, based on prescribing information [78–81]. Prescribing information describing the use of antipsychotics for the treatment of schizophrenia in elderly adults does not specify an upper age range, but suggests that dose selection should be cautious, usually starting at the low end of the dosing range because of the potential for hepatic, renal, or cardiac function adverse effects or concomitant disease or the use of other drug therapy [78–81]. Use of antipsychotics in older adults has been associated with increased adverse events, including mortality [82]; however, the boxed warning related to an increased risk of mortality in elderly patients treated with antipsychotics is specific to the treatment of dementia-related psychosis, not schizophrenia [78–85]. While dosing considerations are needed, people with comorbid schizophrenia and other chronic conditions could derive an additional benefit from concurrent improved adherence to treatments for both conditions. Adherence to antipsychotics and to other medications including cardiometabolic medications are related, and antipsychotic adherence has been associated with improvements in diabetes outcomes [86–88]. Untreated psychosis in elderly patients is associated with poor clinical outcomes, including increased mortality [89]. Some studies have shown that LAI formulations may reduce mortality in elderly patients compared to oral antipsychotics by improving adherence and reducing relapse-related hospitalizations and emergency department visits [90, 91], consistent with data indicating that relapses are associated with greater mortality risk in people with schizophrenia [92].

Antipsychotic Treatment Resistance

Given a greater certainty that a patient will receive continuous medication and have inherent awareness of missed injections, a trial of an LAI can provide critical information in the setting of suspected treatment resistance [93]. Guidelines from the Treatment Response and Resistance in Psychosis (TRRIP) working group have standardized the assessment of treatment resistance, and these guidelines identify 3 key elements: (1) confirmed diagnosis of schizophrenia based on validated criteria, (2) adequate pharmacological treatment, and (3) persistence of significant symptoms despite adequate treatment [93]. Adequate pharmacological treatment requires in part a high level of adherence to antipsychotic treatment. However, as mentioned, adherence can be difficult if not impossible to assess completely, and it may fluctuate [51–53]. To avoid challenges to the definition of inadequate treatment related to nonadherence, a trial of an LAI given for ≥ 6 weeks after it has achieved steady state (generally ≥ 4 months from starting treatment) is recommended before identifying a patient as having treatment-resistant disease [93]. Thus, LAIs are an important tool in assessing both nonadherence and treatment resistance (statement C2).

The Importance of Education in Terms of Personal Biases to and Acceptability of LAIs

Concerns and misconceptions about the use of an injectable medication impact both HCP and patient willingness to consider LAIs [9]. These range from concerns that people will not accept an injectable medication to uncertainty about administering injections and managing an injectable treatment [54, 74, 94–97]. Indeed, an international survey of psychiatrists found that fear/dislike of needles was considered a top barrier to using LAIs [94]. Some HCPs may fear that offering an LAI could negatively impact the patient relationship because of a perception of lack of trust in them by the patient. However, these perceptions may not accurately reflect the clinical situation. A survey of patients taking LAIs found that the majority felt that side effects were milder and relapse prevention and efficacy were better [97]. Furthermore, fewer than one-third of the LAI-treated patients felt that the LAI was painful. Thus, the panel noted the importance of HCPs examining personal biases associated with LAIs (statement F2). Education and training can help HCPs, the care team (e.g., nurses, pharmacists, counselors, social workers, and therapists), and administrators move beyond any biases and address knowledge gaps related to the use of LAIs (statements D1 and D2) [98]. Training on how to discuss LAIs with patients and caregivers is also critical (statement F1), as a major barrier to patients accepting LAIs may be lack of information; well-informed patients are more accepting of LAIs [9].

Procedures Related to Initiation and Switching, Monitoring, and Maintenance of LAIs

The panel also addressed procedures related to the use of LAIs for schizophrenia, including initiation, switching, monitoring, and maintenance. The panel agreed that it is necessary to establish tolerability and safety of an oral formulation before initiating an LAI (statement K1), in line with other expert recommendations and prescribing information [2, 43, 78–80, 99]. The duration of the trial of the corresponding OA requires clinical judgment, considering the person’s individual situation and treatment history. A survey of high LAI prescribers revealed a range of recommended antipsychotic trial periods prior to initiating the LAI. However, most respondents preferred a trial of 4–14 days, and there was consensus that the pre-LAI trial should be ≤ 6 weeks [43]. After a successful oral antipsychotic trial has been completed, prescribing information for the LAI generally includes guidance on how to initiate LAI treatment from the OA of the respective molecule. Once an LAI is initiated, HCPs may need to navigate switching to an LAI or OA with a different active agent due to intolerability, inefficacy, or patient choice (Table 4). These scenarios require consideration of the pharmacokinetic and pharmacodynamic profiles of the pre- and post-switch treatments as well as their drug-delivery mechanisms (statement K2) [14]. Formulation (e.g., vehicle medium) and administration (e.g., injection site) characteristics can affect the rate of absorption of LAIs, severity and frequency of adverse events, and drug–drug interactions. Højlund and Correll [99] compiled a detailed review of switching to, off, and between LAIs, which requires consideration of properties such as time to peak concentration, molecule half-life, and time to steady state. In general, if the active substance of the new LAI is not released immediately, or is released in amounts too low to achieve clinically effective plasma levels within days, oral supplementation is necessary. If the active substance of the new LAI is released immediately and in sufficient amounts, oral supplementation is not necessary. Nevertheless, switching requires consideration of avoiding rebound effects when coming from a more to a less antagonist antipsychotic at dopamine, histamine, or cholinergic receptors or overlapping pharmacodynamic effects that can increase adverse effect burden [99, 100]. In cases where an LAI is not selected as the treatment of choice, it may be beneficial to select OAs that have LAI formulations to facilitate a future switch to an LAI, as appropriate.

Patient monitoring is an important aspect of the treatment plan (statement L1). Notably, monitoring requirements for LAIs are equivalent to those for OAs [2]. However, ongoing support that may be particularly useful to people starting LAIs might include appointment reminders and assessment or treatment of potential adverse events [43, 101]. These measures can help patients and care partners adjust to and maintain treatment. Regular monitoring is also necessary to evaluate dosing, and maintenance doses should reflect a balance between tolerability and efficacy (statement M1). The panelists noted that HCPs may find that an effective maintenance dose of an LAI can be lower than that of the corresponding OA because of the long-term consistency provided by a long-acting agent, in contrast to possible inconsistencies in adherence to an oral treatment regimen. However, doses should also not be too low that they result in relapses [102].

Evidence from cohort studies suggests that treatment discontinuation is lower with LAIs than with OAs [31], and, even after discontinuing an antipsychotic, patients were protected against relapse longer and more effectively if they had been on an LAI versus an OA before discontinuing treatment [70]. However, if psychotic symptoms persist or recur during LAI treatment [68, 103, 104], several factors can be investigated before declaring that the LAI was ineffective (statements M2 and M3). These include medical illness, substance misuse, psychosocial stressors, psychiatric comorbidity, and problems with injections, such as incorrect administration, repeatedly late receipt of injections, or adherence issues with co-prescribed medications [6]. HCPs should also investigate whether systemic barriers such as scheduling or insurance reimbursement may be affecting the patient’s treatment. When symptoms persist after addressing these factors, changes related to the LAI dosage or administration schedule may need to be considered [6]. TRRIP guidelines specify that treatment resistance requires 2 or more failed antipsychotic treatments, ideally including at least 1 LAI [93]. In such cases, increased duration of treatment, higher doses, trials of additional non-clozapine antipsychotics, or polypharmacy with a second antipsychotic or another psychotropic medication may be unlikely to lead to an adequate clinical response [105–108]. While treatment administration requires a careful evaluation of risks and benefits [109], clozapine may be considered, as it is an approved and evidence-based treatment option for treatment-resistant schizophrenia [105, 109–112].

The Importance of Education to Facilitate Shared Decision-Making

Treatment decisions that take into account convenience and patient preferences, misconceptions about whether patients will accept injectable medications, and broadening perspectives on the early use of LAIs underscore the importance of shared decision-making with patients and any available care partners. Accordingly, the importance of shared decision-making [113, 114] was mentioned in multiple recommendations regarding barriers (statements A3 and G2). Educating patients and care partners on the benefits of continued antipsychotic treatment and on the options, characteristics, and risks and benefits of LAIs will facilitate informed choices. Indeed, the engagement and education of care partners should not be neglected; care partners may have a strong and meaningful role in treatment decisions for people with schizophrenia. Furthermore, as there are many LAIs available [9], a person’s history and treatment preferences can help guide clinical decision-making when considering which characteristics of the available LAIs [115] are of greatest importance in successfully selecting a specific LAI for a specific patient (statements H1 and J1). Characteristics may include, for example, the active molecule, administration route or site, frequency of administration, injection volume, and needle size. Notably, when staff underwent training on how to discuss LAIs with patients, it was possible to engage patients in shared decision-making that led to high acceptance of LAIs [8, 20]. Thus, clinical teams should be capable of answering frequently asked questions about LAIs, the array of available options, and their use, and be trained on how to communicate with patients and families about such information [114, 116, 117]. Motivational interviewing is a technique that can be helpful when discussing treatment options and treatment in general by aiming to move people along the continuum from decision-making to enactment [118, 119]. People with lived experience and peer counselors can also be very valuable in providing patient-oriented perspectives.

Panel recommendations describe the role and importance of multidisciplinary teams in the use of LAIs (statements D2 and E1). The need for education about the appropriate use of LAIs extends across the care team. Education of and buy-in by nonprescribing HCPs, including nurses, pharmacists, clinic/hospital administrators, counselors, social workers, and therapists, have an important impact on the successful implementation of LAIs (statement D2). Task sharing can shift responsibilities between prescribers and other members of the care team to address barriers related to lack of time and support for implementing LAIs. Decision-makers in institutions (e.g., administrative personnel, department chair, treatment team leader) have an important role in addressing implementation barriers on a system level. Finally, the panel emphasized the importance of HCPs leading quality improvement strategies, with such strategies being critical to supporting the use of LAIs (statement E3).

Limitations

Because these consensus recommendations are new, data are lacking to evaluate their acceptability to clinicians and patients and the impact on outcomes when implemented compared with usual care. Such studies should be conducted. Another limitation was that, with the exception of 1 person with lived experience, the panel did not include multiple patient or caregiver representatives. Of note, panelists were added after the first meeting and therefore some panelists did not participate in the initial discussions of the consensus recommendations. However, this provided greater breadth in the perspectives and expertise included and thus overall is a strength of the panel recommendations.

Conclusions

LAIs have important benefits that go beyond the treatment of people with a documented history of antipsychotic nonadherence or multiple relapses. This expert consensus panel provided recommendations for HCPs with guidance on overcoming barriers to the consideration, offering, and use of LAIs, and on procedures for implementing, monitoring, and maintaining LAIs as a routine choice for the treatment of people with schizophrenia.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

John M. Kane contributed to the drafting/revision of the manuscript for content, including medical writing for content, and had a major role in the conceptualization, data curation, methodology, data analysis, supervision, validation, and reviewing. Ofer Agid, David J. Castle, Leslie Citrome, Christoph U. Correll, Andrea Fagiolini, Taishiro Kishimoto, Carlos A. Larrauri, Stefan Leucht, Jose M. Rubio, Martha Sajatovic, and Nina Schooler contributed to the drafting/revision of the manuscript for content, including medical writing for content, and had a major role in the acquisition of data and the analysis or interpretation of data. All authors reviewed and approved the final manuscript.

Funding

This consensus panel was supported by Teva Branded Pharmaceutical Products R&D LLC. The sponsor had no control over the content of the article or the decision to submit the final version of the article. The study sponsor funded the journal’s Rapid Service Fees.

Data Availability

Additional data are available upon reasonable request. Please email USMedInfo@tevapharm.com to make your request.

Declarations

Disclosures

John M. Kane has been a consultant for or received honoraria from Alkermes, Allergan, Boehringer Ingelheim, Cerevel, Dainippon Sumitomo, Lundbeck, Health Rhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, Karuna/Bristol Myers Squibb, LB Pharmaceuticals, Mapi, Maplight, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, and Teva Pharmaceuticals; has served on advisory boards for AbbVie, Alkermes, Boehringer Ingelheim, Cerevel, Click Therapeutics, Karuna/Bristol Myers Squibb, Lundbeck, Merck, Newron, Novartis, Otsuka, Sumitomo, Teva Pharmaceuticals, and Terran; has received grant support from Lundbeck, Janssen Pharmaceutical, Otsuka, and Sunovion; and is a shareholder of Medincell, Health Rhythms (private/stock options), LB Pharmaceuticals (private/stock options), North Shore Therapeutics (private/stock options), Vanguard Research Group (private/40% owner), NW Pharmatech (private/stock options), Saladax (private/stock options), Reviva (stock options), and Terran (private/stock options). Ofer Agid has been a consultant and/or advisor to or has received honoraria from Janssen Ortho (Johnson & Johnson), Otsuka, Lundbeck, Allergan/AbbVie, Teva Pharmaceuticals, and Newron; has been a speaker for Janssen Ortho (Johnson & Johnson), Lundbeck, Otsuka, Mylan Pharmaceuticals, and HLS Therapeutics; and has received grant support from Janssen Ortho (Johnson & Johnson), Otsuka, Boehringer Ingelheim, and Neurocrine Bioscience. David J. Castle, in the past 5 years, has received grant monies for research from NHMRC, MRFF, Barbara Dicker Brain Sciences Foundation, CIHR (Canada), Brain Canada, Servier, Boehringer Ingelheim, and Inova; has received travel support and honoraria for talks and consultancy from Servier, Seqirus, Lundbeck, Mindcafe, Psych Scene, and Inside Practice; is a founder of the Optimal Health Program (OHP) and holds 50% of the IP for OHP; is part owner (8%) of Clarity Healthcare; has received royalties for books from Allen and Unwin, Elsevier, Oxford University Press, and Cambridge University Press; is an unpaid chair of an advisory board for Psychae, an Australian not-for-profit institute specializing in psychedelic medicines research; is an advisor for Tryp, a for-profit psychedelics company; was a member of the Royal Australian and New Zealand College of Psychiatrists Psychedelic Assisted Therapy Working Group; and does not knowingly have stocks or shares in any pharmaceutical company. Leslie Citrome, has served as a consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Bristol Myers Squibb, Cadent Therapeutics, Cerevel, Clinilabs, Compass Pathways, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Marvin, Merck, Mitsubishi Tanabe Pharma, Neurocrine, Neurelis, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sunovion, Supernus, Teva Pharmaceuticals, and University of Arizona; has provided one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; has been a speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Bristol Myers Squibb, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, and Teva Pharmaceuticals and for CME activities organized by medical education companies such as Medscape, NACCME, NEI, and Vindico and universities and professional organizations/societies; owns stock (small number of shares of common stock) in Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer (purchased > 10 years ago) and stock options in Reviva; earns royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research & Opinion, 2022–present), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end of 2019), UpToDate (reviewer), Springer Healthcare (book), and Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). Andrea Fagiolini is/has been a consultant and/or speaker and/or has received research grants from Angelini, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, ROVI, Sunovion, Teva Pharmaceuticals, and Viatris. Taishiro Kishimoto, in the past 3 years, has received consultant fees from Chugai, Otsuka, Sumitomo Pharma, and Teva Pharmaceuticals; has received speaker’s honoraria from Eisai, Janssen, Mitsubishi Tanabe, Mochida, MSD, Novartis, Otsuka, Pfizer, and Sumitomo Pharma; received licensing fees from Sumitomo Pharma; and has received donation courses from Mori building, outside the scope of the submitted work. Carlos A. Larrauri, in the past 3 years, has received presentation and speaker fees from Merck, Biogen, Teva Pharmaceuticals, Intra-Cellular Therapies, Karuna/Bristol Myers Squibb, Cerevel, and the Center for Patient Advocacy Leaders; has received personal fees from Klick Health, Alkermes, K Therapy/Health, Janssen, Discern Health, Neurocrine, and Boehringer Ingelheim; and has received travel expenses for a poster presentation from Boehringer Ingelheim, outside the scope of the submitted work. Stefan Leucht has received honoraria for advising/consulting and/or lectures and/or for educational materials from Angelini, Apsen, Boehringer Ingelheim, Janssen, Karuna, Kynexis, Lundbeck, Medscape, Otsuka, Neurotorium, NovoNordisk, Orion Pharma, Otsuka, Roche, Rovi, and Teva Pharmaceuticals. Jose M. Rubio has received honoraria from Teva Pharmaceuticals, Janssen, Karuna, Bristol Myers Squibb, Medscape, and TotalCME; has received research support from Alkermes, Neurocrine, Saladax, and National Institutes of Health; and has received royalties from UpToDate. Martha Sajatovic has been awarded grants from Neurelis, Intra-Cellular Therapies, Merck, Otsuka, Alkermes, and Teva within the past 3 years; has been a consultant for Alkermes, Otsuka, Lundbeck, Janssen, and Teva Pharmaceuticals over the past year; has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, and UpToDate over the past year; and has been compensated for preparation of and/or participation in CME activities over the past year for the American Physician Institute (CMEtoGO), Psychopharmacology Institute, American Epilepsy Society, and Clinical Care Options. Nina Schooler, in the past 5 years, has received honoraria, consulted with, or received grant support from AbbVie, Alkermes, Bristol Myers Squibb, Boehringer Ingelheim, US Food and Drug Administration, GW Pharmaceuticals, Indivior, Intra-Cellular Therapies, Lundbeck, Miranda, Otsuka, Janssen, and Teva Pharmaceuticals. Christoph U Correll has been a consultant and/or advisor to or has received honoraria from AbbVie, Acadia, Adcock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Eli Lilly, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/Johnson & Johnson, Karuna, LB Pharmaceuticals, Lundbeck, Medincell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, ROVI, Sage, Saladax, Sanofi, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva Pharmaceuticals, Terran, Tolmar, Vertex, Viatris, and Xenon Pharmaceuticals; has provided expert testimony for Janssen, Lundbeck, and Otsuka; has served on a data safety monitoring board for Compass Pathways, Intra-Cellular Therapies, Relmada, Reviva, and ROVI; has received grant support from Boehringer Ingelheim, Janssen, and Takeda; has received royalties from UpToDate; and holds stock options in Cardio Diagnostics, Kuleon Biosciences, LB Pharmaceuticals, MedLink, Mindpax, Quantic, and Terran.

Ethical Approval

Ethical approval was not required, as all panelists were authors on the manuscript.