Clinical Scenario: A 31 y/o M undomiciled, unemployed male is brought in by EMS services activated by a neighborhood resident who saw the patient wandering around in the street and talking to himself. The patient is minimally compliant, seems internally preoccupied, and speaks with a flat affect. After agreeing to take medication, the patient explains that he hears voices telling him to self-harm. Upon review, the patient had an ER visit as recently as one month ago with the same symptoms, and he has been non-compliant with his prescribed oral medication.

Search Question:

Can a long acting injectable antipsychotic (LAIA) that requires dosing every 4-12 weeks  increase medication compliance and reduce remission rates among schizophrenic patients?

Question Type: What kind of question is this?

Treatment

Assuming that the highest level of evidence to answer your question, will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

Randomized Controlled Trials (RCTs) will be very useful to directly compare a randomized oral antipsychotic or short acting injectable group, which is the first line therapy, to the group receiving long acting IM injections. An RCT will help reduce bias by researchers and the patients by randomizing the cohort.

PICO search terms:

P	I	C	O
Schizophrenia	Long Acting Injectable antipsychotic	Aripiprazole	Reduction in relapse
Schizophrenics	Invega Trinza	Risperidone	Increased time in remission
Schizoaffective	LAIA	Placebo	Efficacy
	PP3M	Haldol	Persistence over time

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

PubMed

• Schizophrenia Injectible Paliperidone 396
  • Filters: 10 years, meta-analysis 12
  • Invega Haldol 13
    • Filters: 10 years, meta-analysis 15

Cochrane

• Paliperidone 4
  • Filters: 10 years11

The studies I chose were reviews that provided good comparison between long and short acting antipsychotics or placebo. Some directly compared the antipsychotics, and others indirectly. The studies looked at the safety profile of each drug and possible side effects, as well as the effect on patient compliance. I looked for studies that compared a multitude of drugs, as schizophrenia can be treated with several different first line drugs, in order to determine if the evidence was strong.

Results found:

1. Morris, Matthew T, and Sandip P Tarpada. “Long-Acting Injectable Paliperidone Palmitate: A Review of Efficacy and Safety.” Psychopharmacology bulletin vol. 47,2 (2017): 42-52.

Type of Article: Review

Abstract

Objective: Summarize and synthesize the current literature regarding longacting injectable paliperidone palmitate for the treatment of schizophrenia. Methods: A literature search of PubMed, Embase, and Web of Science was conducted in February 2016, using the following search terms in varying permutations: schizophrenia; antipsychotic medication; long-acting injectable; paliperidone palmitate; 3-monthly injectable. Results: Once-monthly injectable paliperidone palmitate (PDP) has demonstrated comparable efficacy as 1st-generation long-acting injectable antipsychotics (LAIAs) in reducing disease severity and re-hospitalizations in schizophrenic patients. However, PDP leads to significantly less extrapyramidal symptoms than these older medications indicating a superior safety profile. Compared to oral 2nd-generation antipsychotics, PDP has shown less incidence of disease relapse related to medication non-compliance, particularly in real world populations. It also showed a similar safety profile as oral 2nd-generation antipsychotics, but with greater incidence of mild injection-site pain. A novel 3-monthly formulation of PDP has shown similar safety and efficacy as once-monthly PDP compared to placebo. Conclusions: Overall, both 1-month and 3-month formulations of PDP are safe and effective in the treatment of schizophrenia and schizoaffective disorder. They may be most effective in patients with prior failed treatment of oral antipsychotics or other LAIAs, in patients with a history of medication noncompliance, or in patients with an individual preference for less frequent dosing. Psychopharmacology Bulletin. 2017;47(2):42–52.

2. Brasso, Claudio et al. “Role of 3-monthly long-acting injectable paliperidone in the maintenance of schizophrenia.” Neuropsychiatric disease and treatment vol. 13 2767-2779. 7 Nov. 2017, doi:10.2147/NDT.S150568

Type of Article: Review

Abstract

Aims: Paliperidone palmitate 3-month (PP3M) represents a new long-acting injectable antipsychotic therapeutic option. This review aims: 1) to summarize available data relating to efficacy, safety, tolerability and costs of PP3M; 2) to describe hospitalization rate, occupational status, treatment preference, satisfaction, adherence and caregiver burden of patients with schizophrenia who participate in PP3M clinical trials; 3) to examine ethical implications, pros and cons of PP3M use and 4) to propose study designs to further assess PP3M. Methods: On August 21, 2017, a search on PubMed about PPM3, without any filter restriction, was conducted and all available records were analyzed. Records written in a language other than English were excluded. Results: Twenty-two records were included in this review: 6 reviews, 1 report, 4 pharmacokinetic studies, 2 cost-effectiveness analyses, 1 open-label clinical trial, 2 randomized controlled trials (RCTs), 5 studies based on these 2 RCTs and 1 observational study. Discussion: According to these last 9 studies, when compared with placebo, PP3M showed a longer time to relapse and good safety and tolerability profiles. Furthermore, when compared with paliperidone palmitate 1 month (PP1M), PP3M treatment showed: 1) non-inferiority in terms of efficacy, safety, tolerability, rate of hospitalization, symptomatic and functional remission, treatment preference and variations of the occupational status; 2) a longer time to relapse after treatment discontinuation and 3) a similar reduction of the caregiver burden. Conclusion: PP3M is the only 3-monthly long-acting injectable antipsychotic available on the market. This makes it a unique option of treatment, which could be chosen both in early and advanced phases of illness. Nonetheless, longer naturalistic follow-up studies, two-arm head-to-head superiority trials and mirror studies, based on real-world samples of patients, are needed to further assess long-term safety and advantages of this new option of treatment and to define patients’ sub-populations that would most beneficiate from it.

3. Jann, M. W., & Penzak, S. R. (2018). Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents. CNS Drugs, 32(3), 241–257. doi:10.1007/s40263-018-0508-6 

Type of Article: Review

Abstract

Schizophrenia is a chronic medical condition with periods of remission and relapses over a patient’s lifetime. Antipsychotic medications represent the mainstay of treatment for this disease. Long-acting injectable (LAI) formulations of antipsychotics are an attractive alternative to their oral counterparts, as they enhance patient adherence. A number of second-generation antipsychotics (SGAs) are available in LAI formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved of these formulations-aripiprazole monohydrate, aripiprazole lauroxil, and paliperidone palmitate. While all were initially available as once-monthly formulations, a paliperidone palmitate 3-monthly injection formulation has been approved and is the first LAI agent to extend the dosing administration beyond the typical monthly time period. In addition, aripiprazole lauroxil every 6-week and 8-week administration preparations have been developed. LAI preparations of the SGAs have all demonstrated superiority over placebo and are comparable to their oral counterparts in terms of safety and tolerability, if injection site reactions are not taken into account. First-generation antipsychotic LAI preparations (e.g., haloperidol decanoate) have recently been compared with SGA LAI agents, and both formulations demonstrated comparable efficacy with the expected adverse events seen with each drug. Despite their availability, barriers to the use of LAIs remain. Education of both patients and clinicians on the use of LAI formulations and the continued development of these agents are important steps in ensuring these medications are available to the patients they would be most likely to benefit.

4. Biagi, Enrico et al. “Long-Acting Injectable Antipsychotics in Schizophrenia: Literature Review and Practical Perspective, with a Focus on Aripiprazole Once-Monthly.” Advances in therapy vol. 34,5 (2017): 1036-1048. doi:10.1007/s12325-017-0507-x

Type of Article: Review

Abstract:

Introduction

Prevention of relapse is a major challenge in schizophrenia, a disease characterized by poor adherence to antipsychotic medication leading to multiple rehospitalizations and a substantial burden-of-care.

Methods

We narratively review published clinical data from the development of long-acting injectable (LAI) formulations of antipsychotic drugs and examine the comparative effectiveness of oral versus LAIs in schizophrenia, with a focus on the second-generation LAI antipsychotic aripiprazole. Evidence is presented from studies with naturalistic/pragmatic as well as explanatory trial designs, supported by the clinical experience of the authors.

Results

LAI formulations of antipsychotic drugs offer advantages over oral medications and there is good evidence for their use as a first-choice treatment and in younger patients. Key phase III studies have shown aripiprazole once-monthly 400 mg (AOM 400) to be effective and well tolerated, with high rates of adherence and low rates of impending relapse. In a recent randomized trial with a “naturalistic” study design more representative of routine clinical practice, AOM 400 was well tolerated and had significantly greater effectiveness than paliperidone LAI overall and in younger patients aged ≤35 years.

Conclusion

Results across the “full spectrum” of efficacy in traditional clinical trials as well as those encompassing the concept of effectiveness in a more naturalistic setting of real-life clinical practice support the use of AOM 400 as a valid long-term treatment option in schizophrenia overall, as well as earlier in the treatment course, and not solely in situations of poor adherence or when oral antipsychotics have failed.

Keywords: Adherence, Hospitalization, LAI antipsychotics, Relapse, Remission, Schizophrenia and related psychotic disorders, Second-generation

5. Fernández-Miranda, Juan J et al. “Effectiveness, Good Tolerability, and High Compliance of Doses of Risperidone Long-Acting Injectable Higher Than 75 mg in People With Severe Schizophrenia: A 3-Year Follow-Up.” Journal of clinical psychopharmacology vol. 35,6 (2015): 630-4. doi:10.1097/JCP.0000000000000400

Typee of Article:

Prospective Observational

Abstract:

Tolerability and effectiveness of antipsychotics are important to increase treatment compliance in people with schizophrenia. The aim of this study was to evaluate effectiveness, tolerability, and adherence to treatment with high doses of risperidone long-acting injectable (RLAI) in patients with severe schizophrenia.It is a 3-year prospective, observational study of patients with severe (Clinical Global Impression Severity scale [CGI-S] score of ≥5) schizophrenia according to International Classification of Diseases (ICD-10) criteria. Subjects were the consecutive 60 who first underwent treatment with RLAI with doses of 75 mg or higher every 14 days to get clinical stabilization.Assessment included the following: CGI-S, World Health Organization Disability Assessment Schedule, Camberwell Assessment of Need (CAN), Medication Adherence Rating Scale, laboratory tests, weight, and hospital admissions.The mean (SD) dose of RLAI was 111.2 (9.1) mg per 14 days. Tolerability was good and there were almost no interruptions due to adverse effects or to relevant biological parameters alterations. Also, weight gain was not significant.Retention rate in treatment after 3 years was 95%. Clinical Global Impression Severity (P < 0.01) and Camberwell Assessment of Need (P < 0.01) decreased and also Disability Assessment Schedule in the 4 areas (P < 0.01). Medication Adherence Rating Scale score increased from 3.6 (0.7) to 8.9 (0.9) (P < 0.001). There were significantly few hospital admissions than during the previous 36 months (1.9 [1.3] vs 0.31 [0.2], P < 0.001).As a conclusion, we highlight that the effectiveness and tolerability of 75 mg or higher every 14 days of RLAI were high, being useful in improving treatment adherence in patients with severe schizophrenia, getting good clinical and functional outcomes.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting	Outcome(s) Studied	Key Findings	Limitations And Biases
Morris, Matthew T, and Sandip P Tarpada (2017)	Review	A literature search of PubMed, Embase, and Web of Science was conducted in February 2016, using the following search terms in varying permutations: schizophrenia; antipsychotic medication; long-acting injectable; paliperidone palmitate; 3-monthly injectable.	Rehospitalization rate   Side-effects   Disease severity	The authors observed significantly greater rates of disease relapse with placebo than with PDP3P, supporting its efficacy in maintaining remission in schizophrenia.    PDP3M has demonstrated equal safety and efficacy as PDP, and may be preferable to select patients due to less frequent dosing schedule.   Compared to oral antipsychotics, LAIAs have been shown to improve compliance and lead to lower disease relapse and re-hospitalization rates in real-world populations. PDP, a once-monthly LAIA, has demonstrated good efficacy in reducing disease severity and re-hospitalizations in schizophrenic patients, with a similar safety profile as many 2nd-generation oral antipsychotics.	Need to compare PDP to other injectable antipsychotics   Need to follow patients for longer periods of time to evaluate compliance   More research to directly compare clinical use between oral and injectable forms of medication
Brasso,Claudio et al. (2017)	Review	On August 21, 2017, a search on PubMed about PPM3, without any filter restriction, was conducted and all available records were analyzed. Results: Twenty-two records were included in this review: 6 reviews, 1 report, 4 pharmacokinetic studies, 2 cost-effectiveness analyses, 1 open-label clinical trial, 2 randomized controlled trials (RCTs), 5 studies based on these 2 RCTs and 1 observational study.	Time to relapse   Noninferiority in terms of efficacy, safety, tolerability, reduction of caregiver burden	A study by Gopal et al showed that switching from an oral antipsychotic to either PP1M or PP3M can significantly reduce caregiver burden.    One of the most positive features of PP3M is notable that patients need to receive an injection just 4 times per year. The lower number of injections is more comfortable for patients, especially for those patients who cannot easily reach the place of administration.   According to this study, patients and physicians preferred LAIs over oral antipsychotics and were willing to accept reduced efficacy in exchange for switching from an oral formulation to an LAI. Physicians showed a greater preference for 3-month over 1-month LAI.	Adverse events may be more difficult to treat with a long acting injectable medication   Psychiatrists may see patients less often with a 3 month dosing schedule   Longer follow up studies, two arm superiority trials and mirror studies are needed to further assess long-term safety and advantages
Jann, M. W., & Penzak, S. R. (2018)	Review	6 Studies, N = 2,739   A comprehensive PubMed search with the keywords depot, long-acting injectable, SGA, paliperidone palmitate, aripiprazole, iloperidone, pharmacokinetic, deltoid, gluteal, and switching was conducted	Time to relapse   Side effect and safety comparisons   Efficacy compared between different drugs	The lack of patient insight into their illness often leads to long-term medication adherence challenges. FGA and SGA LAI preparations were developed to address the unmet needs of patients with antipsychotic adherence problems.   Studies have reported that LAI antipsychotics enhance patient compliance to continued treatment and reduce the risk of rehospitalization by 20–30% compared with oral agents.   The pharmacodynamic actions of LAI antipsychotics are similar to those produced by their corresponding oral preparations once the medication enters the systemic Long-Acting Injectable Second-Generation Antipsychotics 245 circulation from the injection site.	Patients and providers have limited knowledge of LAIA   Some studies have a lack of randomized design, or post hoc study design.
Biagi E, Capuzzi E, Colmegna F, Mascarini A, Brambilla G, Ornaghi A, Santambrogio J, Clerici M. (2017)	Review	We narratively review published clinical data from the development of long-acting injectable (LAI) formulations of antipsychotic drugs and examine the comparative effectiveness of oral versus LAIs in schizophrenia, with a focus on the second-generation LAI antipsychotic aripiprazole	Monitoring for adherence   Adverse effects   Quality of life improvements	Patient-reported treatment satisfaction with AOM is high after switching to AOM 400 maintenance therapy, with patients describing positive perceptions of tolerability with no or fewer side effects with AOM 400 than with prior antipsychotic medication   The effective control of symptoms, reduced rates of sexual dysfunction, hyperprolactinemia, metabolic effects, and extrapyramidal symptoms with AOM 400 make it particularly suited for patients with these side effects from other antipsychotic medications   AOM 400 was shown to be well tolerated in both studies, with minimal injection site pain and a safety profile consistent with comparators and with that reported for oral aripiprazole in previous registrational maintenance studies.	Studies found greater effect for aripiprazole in younger patients, may be somewhat less effective in older patients.   Studies may be limited by smaller sample sizes and inadequate comparison to other long acting injectables.   Authors may be biased as they admit to prescribing AOM in their practice
Sanchez-Garcia (2015)	Prospective, Observational	It is a 3-year prospective, observational study of patients with severe (Clinical Global Impression Severity scale [CGI-S] score of ≥5) schizophrenia according to International Classification of Diseases (ICD-10) criteria. Subjects were the consecutive 60 who first underwent treatment with RLAI with doses of 75 mg or higher every 14 days to get clinical stabilization.	Medication Adherence   Time until relapse	There were significantly few hospital admissions than during the previous 36 months (1.9 [1.3] vs 0.31 [0.2], P < 0.001).   Good tolerability and effectiveness are supported by low discontinuation during this study, which we have to highlight as outcome. Low discontinuation rates also support good patient acceptance of an injectable antipsychotic formulation   Risperidone long-acting injectable at high doses shows a very low discontinuation rate, being useful in improving treatment adherence in patients with schizophrenia who have severe symptoms and impairment.	No randomization in study design

Conclusions:

Morris (2017) concluded that the long-term efficacy of paliperidone was comparable to oral antipsychotics, and that they had a similar safety profile. They also emphasized that the purpose of LAIA were developed in order to improve adherence and prevent rehospitalization, which places immense burdens on the health care system.

Brasso (2017) concluded that studies showed longer time to relapse after PP3M treatment discontinuation compared to that of oral paliperidone and PP1M: in particular, after suspension of the treatment, 50% of patients treated with PP3M remained relapse free for ~13 months, instead of 6 months with PP1M treatment withdrawal.

Jann (2017) concluded in number of patients that relapse in control and placebo groups were significantly higher than in the injectable aripiprazole and paliperidone trials.

Biagi (2017) concluded significantly reduced rates of hospitalization for LAIA compared with oral antipsychotics. During a mean follow-up of 2 years, the adjusted hazard ratio (HR) for rehospitalization for LAIs was about a third that associated with oral antipsychotics (HR 0.36, 95% CI 0.17–0.75, P = 0.007) [29], indicating that LAIs were associated with substantially better outcomes.

Sanchez-Garcia (2015) concluded that risperidone long-acting injectable at high doses shows a very low discontinuation rate, being useful in improving treatment adherence in patients with schizophrenia who have severe symptoms and impairment.

Clinical Bottom Line

Articles Ranked:

Jann (2018) – I weighted this strongest, as it is the most recent and directly compares several different long acting injectable formulations. They also show in numerous studies that there is either significantly reduced rates of relapse in the LAIA groups compared to placebo and oral SGA, and they also compare efficacy between gluteal and deltoid injection sites.

Morris (2017) – I weighted this second strongest, because it compared in a large number of studies that LAIA significantly reduced rates of relapse compared to oral SGA, as well as comparable efficacy to injectable FGA, with a better safety profile with reduced side effects.

Brasso (2017) – I weighted this article the third strongest because it outlines the types of studies that were accounted for in the review, and they showed studies that directly compared 3 month injectable paliperidone with both placebo and 1 month injectable paliperidone, showing longer times to relapse and noninferiority in terms of efficacy, safety, and tolerability.

Biagi (2017) – I weighted this the fourth strongest, as the authors themselves currently prescribe injectable aripiprazole which can lead to some biases, but they also demonstrate that there are higher rates of adherence for LAIA compared to placebo and oral SGA, as well as improved quality of life considerations.

Sanchez-Garcia (2015) I rated this the weakest, as it was a prospective observational study that lacked randomization and was the oldest. However, their findings showing that LAIA increased medication adherence over 3 years compared to the 1 year of monitoring found in other studies was useful.

Magnitude of Effects

Across nearly all studies evaluated in the reviews, LAIA increased compliance and reduced rates of hospitalization compared to placebo and oral SGA.

Jann (2018) – The LS mean (LSM) change in total PANSS scores and CGIS scores from baseline to week 10 was significantly greater in the AOM 400-mg group than in the placebo group: PANSS – 15.1; 95% CI – 19.4 to – 10.8 (p\ 0.0001) and CGIS – 0.8; 95% CI – 1.1 to – 0.6 (p\ 0.0001).

Morris (2017) – The authors observed similar disease relapse rates and clinical measures of disease severity between groups. They also observed similar safety/tolerability profiles between groups, with the most common treatment-emergent adverse event being weight gain, experienced by 21% of patients in each group.

Brasso (2017) – 50% of patients treated with PP3M remained relapse free for ~13 months, instead of 6 months with PP1M treatment withdrawal. Also, according to this study, the relapse risk (hazard ratio) was 2.08 higher for patients discontinuing PP1M than for those discontinuing PP3M.

Biagi (2017) – During a mean follow-up of 2 years, the adjusted hazard ratio (HR) for rehospitalization for LAIs was about a third that associated with oral antipsychotics (HR 0.36, 95% CI 0.17–0.75, P = 0.007).

Sanchez-Garcia (2015) – Retention rate in treatment after 3 years was 95%. Clinical Global Impression Severity (P < 0.01) and Camberwell Assessment of Need (P < 0.01) decreased and also Disability Assessment Schedule in the 4 areas (P < 0.01). Medication Adherence Rating Scale score increased from 3.6 (0.7) to 8.9 (0.9) (P < 0.001).

 Clinical Significance:

The clinical significance of these articles is that they all underscore that patient compliance and disease remission is greatly enhanced compared to oral drugs. The nature of schizophrenia and the psychotic symptoms associated with it frequently cause issues with remembering to take medication each day. If patients require only an injection every month or every 3 months, this can greatly reduce risks of rehospitalization and promote patient functioning and independence. This can also reduce the burden placed on health care providers that may typically have to see patients repeatedly after they discontinue taking their medication, and instead only see the patients every few weeks to administer the injection, while still following up with them in order to “check in” and further enhance adherence. The LAIA appear to be just as effective as the oral medications, with the same risk and efficacy profiles. Furthermore, at least one prospective study showed increased medication compliance over a 3 year period with the usage of injectable risperidone compared to oral agents. Therefore, I believe more efforts should be made to get patients on-board with the idea of LAIA, to educate more providers about the benefits of LAIA, and and for these formulations to become first line therapies for maintenance of disease remission.

Additional Considerations:

More randomized studies should be conducted that directly compare the various injectable SGA agents, as well as mirror studies that compare an equal period of time before and after an intervention is introduced. This can help determine whether a LAIA is more efficacious than medication that a previously non-compliant patient was taking. More long-term studies that go beyond 1-2 years will also be valuable in evaluating whether the adherence effects persist over longer time periods.