Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2016;16(Suppl 2):e6447 doi: 10.5867/medwave.2016.6447
Are depot as effective as oral antipsychotics on first-episode psychosis?
Cristián Orus, David Aceituno
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Abstract

Depot antipsychotics have been generally used in patients with chronic schizophrenia with adherence problems to oral therapy. However, it has been suggested they can be a good alternative in earlier stages too. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including two pertinent randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether there are differences between depot and oral antipsychotics in first-episode psychosis because the certainty of the available evidence is very low.


 
Problem

The long-acting injectable (depot) antipsychotics were designed initially for patients with chronic schizophrenia with poor adherence to oral antipsychotics.

However, adherence problems are also common at initial stages, resulting in high rates of relapse, partial symptomatic remission and suicidal risk.

While long-acting injectable antipsychotics are considered safe and effective, doubts about its efficacy compared with oral antipsychotics persist.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • It is not clear whether there are differences between depot and oral antipsychotics in first-episode psychosis because the certainty of the available evidence is very low.
  • There are randomized controlled trials not yet included in the existing systematic reviews, so a new review including these would increase the certainty of the evidence.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found three systematic reviews [1],[2],[3] including five primary studies [4],[5],[6],[7],[8], of which two correspond to randomized controlled trials [4],[8]. This table and the summary in general are based on the latter.

What types of patients were included

Both studies included adult patients with a recent diagnosis of schizophrenia (DSM IV) [4],[8]. One study included patients with first-episode psychosis only within the last two years prior to the initiation of the study [4].

The other study required all patients had been in contact with antipsychotics for no more than four months before the start of the study [8].

What types of interventions were included

Both studies compared long-acting injectable risperidone to oral risperidone [4],[8]. In one study patients were treated with oral antipsychotics for an average of 7.2 months before randomization, and then for 6 more months [4]. The other study maintained treatment for 12 weeks [8].

What types of outcomes
were measured

The reviews addressed the following outcomes:

- Acceptance by patients to switch from oral to injectable risperidone.
- Non-adherence was defined as the absence of medication during 14 days or more.
- Subjective perception of patients regarding adherence by the Rating Scale of Medication Influences (ROMI) [8].

One study measured changes in the volume of white matter in the frontal lobe by using magnetic resonance imaging (MRI) and neurocognitive assessment by CogState computerized cognitive battery [4]

Summary of findings

The information on the effects of depot antipsychotics compared to oral antipsychotics in patients with first-episode psychosis is based on two randomized trials including 65 patients. One study evaluated adherence [8] and one study reported some measure of efficacy [4]. None of the studies reported remission, relapse or rehospitalization.

  • It is not clear whether there are differences in adherence between depot and oral antipsychotics in first-episode psychosis because the certainty of the available evidence is very low.
  • No studies were found that evaluated the impact of depot versus oral antipsychotics on remission, relapse or rehospitalization in first-episode psychosis.
  • It is not clear whether there are differences in efficacy between depot and oral antipsychotics in first-episode psychosis because the certainty of the available evidence is very low.

Other considerations for decision-making

To whom this evidence does and does not apply

  • This evidence applies to all adult patients with first-episode schizophrenia. 
About the outcomes included in this summary
  • The outcomes presented in this summary are those considered critical for decision making by the authors of this summary. 
Balance between benefits and risks, and certainty of the evidence
  • The certainty of the available evidence is very low so it is not possible to make an adequate risk/benefit balance.
What would patients and their doctors think about this intervention
  • Despite the high rate of non-adherence in these patients, there is still underuse of depot antipsychotics, particularly in patients who present with a first-episode psychosis. One study [9] observed three factors that influenced that pattern: (a) limited availability of long-acting second generation antipsychotics; (b) preconceived notion of rejection by the patient; and (c) patient's skepticism based on an absence of previous relapses, demonstrating the importance of a patient-centered approach, evaluating this treatment in all patients with first-episode psychosis.
  • Independent of the therapeutic option chosen, it is important to inform the patient about the existing uncertainty of the evidence. 
Resource considerations
  • The certainty of the evidence is very low, so it is not possible to make an appropriate cost/effectiveness analysis.

Differences between this summary and other sources

  • The conclusions of our summary are consistent with the conclusions of the individual systematic reviews identified.
  • Clinical guidelines recommend the use of depot antipsychotics as first line in schizophrenic patients with adherence problems, frequent recurrences, which pose a risk to others, with low insight, for patient preference or when there is a previous positive response. Second generation antipsychotics are also recommended in cognitive deficits and social isolation [10].
Could this evidence change in the future?
  • The probability that the main findings of this summary change in the future is very high, due to the very low certainty of the evidence so far.
  • There are at least three randomized controlled trials [11],[12],[13] which have not yet been included in systematic reviews. So a new review including these would increase the certainty of the evidence.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version:  Oral versus long-acting injectable (depot) antipsychotics for first psychotic episode

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Los antipsicóticos de depósito han sido utilizados generalmente en pacientes que padecen esquizofrenia crónica con problemas de adherencia a antipsicóticos orales. Sin embargo, se ha planteado que en etapas psicóticas precoces el uso de antipsicóticos de depósito podría ser más efectivo, aunque esto es materia de debate. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos tres revisiones sistemáticas que en conjunto incluyen dos estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los antipsicóticos de depósito son superiores o inferiores a los orales en un primer episodio psicótico porque la certeza de la evidencia disponible es muy baja.

Authors: Cristián Orus[1,3], David Aceituno[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[3] Proyecto Epistemonikos, Santiago, Chile

E-mail: daceituno@med.puc.cl

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Orus C, Aceituno D. Are depot as effective as oral antipsychotics on first-episode psychosis?. Medwave 2016;16(Suppl 2):e6447 doi: 10.5867/medwave.2016.6447

Publication date: 23/5/2016

PubMed record

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  1. Taylor M, Ng KY. Should long-acting (depot) antipsychotics be used in early schizophrenia? A systematic review. Aust N Z J Psychiatry. 2013 Jul;47(7):624-30. | CrossRef | PubMed |
  2. Haddad PM, Taylor M, Niaz OS. First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: systematic review of randomised controlled trials and observational studies. Br J Psychiatry Suppl. 2009 Nov;52:S20-8. | CrossRef | PubMed |
  3. Kirson NY, Weiden PJ, Yermakov S, Huang W, Samuelson T, Offord SJ, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry. 2013 Jun;74(6):568-75. | CrossRef | PubMed |
  4. Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL, et al. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011 Oct;132(1):35-41. | CrossRef | PubMed |
  5. Kim B, Lee SH, Choi TK, Suh S, Kim YW, Lee E, et al. Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jul 1;32(5):1231-5. | CrossRef | PubMed |
  6. Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011 Jun;168(6):603-9. | CrossRef | PubMed |
  7. Tiihonen J, Wahlbeck K, Lönnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 2006 Jul 29;333(7561):224. | PubMed |
  8. Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa A, Goldfinger SM. A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry. 2009 Oct;70(10):1397-406. | CrossRef | PubMed |
  9. Heres S, Reichhart T, Hamann J, Mendel R, Leucht S, Kissling W. Psychiatrists' attitude to antipsychotic depot treatment in patients with first-episode schizophrenia. Eur Psychiatry. 2011 Jul-Aug;26(5):297-301. | CrossRef | PubMed |
  10. Llorca PM, Abbar M, Courtet P, Guillaume S, Lancrenon S, Samalin L. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013 Dec 20;13:340. | CrossRef | PubMed |
  11. Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa-McMillan A. Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 2012 Sep;73(9):1224-33. | CrossRef | PubMed |
  12. Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, et al. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015 Aug;72(8):822-9. | CrossRef | PubMed |
  13. Alphs L, Bossie C, Mao L, Lee E, Starr HL. Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement. Early Interv Psychiatry.2015 Sep 25. [Epub ahead of print] | CrossRef | PubMed |
Taylor M, Ng KY. Should long-acting (depot) antipsychotics be used in early schizophrenia? A systematic review. Aust N Z J Psychiatry. 2013 Jul;47(7):624-30. | CrossRef | PubMed |

Haddad PM, Taylor M, Niaz OS. First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: systematic review of randomised controlled trials and observational studies. Br J Psychiatry Suppl. 2009 Nov;52:S20-8. | CrossRef | PubMed |

Kirson NY, Weiden PJ, Yermakov S, Huang W, Samuelson T, Offord SJ, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry. 2013 Jun;74(6):568-75. | CrossRef | PubMed |

Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL, et al. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011 Oct;132(1):35-41. | CrossRef | PubMed |

Kim B, Lee SH, Choi TK, Suh S, Kim YW, Lee E, et al. Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jul 1;32(5):1231-5. | CrossRef | PubMed |

Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011 Jun;168(6):603-9. | CrossRef | PubMed |

Tiihonen J, Wahlbeck K, Lönnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 2006 Jul 29;333(7561):224. | PubMed |

Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa A, Goldfinger SM. A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry. 2009 Oct;70(10):1397-406. | CrossRef | PubMed |

Heres S, Reichhart T, Hamann J, Mendel R, Leucht S, Kissling W. Psychiatrists' attitude to antipsychotic depot treatment in patients with first-episode schizophrenia. Eur Psychiatry. 2011 Jul-Aug;26(5):297-301. | CrossRef | PubMed |

Llorca PM, Abbar M, Courtet P, Guillaume S, Lancrenon S, Samalin L. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013 Dec 20;13:340. | CrossRef | PubMed |

Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa-McMillan A. Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 2012 Sep;73(9):1224-33. | CrossRef | PubMed |

Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, et al. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015 Aug;72(8):822-9. | CrossRef | PubMed |

Alphs L, Bossie C, Mao L, Lee E, Starr HL. Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement. Early Interv Psychiatry.2015 Sep 25. [Epub ahead of print] | CrossRef | PubMed |