. 2020 Feb 7;21(1):147.

doi: 10.1186/s13063-019-3822-5.

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Marieke J H Begemann¹, Ilse A Thompson², Wim Veling³, Shiral S Gangadin^{2

4}, Chris N W Geraets³, Erna van 't Hag³, Sanne J Müller-Kuperus⁴, Priscilla P Oomen², Alban E Voppel², Mark van der Gaag^{5

6}, Martijn J Kikkert⁷, Jim Van Os^{4

8

9}, H Filip E Smit^{10

11

12}, Rikus H Knegtering^{13

14}, Sybren Wiersma¹⁵, Luyken H Stouten¹⁶, Harm J Gijsman¹⁷, Lex Wunderink^{3

18}, Anton B P Staring¹⁹, Selene R T Veerman²⁰, Amrita G S Mahabir²¹, Jörg Kurkamp²², Gerdina H M Pijnenborg²³, Natalie D Veen²⁴, Machteld Marcelis^{8

25}, Koen P Grootens^{26

27}, Gunnar Faber²⁸, Nico J van Beveren^{29

30

31}, Agaath Been³², Truus van den Brink³³, Maarten Bak^{8

34}, Therese A M J van Amelsvoort^{8

34}, Andrea Ruissen³⁵, Christine Blanke³⁶, Karin Groen³⁷, Lieuwe de Haan³⁸, Iris E C Sommer²

Affiliations

¹ Department of Biomedical Sciences of Cells & Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands. m.j.h.begemann@umcg.nl.
² Department of Biomedical Sciences of Cells & Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
³ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵ Parnassia Psychiatric Institute, The Hague, The Netherlands.
⁶ Department of Clinical Psychology, VU University, Amsterdam, The Netherlands.
⁷ Department of Research, Arkin Mental Health Care, Amsterdam, The Netherlands.
⁸ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, EURON, Maastricht University Medical Center, Maastricht, The Netherlands.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁰ Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
¹¹ Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
¹² Centre of Economic Evaluation, Trimbos Institute (Netherlands Institute of Mental Health), Utrecht, The Netherlands.
¹³ Lentis Research, Lentis Psychiatric Institute, Groningen, The Netherlands.
¹⁴ Rob Giel Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ Early Intervention Psychosis Team, GGZ inGeest Specialized Mental Health Care, Hoofddorp, The Netherlands.
¹⁶ Centre for Early Psychosis, Parnassia Psychiatric Institute, The Hague, The Netherlands.
¹⁷ Program for Psychosis & Severe Mental Illness, Pro Persona Mental Health, Wolfheze, The Netherlands.
¹⁸ Department of Education and Research, Friesland Mental Health Care Services, Leeuwarden, The Netherlands.
¹⁹ Department ABC, Altrecht Psychiatric Institute, Utrecht, The Netherlands.
²⁰ Community Mental Health, Mental Health Service Noord-Holland Noord, Alkmaar, The Netherlands.
²¹ Early Psychosis Team, GGNet, Apeldoorn, The Netherlands.
²² Center for Youth with Psychosis, Mediant ABC Twente, Enschede, The Netherlands.
²³ Department of Psychotic Disorders, GGZ-Drenthe, Assen, The Netherlands.
²⁴ GGZ Delfland, Delfland Institute for Mental Health Care, Delft, The Netherlands.
²⁵ Institute for Mental Health Care Eindhoven (GGzE), Eindhoven, The Netherlands.
²⁶ Reinier van Arkel Institute for Mental Health Care, 's Hertogenbosch, The Netherlands.
²⁷ Radboud University Medical Centre, Nijmegen, The Netherlands.
²⁸ Yulius, Mental Health Institute, Dordrecht, The Netherlands.
²⁹ Antes Center for Mental Health Care, Rotterdam, The Netherlands.
³⁰ Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
³¹ Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
³² Center for Developmental Disorders, Dimence Institute for Mental Health, Deventer, The Netherlands.
³³ Early Intervention Team, GGZ Centraal, Amersfoort, The Netherlands.
³⁴ Mondriaan Mental Health Care, Heerlen, The Netherlands.
³⁵ Emergis, Kenniscentrum, Goes, The Netherlands.
³⁶ Anoiksis, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁷ MIND Ypsilon, Organization of Relatives and Carers of People with a Vulnerability to Psychosis, The Hague, The Netherlands.
³⁸ Department of Early Psychosis, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands.

PMID: 32033579
PMCID: PMC7006112
DOI: 10.1186/s13063-019-3822-5

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Marieke J H Begemann et al. Trials. 2020.

. 2020 Feb 7;21(1):147.

doi: 10.1186/s13063-019-3822-5.

Authors

Affiliations

¹ Department of Biomedical Sciences of Cells & Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands. m.j.h.begemann@umcg.nl.
² Department of Biomedical Sciences of Cells & Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
³ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵ Parnassia Psychiatric Institute, The Hague, The Netherlands.
⁶ Department of Clinical Psychology, VU University, Amsterdam, The Netherlands.
⁷ Department of Research, Arkin Mental Health Care, Amsterdam, The Netherlands.
⁸ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, EURON, Maastricht University Medical Center, Maastricht, The Netherlands.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁰ Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
¹¹ Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
¹² Centre of Economic Evaluation, Trimbos Institute (Netherlands Institute of Mental Health), Utrecht, The Netherlands.
¹³ Lentis Research, Lentis Psychiatric Institute, Groningen, The Netherlands.
¹⁴ Rob Giel Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ Early Intervention Psychosis Team, GGZ inGeest Specialized Mental Health Care, Hoofddorp, The Netherlands.
¹⁶ Centre for Early Psychosis, Parnassia Psychiatric Institute, The Hague, The Netherlands.
¹⁷ Program for Psychosis & Severe Mental Illness, Pro Persona Mental Health, Wolfheze, The Netherlands.
¹⁸ Department of Education and Research, Friesland Mental Health Care Services, Leeuwarden, The Netherlands.
¹⁹ Department ABC, Altrecht Psychiatric Institute, Utrecht, The Netherlands.
²⁰ Community Mental Health, Mental Health Service Noord-Holland Noord, Alkmaar, The Netherlands.
²¹ Early Psychosis Team, GGNet, Apeldoorn, The Netherlands.
²² Center for Youth with Psychosis, Mediant ABC Twente, Enschede, The Netherlands.
²³ Department of Psychotic Disorders, GGZ-Drenthe, Assen, The Netherlands.
²⁴ GGZ Delfland, Delfland Institute for Mental Health Care, Delft, The Netherlands.
²⁵ Institute for Mental Health Care Eindhoven (GGzE), Eindhoven, The Netherlands.
²⁶ Reinier van Arkel Institute for Mental Health Care, 's Hertogenbosch, The Netherlands.
²⁷ Radboud University Medical Centre, Nijmegen, The Netherlands.
²⁸ Yulius, Mental Health Institute, Dordrecht, The Netherlands.
²⁹ Antes Center for Mental Health Care, Rotterdam, The Netherlands.
³⁰ Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
³¹ Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
³² Center for Developmental Disorders, Dimence Institute for Mental Health, Deventer, The Netherlands.
³³ Early Intervention Team, GGZ Centraal, Amersfoort, The Netherlands.
³⁴ Mondriaan Mental Health Care, Heerlen, The Netherlands.
³⁵ Emergis, Kenniscentrum, Goes, The Netherlands.
³⁶ Anoiksis, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁷ MIND Ypsilon, Organization of Relatives and Carers of People with a Vulnerability to Psychosis, The Hague, The Netherlands.
³⁸ Department of Early Psychosis, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands.

PMID: 32033579
PMCID: PMC7006112
DOI: 10.1186/s13063-019-3822-5

Abstract

Background: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study.

Methods/design: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years.

Discussion: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse.

Trial status: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026.

Trial registration: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017.

Keywords: Antipsychotic medication, first episode psychosis; Discontinuation; Maintenance; Randomized controlled trial; Tapering, global functioning; Treatment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
An overview of the procedure when early warning signs or psychotic symptoms reappear while tapering off medication. *EWS* early warning signs

See this image and copyright information in PMC

References

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To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Affiliations

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical