– Marieke Begemann, 17th January, 2020

Postdoctoral Fellow at the UMC Groningen (department of Biomedical Sciences of Cells and Systems, section of Cognitive Neurosciences), ECHR 2019 Bursary Awardee

Background 
Antipsychotic medication is effective in treating psychotic symptoms, such as hallucinations. Continuing antipsychotic medication after symptoms have remitted seems wise, as a meta-analysis on 65 studies estimated that this reduces the risk of relapse more than twofold:  27% relapse rate with maintenance treatment versus 64% relapse in a year without medication (Leucht et al., 2012). Most current guidelines state that individuals with a first episode psychosis (FEP) should be offered antipsychotic medication for at least one year after remission of psychotic symptoms (National Institute for Clinical Excellence guidelines 2014, [UK]; Early Psychosis Guidelines Writing Group, 2010 [Australia]; Multidisciplinaire Richtlijn Schizofrenie, 2012 [the Netherlands]). However, during the last few years, these guidelines have been questioned. 

In clinical practice, we see that patients often have a strong wish to stop medication earlier. This wish partly reflects side-effects such as weight gain, losing interest in activities, sleepiness and movement problems, known as ‘parkinsonism’ (Longden & Read, 2016).  While previous research in this area has mainly focused on relapse prevention and lower symptom severity, we now know that long-term outcome in terms of recovery should also include social functioning and quality of life. Recovery in these dimensions may not benefit from continuation treatment with standard dose antipsychotic medication. 

Until now, only two randomized controlled study with a long follow-up time have been conducted. The Dutch Mesifos study initially observed higher relapse rates in the discontinuation strategy (43%) versus maintenance (21%), after a follow-up period of two years (Wunderink et al., 2007). However, after seven years, patients who discontinued or reduced their antipsychotic medication in the early phase after remission more often reached recovery (40.4%) than those who continued treatment (17.6%). In response to this finding, many clinicians now recommend discontinuation following remission of first episode psychosis, thereby diverging from current guidelines. Yet, Hui and colleagues (2018) could not replicate these findings when performing a similar study in Hong Kong. After ten years, their discontinuation group had higher rates of poor long-term clinical outcome (39%) as compared to the maintenance treatment group (21%). 

Psychiatrists, patients and family are currently unsure which regime to follow: to continue or not to continue? To answer this question, we are conducting the HAMLETT study: an acronym for Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment.

Methods

HAMLETT is a multicenter pragmatic single-blind randomized controlled trial (Begemann et al., 2019, soon to be published in Trials). Participants (n=512) are aged 16-55 years and in stable remission from a first episode of psychosis for 3-6 months. Their psychosis was not associated with life threatening self-harm or violence.Recruitment takes place at 24 Dutch sites. Patients are randomised 1:1 to:

  1. Treatment as usual: continuation of antipsychotic medication (original dose +/- 25% or other antipsychotic drug in similar dose range) until at least 1 year after remission. 
  2. Dose reduction/discontinuation: gradual dose reduction according to a tapering schedule of approximately 12 weeks, until medication is maximally reduced or completely stopped. 

Findings/research question

Is long-term functioning better if patients reduce/discontinue antipsychotic medication at an early stage (3-6 months after remission), compared to continuation of medication >1 year? Can we predict which patients will relapse, and who will not?

Main study parameters/endpoints

We evaluate the effects on personal and social functioning, psychotic symptom severity and health-related quality of life. Measurements will be conducted at baseline, and at 3 and 6 months post baseline. Further follow-ups are scheduled over 4 consecutive years in cycles of one year. 

The primary outcome measure is social recovery (World Health Organization’s Disability Assessment Schedule (WHO-DAS–II). Secondary outcome measures include, amongst others, severity of psychotic symptoms, medication side effects, cognitive functioning and other aspects of well-being in daily life. A subset of participants also fill in a dairy app on their smartphone (Ecological momentary assessments – EMA), as measure of social and personal functioning. We will perform prognostic modelling analyses to determine patient and treatment characteristics that predict long-term social recovery (main outcome) and sustained gains in health-related quality of life. Furthermore, we will perform cost-effectiveness and cost-utility analyses with social recovery and quality adjusted life years gained as the main outcomes, respectively. 

Discussion

At present, patients, their family as well as clinicians need to know whether continued standard dose antipsychotic medication is beneficial or harmful after remission of first episode psychosis. This question not only concerns the short-term (i.e. after 1 or 2 years), but also the more relevant long-term (after 3 and 4 years) outcome. The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration. HAMLETT has currently included 180 patients. The question to continue or not to continue is of worldwide concern, and other (dis)continuation studies are now conducted: TAILOR (Denmark), RADAR (United Kingdom) and REDUCE (Australia).

References

Begemann MJH, Thompson IA, Veling W, et al. To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction / discontinuation in first episode psychosis. HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment): a pragmatic multicenter single-blind randomized controlled trial. Trials, under review. 

Hui CL, Honer WG, Lee EH, Chang WC, Chan SK, Chen ES, Pang EP, Lui SS, Chung   DW, Yeung WS, Ng RM. Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial. The Lancet Psychiatry. 2018;5(5):432-42.

Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Davis JM. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews. 2012(5).

Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. Journal of Clinical Psychiatry. 2007;68(5):654-61.

Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA psychiatry. 2013;70(9):913-20.