*The MEtformin-LIfestyle in Antipsychotic users trial (MELIA): optimizing the use of metformin in the management of antipsychotic-induced weight gain.*

Rationale: Antipsychotics are the mainstay treatment modality for schizophrenia
and are also indicated for treatment of bipolar disorder. Of the insidious
adverse drug reactions (ADRs) to antipsychotics, Antipsychotic-induced Weight
Gain (AiWG) is the most debilitating and prevalent ADR. AiWG negatively impacts
life expectancy, quality of life, treatment adherence, chances of developing
type-2 diabetes and likelihood of readmission. Treatment of AiWG is currently
very challenging and few interventions have been investigated in well powered
trials of sufficient quality.

Metformin is a very promising agent in the treatment of AiWG. Metformin
generally promotes satiety and increases Glucagon-like Peptide (GLP-1), thus
often resulting in reduced energy intake. Meta-analyses conclude that of all
agents studied as monotherapy, metformin is most effective (albeit still of
limited benefit) in attaining weight loss for child and adolescent
schizophrenia patients and for those patients who use clozapine.

In sum, treatment of AiWG is currently very challenging and few interventions
have been investigated in well powered trials of sufficient quality.

We aim to optimize the application of an existing drug, metformin, for a new
indication, AiWG, by showing that metformin in combination with lifestyle
interventions reduces AiWG compared to placebo in combination with lifestyle
interventions.

For more information see chapter 1 and 2 in the protocol.

Objective: We aim to optimize the application of an existing drug, metformin,
for a new indication, AiWG, by showing that metformin in combination with
lifestyle interventions reduces AiWG compared to placebo in combination with
lifestyle interventions. The following subgroup analyses within subtypes of
patients will be conducted using the same model to explore possible differences
in treatment effects: those on clozapine vs. those on other antipsychotics,
those with bipolar disorder versus schizophrenia spectrum disorder and those on
high-risk agents -risperidone, olanzapine, clozapine and quetiapine- vs. all
other antipsychotics.
In post hoc sensitivity analysis, the quantitative measure of the amount of
self-reported AiWG will be used to examine differences between AiWG and weight
gain due to other reasons. At last, we aim to assess whether metformin compared
to placebo improves metabolic traits, quality of life, general physical and
psychological health, cost effectiveness and whether genetic liability to BMI
and metabolic syndrome may help estimate weight reduction following initiation
of metformin treatment.

Study design: A randomized, double blind, multicenter, placebo-controlled,
pragmatic trial.

The pragmatic design of MELIA allows for a comparison of the efficacy of
lifestyle interventions (i.e. exercise training and consultations with a
dietician) with or without concomitant use of metformin in the treatment of
Antipsychotic induced Weight Gain (AiWG).

We will conduct a pragmatic, randomized, double blind, placebo-controlled
multicenter trial of metformin in patientswith schizophrenia/ bipolar disorder
suffering from AiWG and undergoing lifestyle interventions. The estimated
length of the study will be 3.5 years (including a participants* enrolment
phase) and participants will be followed-up for one year. This design was
chosen to investigate the possible added value of metformin over lifestyle
interventions and to align the design as much as possible with clinical
practice where lifestyle interventions are offered in most institutes across
the country for patients on antipsychotics who suffer from relatively high
weight. Lifestyle interventions are standardized across sites as follows. This
will be a combination of an exercise program and dietary interventions. The
dietary intervention consists of five consultations with a dietician (referral
by G.P.) to ensure both healthy food and appropriate caloric intake and
measurement of weight, BMI and waist circumference. The exercise program
consists of minimally 60 minutes per week of unsupervised exercise by choice,
i.e. walking, dancing or jogging, either privately, group endurance workouts or
strength training. Furthermore, participants gather in weekly lifestyle group
sessions under supervision of a lifestyle coach including weekly weight
measurements and assessment of physical activity using the Physical Activity
Vital Sign questionnaire (PAVS). During those sessions participants perform a
low-intensity exercise, such as strolling, reflect how their exercise program
and dietary interventions are getting along, report whether they exercised 60
minutes that week, and provide tips to one another about how to overcome
certain barriers. Participants may wish to discontinue lifestyle interventions
at any moment and still continue with the current trial. Similarly, patients
may continue with the trial after switching or stopping antipsychotic use.

Participants will undergo four main, face-to-face visits, as well as one short
telephone visit. Every face to face study visit multiple questionnaires are
done, blood tubes are drawn and physical examination is done including weight,
waist circumference, blood pressure and a physical endurance test. One year
after the first study visit body weight, waist circumference, blood pressure
and physical endurance are measured and medication use is assessed during a 20
minute follow-up visit.

Week 0- Visit 1 - Face to face visit, screening & randomisation. Start dose
500mg B.I.D.
Week 2 - Visit 2 - Phone call visit, dose and side effects verification and
evaluation. Dose 1000 mg B.I.D.
Week 13 - Visit 3 Face to face visit.
Week 26 - Visit 4 Face to face visit.
Week 52 - Visit 5 Face to face visit (not included in flowchart).

Questionnaires done during face-to-face visits:
M.I.N.I. plus section M
WHOQOL-BREF
EQ-5D-3L
CGI
PHQ
BPRS
CAPE
6MTWT
iPCQ
iMCQ
SIMPAQ

If participants want to stop taking study medication before the end of the
study and similarly do not want to revoke their informed consent, they will be
offered a naturalistic follow up. Participants thus may quit taking
studymedication and still continue with the study visits and procedures conform
this protocol. If participants do not want to continue with study visits after
quitting studymedication before the end of the study and similarly do not want
to revoke their informed consent, the primary outcome of this study (weight)
will be requested at the G.P. or treating physician, psychiatrist or
psychiatric nurse after 3 and/ or 6 months and/or 12 months after study
medication initiation after obtaining written informed consent of the
participant by the research-physician.

For more information see chapter 3 in the protocol.

Intervention (if applicable): Metformin or placebo started at 2dd500mg and then
increased to 2dd1000mg after two weeks.

The risks associated with participation are minimal considering the wide
experience, well known safety profile and generally mild side effect profile of
metformin. The burden for participants consists of taking medication daily
(either placebo or metformin), one short telephone visit of five minutes, three
face-to-face visits of approximately 20-120 minutes during which questionnaires
are filled out, three blood tubes are drawn, physical examination and a
physical endurance test are done, and one face-to-face visit of 20 minutes one
year after the first study visit. Their weight and waist circumference will be
assessed during all live visits. Except for the blood draw and time investment,
also including travelling to the institute, we expect no physical or
physiological discomfort associated with participation. We do not include
incapacitated persons in our study.