Metformin in the management of antipsychotic-induced weight gain in adults with psychosis: development of the first evidence-based guideline using GRADE methodology

Abstract

BackgroundAdjunctive metformin is the most well-studied intervention in the pharmacological management of antipsychotic-induced weight gain (AIWG). Although a relatively unaddressed area, among guidelines recommending consideration of metformin, prescribing information that would facilitate its applied use by clinicians, for example, provision of a dose titration schedule is absent. Moreover, recommendations differ regarding metformin’s place in the hierarchy of management options. Both represent significant barriers to the applied, evidence-based use of metformin for this indication.ObjectiveTo produce a guideline solely dedicated to the optimised use of metformin in AIWG management, using internationally endorsed guideline methodology.MethodsA list of guideline key health questions (KHQs) was produced. It was agreed that individual recommendations would be ‘adopted or adapted’ from current guidelines and/or developed de novo, in the case of unanswered questions. A systematic literature review (2008–2020) was undertaken to identify published guidelines and supporting (or more recent) research evidence. Quality appraisal was undertaken using the Appraisal of Guidelines Research and Evaluation II tool, A Measurement Tool to Assess Systematic Reviews (AMSTAR) assessment,and the Cochrane Risk of Bias 2 tool, where appropriate. Assessment of evidence certainty and recommendation development was undertaken using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.FindingsWe confirmed that no published guideline—of appropriate quality, solely dedicated to the use of metformin to manage AIWG was available. Recommendations located within other guidelines inadequately addressed our KHQs.ConclusionAll 11 recommendations and 7 supporting good practice developed here were formulated de novo.Clinical implicationsThese recommendations build on the number and quality of recommendations in this area, and facilitate the optimised use of metformin when managing AIWG.

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

“…For clozapine, the prevalence of metabolic syndrome is estimated to be approximately 50 percent 220,221 . Weight gain represents a crucial risk factor for developing metabolic syndrome 222 and an important psychological stressor [223][224][225][226] .…”

“…Among pharmacological interventions adjunctive metformin shows a good safety profile and the best efficacy for stabilizing weight gain 223,[238][239][240] . Consequently, the first guideline for metformin use during antipsychotic treatment advocates a routine early initiation in addition to behavioral interventions to most effectively minimize weight gain and cardiometabolic risk 223 . On average, treatment with metformin leads to a weight Qubad & Bittner -Clozapine treatment in schizophrenia loss of about 3.2 kg.…”

“… Lifestyle changes, psychotherapy 211,223 Pharmacological treatment: topiramate [242][243][244]246  Hypertension: Antihypertensive drugs 211,369,370  Dyslipidemia: statins 211 Qubad & Bittner -Clozapine treatment in schizophrenia 32 Hypersalivation (increases risk for pneumonia) 255,258,[371][372][373]  Regular clinical assessment using standardized rating scales e.g. the Drooling severity scale or Nocturnal Hypersalivation Rating Scale 374,375  Sugar free chewing gum during the day; elevation of upper body during the night 375  Pirenzepine (25-100 mg/d); Cave: anticholinergic load 16, 91,371  Alternative options: atropine drops s.l., ipratropium bromide s.l.…”

Metformin for the prevention of clozapine‐induced weight gain: A retrospective naturalistic cohort study

“…In non‐psychiatric populations, it has variably been associated with weight loss and improvement in insulin resistance 17 . In severe mental illness, metformin has been widely studied “off‐label” as a pharmacological intervention for the treatment of AP‐related weight gain, with the most evidence supporting its efficacy and safety 18,19 . Importantly, the reporting literature demonstrates good tolerability with no significant difference in reports of nausea compared with placebo, and no concerns of changes in psychiatric symptomatology 16,20 .…”

“…17 In severe mental illness, metformin has been widely studied "off-label" as a pharmacological intervention for the treatment of AP-related weight gain, with the most evidence supporting its efficacy and safety. 18,19 Importantly, the reporting literature demonstrates good tolerability with no significant difference in reports of nausea compared with placebo, and no concerns of changes in psychiatric symptomatology. 16,20 As such, metformin is now recommended in several guidelines, including the World Health Organization (WHO) and British Association of Psychopharmacology (BAP) as well as the Mental Health section of the Canadian Obesity Guidelines, for the treatment of AP-induced weight gain in conjunction with lifestyle modification.…”