Adverse events of common psychiatric medications: an umbrella review

Adverse events of common psychiatric medications: an umbrella review Katrina Bartellas, 1 Thomas Bajorek 1 Sarah Stockton, 1 Stefan Leucht, 2 Andrea Cipriani, 1 Seena Fazel 1 1 Department of Psychiatry, University of Oxford; 2 Department of Psychiatry and Psychotherapy, University of Munich, Germany. Corresponding author: Professor Seena Fazel Department of Psychiatry University of Oxford Warneford Hospital OXFORD OX3 7JX seena.fazel@psych.ox.ac.uk 1

Condition or domain being studied In 2014, there were approximately 537 million dispensed prescriptions of psychiatric medications in the United States (IMS, 2015). Psychiatric medications were prescribed more than almost every other therapeutic class of medications, second only to antihypertensives (705 million dispensed prescriptions). Furthermore, IMS Institute for Healthcare Informatics estimates that in 2014 with a figure of US$23.1 billion that more money was spent on psychiatric medications in the United States than almost any other therapeutic class, ranking third only to antidiabetic medications (US$ 32.2 Bn) and oncological medications (US$ 32.6 Bn). The World Health Organization states that psychotropic medications have the ability to ameliorate symptoms, reduce disability, shorten the course of many disorders, and prevent relapse (WHO, 2009). Certainly, psychopharmacotherapy can play a pivotal role in the treatment and management of psychiatric illness. The major classes of psychiatric medications include antidepressants, antipsychotics, stimulants, anxiolytics and mood stabilizers. Antidepressants are mainly used to treat moderate to severe depressive illness, severe anxiety, panic attacks, obsessive compulsive disorders, chronic pain, eating disorders and post-traumatic stress disorders. The main types of antidepressants include selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, noradrenaline and specific serotoninergic antidepressants, tricyclic antidepressants and monoamine oxidase inhibitors. Antipsychotics are the main treatment for schizophrenia and are used for a wide variety of other psychiatric disorders. This class of medications is divided into typical (or first generation) antipsychotics and atypical (or second generation) antipsychotics. Stimulants are primarily prescribed to treat attention deficit hyperactivity. Due to their addictive profile, however, misuse and diversion are common problems experienced with prescribed 2

stimulant medications (Wilens et al., 2008). Anxiolytics are primarily used in the treatment of anxiety disorders. Benzodiazepines are hypnotic and anxiolytic agents primarily used to treat insomnia and acute anxiety. Mood stabilizers are primarily used in the treatment of bipolar disorders. Many AE, ranging from mild to severe, have been linked to psychiatric medications. In fact, before clozapine was developed, the ability of an agent to induce extrapyramidal symptoms validated its potential as an effective antipsychotic medication (Divac et al., 2014). Notably, a basic principle of prescribing pharmacological treatment is to inform the patient of any potential AE and on how to manage them should they occur (WHO, 2009). AE may be distressing or even frightening to patients yet are often underreported (Parker, C., 2012). As a response and solution to this problem, national systems have been developed in certain countries, such as the UK s Yellow Card Scheme, so that patients may be accountable to document any AE, especially those that are unprecedented or pose a serious health risk. The Yellow Card Scheme explains that any information provided by the public may help to identify previously unrecognised side effects, and thereby improve the safe use of medicines (MHRA, 2016). The documentation of AE for psychiatric medications is particularly important given not only the volume but the growth of dispensed prescriptions of this therapeutic class each year (IMS, 2015). There has been progress in terms of the output of systematic reviews and meta-analyses in the literature on AE but it is still fragmented. The Cochrane Database of Systematic Reviews has published comprehensive data on AE in numerous systematic reviews that focus on individual anti-depressive agents such as venlafaxine, escitalopram and duloxetine among others (Cipriani et al., 2007; Cipriani et al., 2010; Cipriani et al., 2012). Also, in contrast to focusing on a particular agent certain meta-analyses have pre-specified one or two AE of psychiatric 3

medications to analyze such as insomnia and somnolence (Alberti et al., 2015), dizziness (Thorlund et al, 2015), upper gastro intestinal bleeding (Jiang et al., 2015) and suicidal behavior and ideation (Hammad et al., 2006). The most comprehensive review identified to date that has accomplished a similar objective to our own analyzed the AE of antipsychotics, antidepressants and mood stabilizers on the risk for physical diseases in individuals with schizophrenia, depression and bipolar disorder (Correll et al., 2015). We want to build on the work of Correll et al. by centralizing the data on AE for clinicians and patients, however, we will undertake a wider search in order to include all relevant AE (not exclusively limited to physical diseases) and all classes of psychiatric medications. In 2015, Leucht et al. emphasized the importance of synthesizing the growing clinical literature on medications to provide practitioners with greater insight into this complex field (Leucht et al., 2015). We aim to achieve this outcome with our umbrella review on the AE of the most commonly prescribed psychiatric medications. Although the umbrella review research design is relatively new and has many limitations, it is becoming more widely adopted in the literature (Ioannidis, 2009). Umbrella reviews may analyze multiple treatments in contrast to a traditional systematic review or meta-analysis that focuses on a single treatment comparison or outcome. To our knowledge, there is no umbrella review to date synthesizing and analyzing the clinical data on the AE of the most commonly prescribed psychiatric medications across classes and diagnoses. This type of analysis, due to its large scale, may provide greater insights into the strengths and limitations of the literature and will aim to aid clinicians and patients who are weighing various treatment options. 4

The outcome to be examined is any AE reported in a meta-analysis focused on one or more of the interventions specified in our inclusion criteria. Our preliminary search using only the ten most commonly prescribed psychiatric medications yielded meta-analyses on the following AEs: suicidal behavior or ideation, insomnia, somnolence, falls, all cause mortality, upper gastro intestinal bleeding, hostility, major adverse cardiovascular events, nausea and dizziness. The former list is not exhaustive. Given that data on AE for individual psychiatric medications may be challenging to access, we decided against defining upfront a specific range of outcomes to be analyzed. Alternatively, we will look to include any AE that we find in the results section during our search. We will include the prevalence rates and effect sizes for the most relevant and important AE in our results, however, we will include a comprehensive list of the prevalence rates and effect sizes for all AE retrieved in the appendix. Review question(s) The aim of this umbrella review is to compare the prevalence rates and effect sizes of adverse events (AE) among the most common psychiatric medications. Searches Searches for published meta-analyses will be undertaken in the following electronic databases: CDSR, DARE, Embase, Medline, PreMedline, PsycINFO and PubMed. Studies will be identified by combining search terms for each drug with generic and specific adverse events and a study design limit for systematic reviews and meta-analyses. The following terms will eb used: antidepressive agents; antidepressive agents, second generation; antidepressive agents, tricyclic; serotonin uptake inhibitors; serotonin and noradrenaline reuptake inhibitors; amitriptyline; 5

bupropion; citalopram; citalopram; clomipramine; desvenlafaxine succinate; duloxetine hydrochloride; fluoxetine; paroxetine; sertraline; trazodone; venlafaxine hydrochloride; antipsychotic agents; aripiprazole; chlorpromazine; clozapine; fluphenazine; haloperidol; quetiapine fumarate; risperidone; anticonvulsants; carbamazepine; lithium carbonate; lithium; valproic acid; central nervous system stimulants; lisdexamfetamine dimesylate; methylphenidate; amphetamines; anti anxiety agents; buspirone; hydroxyzine; benzodiazepines; alprazolam; diazepam; lorazepam; "drug-related side effects and adverse reactions"; dizziness; nausea; suicide; suicide, attempted; suicidal ideation; hostility; mortality; "sleep initiation and maintenance disorders"; "disorders of excessive somnolence"; accidental falls; gastrointestinal hemorrhage; cardiovascular diseases; "meta-analysis as topic"; review literature as topic"; observational study; placebo; prevalence; randomized controlled trial; randomized controlled trial (topic). No date or language restrictions will be applied. The electronic database search will be supplemented by a manual search of reference lists from relevant studies. We will also undertake a search for unpublished meta-analyses by searching PROSPERO. Types of studies Meta-analyses of randomized controlled trials (RCTs) based on a systematic review of the literature and comparing with placebo will be included. Observational studies will be included for a separate comparative analysis. Meta-analyses comprised of more than 25% quasirandomized controlled trials or meta-analyses based on a non-systematic search strategy (for instance, pooled analyses of RCTs carried out by the drug manufacturer) will be excluded. Network meta-analyses will be excluded as network meta-analyses do not exist for every agent 6

that meets our inclusion criteria. Results without systematic review or meta-analysis in the title or abstract will be excluded. Participants/ population We will include participants of both sexes and any setting (either inpatients or outpatients) who were prescribed one of the psychiatric medications that met our intervention inclusion criteria. We will include both patient populations who are taking the medications for psychiatric and nonpsychiatric disorders. Meta-analyses of specific subgroups (i.e. pediatric or older adult population) will be excluded. Interventions We will include meta-analyses that evaluate one or more of the most commonly prescribed psychiatric medications in the United States in 2013 as reported by IMS Health. Our preliminary search included the ten most commonly prescribed medications-eight of which were primarily antidepressants and two of which were primarily benzodiazepines. Resultantly, the scope was limited so we expanded the list to include the twenty-five most commonly prescribed medications. We merged the following pairs of similar medications into single categories: bupropion HCL XL and bupropion HCL SR W; methylphenidate ER and generic methylphenidate; amphetamine salts ER and generic amphetamine salts. The updated version of the list comprises of the following pharmacological interventions: alprazolam, sertraline, citalopram, fluoxetine, lorazepam, trazodone, escitalopram, duloxetine, bupropion, venlafaxine, diazepam, paroxetine, quetiapine, risperidone, lisdexamfetamine, methylphenidate, aripiprazole, buspirone, hydroxyzine, olanzapine, amphetamine salts and desvenlafaxine. The psychotropic 7

medications included in the updated list belong to the following categories: antidepressants, anxiolytics, stimulants, antipsychotics and mood stabilizers. We will also include lithium, valproate, amitriptyline, clomipramine, fluphenazine, haloperidol, carbamazepine, clozapine and chlorpromazine to the list of medications as they are commonly used agents that are also included in the World Health Organization Essential Medicine List. Meta-analyses of depot medications will be included. If our search yields insufficient data on AE of individual psychiatric medications, we will redefine our intervention inclusion criteria to examine classes of medication. No restriction will be placed on timing, dose and duration, however, papers that focused on overdose and meta-analyses of augmentation or combination therapy will be excluded. Comparator(s)/ control Placebo will be the comparator for all meta-analyses of RCTs. Outcome(s) Prevalence rates and effect sizes for AE as presented as relative risks. Data extraction (selection and coding) Two researchers (KB and TB) will independently extract data retrieved by the search. If the reviewers agree that the meta-analysis does not meet eligibility criteria, we will exclude it. All disagreements will be resolved through discussion, and in case of persistent disagreement, by a third member of the reviewing team. 8

Risk of bias (quality) assessment We will assess the quality of the included meta-analyses using the AMSTAR measurement tool. Where inadequate details of the AMSTAR score is provided, we will contact the authors to obtain further information. Strategy for data synthesis We will perform a descriptive analysis for each meta-analysis. Specifically, we will provide a table that includes the first author s family name, title of the meta-analysis, publication year, sample size, patient characteristics, time to exposure to treatment and primary outcomes. Our preliminary search using only the ten most commonly prescribed psychiatric medications yielded meta-analyses on the following AEs: suicidal behavior or ideation, insomnia, somnolence, falls, all-cause mortality, upper gastro intestinal bleeding, hostility, major adverse cardiovascular events, nausea and dizziness. The results provided a framework summarizing the effects of antidepressants because eight of the ten medications searched were antidepressants. No AE common to antipsychotics (i.e. extra pyramidal effects) were found in the preliminary search. We recognize that the list of interventions used is biased given that they were the medications prescribed the most in 2013. In order for our meta-review to be fully representative of all classes of psychotropic agents we decided to include the top twenty-five instead of the top ten most commonly prescribed medications and to add medications for mental and behavioural disorders from the WHO Essential Medicine List. As a result, our final list includes not only antidepressants, but also anxiolytics, stimulants, mood stabilizers and antipsychotics. Also, the preliminary search yielded no results for the benzodiazepines searched (alprazolam and lorazepam). Therefore, a possible limitation of this meta-review may be an insufficient amount 9

of available data. Also, this reinforces the importance of our team searching for unpublished meta-analyses to supplement our database search. Certain pharmacological agents on the updated edited list are used to treat multiple psychiatric disorders. If during the study selection process we find that for the same intervention there are multiple meta-analyses that meet the inclusion criteria but focus on populations with different primary psychiatric diagnoses, we will subcategorize the meta-analyses in our table under intervention by diagnosis and examine each separately (see example of table below). Resultantly, we will be able to compare the effect sizes for the same AEs and the same intervention across psychiatric diagnoses. However, if during the study selection process we find multiple metaanalyses on both the same intervention and population, we will compare effect direction, significance and magnitude. The largest meta-analysis will be used in the main analysis so that the scope of AE under review will not be compromised. AE Intervention Effect estimates Meta-analysis A with primary diagnosis X Meta-analysis B with primary diagnosis Y The number of trials and patients included, the average duration of the studies in the metaanalyses, the proportion of patients with each AE, the relative risk, the absolute risk and the 95% confidence intervals (using both fixed- and random-effects models), I-squared statistics, as well 95% prediction intervals will be presented for each intervention. Furthermore, we will perform tests to determine the presence or absence of small study effects and excess significance bias. 10

The preliminary search illustrated methodological differences of published meta-analyses on AEs. Therefore, we will compare the effect sizes of AEs in meta-analyses comprising of RCTs using placebo with those comprising of observational studies. Also, we will attempt to also calculate the Number Needed to Harm (NNH) for our primary outcome from the overall effect estimates. Analysis of subgroups or subsets We will conduct subgroup analyses using the following characteristics as possible sources of inconsistency and or heterogeneity: (i) (ii) (iii) (iv) Methodology (RCTs comparing with placebo and observational studies) Diagnosis Year of publication Sponsorship 11

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