Description of the condition
Depressive disorders are the most common psychiatric comorbidity in patients with epilepsy (Tellez-Zenteno 2007), and they are the strongest predictor of poor quality of life (Boylan 2004). Symptoms of depression include low mood, tiredness and apathy. Sleep and cognitive functioning may also be affected. Reported prevalence rates of depressive disorders in patients with epilepsy range between 21 to 55% (Baker 1996; Indaco 1992; Jacoby 1996; Mendez 1986). These disorders are broadly divided into unipolar (depression only) and bipolar disorders (depression associated with mania or hypomania) (American Psychiatric Association 2000). Depressive disorders in epilepsy may be mediated via the interplay of neurobiological, psychosocial and iatrogenic factors (Lambert 1999). Depressive symptoms or episodes may occur interictally (i.e. they appear unrelated to seizures) or periictally (preceding, during or following seizures). This is an important distinction as patients may require modification of their anti-epileptic drug regime and/or commencement of antidepressant drug therapy. In some patients the depressive symptoms may follow a significant period of seizure remission in previously uncontrolled epilepsy, thought to occur via neuro-biochemical changes and termed 'forced normalisation' (Trimble 1998). Studies examining clinical predictors of risk for depression in patients with epilepsy have produced inconsistent results (Lin 2012). There is a perceived greater risk of depression in patients with temporal lobe epilepsy, although elevated rates of depression have been found in generalised and extra-temporal focal epilepsy (Adams 2008). Duration of epilepsy appears to predict the severity of depression (New Reference). Psychosocial factors such as life stress, coping style, social support, perceived stigma and personality are more consistent predictors of depression in patients with epilepsy (Hermann 2000).
In 2008 the Food and Drug Administration issued a health alert about an increase risk of suicidal ideation in patients taking anti-epileptic drugs (Hesdorffer 2009). This alert was based on a meta-analysis of approximately 28000 patients who had participated in randomised controlled trials (RCTs) investigating 11 anti-epileptic drugs. There were four completed suicides, all of whom had taken anti-epileptic drugs compared to no cases of suicide in the placebo groups (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.24 to 2.66). Since this alert, a number of observational studies have investigated the association reporting conflicting results, and a recent consensus statement on risk of suicide with anti-epileptic drugs has been published by the International League Against Epilepsy (ILAE) Commission on Neuropsychobiology (Mula 2013). Whilst the exact risk of suicide with anti-epileptic drugs is unknown, depression as a treatment-emergent adverse effect is associated with some anti-epileptic drugs (GABAergic anti-epileptic drugs; benzodiazepines, vigabatrin, gabapentin and also topiramate, levetiracetam and zonisamide) (Mula 2009). Other anti-epileptic drugs appear to have mood stabilising properties (valproic acid, lamotrigine, carbamazepine, oxcarbazepine) which may benefit patients with epilepsy and depression. Enzyme-inducing anti-epileptic drugs (i.e. carbamazepine) may lower plasma levels of antidepressants thus impacting on their effectiveness.
Case-control studies have shown that patients with depression have a two- to seven-fold higher risk of developing epilepsy implying a bi-directional relationship (Hesdorffer 2000; Hesdorffer 2006; Hesdorffer 2012). There could be a number of factors to explain this, for example shared pathophysiology involving disturbance in several key neurotransmitter systems (Bagdy 2007), structural lesions (frontal lobe tumours) or a genetic susceptibility. However, there is also the possibility that use of antidepressants may trigger seizures. This is a common concern for healthcare professionals and may influence decisions to start antidepressant treatment (Cotterman-Hart 2010).
Description of the intervention
Antidepressants are a heterogeneous class of drugs that have been the mainstay of pharmacological treatment in treating depressive disorders. There are ten classes of antidepressantss used to treat depressive disorders, with 60-70% of depressive episodes responding to current treatment (Klerman 1990; Sackeim 2006). These are:
- tricyclic antidepressants;
- selective serotonin reuptake inhibitors;
- serotonin-norepinephrine reuptake inhibitors;
- monoamine oxidase inhibitors;
- serotonin/antagonist reuptake inhibitors (i.e. trazodone);
- dopamine and norepinephrine reuptake inhibitors (i.e. bupropion);
- a-2 antagonists (i.e. mirtazapine);
- norepinephrine reuptake inhibitors (i.e. reboxetine);
- selective serotonin reuptake enhancers (i.e. tianeptine); and
- serotonin 5HT
2C receptor antagonists (i.e. agomelantine).
These drugs work by targeting serotonergic and/or noradrenergic and/or dopaminergic neurotransmission,with the aim of increasing their synaptic concentrations (Stahl 2000). Glutamate antagonists represent a novel class of drug currently being tested in refractory depression (Zarate 2006).
The risk of seizures with antidepressants was reported in early studies of the first-generation antidepressants, notably tricyclic antidepressants (Preskorn 1992; Wroblewski 1990). Alper 2007 reviewed the incidence of seizures in 75,000 non-epileptic patients in phase II and phase III trials of antidepressant treatment. It reported lower incidence rates of seizures in those randomised to an antidepressant versus placebo (standardised incidence ratio = 0.48; 95% CI 0.36 to 0.61)Alper 2007. Coupland 2011 examined 60,746 primary care patients aged 65 and over and treated for depression with antidepressants between 1996 and 2007 showed increased risks of epilepsy/seizures for selective serotonin reuptake inhibitors (hazard ratio (HR) 1.80, 95% CI 1.32 to 2.43) and other antidepressant classes (HR 2.20, 95% CI 1.46 to 3.30) versus tricyclic antidepressants. Venlafaxine was associated with the highest risk of seizures.
How the intervention might work
There appears to be a significant relationship between epilepsy and depression. It is emerging from the studies that they both share common neurobiological substrates involving hyperactivity of the hypothalamic pituitary adrenal axis and disturbance of different neurotransmitter systems mainly serotonin and norepinephrine (Dell'osso 2013). The density of serotonin receptors are high in the mesial temporal and prefrontal areas (Gilliam 2005). In critical brain regions such as limbic system and prefrontal areas, enforced serotonergic circuits seems to be responsible for increasing seizure threshold (Kondziella 2009).
Antidepressants of the selective serotonin reuptake inhibitors family have been reported not only to be safe in treating depression in patients with epilepsy but to possess antiepileptic properties as shown in the animal models of epilepsy (Hamid 2013). It has been suggested in clinical data that selective serotonin reuptake inhibitors can decrease the seizure frequency in refractory epilepsy (Kondziella 2009). This is believed to be due to the increase in the concentration of serotonin. The study shows that the concentration of endogenous serotonin (5-HT) and the activity of its receptor subtypes, 5–HT(1A), 5-HT(2C), 5-HT(3) and 5–HT(7) play a significant role in the pathogenesis of epilepsies (Bagdy 2007). The medications with serotonin agonist and antagonist properties therefore can play a significant role in the pathogenesis of epilepsies.
Why it is important to do this review
Depression is common in patients with epilepsy and has a significant negative impact on quality of life (Gilliam 2005; Kondziella 2009). There is concern that patients may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best and the perceived risk of exacerbating seizures. This review aims to address these issues and inform clinical practice and future research.
We aim to review and synthesise evidence from randomised controlled trials of antidepressants and non-randomised studies of antidepressants used for treating depression in patients with epilepsy. The primary objectives are to evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence.
Criteria for considering studies for this review
Types of studies
- Prospective non-randomised cohort controlled and uncontrolled studies
Types of participants
We will consider participants who satisfy all of the following criteria:
- any age;
- diagnosis of epilepsy (any type);
- treated with antidepressants for co-existing depression (includes patients with major depressive disorder, adjustment disorder and dysthymic disorder) based on standardised criteria and/or according to participant scores on validated tools (e.g. Hamilton Rating Scale for Depression).
Types of interventions
- The intervention group, where patients received an antidepressant drug in addition to an existing anti-epileptic drug regime
- The control group(s), where patients received a placebo, comparative antidepressant, psychotherapy or no treatment in addition to an existing antiepileptic drug regime
Types of outcome measures
- Depression scores
- The proportion of people with a >50% improvement in depressive symptoms (defined as a 'response')
- Mean difference in depression scores
If data allows, outcomes will be analysed at ≤ 12 weeks (short-term), 13-26 weeks and ≥ 26 weeks (long-term)
- Change in seizure frequency
- The mean difference in seizure frequency
- The proportion of people with a seizure recurrence
- The proportion of people with an episode of status epilepticus
- Leaving the study early
- For specific reasons
- For general reasons
- Global state
- Clinically important change in global state (as defined by individual studies)
- Relapse (as defined by the individual studies)
- Mental state
- Clinically important change in general mental state score
- General mental state score (average and endpoint)
- Clinically important change in specific symptoms (sleep, anhedonia, suicidal ideas)
- Specific symptom score (average and endpoint)
- General functioning
- Clinically important change in general functioning
- General functioning score (average and endpoint)
- Cognitive functioning
- Clinically important change in overall cognitive functioning
- Overall cognitive functioning score (end point and average)
- Clinically important change in specific cognitive functioning (attention, concentration, memory, language, executive functioning)
- Specific cognitive score (average and endpoint)
- Quality of life
- Clinically important change in quality of life
- Any change in quality of life score (average and endpoint)
- Clinically important change in general behaviour
- Any important change in general behaviour (average and end point)
- Clinically important change in specific aspects of behaviour
- Any important change in specific aspects of behaviour score (average and end point)
- Adverse effects
- Any non-serious general adverse effects (gastrointestinal effects, anorexia, dizziness, dry mouth, insomnia, sexual dysfunction, hypotension)
- Any serious, specific adverse effects (hypersensitivity reaction)
- Any change in general adverse effect score (average and end point)
- Clinically important change in specific adverse effects
- Any change in specific adverse effects score (average and end point)
Search methods for identification of studies
We will search the following databases:
- the Cochrane Epilepsy Group Specialized Register;
- the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (Appendix 1);
- MEDLINE (Ovid) (Appendix 2);
- SCOPUS; and
The MEDLINE search strategy will be adapted for the SCOPUS and PsycINFO databases. We will not impose any language restrictions.
Searching other resources
We will check reference lists of retrieved studies for additional reports of relevant studies.
We will contact lead authors for any relevant unpublished material.
We will identify duplicate studies by screening reports according to title, authors names, location and medical institute. Any duplicated studies will be omitted.
We will also identify any grey literature studies published in the last five years by searching:
- Zetoc database;
- ISI proceedings;
- International Bureau for Epilepsy (IBE) congress proceedings database;
- ILAE congress proceedings database; and
- Abstract books of symposia congresses, meeting abstracts and research reports.
Data collection and analysis
Selection of studies
Two authors (MM, JP) will independently assess all citations generated from the searches for inclusion. A random sample of 30% of citations will be re-inspected by a third author (JS) to ensure reliability. Where disputes arise, the full report will be acquired for more detailed scrutiny.
Data extraction and management
Two authors (MM, JP) will undertake data extraction separately on each included study. Data extraction will then be cross-checked. Data will be extracted using pre-standardised data extraction forms. A random 30% sample will be re-inspected by a third author (JS) to ensure reliability. Any disagreement will be discussed, decisions documented and, if necessary, trialists will be contacted for clarification.
The following information from the included studies will be extracted:
Methodological and trial design
- Year of publication
- Number of study centres
- Industry funding
- Study design (RCT, prospective cohort study, retrospective cohort study)
- Type of control group (placebo, comparative antidepressant, no treatment)
- Sample size
- Follow-up period
- Class of antidepressant as intervention
- Dose range of intervention
- Inclusion and exclusion criteria
Patient demographic information
- Age range
- Number of male/female participants
- Duration of epilepsy
- Previous number of anti-epileptic drugs
- Epilepsy type (focal, generalised, unclassified)
- Location of epilepsy (temporal, extra-temporal)
- Baseline mean depression score or severity
- Baseline mean seizure frequency/month
- The number of patients experiencing each outcome recorded per treatment group.
- Number of drop-outs
Assessment of risk of bias in included studies
Two authors (JP, MM) will assess risk of bias in each included study separately. Risk of bias assessment will be cross-checked. Due to the observational design of some of the studies, we will utilise a version of the extended Cochrane Collaboration's tool for assessing risk of bias, currently being developed by the Cochrane Non-Randomised Studies Methods Group. The tool examines selection bias (sequence generation, allocation concealment), performance bias (blinding), attrition bias (incomplete outcome data, blinding), detection bias (blinding, other potential threats to validity), reporting bias (selective outcome reporting), and the influence of confounding variables. The domains of blinding, incomplete outcome data, selective outcome reporting, confounding variables and other bias will be rated on a five-point scale ranging from low in bias to high risk of bias according to the risk on the outcome (Appendix 3).. The parameters of this scale were determined by the review authors ( Table 1).
For RCTs, all domains of the current Cochrane Collaboration's tool for assessing risk of bias will be assessed (Higgins 2011).
An overall summary judgement of risk of bias will be made for each study per outcome, followed by an overall judgement per outcome across studies. The risk of bias judgements will be incorporated into the analysis using sensitivity analysis in that a secondary analysis of the data will include only studies rated as low in risk of bias. Both results will be presented in the results section of the review. Where applicable, "Summary of findings" tables will be created for outcomes and each outcome will be graded accordingly using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2008).
Measures of treatment effect
For binary outcomes (50% or greater improvement in depressive symptoms and % treatment withdrawal), we will present the results as risk ratios (RRs) and 95% CIs.
For continuous outcome (mean change in depression score), we will present the standardised mean differences (SMDs).
Unit of analysis issues
Studies are likely to use a variety of depression measures creating issues for combining results in meta-analysis. Where appropriate we will use the SMDs to allow for these variances.
Dealing with missing data
Missing statistics from studies will be sought through contact with the study authors. Reasons for missing data will be sought to determine if missing at random or not.
Assessment of heterogeneity
We aim to assess clinical heterogeneity by comparing the distribution of important patient factors between studies (age, epilepsy type, duration of epilepsy, baseline depression score, baseline seizure frequency) and trial factors (study design, type of control group, antidepressant drug class, type of depression disorder). We will assess statistical heterogeneity by using the I
Assessment of reporting biases
1. Protocol versus full study
We will investigate outcome reporting bias using the ORBIT matrix system (Kirkham 2010).
2. Funnel plot
Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Higgins 2011; Sterne 2000). Funnel plots will be used in investigating reporting biases but are of limited power to detect small-study effects. We will not use funnel plots for outcomes where there are ten or fewer studies, or where all studies are of similar sizes. In other cases, where funnel plots are possible, we will seek statistical advice in their interpretation.
We will synthesise data using the RR or the SMD depending on the measures used in studies. A sensitivity analysis to check for differences between a random-effects model and fixed-effect model in influencing conclusions will be carried out. If differences between the models exist, we intend to report outcomes based on the random effects models which incorporates an assumption that the different studies are estimating different, yet related, intervention effects.
Comparisons we expect to carry out will include:
- intervention group versus controls for change in mean depression score;
- intervention group versus controls on % achieving a 50% improvement in depression scores;
- intervention group versus controls for change in mean seizure frequency;
- intervention versus controls on % of patients withdrawing from treatment.
Each comparison will be stratified by type of control group, study design and/or study characteristics to ensure appropriate combination of study data.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be stratified by antidepressant drug class, epilepsy type and age. For investigation of heterogeneity, please see Assessment of heterogeneity.
We intend to carry out sensitivity analysis if peculiarities between study quality are found (Assessment of risk of bias in included studies). The analysis for all studies will be reported and then compared to an analysis of only studies at low risk of bias.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Depression] explode all trees
#2 MeSH descriptor: [Depressive Disorder] explode all trees
#3 depression* or depressive*:ti,ab,kw (Word variations have been searched)
#4 "respiratory depression":ti,ab,kw (Word variations have been searched)
#5 (#1 or #2 or #3) not #4
#6 MeSH descriptor: [Antidepressive Agents] explode all trees
#7 (antidepressant or antidepressive or "af 1161" or "ba 34276" or "bc 105" or "brl 29060" or "brl 29060" or "cl 67772" or "cp 15467 61" or "du 23000" or "fg 7051" or "ici 58834" or "l deprenyl" or "leo 640" or "lilly 110140" or "lu 10 171" or "ma 1291" or "nsc 16895" or "org gb 94" or "r 55667" or "ro 11 1163" or "trans 2 phenylcyclopropylamine" or "ym 35 995" or "ym 992" or "zk 62711" or *amitriptyline or *doxepin or *moclobemide or *nortriptyline or *phenylethylhydrazine or *sertraline or *trimip or *trimipramine or *tripramine or *tryptophan or abilify or adapin or adaptol or adderall or agomelatine or aiglonyl or allegron or altruline or amfebutamone or amineptine or amineurin or amisulpride or amitrip or amitriptylin* or amitrol or amiz?l or amoxapine or amphetamine or anafranil or anapsique or aponal or ardeydorm or ardeytropin or aremis or arima or aripiprazole or arminol or aropax or asenapine or asendin or astyl or atomoxetine or auror?x or aventyl or axiomin or benactyzine or benzeneacetic acid or besitran or bolvidon or bosnyl or brofaramine or bupropion or buspar or buspirone or butriptyline or carbamazepine or celexa or chlomipramine or chlorgyline or cipralex or cipramil or citalopram or clomipramine or clorgilin* or clorgyline or concerta or cymbalta or cytalopram or dalcipran or damilen or de*methylimipramine or deanol or defanyl or deftan or deman?l or demolox or depakote or deponerton or deprax or deprenorm or deprilept or deptran or desidox or desiflu or desipramine or desisulpid or desitriptyline or desmethylamitriptylin or desmethylloxapine or desvenlafaxine or desyrel or dexedrine or dexmethylphenidate or dextroamphetamine or dibencycladine or digton or dilithium carbonate or dimethylaminoethanol or dimethylethanolamine or dogmatil or dolmatil or domical or doneurin or dosulepin or dothiepin or doxepia or doxepin* or duloxetine or dumirox or edronax or ef*exor or eglonyl or ekilid or elavil or eldepryl or eldoral or emovit or emsam or endep or escitalopram or eskalith or espadox or espiride or etonin or etoperidone or evadene or favarin or fenelzin or feprapax or feraken or fevarin or floxyfral or fluoxetin* or fluvoxadura or fluvoxamin* or focalin or gam?nil or gladem or guastil or herphonal or hydiphen or imidobenzyle or imipramine or imizin or insidon or iprazid or iprindole or iproniazid or isocarboxazid or ixel or janimine or jatrosom or lamictal or lamotrigine or laroxyl or lebopride or lentizol or lerivon or lexapro or lisdexamfetamine or lithane or lithium or lithobid or lofepramine or lomont or lopramine or lubazodone or lucidil or ludiomil or lustral or luvox or lyphan or manerix or maprolu or maprotilin* or mareen or marplan or melitracen or meresa or meridia or methylphenidate or mianserin or micalith or midalcipran or milnacepra* or mirpan or mirtazapine or moclamine or moclix or moclob?mide or moclobemid* or moclobeta or moclodura or moclonorm or modal or molipaxin or nardelzine or nardil or naturruhe or nefadar or nefazodone or neogama or nialamide or norfenazin or norpramin or nortrilen or norval or novoprotect or olanzapine or opipramol or optimax or oxitriptan or pamelor or parnate or paroxetine or paxil or paxtibi or pertofran* or pertrofran or petylyl or phenelzine or phenethylhydrazine or pirazidol or pirlindole or pizotifen or pizotyline or polomigran or pontiride or pramolan or priadel or pristiq or prondol or prothiaden or protriptyline or prozac or prudoxin or pryleugan or psicocen or psymion or quetiapine or quilinorm* or quipazine or quitaxon or quomen or r55667 or reboxetine or reductil or remeron or rhotrimine or rimoc or ritalin or ritanserin or rolipram or sandomigran or saphris or sarafem or saroten or sarotex or savella or sealdin or sediel or selegiline or sendis or seroquel or seroxat or serzone or sibutramine or sin*quan or solian or stangyl or strattera or sulp or sulpiride or sulpitil or sulpivert or sulpor or surmontil or sycrest or symbyax or synedil or syneudon or tandospirone or tegretol or tepavil or thombran or tianeptine or tofranil or toledomin or tolvon or tonibral or tradozone or tramadol or tramal or transamine or tranylcypromine or trazodon* or trimeprimin* or trimidura or trimineurin or triptafen or trittico or trofan or tryptacin or tryptan or tryptanol or tryptine or tryptizol or tyrima or ultram or valdoxan or valproic acid or venlafaxine or viibryd or vilazodone or viloxazine or vivactil or vivalan or vyvanse or wellbutrin or xepin or yentreve or zelapar or zimelidine or zispin or zoloft or zonalon or zyban or zyntabac):ti,ab,kw (Word variations have been searched)
#8 #6 or #7
#9 (epilep* or seizure* or convuls*):ti,ab,kw (Word variations have been searched)
#10 MeSH descriptor: [Epilepsy] explode all trees
#11 MeSH descriptor: [Seizures] explode all trees
#12 (#9 or #10 or #11) in Trials
#13 #5 and #8 and #12
#14 MeSH descriptor: [Electroconvulsive Therapy] explode all trees
#15 #13 not #14
Appendix 2. MEDLINE search strategy
1. (validation studies or clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv or comparative study or evaluation studies or multicenter study).pt.
2. ((observation$ or cohort or case$ or cross?section$ or "cross section$" or "time-series" or "time series" or "before and after" or "before-and-after" or retrospective) adj2 (study or trial or method)).mp.
3. (randomized controlled trial or controlled clinical trial).pt. or (randomized or placebo or randomly).ab.
4. clinical trials as topic.sh.
6. 1 or 2 or 3 or 4 or 5
7. exp animals/ not humans.sh.
8. 6 not 7
9. exp Depression/ or exp Depressive Disorder/ or exp Dysthymic Disorder/ or (depression$ or depressive$).tw.
10. "respiratory depression".tw.
11. 9 not 10
12. exp Antidepressive Agents/ or anti?depress$.tw.
13. ("af 1161" or "bc 105" or "brl 29060" or "cl 67772" or "cp 15467 61" or "du 23000" or "ici 58834" or "leo 640" or "lilly 110140" or "ma 1291" or "nsc 16895" or "org gb 94" or "r 55667" or "ro 11-1163" or "trans 2 phenylcyclopropylamine" or "ym-35,995" or "zk 62711" or abilify or adapin or adaptol or adderall or af?1161 or agomelatine or aiglonyl or allegron or altruline or amfebutamone or amineptine or amineurin or amisulpride or amitrip or amitriptylin$ or amitrol or amiz?l or amoxapine or amphetamine or anafranil or anapsique or apo?doxepin or apo?moclob?mide or apo?nortriptyline or apo?sertraline or apo?trimip or apoamitriptyline or aponal or ardeydorm or ardeytropin or aremis or arima or aripiprazole or arminol or aropax or asenapine or asendin or astyl or atomoxetine or auror?x or aventyl or axiomin or ba?34276 or bc?105 or benactyzine or benzeneacetic acid or besitran or beta?phenylethylhydrazine or bolvidon or bosnyl or brl?29060 or brofaramine or bupropion or buspar or buspirone or butriptyline or carbamazepine or celexa or chlomipramine or chlorgyline or cipralex or cipramil or citalopram or cl?67772 or clomipramine or clorgilin$ or clorgyline or concerta or cp?15467?61 or cymbalta or cytalopram or dalcipran or damilen or de?methylimipramine or deanol or defanyl or deftan or deman?l or demolox or depakote or deponerton or deprax or deprenorm or deprilept or deptran or desidox or desiflu or desipramine or desisulpid or desitriptyline or desmethylamitriptylin or desmethylloxapine or desvenlafaxine or desyrel or dexedrine or dexmethylphenidate or dextroamphetamine or dibencycladine or digton or dilithium carbonate or dimethylaminoethanol or dimethylethanolamine or dogmatil or dolmatil or domical or doneurin or dosulepin or dothiepin or doxepia or doxepin$ or du?23000 or duloxetine or dumirox or edronax or ef?exor or eglonyl or ekilid or elavil or eldepryl or eldoral or emovit or emsam or endep or escitalopram or eskalith or espadox or espiride or etonin or etoperidone or evadene or favarin or fenelzin or feprapax or feraken or fevarin or fg?7051 or floxyfral or fluoxetin$ or fluvoxadura or fluvoxamin$ or focalin or gam?nil or gen?nortriptyline or gen?sertraline or gladem or guastil or herphonal or hydiphen or ici?58834 or imidobenzyle or imipramine or imizin or insidon or iprazid or iprindole or iproniazid or isocarboxazid or ixel or janimine or jatrosom or lamictal or lamotrigine or laroxyl or l-deprenyl or lebopride or lentizol or lerivon or levo?tryptophan or lexapro or lilly?110140 or lisdexamfetamine or lithane or lithium or lithobid or lofepramine or lomont or lopramine or l-tryptophan or lu?10?171 or lubazodone or lucidil or ludiomil or lustral or luvox or lyphan or ma?1291 or manerix or maprolu or maprotilin$ or mareen or marplan or melitracen or meresa or meridia or methylphenidate or mianserin or micalith or midalcipran or milnacepram or milnacipra? or mirpan or mirtazapine or moclamine or moclix or moclob?mide or moclobemid$ or moclobeta or moclodura or moclonorm or modal or molipaxin or nardelzine or nardil or naturruhe or nefadar or nefazodone or neogama or nialamide or nor?nortriptyline or norfenazin or norpramin or nortrilen or nortriptyline or norval or novo?doxepin or novo?moclob?mide or novo?nortriptyline or novo?sertraline or novo?tripramine or novoprotect or nsc?16895 or nu?moclob?mide or nu?nortriptyline or nu?trimipramine or nu?tripramine or numo?moclob?mide or olanzapine or opipramol or optimax or oxitriptan or pamelor or parnate or paroxetine or paxil or paxtibi or pert?ofran$ or petylyl or phenelzine or phenethylhydrazine or phenylethylhydrazine or pirazidol or pirlindole or pizotifen or pizotyline or pms?moclob?mide or pms?nortriptyline or pms?tryptophan or polomigran or pontiride or pramolan or priadel or pristiq or prondol or prothiaden or protriptyline or prozac or prudoxin or pryleugan or psicocen or psymion or quetiapine or quilinorm?retard or quipazine or quitaxon or quomen or r55667 or r-55667 or ratio?nortriptyline or ratio?sertraline or ratio?tryptophan or reboxetine or reductil or remeron or rhotrimine or rhoxal?sertraline or rimoc or ritalin or ritanserin or ro-11-1163 or rolipram or sandomigran or saphris or sarafem or saroten or sarotex or savella or sealdin or sediel or selegiline or sendis or seroquel or seroxat or sertraline or serzone or sibutramine or sin?quan or solian or stangyl or strattera or sulp or sulpiride or sulpitil or sulpivert or sulpor or surmontil or sycrest or symbyax or synedil or syneudon or tandospirone or tegretol or tepavil or thombran or tianeptine or tofranil or toledomin or tolvon or tonibral or tradozone or tramadol or tramal or trans-2-phenylcyclopropylamine or transamine or tranylcypromine or trazodon$ or trim?pr?min$ or trimidura or trimineurin or trimip or tripramine or triptafen or trittico or trofan or tryptacin or tryptan or tryptanol or tryptine or tryptizol or tryptophan or tyrima or ultram or valdoxan or valproic acid or venlafaxine or viibryd or vilazodone or viloxazine or vivactil or vivalan or vyvanse or wellbutrin or xepin or yentreve or ym-992 or zelapar or zimelidine or zispin or zk?62711 or zoloft or zonalon or zyban or zyntabac).mp.
14. 12 or 13
15. exp Epilepsy/
16. exp Seizures/
17. (epilep$ or seizure$ or convuls$).tw.
18. 15 or 16 or 17
19. exp Pre-Eclampsia/ or exp Eclampsia/
20. 18 not 19
21. 8 and 11 and 14 and 20
22. exp Electroconvulsive Therapy/
23. 21 not 22
24. 23 not case reports.pt.
Appendix 3. Extended risk of bias tool for non-randomised studies
Studies for which the risk of bias tool is intended
Only suitable for 'cohort-like' studies, individually or cluster-allocated. This can include secondary analyses of clinical databases providing the analysis is clearly structured as a comparison of control and intervention participants:
Individually allocated study designs
- Randomised controlled trial
- Quasi randomised controlled trial
- Non-randomised controlled trial
- Controlled before and after study (not common use of this label, see controlled cohort before and after study below)
- Prospective cohort study
- Retrospective cohort study
Cluster allocated study designs
- Cluster randomised controlled trial
- Cluster quasi randomised controlled trial
- Cluster non-randomised controlled trial
- Controlled interrupted time series
- Controlled cohort before and after study
Assessment of risk of bias
Issues when using the modified risk of bias tool to assess cohort-like non-randomised studies:
- follow principle for existing Cochrane Collaboration's tool for risk of bias: score judgement and provide information (preferably direct quote) to support judgement
- modified risk of bias tool include an additional item on confounding.
- five-point scale for some items (distinguish "unclear" from intermediate risk of bias).
- keep in mind the general philosophy – assessment is not about whether researchers could have done better but about risk of bias; the assessment tool must be used in a standard way whatever the difficulty/circumstances of investigating the research question of interest and whatever study design features were used.
- use of a five-point scale is uncharted territory; very interested to know whether this makes things easier or more difficult for reviewers.
- anchors for five-point scale: "1/No/low risk" of bias should correspond to a high quality RCT. "5/high risk" of bias should correspond to a risk of bias that means the findings should not be considered (too risky, too much bias, more likely to mislead than inform).
- Low/high/unclear risk of bias item
- Always high risk of bias (not random) for a non-randomised study
- Might argue that this item is redundant for non-randomised studies since they are always of high risk of bias – but important to include in risk of bias table ('level playing field' argument)
- Low/high/unclear risk of bias item
- Potentially low risk of bias for a non-randomised study, e.g. quasi-randomised (high risk of bias due to sequence generation) but concealed (author judges that the people making decisions about including participants did not know how allocation was being done, e.g. odd/even date of birth/hospital number)
Risk of bias from confounding (additional item for non-randomised studies; assess for each outcome)
- Assumes a prespecified list of potential confounders defined in the protocol for the systematic review
- Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item
- Judgement needs to factor in (see 'worksheet'):
- proportion of confounders (from pre-specified list) that were considered
- whether most important confounders (from pre-specified list) were considered
- resolution/precision with which confounders were measured
- extent of imbalance between groups at baseline
- care with which adjustment was done (typically a judgement about the statistical modelling carried out by authors)
- Low risk of bias requires that all important confounders are balanced at baseline, i.e.:
- not primarily / not only a statistical judgement; or
- measured 'well' and 'carefully' controlled for in the analysis.
We have provided an optional 'worksheet' to help reviewers to focus on the task (rows = confounders and columns = factors to consider). Authors should make a risk of bias judgement about each factor first and then combine these (by eyeballing rather than quantitatively) to make the judgement in the main risk of bias table.
Risk of bias from lack of blinding (assess for each outcome, as per the existing risk of bias tool)
- Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item
- Judgement needs to factor in:
- nature of outcome (subjective / objective; source of information);
- who was/was not blinded and the risk that those who were not blinded could introduce performance or detection bias.
Risk of bias from incomplete outcome data (assess for each outcome, as per the existing risk of bias tool)
- Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item
- Judgement needs to factor in:
- reasons for missing data;
- whether amount of missing data balanced across groups, with similar reasons;
- whether group comparison appropriate (e.g. 'analysed in allocated group' issue).
Risk of bias from selective reporting (assess for each outcome)
- More wide ranging than existing assessment recommendation. Key issue is whether outcomes were clearly defined, and methods of analysis, were pre-specified and adhered to
- Low(1) / 2 / 3 / 4 / high(5) /unclear risk of bias item
- Judgement needs to factor in:
- existing risk of bias guidance on selective outcome reporting;
- also, extent to which analyses (and potentially other choices) could have been manipulated to bias the findings reported, e.g. choice of method of model fitting, potential confounders considered/included;
- look for evidence that there was a protocol in advance of doing any analysis/obtaining the data (difficult unless explicitly reported); non-randomised studies are very different from RCTs. RCTs must have a protocol in advance of starting to recruit (for research ethics committee/institutional review board/other regulatory approval); non-randomised studies need not (especially older studies);
- Hence, separate yes/no items asking reviewers whether they think the researchers had a prespecified protocol and analysis plan?
Appendix 4. Assessment of confounding variables
Contributions of authors
MM, JP, JS have written the review protocol. MM holds responsibility for managing the review process. AM has provided supervision throughout he development of the protocol and provided comments on drafts.
Declarations of interest
MM, JP, JS and AM have no declarations of interest.
Sources of support
- No sources of support supplied
- National Institute for Health Research, UK.This review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.