Efficacy of Antidepressants in Animal Models of Ischaemic Stroke A Systematic Review and Meta-Analysis

Transcription

1 Efficacy of Antidepressants in Animal Models of Ischaemic Stroke A Systematic Review and Meta-Analysis Background Current treatment options for ischaemic stroke victims remain severely limited. Survivors typically experience varying degrees of motor and neuropsychological deficits. Post-stroke depression (PSD) has around 33% prevalence among stroke survivors 1 and a significant correlation exists between severity of depressive symptoms and severity of post-stroke functional impairment 2. Evidence from a recent clinical trial indicates the potential for a dual role of antidepressants in stroke survivor populations: in addition to lower depression rates, fluoxetine treatment resulted in enhanced motor recovery and a reduction in the number of dependent patients 3. There has been some evidence for these effects in previous smaller trials and a systematic review of the literature by the Cochrane Collaboration which investigated the extent of motor recovery in clinical trials found higher recovery rates for a number of pharmacological agents which affect neurotransmitter activity 6. The ability of antidepressants to promote functional improvement in non-depressed patients suggests effects on motor recovery that are independent of mood-altering actions. A single dose of fluoxetine, unlikely to affect mood, improved motor function when compared to placebo in human stroke survivors. Experimental literature suggests that antidepressants may directly influence neuroregeneration by enhancing trophic factors, neural plasticity and/or neurogenesis in the brain. Following stroke, endogenous functional repair within the damaged circuitry has been detected. Temporal and spatial remapping compensate for damaged connections by exploiting redundant networks 8. Early studies reporting that antidepressant agents enhance the expression of brain-derived neurotrophic factor (BDNF) indicated that these agents could promote neuronal survival 9. Antidepressants have since been shown to enhance neurogenesis in human, primate and rodent adult brains and could thus help potentiate the re-wiring of damaged brain areas, facilitating functional recovery This phenomenon has been attributed to their ability to promote neurotrophic factors involved in mechanisms of neural plasticity. Despite some promising data, conflicting results exist in both clinical and preclinical studies involving antidepressant treatment for post-stroke recovery. We are interested in carrying out a systematic review and meta-analysis to investigate the efficacy of antidepressants in animal models of focal ischaemic stroke to inform future research direction. If proven to be effective for stroke therapy, therapeutic and economic benefits exist in using antidepressants already approved for human use, including known dose tolerability, drug interactions and side effects. Protocol history 2011 Systematic review and meta-analysis of selective serotonin uptake inhibitors (SSRIs) in animal models of focal ischaemia carried out (unpublished).

2 2013 Study extended and protocol updated to include analysis of all antidepressant subtypes in animals models of focal ischaemia. Specific changes to the protocol noted in text and outlined in footnotes. Objective To assess whether there is any significant evidence, from relevant extracted data, to suggest that the use of antidepressants in animal models of stroke has any beneficial potential in ameliorating stroke outcome a. Specific aims In animal models of focal ischaemic stroke: Evaluate the effectiveness of antidepressant treatment on ameliorating histological and functional/cognitive outcome. Evaluate the effect of antidepressant treatment on neuroregeneration measures. Evaluate the relative effectiveness of individual antidepressants and various antidepressant subtypes e.g. SSRIs, MAOIs, TCAs b on outcome measures. Methods 1. Criteria for selecting studies for the review Studies describing the effect of antidepressant drugs a in whole live animal models of focal ischaemic stroke, compared with control animals receiving vehicle or no treatment will be included, regardless of randomisation. Studies investigating the effect on stroke outcome of currently prescribed antidepressants, or putative antidepressants under development, will be reviewed. Studies in which focal ischaemic stroke was established by either permanent or transient occlusion of the middle cerebral artery or its branches, via any method, will be included. Studies inducing global ischaemia or non-ischaemic brain lesions will be excluded. All species/strains of animals are eligible, regardless of age and sex. Human studies will be excluded. Studies with any route and dose of drug administration are eligible. Any time of delivery will be considered, whether prior- or post-induction of ischaemia. a Updated to include all antidepressant subtypes ( ) b Updated to include comparison between different antidepressant subtypes ( )

3 Studies reporting infarct volume and/or functional outcome data will be included. Studies involving induction of post-stroke depression (e.g. via a chronic mild stress paradigm), that also report infarct volume and/or functional outcome after antidepressant treatment will be included. Studies reporting post-stroke depression as the outcome measure, without concurrent infarct volume and/or neurobehavioural scores will be excluded. 2. Search strategy Searches of PubMed (1966-present), Embase (1947-present), Web of Science (1900-present) and BIOSIS (1926-present) will be carried out for articles on the effect of antidepressant therapies on focal ischaemic stroke outcome. Search strategies have been developed for use with all databases*. The results returned from the searches of each of the electronic databases will be exported to a single Reference Manager file. Duplicate references will be deleted. Two investigators will independently evaluate the titles and abstracts obtained to assess if they meet the broad inclusion criteria and compare results of included papers. If there is any discrepancy in included titles, consensus will be reached through discussion. Existing data in the CAMARADES database on SSRIs used in ischaemic stroke models (2011) will be included in analysis. Abstracts (and if necessary articles) of studies not already in the CAMARADES database will then be examined further to identify reports where the therapies described fall into the listed inclusion criteria. Full text of all the included studies will be obtained. Articles in foreign languages will be translated, and the references listed in the selected articles will be assessed to identify additional studies not located by the initial search. Any disagreement will be resolved by discussion and, if necessary, a third review author will be consulted. 3. Data extraction Primary outcome measure: infarct volume or area. Secondary outcome measures: post-stroke mortality, neurobehavioural score and neurogenesis. Data on the characteristics of study design and attributes of study quality will be recorded. One investigator will carry out initial data extraction and a second investigator will then check all data entered. Data will be recorded in the CAMARADES Microsoft Access 2003 data manager application. 3.1 Design of study Data on study design will be recorded, including: species, strain, age, and sex of animals used; co-morbidities; anaesthetics and ventilation; permanent vs. transient ischaemic injury; method of ischaemia induction and duration of

4 ischaemia; mode of action of administered antidepressant c ; dose, route and timing of drug administration; time-point of outcome measured; methods of outcome measurement; timing of drug administration in relation to neurobehavioural training and type of training d. 3.2 Quality of study Study quality will be assessed according to the CAMARADES quality checklist with 10 points in total, and the group median scores will be calculated: (1) peerreviewed publication; (2) statement of control of temperature; (3) use of animals with co-morbidities; (4) use of anaesthetic without prominent intrinsic neuroprotective abilities; (5) reporting of sample size calculation; (6) randomization of treatment allocation; (7) concealment of treatment allocation; (8) blinded assessment of outcome; (9) statement of compliance with animal welfare regulations; and (10) statement of possible conflicts of interest. 3.3 Outcome extraction The number of animals, the mean outcome and its standard deviation (SD) or standard error (SE) will be extracted for each treatment comparison. Neurobehavioural scores and the type of neurobehavioural measures used will be extracted. When neurobehavioural tests were performed at different times, only the final test will be included. Measures of neurogenesis (including cell proliferation, differentiation and/or survival) will be extracted. Values of graphical data will be requested from the authors, and if unavailable, digital ruler software will be used to measure data from graphs. In cases where the full data required for meta-analysis are not available from abstracts or publications, they will be requested directly from authors. When data required are not obtainable, such studies will be excluded from the analysis. 4. Statistical analysis Normalised mean difference will be used as the effect size (ES), and ES and its SE will be calculated for each comparison. In addition, the 95% confidence interval of the effect size will be calculated. Data will be aggregated using a weighted average method in which greater weight is given to more precise studies. For anticipated heterogeneity between studies, the random-effects model of Dersimonian and Laird will be used, which is more conservative than fixed-effect model, given the weighting towards individual comparisons depends on the variance within those comparisons and on overall heterogeneity. The heterogeneity between studies will be assessed by using the Chi-square statistic with n-1 degrees of freedom (df). To allow for multiple comparisons, a significance level will be set using Bonferroni correction taking into the number of comparisons. Publication bias will be looked for using funnel plotting [36], Egger regression and trim and fill. c Updated to reflect inclusion of drugs with differing physiological actions (in addition to SSRIs; ) d Included to enable analysis of the effect of drug timing in relation to any training protocols carried out. The effects of certain drugs that mediate neurotransmitter levels are dependent on concomitant behavioural experience and tight coupling between drug administration and learning may occur ( ).

5 Subgroup meta-analysis will be performed where possible according to characteristics of study design and study quality to assess their impact on efficacy, as the following subgroups: species, strain, age, co-morbidities (present/absent), antidepressant subtype, dose (low or high dose, single or multiple), time of administration (before/after ischaemia), timing of drug administration relative to training, time of assessment (acute phase or long term), types of ischaemia (transient or permanent), duration of ischaemia, as well as scores of quality checklist, especially the use of randomisation and blinded assessment of outcome. e *Search strategies f : Searches contain common antidepressant drug groups including: Selective serotonin reuptake inhibitors (SSRI) Serotonin-noradrenaline/norepinephrine reuptake inhibitors (SNRI) Tricyclic antidepressants (TCA) Serotonin antagonist and reuptake inhibitors (SARI) Noradrenaline/norepinephrine reuptake inhibitors (NRI) Noradrenaline/norepinephrine-dopamine reuptake inhibitors (NDRI) Noradrenaline/norepinephrine dopamine releasing agents (NDRA) Tetracyclic antidepressants (TeCA) Monoamine oxidase inhibitors (MAOI) Within each drug group, the generic names of some commonly used agents are listed. Trade names have been excluded from the search terms. PubMed search strategy: stroke OR ((cerebral OR brain OR focal) AND (ischemia OR ischemic OR ischaemia OR ischaemic)) OR cerebrovascular OR middle cerebral artery OR MCA OR middle cerebral artery occlusion OR MCAO OR anterior cerebral artery OR ACA OR anterior cerebral artery occlusion OR ACAO OR experimental stroke AND (SSRI) OR (SSRIs) OR (selective serotonin reuptake inhibitor) OR (selective serotonin reuptake inhibitors) OR (selective serotonin re-uptake inhibitor) OR (selective serotonin re-uptake inhibitors) OR (selective serotonin-reuptake inhibitors) OR (selective serotonin-reuptake inhibitor) OR (fluoxetine) OR (citalopram) OR (Escitalopram) OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR (dapoxetine) OR (SNRI) OR (SNRIs) OR (serotonin and noradrenaline reuptake inhibitors) OR (serotonin and noradrenaline reuptake inhibitor) OR (serotonin and noradrenaline re-uptake inhibitors) OR (serotonin and noradrenaline re-uptake inhibitor) OR (serotonin-noradrenaline reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitor) OR (serotonin and norepinephrine re-uptake inhibitors) OR (serotonin and norepinephrine re-uptake inhibitor) OR (serotonin-norepinephrine reuptake e Updated to include analysis of antidepressant subtypes and timing of drug administration relative to training ( ) f Search strategies updated to include common antidepressant subtypes, in addition to SSRIs ( )

6 inhibitors) OR (Duloxetine) OR (Levomilnacipran) OR (Sibutramine) OR (Bicifadine) OR (Venlafaxine) OR (Desvenlafaxine) OR (Milnacipran) OR (Tramadol) OR (TCA) OR (TCAs) OR (tricyclic antidepressant) OR (tricyclic antidepressants) OR (tricyclic anti-depressant) OR (tricyclic anti-depressants) OR (Amitriptyline) OR (Butriptyline) OR (Clomipramine) OR (Desipramine) OR (Dosulepin) OR (Doxepin) OR (Imipramine) OR (Iprindole) OR (Lofepramine) OR (Melitracen) OR (Melitracene) OR (Nortriptyline) OR (Opipramol) OR (Protriptyline) OR (Trimipramine) OR (SARI) OR (SARIs) OR (serotonin antagonist and reuptake inhibitor) OR (serotonin antagonist and reuptake inhibitors) OR (serotonin antagonist and re-uptake inhibitor) OR (serotonin antagonist and reuptake inhibitors) OR (Etoperidone) OR (Lorpiprazole) OR (Mepiprazole) OR (Lubazodone) OR (Nefazodone) OR (Trazodone) OR (NRI) OR (NRIs) OR (noradrenaline reuptake inhibitor) OR (noradrenaline reuptake inhibitors) OR (noradrenaline re-uptake inhibitor) OR (noradrenaline re-uptake inhibitors) OR (norepinephrine reuptake inhibitor) OR (norepinephrine reuptake inhibitors) OR (norepinephrine re-uptake inhibitor) OR (norepinephrine re-uptake inhibitors) OR (Atomoxetine) OR (Reboxetine) OR (Viloxazine) OR (NDRI) OR (NDRIs) OR (norepinephrine dopamine reuptake inhibitor) OR (norepinephrine dopamine reuptake inhibitors) OR (norepinephrine dopamine re-uptake inhibitor) OR (norepinephrine dopamine re-uptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine-dopamine re-uptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine and dopamine reuptake inhibitor) OR (norepinephrine and dopamine reuptake inhibitors) OR (norepinephrine and dopamine re-uptake inhibitor) OR (norepinephrine and dopamine re-uptake inhibitors) OR (noradrenaline dopamine reuptake inhibitor) OR (noradrenaline dopamine reuptake inhibitors) OR (noradrenaline dopamine re-uptake inhibitor) OR (noradrenaline dopamine re-uptake inhibitors) OR (noradrenaline-dopamine reuptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline-dopamine re-uptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline and dopamine reuptake inhibitor) OR (noradrenaline and dopamine reuptake inhibitors) OR (noradrenaline and dopamine re-uptake inhibitor) OR (noradrenaline and dopamine re-uptake inhibitors) OR (Bupropion) OR (Dexmethylphenidate) OR (Methylphenidate) OR (NDRA) OR (NDRAs) OR (norepinephrine dopamine releasing agent) OR (norepinephrine dopamine releasing agents) OR (norepinephrine-dopamine releasing agent) OR (norepinephrine-dopamine releasing agents) OR (norepinephrine and dopamine releasing agent) OR (norepinephrine and dopamine releasing agents) OR (noradrenaline dopamine releasing agent) OR (noradrenaline dopamine releasing agents) OR (noradrenaline-dopamine releasing agent) OR (noradrenaline-dopamine releasing agents) OR (noradrenaline and dopamine releasing agent) OR (noradrenaline and dopamine releasing agents) OR (Amphetamine) OR (Dextroamphetamine) OR (Dextromethamphetamine) OR (Lisdexamfetamine) OR (TeCA) OR (TeCAs) OR (tetracyclic antidepressant) OR (tetracyclic antidepressants) OR (tetracyclic antidepressant) OR (tetracyclic anti-depressants) OR (Amoxapine) OR (Maprotiline) OR (Mianserin) OR (Mirtazapine) OR (MAOI) OR (MAOIs) OR (monoamine oxidase inhibitor) OR (monoamine oxidase inhibitors) OR (Isocarboxazid) OR (Moclobemide) OR (Phenelzine) OR (Pirlindole) OR (Selegiline) OR (Tranylcypromine) OR (antidepressant) OR (antidepressants) OR (antidepressant) OR (anti-depressants)) NOT

7 (review[publication Type] OR liver OR kidney OR coronary OR myocardial OR testis OR testicular OR gastric OR mesenteric OR skeletal OR prostate) Filters: Other Animals WOS search strategy: Science Citation Index Expanded (SCI-EXPANDED) 1900-present Conference Proceedings Citation Index Science (CPCI-) 1900-present Document Types=(Article OR Abstract of Published Item OR Correction OR Correction, Addition OR Letter OR Meeting Abstract OR Proceedings Paper OR Reprint) TS=(stroke OR ((cerebral OR brain OR focal) AND (ischemia OR ischemic OR ischaemia OR ischaemic)) OR cerebrovascular OR middle cerebral artery OR MCA OR middle cerebral artery occlusion OR MCAO OR anterior cerebral artery OR ACA OR anterior cerebral artery occlusion OR ACAO OR experimental stroke) AND TS=((SSRI) OR (SSRIs) OR (selective serotonin reuptake inhibitor) OR (selective serotonin reuptake inhibitors) OR (selective serotonin re-uptake inhibitor) OR (selective serotonin re-uptake inhibitors) OR (selective serotonin-reuptake inhibitors) OR (selective serotonin-reuptake inhibitor) OR (fluoxetine) OR (citalopram) OR (Escitalopram) OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR (dapoxetine) OR (SNRI) OR (SNRIs) OR (serotonin and noradrenaline reuptake inhibitors) OR (serotonin and noradrenaline reuptake inhibitor) OR (serotonin and noradrenaline re-uptake inhibitors) OR (serotonin and noradrenaline re-uptake inhibitor) OR (serotonin-noradrenaline reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitor) OR (serotonin and norepinephrine re-uptake inhibitors) OR (serotonin and norepinephrine re-uptake inhibitor) OR (serotonin- norepinephrine reuptake inhibitors) OR (Duloxetine) OR (Levomilnacipran) OR (Sibutramine) OR (Bicifadine) OR (Venlafaxine) OR (Desvenlafaxine) OR (Milnacipran) OR (Tramadol) OR (TCA) OR (TCAs) OR (tricyclic antidepressant) OR (tricyclic antidepressants) OR (tricyclic anti-depressant) OR (tricyclic anti-depressants) OR (Amitriptyline) OR (Butriptyline) OR (Clomipramine) OR (Desipramine) OR (Dosulepin) OR (Doxepin) OR (Imipramine) OR (Iprindole) OR (Lofepramine) OR (Melitracen) OR (Nortriptyline) OR (Opipramol) OR (Protriptyline) OR (Trimipramine) OR (SARI) OR (SARIs) OR (serotonin antagonist and reuptake inhibitor) OR (serotonin antagonist and reuptake inhibitors) OR (serotonin antagonist and re-uptake inhibitor) OR (serotonin antagonist and re-uptake inhibitors) OR (Etoperidone) OR (Lorpiprazole) OR (Mepiprazole) OR (Lubazodone) OR (Nefazodone) OR (Trazodone) OR (NRI) OR (NRIs) OR (noradrenaline reuptake inhibitor) OR (noradrenaline reuptake inhibitors) OR (noradrenaline re-uptake inhibitor) OR (noradrenaline re-uptake inhibitors) OR (norepinephrine reuptake inhibitor) OR (norepinephrine reuptake inhibitors) OR (norepinephrine re-uptake inhibitor) OR (norepinephrine re-uptake inhibitors) OR (Atomoxetine) OR (Reboxetine) OR (Viloxazine) OR (NDRI) OR (NDRIs) OR (norepinephrine dopamine reuptake inhibitor) OR (norepinephrine dopamine

8 reuptake inhibitors) OR (norepinephrine dopamine re-uptake inhibitor) OR (norepinephrine dopamine re-uptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine-dopamine re-uptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine and dopamine reuptake inhibitor) OR (norepinephrine and dopamine reuptake inhibitors) OR (norepinephrine and dopamine re-uptake inhibitor) OR (norepinephrine and dopamine re-uptake inhibitors) OR (noradrenaline dopamine reuptake inhibitor) OR (noradrenaline dopamine reuptake inhibitors) OR (noradrenaline dopamine re-uptake inhibitor) OR (noradrenaline dopamine re-uptake inhibitors) OR (noradrenaline-dopamine reuptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline-dopamine re-uptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline and dopamine reuptake inhibitor) OR (noradrenaline and dopamine reuptake inhibitors) OR (noradrenaline and dopamine re-uptake inhibitor) OR (noradrenaline and dopamine re-uptake inhibitors) OR (Bupropion) OR (Dexmethylphenidate) OR (Methylphenidate) OR (NDRA) OR (NDRAs) OR (norepinephrine dopamine releasing agent) OR (norepinephrine dopamine releasing agents) OR (norepinephrine-dopamine releasing agent) OR (norepinephrine-dopamine releasing agents) OR (norepinephrine and dopamine releasing agent) OR (norepinephrine and dopamine releasing agents) OR (noradrenaline dopamine releasing agent) OR (noradrenaline dopamine releasing agents) OR (noradrenaline-dopamine releasing agent) OR (noradrenaline-dopamine releasing agents) OR (noradrenaline and dopamine releasing agent) OR (noradrenaline and dopamine releasing agents) OR (Amphetamine) OR (Dextroamphetamine) OR (Dextromethamphetamine) OR (Lisdexamfetamine) OR (TeCA) OR (TeCAs) OR (tetracyclic antidepressant) OR (tetracyclic antidepressants) OR (tetracyclic antidepressant) OR (tetracyclic anti-depressants) OR (Amoxapine) OR (Maprotiline) OR (Mianserin) OR (Mirtazapine) OR (MAOI) OR (MAOIs) OR (monoamine oxidase inhibitor) OR (monoamine oxidase inhibitors) OR (Isocarboxazid) OR (Moclobemide) OR (Phenelzine) OR (Pirlindole) OR (Selegiline) OR (Tranylcypromine) OR (antidepressant) OR (antidepressants) OR (antidepressant) OR (anti-depressants)) AND TS=(( animal experimentation OR models, animal OR invertebrates OR Animals OR animal population groups OR chordata OR chordata, nonvertebrate OR vertebrates OR amphibians OR birds OR fishes OR reptiles OR mammals OR primates OR artiodactyla OR carnivora OR cetacea OR chiroptera OR elephants OR hyraxes OR insectivora OR lagomorpha OR marsupialia OR monotremata OR perissodactyla OR rodentia OR scandentia OR sirenia OR xenarthra OR haplorhini OR strepsirhini OR platyrrhini OR tarsii OR catarrhini OR cercopithecidae OR hylobatidae OR hominidae OR gorilla gorilla OR pan paniscus OR pan troglodytes OR pongo pygmaeus ) OR (animals OR animal OR mice OR mus OR mouse OR murine OR woodmouse OR rats OR rat OR murinae OR muridae OR cottonrat OR cottonrats OR hamster OR hamsters OR cricetinae OR rodentia OR rodent OR rodents OR pigs OR pig OR swine OR swines OR piglets OR piglet OR boar OR boars OR sus scrofa OR ferrets OR ferret OR polecat OR polecats OR mustela putorius OR guinea pigs OR guinea pig OR cavia OR callithrix OR marmoset OR marmosets OR cebuella OR hapale OR octodon OR chinchilla OR chinchillas OR gerbillinae OR gerbil OR gerbils OR jird OR jirds OR merione OR meriones OR rabbits OR rabbit OR hares OR hare OR diptera OR flies

9 OR fly OR dipteral OR drosophila OR drosophilidae OR cats OR cat OR carus OR felis OR nematoda OR nematode OR nematodes OR sipunculida OR dogs OR dog OR canine OR canines OR canis OR sheep OR sheeps OR mouflon OR mouflons OR ovis OR goats OR goat OR capra OR capras OR rupicapra OR rupicapras OR chamois OR haplorhini OR monkey OR monkeys OR anthropoidea OR anthropoids OR saguinus OR tamarin OR tamarins OR leontopithecus OR hominidae OR ape OR apes OR pan paniscus OR bonobo OR bonobos OR pan troglodytes OR gibbon OR gibbons OR siamang OR siamangs OR nomascus OR symphalangus OR chimpanzee OR chimpanzees OR prosimian OR prosimians OR bush baby OR bush babies OR galagos OR galago OR pongidae OR gorilla OR gorillas OR pongo pygmaeus OR orangutan OR orangutans OR lemur OR lemurs OR lemuridae OR horse OR horses OR equus OR cow OR calf OR bull OR chicken OR chickens OR gallus OR quail OR bird OR birds OR quails OR poultry OR poultries OR fowl OR fowls OR reptile OR reptilia OR reptiles OR snakes OR snake OR lizard OR lizards OR alligator OR alligators OR crocodile OR crocodiles OR turtle OR turtles OR amphibian OR amphibians OR amphibia OR frog OR frogs OR bombina OR salientia OR toad OR toads OR epidalea calamita OR salamander OR salamanders OR eel OR eels OR fish OR fishes OR pisces OR catfish OR catfishes OR siluriformes OR arius OR heteropneustes OR sheatfish OR perch OR perches OR percidae OR perca OR trout OR trouts OR char OR chars OR salvelinus OR minnow OR cyprinidae OR carps OR carp OR zebrafish OR zebrafishes OR goldfish OR goldfishes OR guppy OR guppies OR chub OR chubs OR tinca OR barbels OR barbus OR pimephales OR promelas OR poecilia reticulata OR mullet OR mullets OR eel OR eels OR seahorse OR seahorses OR mugil curema OR atlantic cod OR shark OR sharks OR catshark OR anguilla OR salmonid OR salmonids OR whitefish OR whitefishes OR salmon OR salmons OR sole OR solea OR lamprey OR lampreys OR pumpkinseed OR sunfish OR sunfishes OR tilapia OR tilapias OR turbot OR turbots OR flatfish OR flatfishes OR sciuridae OR squirrel OR squirrels OR chipmunk OR chipmunks OR suslik OR susliks OR vole OR voles OR lemming OR lemmings OR muskrat OR muskrats OR lemmus OR otter OR otters OR marten OR martens OR martes OR weasel OR badger OR badgers OR ermine OR mink OR minks OR sable OR sables OR gulo OR gulos OR wolverine OR wolverines OR mustela OR llama OR llamas OR alpaca OR alpacas OR camelid OR camelids OR guanaco OR guanacos OR chiroptera OR chiropteras OR bat OR bats OR fox OR foxes OR iguana OR iguanas OR xenopus laevis OR parakeet OR parakeets OR parrot OR parrots OR donkey OR donkeys OR mule OR mules OR zebra OR zebras OR shrew OR shrews OR bison OR bisons OR buffalo OR buffaloes OR deer OR deers OR bear OR bears OR panda OR pandas OR wild hog OR wild boar OR fitchew OR fitch OR beaver OR beavers OR jerboa OR jerboas OR capybara OR capybaras)) NOT TS=(liver OR kidney OR coronary OR myocardial OR testis OR testicular OR gastric OR mesenteric OR skeletal) BIOSIS search strategy: Document Types= (Article OR Letter OR Meeting OR Meeting Paper OR Reprint OR Thesis Dissertation) AND Taxa Notes=(Nonhuman Mammals OR Nonhuman Primates OR Nonhuman Vertebrates) TS=(stroke OR ((cerebral OR brain OR focal) AND (ischemia OR ischemic OR

10 ischaemia OR ischaemic)) OR cerebrovascular OR middle cerebral artery OR MCA OR middle cerebral artery occlusion OR MCAO OR anterior cerebral artery OR ACA OR anterior cerebral artery occlusion OR ACAO OR experimental stroke) AND TS=((SSRI) OR (SSRIs) OR (selective serotonin reuptake inhibitor) OR (selective serotonin reuptake inhibitors) OR (selective serotonin re-uptake inhibitor) OR (selective serotonin re-uptake inhibitors) OR (selective serotonin-reuptake inhibitors) OR (selective serotonin-reuptake inhibitor) OR (fluoxetine) OR (citalopram) OR (Escitalopram) OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR (dapoxetine) OR (SNRI) OR (SNRIs) OR (serotonin and noradrenaline reuptake inhibitors) OR (serotonin and noradrenaline reuptake inhibitor) OR (serotonin and noradrenaline re-uptake inhibitors) OR (serotonin and noradrenaline re-uptake inhibitor) OR (serotonin-noradrenaline reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitor) OR (serotonin and norepinephrine re-uptake inhibitors) OR (serotonin and norepinephrine re-uptake inhibitor) OR (serotonin- norepinephrine reuptake inhibitors) OR (Duloxetine) OR (Levomilnacipran) OR (Sibutramine) OR (Bicifadine) OR (Venlafaxine) OR (Desvenlafaxine) OR (Milnacipran) OR (Tramadol) OR (TCA) OR (TCAs) OR (tricyclic antidepressant) OR (tricyclic antidepressants) OR (tricyclic anti-depressant) OR (tricyclic anti-depressants) OR (Amitriptyline) OR (Butriptyline) OR (Clomipramine) OR (Desipramine) OR (Dosulepin) OR (Doxepin) OR (Imipramine) OR (Iprindole) OR (Lofepramine) OR (Melitracen) OR (Nortriptyline) OR (Opipramol) OR (Protriptyline) OR (Trimipramine) OR (SARI) OR (SARIs) OR (serotonin antagonist and reuptake inhibitor) OR (serotonin antagonist and reuptake inhibitors) OR (serotonin antagonist and re-uptake inhibitor) OR (serotonin antagonist and re-uptake inhibitors) OR (Etoperidone) OR (Lorpiprazole) OR (Mepiprazole) OR (Lubazodone) OR (Nefazodone) OR (Trazodone) OR (NRI) OR (NRIs) OR (noradrenaline reuptake inhibitor) OR (noradrenaline reuptake inhibitors) OR (noradrenaline re-uptake inhibitor) OR (noradrenaline re-uptake inhibitors) OR (norepinephrine reuptake inhibitor) OR (norepinephrine reuptake inhibitors) OR (norepinephrine re-uptake inhibitor) OR (norepinephrine re-uptake inhibitors) OR (Atomoxetine) OR (Reboxetine) OR (Viloxazine) OR (NDRI) OR (NDRIs) OR (norepinephrine dopamine reuptake inhibitor) OR (norepinephrine dopamine reuptake inhibitors) OR (norepinephrine dopamine re-uptake inhibitor) OR (norepinephrine dopamine re-uptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine re-uptake inhibitors) OR (norepinephrine and dopamine reuptake inhibitor) OR (norepinephrine and dopamine reuptake inhibitors) OR (norepinephrine and dopamine re-uptake inhibitor) OR (norepinephrine and dopamine re-uptake inhibitors) OR (noradrenaline dopamine reuptake inhibitor) OR (noradrenaline dopamine reuptake inhibitors) OR (noradrenaline dopamine re-uptake inhibitor) OR (noradrenaline dopamine re-uptake inhibitors) OR (noradrenaline-dopamine reuptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline-dopamine re-uptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline and dopamine reuptake inhibitor) OR (noradrenaline and dopamine reuptake inhibitors) OR (noradrenaline and dopamine re-uptake inhibitor) OR (noradrenaline and dopamine re-uptake inhibitors) OR (Bupropion) OR (Dexmethylphenidate) OR (Methylphenidate) OR (NDRA) OR (NDRAs) OR (norepinephrine dopamine releasing agent) OR (norepinephrine dopamine releasing agents) OR (norepinephrine-dopamine

11 releasing agent) OR (norepinephrine-dopamine releasing agents) OR (norepinephrine and dopamine releasing agent) OR (norepinephrine and dopamine releasing agents) OR (noradrenaline dopamine releasing agent) OR (noradrenaline dopamine releasing agents) OR (noradrenaline-dopamine releasing agent) OR (noradrenaline-dopamine releasing agents) OR (noradrenaline and dopamine releasing agent) OR (noradrenaline and dopamine releasing agents) OR (Amphetamine) OR (Dextroamphetamine) OR (Dextromethamphetamine) OR (Lisdexamfetamine) OR (TeCA) OR (TeCAs) OR (tetracyclic antidepressant) OR (tetracyclic antidepressants) OR (tetracyclic antidepressant) OR (tetracyclic anti-depressants) OR (Amoxapine) OR (Maprotiline) OR (Mianserin) OR (Mirtazapine) OR (MAOI) OR (MAOIs) OR (monoamine oxidase inhibitor) OR (monoamine oxidase inhibitors) OR (Isocarboxazid) OR (Moclobemide) OR (Phenelzine) OR (Pirlindole) OR (Selegiline) OR (Tranylcypromine) OR (antidepressant) OR (antidepressants) OR (anti-depressant) OR (anti-depressants)) NOT TS=(liver OR kidney OR coronary OR myocardial OR testis OR testicular OR gastric OR mesenteric OR skeletal) Embase search strategy: limited to (animals and (article or conference abstract or conference paper or erratum or letter or note or report)) stroke OR ((cerebral OR brain OR focal) AND (ischemia OR ischemic OR ischaemia OR ischaemic)) OR cerebrovascular OR middle cerebral artery OR MCA OR middle cerebral artery occlusion OR MCAO OR anterior cerebral artery OR ACA OR anterior cerebral artery occlusion OR ACAO OR experimental stroke AND (SSRI) OR (SSRIs) OR (selective serotonin reuptake inhibitor) OR (selective serotonin reuptake inhibitors) OR (selective serotonin re-uptake inhibitor) OR (selective serotonin re-uptake inhibitors) OR (selective serotonin-reuptake inhibitors) OR (selective serotonin-reuptake inhibitor) OR (fluoxetine) OR (citalopram) OR (Escitalopram) OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR (dapoxetine) OR (SNRI) OR (SNRIs) OR (serotonin and noradrenaline reuptake inhibitors) OR (serotonin and noradrenaline reuptake inhibitor) OR (serotonin and noradrenaline re-uptake inhibitors) OR (serotonin and noradrenaline re-uptake inhibitor) OR (serotonin-noradrenaline reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitors) OR (serotonin and norepinephrine reuptake inhibitor) OR (serotonin and norepinephrine re-uptake inhibitors) OR (serotonin and norepinephrine re-uptake inhibitor) OR (serotonin- norepinephrine reuptake inhibitors) OR (Duloxetine) OR (Levomilnacipran) OR (Sibutramine) OR (Bicifadine) OR (Venlafaxine) OR (Desvenlafaxine) OR (Milnacipran) OR (Tramadol) OR (TCA) OR (TCAs) OR (tricyclic antidepressant) OR (tricyclic antidepressants) OR (tricyclic anti-depressant) OR (tricyclic anti-depressants) OR (Amitriptyline) OR (Butriptyline) OR (Clomipramine) OR (Desipramine) OR (Dosulepin) OR (Doxepin) OR (Imipramine) OR (Iprindole) OR (Lofepramine) OR (Melitracen) OR (Nortriptyline) OR (Opipramol) OR (Protriptyline) OR (Trimipramine) OR (SARI) OR (SARIs) OR (serotonin antagonist and reuptake

12 inhibitor) OR (serotonin antagonist and reuptake inhibitors) OR (serotonin antagonist and re-uptake inhibitor) OR (serotonin antagonist and re-uptake inhibitors) OR (Etoperidone) OR (Lorpiprazole) OR (Mepiprazole) OR (Lubazodone) OR (Nefazodone) OR (Trazodone) OR (NRI) OR (NRIs) OR (noradrenaline reuptake inhibitor) OR (noradrenaline reuptake inhibitors) OR (noradrenaline re-uptake inhibitor) OR (noradrenaline re-uptake inhibitors) OR (norepinephrine reuptake inhibitor) OR (norepinephrine reuptake inhibitors) OR (norepinephrine re-uptake inhibitor) OR (norepinephrine re-uptake inhibitors) OR (Atomoxetine) OR (Reboxetine) OR (Viloxazine) OR (NDRI) OR (NDRIs) OR (norepinephrine dopamine reuptake inhibitor) OR (norepinephrine dopamine reuptake inhibitors) OR (norepinephrine dopamine re-uptake inhibitor) OR (norepinephrine dopamine re-uptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine reuptake inhibitors) OR (norepinephrine-dopamine reuptake inhibitor) OR (norepinephrine-dopamine re-uptake inhibitors) OR (norepinephrine and dopamine reuptake inhibitor) OR (norepinephrine and dopamine reuptake inhibitors) OR (norepinephrine and dopamine re-uptake inhibitor) OR (norepinephrine and dopamine re-uptake inhibitors) OR (noradrenaline dopamine reuptake inhibitor) OR (noradrenaline dopamine reuptake inhibitors) OR (noradrenaline dopamine re-uptake inhibitor) OR (noradrenaline dopamine re-uptake inhibitors) OR (noradrenaline-dopamine reuptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline-dopamine re-uptake inhibitor) OR (noradrenaline-dopamine reuptake inhibitors) OR (noradrenaline and dopamine reuptake inhibitor) OR (noradrenaline and dopamine reuptake inhibitors) OR (noradrenaline and dopamine re-uptake inhibitor) OR (noradrenaline and dopamine re-uptake inhibitors) OR (Bupropion) OR (Dexmethylphenidate) OR (Methylphenidate) OR (NDRA) OR (NDRAs) OR (norepinephrine dopamine releasing agent) OR (norepinephrine dopamine releasing agents) OR (norepinephrine-dopamine releasing agent) OR (norepinephrine-dopamine releasing agents) OR (norepinephrine and dopamine releasing agent) OR (norepinephrine and dopamine releasing agents) OR (noradrenaline dopamine releasing agent) OR (noradrenaline dopamine releasing agents) OR (noradrenaline-dopamine releasing agent) OR (noradrenaline-dopamine releasing agents) OR (noradrenaline and dopamine releasing agent) OR (noradrenaline and dopamine releasing agents) OR (Amphetamine) OR (Dextroamphetamine) OR (Dextromethamphetamine) OR (Lisdexamfetamine) OR (TeCA) OR (TeCAs) OR (tetracyclic antidepressant) OR (tetracyclic antidepressants) OR (tetracyclic antidepressant) OR (tetracyclic anti-depressants) OR (Amoxapine) OR (Maprotiline) OR (Mianserin) OR (Mirtazapine) OR (MAOI) OR (MAOIs) OR (monoamine oxidase inhibitor) OR (monoamine oxidase inhibitors) OR (Isocarboxazid) OR (Moclobemide) OR (Phenelzine) OR (Pirlindole) OR (Selegiline) OR (Tranylcypromine) OR (antidepressant) OR (antidepressants) OR (anti-depressant) OR (anti-depressants) NOT liver OR kidney OR coronary OR myocardial OR testis OR testicular OR gastric OR mesenteric OR skeletal References 1 Hackett, M. L., Yapa, C., Parag, V. & Anderson, C. S. Frequency of depression after stroke: a systematic review of observational studies. Stroke 36, , doi: /01.str (2005).

13 2 Chen, C., Leys, D. & Esquenazi, A. The interaction between neuropsychological and motor deficits in patients after stroke. Neurology 80, S27-34, doi: /wnl.0b013e (2013). 3 Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 10, , doi: /s (10) (2011). 4 Pariente, J. et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 50, (2001). 5 Acler, M., Robol, E., Fiaschi, A. & Manganotti, P. A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients. J Neurol 256, , doi: /s (2009). 6 Berends, H. I. et al. The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke; a Cochrane systematic review. Eur J Phys Rehabil Med 45, (2009). 7 Berends, H. I., Nijlant, J., van Putten, M., Movig, K. L. & MJ, I. J. Single dose of fluoxetine increases muscle activation in chronic stroke patients. Clin Neuropharmacol 32, 1-5 (2009). 8 Murphy, T. H. & Corbett, D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 10, , doi: /nrn2735 (2009). 9 Nibuya, M., Morinobu, S. & Duman, R. S. Regulation of BDNF and trkb mrna in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15, (1995). 10 Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, , doi: /science (2003). 11 Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, , doi: /j.cell (2008). 12 Boldrini, M. & Arango, V. Antidepressants, age, and neuroprogenitors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35, , doi: /npp (2010). 13 Castren, E. & Rantamaki, T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 70, , doi: /dneu (2010). 14 Groves, J. O. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 12, , doi: /sj.mp (2007).