Study characteristics

Methods

Study type: interventional (clinical trial)

Intervention model: parallel assignment

Primary purpose: treatment

Participants

20 participants

Location: Italy

Setting: inpatient

Inclusion criteria: first‐ever ischaemic stroke, CT or MRI documenting a single monohemispheric lesion, age below 80 years, within 3 months of onset

Exclusion criteria: major affective disorders, alcohol abuse and dementia leading to un‐cooperative behaviour, pacemakers, metal in the head, concomitant neuropathies, systemic vasculopathies, major affective disorders

Treatment: 10 people, mean age 68 ± 7 years, 6 men

Control: 10 people, mean age 65 ± 7 years, 6 men

Interventions

Citalopram 10 mg daily

Placebo: identical pill daily

Duration of treatment: at least 4 months

Duration of follow‐up: not stated

Outcomes

Motor cortex excitability

NIHSS

Lindmark Scale

BI

HDRS

BDI

No data on death, GI upset, bleeds or seizures

Funding source

Source of funding not stated; unclear whether or not a drug company was involved in the study

Notes

Dates of study not stated. Any conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Stated blinded, placebo was 'an identical pill'

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Stated blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

It is not stated whether data from all recruited participants are reported

Selective reporting (reporting bias)

High risk

Side effects were not reported although they were assessed

Other bias

Unclear risk

−

Study characteristics

Methods

Multicentre

Study type: interventional (clinical trial)

Allocation: randomised

Intervention model: parallel assignment

Masking: quadruple (participant, care provider, investigator, outcomes assessor)

Primary purpose: treatment

Participants

1280 participants

Country: Australia (n = 532), New Zealand (n = 42), and Vietnam (n = 706)

Setting: inpatient

At randomisation number allocated: N = 1280: fluoxetine (n = 642); placebo (n = 638)

% male: fluoxetine (64%); placebo (62%)

Age: mean age: fluoxetine = 63.5± 12.5; placebo = 64.6 ± 12.2

Subtype of stroke

• Total anterior circulation infarct: fluoxetine (9%); placebo (9%)

• Partial anterior circulation infarct: fluoxetine (49%); placebo (52%)

• Lacunar infarct: fluoxetine (21%); placebo (105%)

• Posterior circulation infarct: fluoxetine (114%); placebo (103%)

• Uncertain: fluoxetine (2%); placebo (1%)

Inclusion criteria

• Age > 18 years

• Clinical diagnosis of stroke 2 to 15 days previously

• Brain imaging consistent with ischaemic or haemorrhagic stroke (including normal CT brain scan)

• Persisting measurable focal neurological deficits causing a functional deficit at the time of randomisation

Exclusion criteria:

• History of epileptic seizures

• History of bipolar disorder

• History of drug overdose or attempted suicide

• Ongoing treatment with any selective serotonin reuptake inhibitor

• Allergy or contra‐indication to fluoxetine

• Use of medications that may interact seriously with fluoxetine

• Not available for follow‐up over the next 365 days e.g. no fixed home address

• Life‐threatening illness (e.g. advanced cancer) that is likely to reduce 365‐day survival

• Pregnant, breast‐feeding or of child‐bearing potential and not using contraception

• Enrolled in another interventional clinical research trial involving an investigational product (medicine) or device

Interventions

Fluoxetine 20 mg once daily or matching placebo capsules for 6 months

Outcomes

Primary outcome

• Functional outcome as measured by the mRS at 180 days after randomisation

Secondary outcomes at 180 and 365 days after randomisation

• Survival

• Mood (PHQ‐9)

• Cognitive function (TICSm)

• Communication (SIS)

• Motor function (SIS)

• Overall health status (SIS)

• Health‐Related Quality of Life (HRQoL) (EuroQol)

• Functional recovery (smRSq) at the 365‐day assessments

• New diagnosis of depression requiring treatment with antidepressants

• Fatigue (vitality domain of the SF‐36)

• Serious adverse events at any time during follow‐up including new stroke, acute coronary syndrome, epileptic seizures, fall, new fractures or death

Funding source

The AFFINITY trial was funded by the Australian NHMRC Project Grant 1059094. The minimisation algorithm was provided by The Stroke Research Group, Division of Clinical Neuroscience, University of Edinburgh, Edinburgh, UK

Notes

ACTRN12611000774921Recruitment January 11, 2013, and June 30, 2019. GJH has received grants from the NHMRC of Australia, Vetenskapsrådet (The Swedish Research Council), and UK National Institute for Health Research Technology, during the conduct of the study; and personal fees from the American Heart Association, outside of the submitted work. MLH, CE‐B, LB, and TL have received grants from the NHMRC of Australia during the conduct of the study. CSA has received grants from the NHMRC of Australia, and grants and personal fees from Takeda, outside of the submitted work. All other members of the writing group declare no competing interests.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: " The patient’s clinician entered the patient’s baseline data into a secure, password‐protected, centralised, web‐based randomisation system that checked the data for completeness and consistency and generated a unique study identification number and treatment pack number corresponding to fluoxetine or placebo in a 1:1 ratio."

Allocation concealment (selection bias)

Low risk

Quote: " All patients, carers, investigators, and outcome assessors were masked to the allocated treatment by use of placebo capsules that were visually identical to the fluoxetine capsules even when broken open. Success of masking was not assessed."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "All patients, carers, investigators, and outcome assessors were masked to the allocated treatment by use of placebo capsules that were visually identical to the fluoxetine capsules even when broken open. Success of masking was not assessed."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All patients, carers, investigators, and outcome assessors were masked to the allocated treatment by use of placebo capsules that were visually identical to the fluoxetine capsules even when broken open. Success of masking was not assessed."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Less than 5% dropped out or died and there is no compelling evidence of a difference between the 2 groups

Selective reporting (reporting bias)

Low risk

All outcomes in protocol were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

Parallel design

Analysis: ITT (last observation carried forward), withdrawn owing to becoming depressed, AE, treating practitioner started antidepressant, medical advice, no reason given, not contactable ‐ numbers not included

Participants

Location: Australia

Setting: inpatient

Treatment: 55 people, mean ± SD age 68 ± 13 years, 67% men

Control: 56 people, mean ± SD age 67 ± 13 years, 62% men

Stroke criteria: acute ischaemic or haemorrhagic stroke, diagnosis by clinical signs (ICD‐10) and CT (100% imaged, 10/111 CT scan did not show acute ischaemia); stroke on average < 2 weeks prior to randomisation

Not depressed (HADS‐D had to be over 7)

Other entry criteria: not stated

Comparability of treatment groups: more participants in treatment group with previous heart attack and stroke, also higher levels of hypertension

Exclusion criteria: severe communication difficulties, unstable medical condition, severe cognitive impairment and depression (MMSE < 10), taking antidepressants within 4 weeks of stroke, contraindication to sertraline, previous reaction to sertraline, could not speak English

Interventions

Treatment: sertraline 50 mg daily (night)

Control: matched placebo

Duration: treatment continued for 24 weeks

Duration of follow‐up (post‐treatment to study end): 28 weeks

Outcomes

Depression: change in scores from baseline to end of treatment on HDRS, proportion depressed

Change in MMSE scores

mRS

Death

Leaving the trial early

Check list of possible AEs read out to participant by a research nurse

Funding source

Funded by an unrestricted grant from Rotary Health Research Fund

Notes

Recruitment June 2004 to June 2006

Conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Centralised

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Stated in paper, matched placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated in paper

Incomplete outcome data (attrition bias)
All outcomes

High risk

Performed last observation carried forward

Selective reporting (reporting bias)

Low risk

Trial protocol published on www.strokecentre.org/trials . This weblink is no longer available so we have been unable to check whether all the outcomes were reported. We have contacted the author to check this‐who confirm that all endpoints were reported

Other bias

Low risk

No other obvious biases

Study characteristics

Methods

Parallel design

Analysis (ITT) last observation carried forward and per protocol: death (1 treatment, 1 control) withdrawn owing to AE (6 treatment, 1 control), all excluded from analysis

Participants

Location: Denmark

Setting: mixed

Treatment: 33 people, mean ± SD age 68 ± 4 years, 36% men

Control: 33 people, mean ± SD age 66 ± 9 years, 66% men

Stroke criteria: ischaemic stroke and PICH; diagnosis via clinical signs and CT (100%); stroke 2 to 52 weeks prior to randomisation (average time 12 weeks)

Depression criteria: HDRS score > 12 (score transformed to appropriate DSM‐III‐R criteria)

Other entry criteria: none stated

Comparability of treatment groups: balanced

Exclusion criteria: depression within last year, receiving current treatment for depression, severe dementia or communication problems, degenerative or expansive neurological disease, decreased consciousness

Interventions

Experimental: citalopram 10 mg in participants > 66 years, 20 mg in participants < 67 years daily; dose doubled if no response to treatment within 3 weeks

Comparator: matched placebo

Duration: treatment continued for 6 weeks

Duration of follow‐up (post‐treatment to study end): 0

Note that although the protocol on www.strokecentre.org/trials states that mood scores were measured up to 1 year post‐stroke, this probably refers to the time since stroke at the time of randomisation

Outcomes

Depression: change in scores from baseline to end of treatment on HDRS

Melancholia scale

Proportion no longer meeting entry criteria (< 13 on HDRS)

50% reduction in HDRS score

Additional: leaving the study early

Death

AEs (unwanted drug effects were registered and evaluated at the same intervals using a side effect scale)

Unable to use: BI, Social Activities Index, MMSE (data not presented)

Funding source

Funded by Lundbeck Foundation, Medical Research Foundation for North Jutland County, The Aalgorg Diocese Research Foundation, Consultant Otorhinolaryngologist Kopp's Foundation and Stine and Martinus Sorensen's Foundation. Lundbeck Pharma A/S provided the citalopram and placebo; thus we have classified this as 'unclear risk'.

Notes

Recruitment 1 February 1991 to 29 February 1992. Conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Blocks of 4 used

Allocation concealment (selection bias)

Low risk

Centralised opaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Matched placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Those who were blinded were not stated

Incomplete outcome data (attrition bias)
All outcomes

High risk

Although there were dropouts, analysis performed both per protocol and using last observation carried forward

Selective reporting (reporting bias)

High risk

Trial published on www.strokecentre.org/trials

The primary outcome was reported. We have been unable to access this record on 28 September 2021, the paper also describes the social activities index in the list of outcomes but this was not reported in the results so we have changed this to high risk of bias for this 2021 update

Other bias

Unclear risk

−

Study characteristics

Methods

Multicentre

Study type: interventional (clinical trial)

Intervention model: parallel assignment

Primary purpose: treatment

Participants

642 participants

Country: Denmark

Setting: inpatient

At randomisation number allocated: citalopram n = 319; placebo n = 323

% male at baseline: citalopram n = 199/319 (62%); placebo n = 222/323 (69%)

Age at baseline: mean age, citalopram 68 ± 13 (n = 319); placebo 68 ± 13 (n = 323)

Subtype of stroke at baseline: not available

Severity of stroke at baseline: NIHSS, citalopram 5.3 ± 5.6; placebo 4.8 ± 4.8

Time since stroke onset: mean time from last known 'well' to first treatment 1.7 days (median 1, IQR 0 to 6)

Inclusion criteria:

• First ever ischaemic stroke

• Age > 18 years

Exclusion Criteria

• Haemorrhagic stroke

• Dementia or other neurodegenerative disease

• Antidepressant medical treatment within 6 months of admission

• Acute need for antidepressant treatment

• Drug abuse or other conditions that may indicate non‐compliant behaviour

• Liver failure (increased liver enzyme levels up to or more than 2 times upper limit)

• Renal failure (eGFR below 30 mL/min per 1.73 m²)

• Hyponatremia (S‐potassium below 130 mmol/L

• Actively bleeding ulcer

• Fatal stroke or other severe co‐morbidity that markedly decreases expected life span

• Prolonged corrected QT‐interval (QTc above 480 ms)

• Ongoing treatment with drugs known to prolong the QTc interval

Interventions

Experimental: citalopram 20 mg (10 mg if aged ≥ 65 years or having reduced liver/kidney function) or placebo once daily for 6 months

Comparator: ½ to 2 tablets with no intrinsic drug activity per day for 6 months

Outcomes

Primary outcomes

• Vascular death, TIA/stroke and myocardial infarction within 6 months

• Functional status at 6 months (mRS)

Secondary outcomes within or at 6 months

• Vascular death

• Death of any cause

• TIA/stroke

• Bleeding

• Myocardial infarction

• Disability/dependence (mRS and BI)

• Physical activity (PASE)

• Cognitive and organic cerebral impairment (MMSE and the Symbol Digit Modalities Test)

• Fatigue (Multidimensional Fatigue Inventory)

• Post‐stroke depression (Major Depression Inventory test (MDI), Global depression scale (self and clinician and Hamilton Depression Scale ‐ 6 item (HAM‐D6))

• Pathological crying (Pathological Crying Scale)

• Lesion size (FLAIR positive lesion size on MRI 24 hours after treatment with Alteplase)

Funding source

TrygFonden, the Danish Council for Independent Research, the Regional Medicine Fund, and the Aarhus University Research Foundation

Notes

Dates study conducted: September 2013 to December 2016

Declarations of Interest: Dr Kraglund received speaker honoraria from Bristol‐Meyers Squibb and Pfizer. Dr Iversen received speaker honoraria from Boehringer Ingelheim, Bristol‐Myers Squibb, Bayer, AstraZeneca, and Pfizer and has previously participated in advisory board meetings for Boehringer Ingelheim, Bristol‐Myers Squibb, Pfizer, Bayer, AstraZeneca, and Amgen. Dr Grove has received speaker honoraria from AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, MSD, and Pfizer and has previously participated in advisory board meetings for AstraZeneca, Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb. Dr Andersen reports other from MSD, personal fees from AstraZeneca, outside the submitted work

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computer‐generated randomization code was used to randomize patients in blocks of 10."

Allocation concealment (selection bias)

Low risk

Quote: "Citalopram was commercially available (Sandoz, Denmark) and production of the placebo and randomization was prepared by a pharmacy independently of the investigators (Glostrup Pharmacy, Denmark). The tablets were indistinguishable and were supplied in numbered containers."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participant, care provider, and investigator assured and unlikely that the blinding could have been broken

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessor assured and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes

High risk

Attrition/exclusions reported with reasons provided (including did not start on study medication, consent withdrawn, side effects, indication for open label, other reasons (no detail provided)). At < 31 days of study medication, twice as many participants in the citalopram group withdrew consent (n = 29/318 (9%)) compared to the placebo group (n = 14/320 (4%)). However, at < 31 days twice as many participants in the placebo group (n = 12/318(4%)) compared to the citalopram group (n = 6/320 (2%) were switched to open label. Attrition/exclusions: 51/319 (16%) in the citalopram group and 39/319 (11%) in the placebo group.

The investigators use LOCF in their intention‐to‐treat analysis. LOCF assumes that missing values are missing completely at random and ignores improvements or deteriorations in the participants condition since dropout and therefore stops improvements or declines in outcome measures. LOCF introduces risk of false or biased conclusions (Molnar 2008)

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest to the review have been reported in the prespecified way

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

RCT

Study type: interventional (clinical trial)

Allocation: randomised

Intervention model: parallel assignment

Masking: double (participant, outcomes assessor)

Primary purpose: treatment

Participants

90 participants

Country: Iran

Setting: inpatient

At randomisation number allocated: N = 90: citalopram (n = 30); fluoxetine (n = 30); placebo (n = 30)

% male: citalopram (60%) fluoxetine (50%); placebo (56.6%)

Age: mean age: citalopram = 61.7 ± 9.6; fluoxetine = 60.2 ± 8.52; placebo = 58.7 ± 8.56

Inclusion criteria

• > 18 years of age

• suffering from hemiparesis or hemiplegia as a result of a first‐time acute Ischaemic stroke within the past 24 hours

• an initial Fugl‐Meyer Motor Scale score of under 55

Exclusion criteria

• NIHSS score < 5

• Prior disabilities including aphasia, cognitive disorders and motor disorders due to stroke, or any other neurodegenerative disease

• Pregnancy or breastfeeding

• Currently taking antidepressants

• Contraindications of therapy, including renal insufficiency (glomerular filtration rate < 30mL/min), abnormal liver function tests, hyponatremia, and a long QT interval on an electrocardiogram

• Any significant adverse effects (agitation, hypertension, or other signs of serotonin syndrome) after initiation of treatment

Interventions

Participants were randomly allocated to 1 of 3 groups: Group A received 20 mg orally of fluoxetine daily, Group B received 20 mg orally of citalopram daily, and Group C received a placebo orally. The duration of the therapy was 90 days. In addition to the medications, all of the participants received physiotherapy

Outcomes

FMMS

Funding source

No financial support received

Notes

IRCT20141116019971N3. Recruitment January 2015 to January 2016. Authors declared no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computer‐generated schedule was used by investigators to assign the patients into one of three groups by block randomization: Group A—20mg P.O. daily of citalopram, Group B—20mg P.O. daily of fluoxetine, and Group C—a placebo (microcrystalline cellulose)."

Allocation concealment (selection bias)

Low risk

Computer‐generated schedule confirmed with authors

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "All of the drugs for each group of subjects were over‐encapsulated by a pharmacist."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Three evaluators were used in our study, namely, neurology residents who were blind to the interventions."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

5/90 discontinued medication due to moving away‐but this would not have introduced because the reasons for missing data are unlikely to be related to the true outcome (Quote: "The main reason for participants leaving the study was noncompliance in terms of taking their drugs regularly (10 subjects stopped taking the treatment but completed their follow‐up), while five participants intentionally failed to attend follow‐up after two months because they were resident in other cities distant from the location of the study.")

Selective reporting (reporting bias)

Low risk

There was just one outcome measure planned (see reference on Iranian clinical trials register) and this was reported

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

Study type: interventional (clinical trial)

Actual enrolment 61

Allocation: randomised

Intervention model: parallel assignment

Masking: double (participant, care provider)

Primary purpose: treatment

Participants

61 participants

Country: Poland

Setting: inpatient

At randomisation number allocated: N = 61: fluoxetine (n = 30); placebo (n = 31)

% male: fluoxetine (73.3%); placebo (58.1%)

Age: mean age: fluoxetine = 66.6 ± 12.6; placebo = 66.35 ± 12.46

Subtype of stroke

• Total anterior circulation infarct: fluoxetine (40.0%); placebo (38.7%)

• Partial anterior circulation infarct: fluoxetine (23.3%); placebo (35.5%)

• Lacunar infarct: fluoxetine (6.7%); placebo (0.0%)

• Posterior circulation infarct: fluoxetine (20.0%); placebo (16.1%)

• Uncertain: fluoxetine (2%); placebo (2%)

Severity of stroke: NIHSS, Median (IQR) fluoxetine (5 (3 to 8)); placebo (6 (4 to 8))

Inclusion criteria

• Age ≥ 18 years

• Ischaemic or haemorrhagic stroke confirmed by neuroimaging

• Within 2 to 15 days from the stroke onset

• Evidence of neurological deficit at randomisation

Exclusion criteria

• Subarachnoid haemorrhage (unless secondary to intracerebral bleeding)

• High probability that the patient would not be available during follow‐up (e.g. another life‐threatening illness)

• Pregnant or breast‐feeding or of child bearing age not taking contraception

• History of epileptic seizures

• Attempted suicide or self‐harm

• Allergy or contra indication to fluoxetine

• Taken a monoamine oxidase inhibitor in last 5 weeks

• Current or recent depression requiring treatment with selective serotonin reuptake inhibitor

• Already participating in a CTIMP

• Current use of drugs that cause significant interactions with fluoxetine: history of epileptic seizures; history of allergy to fluoxetine; suicide attempt or self‐ harm; hepatic impairment (ALT > 3 above the upper normal limit) and renal impairment (creatinine > 180 micromol/L)

Interventions

Fluoxetine 20 mg daily (1 capsule) for 6 months (180 capsules) vs placebo

Outcomes

The primary outcomes at 6 months

• mRS

Secondary endpoints

• SIS at 6 months

• NIHSS at baseline, 6 and 12 months

• Brunnstrom scale at 6 month follow‐up

• Medical Research Council scale ay 6 month follow‐up

• BI at 6 and 12 month follow‐up

• EuroQol 5D‐5L

• MHI‐5

• Overall recovery on a VAS

• Diagnosis of new depression

• Compliance with drug intake

• Treatment effects and the occurrence of possible adverse reactions are assessed up to 12 months

Funding source

POLPHARMA S.A. manufactured and donated fluoxetine and placebo for this study. Anna Członkowska, Jan Bembenek, and Katarzyna Kurczych were supported by statutory activity of the Institute of Psychiatry and Neurology, Warsaw, Poland

Notes

Recruitment 19 December 2014 and 13 March 201 8. Authors declared no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Patients were randomly assigned in a 1:1 ratio to receive either fluoxetine or a placebo, by use of a computer‐based permuted block randomisation

Allocation concealment (selection bias)

Low risk

Allocation was concealed (further information obtained from the study author Jan Bembenek to confirm this)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Clinicians involved in randomisation and outcome assessments, the patients, and their families, were all masked so as to be unaware of treatment allocation. The placebo capsules were visually identical to the fluoxetine capsules, even when broken open."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Clinicians involved in randomisation and outcome assessments, the patients, and their families, were all masked so as to be unaware of treatment allocation"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

5 withdrew consent (8%) before 6 months but the withdrawals are balanced between groups (3 in the fluoxetine group and 2 in the control group)

From personal communication with the author: a further 2 patients dropped out between 6 and 12 months

Selective reporting (reporting bias)

Low risk

Trial was registered and all outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

Study type: interventional (clinical trial)

Intervention model: parallel assignment

Primary Purpose: treatment

Participants

6 participants

Country: France

Setting: inpatient

At randomisation number allocated: 6 although unclear as to which group

% male: not available

Age: not available

Subtype of stroke: not available

Severity of stroke: not available

Time since stroke onset: not available

Inclusion criteria

• Age 18 to 80 years

• Social security affiliation

• Day 3 to day 15 after stroke or brain haemorrhage

• Hemiparesia with upper limb motor deficit (Fugl‐Meyer score ‐ hand ≤ 10)

• Informed consent

Exclusion criteria

• NIHSS > 20

• Depression (criteria DSM5‐R) with MADRS score > 19

• History of recurrent bipolar or depressive disorders

• History of behavior or suicidal idea

• Family history of extension of the interval QT or congenital long interval QT

• History of clinical stroke

• Aphasia preventing correct evaluation of motor and depression scales.

• Patients treated by antidepressant drugs, IMAO, and neuroleptics in the past month

• Benzodiazepines within 48 hours preceding inclusion.

• Intolerance or allergy to fluoxetine (Sandoz® 20 mg pill)

• Severe swallowing disorders preventing oral administration of the treatment

• Planned carotid surgery

• Pregnant or breast‐feeding woman

• Hepatic failure (TGO and TGP > 2N); severe renal failure (creatinine > 180 micromol/L)

• Concomitant severe disease not allowing follow‐up

• Participation to another therapeutic study

• Contraindication to MRI and TMS

Withdrawal criteria: not stated

Interventions

Experimental: fluoxetine; 1 pill of 20 mg/day, during 3 months

Comparator: placebo of fluoxetine; 1 pill of 20 mg/day, during 3 months

Outcomes

Primary outcome

• Slope of the curve of recruitment of the MEPs at 3 months

Secondary outcomes recorded at 3 and 6 months

• Slope of recruitment of the MEPs (effect of a first dose of fluoxetine on the slope of recruitment of the MEPs)

• Slope of recruitment of the MEPs (persistence of fluoxetine effect on the slope of recruitment of the MEPs to month 6)

• Index finger force control in paretic hand

• Index finger force control in non‐paretic hand

Funding source

Not stated

Notes

No published data, unpublished data say 6 patients, none of whom died, so we have used this information

Dates study conducted: February 2014 to August 2015

Declarations of Interest: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information available

Allocation concealment (selection bias)

Unclear risk

No information available

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information available

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information available

Selective reporting (reporting bias)

Unclear risk

No information available

Other bias

Unclear risk

No information available

Study characteristics

Methods

Parallel design

Analysis: per protocol: 1 withdrawn (treatment), excluded from analysis

Participants

Diagnosis: stroke, time from stroke to randomisation not reported

Randomised 10 to treatment and 10 to control

Treatment: 9 completed treatment, mean ± SD age 61.4 ± 8.6 years, 55% men

Control: 10 people completed placebo, mean ± SD age 63.7 ± 5.4 years, 60% men

Emotionalism criteria: emotionalism of at least 4 weeks' duration assessed during semi‐structured interview using a modified Lawson and MacLeod rating scale, in addition to frequency of outbursts

Exclusion criteria: cognitive impairment, dysphasia, major depressive disorder

Interventions

Treatment: fluoxetine 20 mg daily

Control: matched placebo

Duration: 10 days

Duration of follow‐up: (end of treatment to end of study) 0

Outcomes

Used leaving the study early

Unable to use data from HDRS, Lawson and MacLeod Scale, self‐rating scales (mean and SD not presented)

Also reported emotional outbursts; we have not used these in our analyses

AEs: not presented

Funding source

Funder not stated

Notes

Dates of study not stated; conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation method not stated

Allocation concealment (selection bias)

Unclear risk

Randomised by independent statistician

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States blinding of patients and nursing staff, matched placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

States blinding of rating clinicians

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 withdrawn (5% of participants); we categorised this as low risk

Selective reporting (reporting bias)

Unclear risk

Insufficient information to make judgement

Other bias

Low risk

No other obvious biases, baseline balanced

Study characteristics

Methods

Parallel design

Analysis: ITT: 2 withdrawn and 1 death (treatment), 1 death (placebo), last value carried forward

Participants

Diagnosis: stroke.

Months from stroke: median (range) 10.5 months (1 ± 156) in sertraline group and 5.5 months (1.5 ± 48) in the control group

Treatment: 14 people

Control: 14 people

Exclusion criteria: less than 1 month since stroke, depression or dementia using the DSM III‐R criteria

Interventions

Treatment: sertraline 50 mg daily

Control: matched placebo

Duration: treatment continued for 8 weeks

Duration of follow‐up: 2 weeks off treatment. All scores became non‐significant (though data not reported so could not be used in the analysis)

Outcomes

Able to use

• improved score on lability scale

• improved score on clinician's interview based impression of change

• diminished tearfulness

• leaving the study early

• death

• AEs

Method of collecting AEs was not stated

Unable to use: MADRS, BI, MMSE (data not presented)

Funding source

Funded by an unrestricted personal grant from Pfizer, the manufacturers of sertraline

Notes

Dates of study not stated, conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Blocks of 4 using list produced by medical statistics department

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Matched placebo, both active drug and placebo were packed in gelatine capsules with an identical appearance

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Run‐out was single‐blind, treatment was double‐blind, but unclear whether outcome assessors were blind

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis: ITT, LOCF
4/28 did not complete the study (14%)

Selective reporting (reporting bias)

Low risk

Trial details published on www.strokecentre.org/trials, although unable to use data from MADRS

Given that the main aim was to explore effect on emotionalism, this is unlikely to have biased results

Other bias

Unclear risk

Placebo group younger, uncertain influence on bias

Statistical analysis was carried out independently by the Applied Statistics Research Unit in Canterbury

Study characteristics

Methods

RCT

Study type: interventional (clinical trial)

Primary purpose: prevention

Participants

100 participants

January 2013 to April 2016

Country: China

Setting: inpatient

At randomisation number allocated: N = 99: escitalopram (n = 52); usual care (n = 47)

% male: escitalopram (%); usual care (%)

Inclusion criteria

• First ever acute anterior circulation cerebral infarction

• Met the American Heart Association/American Stroke Association diagnostic criteria for stroke

• Hospitalised within 1 week of stroke onset

• Stroke confirmed cranial MRI

Exclusion criteria

• Recurrent stroke, haemorrhagic stroke and posterior circulation stroke

• Pre‐stroke depression, history of depression, or receiving mood stabilisers, antipsychotics, or any antidepressant before enrolment

• Depression caused by other organic brain diseases, or depression caused by psychoactive substances and non‐addictive substances

• Consciousness disorder, aphasia, and dementia

• HAMD of ≥ 17

• NIHSS score of ≥ 20

• History of cancer and psychosis

• Chronic obstructive pulmonary disease, heart failure, pulmonary, hepatic, or renal failure, or other severe chronic diseases

• Serious suicidal tendencies

• Laboratory and accessory examinations revealing coagulation dysfunction

• Patients who refuse to participate or cooperate

Interventions

Experimental: prophylactic escitalopram in addition to the basic therapies. Started with 5 mg and gradually titrated to 10 mg/d, oral administration in the morning for 90 days

Comparator: usual care. Secondary prevention of cerebral infarction, brain protection therapy and rehabilitation, without any antidepressants. People with difficulty sleeping could receive Zolpidem or benzodiazepines for a short period of time

Outcomes

Primary and secondary outcome measures not stated

• 17‐item HAMD

• NIHSS

• MMSE

• BI

Funding source

Notes

No trial registration information

Dates study conducted: All patients were hospitalised patients treated for acute ischaemic stroke from January 2013 to April 2016

Declarations of Interest: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Control group did not receive a placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Treatment evaluation conducted by a physician blind to patient’s clinical data, but it does not state whether the physician was blind to treatment allocation. So the judgement was that the risk of bias was unclear

Incomplete outcome data (attrition bias)
All outcomes

High risk

There are two publications‐the numbers initially included in the two papers do not match; also two patients out of 49 randomised to escitalopram dropped out. Given the inconsistency in the numbers reported, we judge that there is the potential for high risk of bias

Selective reporting (reporting bias)

Unclear risk

No protocol is available

Other bias

Unclear risk

The authors did not reply to questions and so we have graded this as unclear

Study characteristics

Methods

Randomised trial

Aim: to observe effects of integrative Chinese herb YuLeShu and fluoxetine on the depressive symptoms and rehabilitation of neurological impairment in patients with post‐stroke depression

Participants

Country: China

Setting: not described

Participants: internal carotid system cerebral infarction or haemorrhage within previous 2 months

Fluoxetine: 19 people, mean age 61.71 ± 8.13 years, 8 men

Control: 18 people, mean age 62.85 ± 7.32 years, 7 men

Depression: diagnosis of depression according to DSM‐IV

Inclusion criteria: HDRS ≥ 20 but < 35 and/or Zung SDS ≥ 41

Exclusion criteria: HDRS > 35, previous depression, aphasia, severe cardiac, pulmonary, hepatic and renal diseases, previous stroke

Interventions

3 groups: fluoxetine plus usual care versus YuLeShu plus usual care versus usual care. We are using the fluoxetine plus usual care versus usual care alone in the comparison

Outcomes

HDRS

Zung SDS

BI

Scandinavian Neurological Stroke Scale (also known as CSS)

Stated no side effects, but not clear which side effects were sought, or how they were sought. They were reported at 4, 8 and 12 weeks after treatment

Funding source

Funded by a local scientific academic fund, drug company not involved

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "using a computer", but method not described. Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk'

Allocation concealment (selection bias)

Unclear risk

The method of concealment is not described or not described in sufficient detail to allow a definite judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information about blinding of outcome assessment available to permit a judgement of ‘low risk’ or ‘high risk’

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropouts: 2 people dropped out of the fluoxetine group, 1 dropped out of the YuLeShu group and 2 dropped out of the control group

Selective reporting (reporting bias)

Unclear risk

Protocol not published. Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’

Other bias

Unclear risk

Reported that of the people who completed the tests, there were no differences in baseline

No comment on whether there were differences in baseline for the entire group

Study characteristics

Methods

Parallel group (3 groups: doxepin, paroxetine, placebo; we used the paroxetine and placebo data in our review)

Aim: treat depression and determine effect on neurological function

Participants

Country: China

Setting: unclear

Stroke diagnosis: diagnostic criteria of the 4th National Meeting of the Cerebrovascular Diseases proved by CT or MRI

Time since stroke: not known

Depression diagnosis: Classification and Diagnosis of Psychosis in China (2nd edition)

Treatment: 24 people, age and gender not given

Control: 24 people, age and gender not given

Exclusion: pre‐stroke mental disease, cognition disorder (MMSE < 24), marked deterioration in depression during treatment (HAMD > 24) or suicide mood, intolerance to drug

Interventions

Treatment: paroxetine 20 mg 3 times per day

Control: placebo guvitamine once per day

Duration of treatment: 8 weeks

Duration of follow‐up (post‐treatment to study end): unclear: follow‐up is performed 'after treatment' so we assume this is at 8 weeks (so post‐treatment to study end = 0)

Outcomes

HAMD

BI

CSS

Death/side effects/leaving the trial early

Method of reporting side effects not stated

Funding source

Funder not stated, unclear if there was drug company involvement

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Unclear risk

The method of concealment is not described to allow a definite judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information about blinding of outcome assessment available to permit a judgement of ‘low risk’ or ‘high risk’

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropouts: 4 in placebo and 0 in paroxetine

Selective reporting (reporting bias)

Unclear risk

Insufficient information available to permit a judgement of ‘low risk’ or ‘high risk’

Other bias

Unclear risk

Demographic data not provided, so we cannot determine whether the baseline was balanced

Study characteristics

Methods

To observe the changes of neurotransmitter in people with post‐stroke depression by using encephalofluctuography technology, and observe the effect of antidepression treatment on the activity of neurotransmitter

Participants

48 participants with post‐stroke depression

Interventions

Treatment: 24 people received citalopram 20 mg plus usual care, or fluoxetine if side effects such as nausea, emesis

Control: 24 people usual care alone

Outcomes

Encephalofluctuography technology

Level of sympathin and 5‐hydroxytryptamine at 4 weeks and 3 months after treatment started

Funding source

Not stated

Notes

No data from our endpoints of interest, so data not included in a meta‐analysis

Recruitment March 2001 to December 2001

Conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Randomly divided" but method not stated. Insufficient information about the sequence generation process available to permit a judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)

Unclear risk

The method of concealment is not described or not described in sufficient detail to allow a definite judgement of ‘low risk’ or ‘high risk’

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not described

Selective reporting (reporting bias)

Unclear risk

Unclear

Other bias

Unclear risk

Unclear

Study characteristics

Methods

Parallel group

Analysis: according to allocated treatment group

Participants

Country: China

Setting: inpatient

Stroke criteria: first ever stroke, onset time ≤ 7 days, haemorrhagic and ischaemic, clinical diagnosis plus confirmation by imaging (though not clear whether a stroke lesion had to be present), at least 1 limb with muscle power grade 3 or less, BI ≤ 50, no consciousness disturbance

Mood criteria: HAMD > 16

Treatment: 40 people, mean age 63.5 years, 29 men

Control: 38 people, mean age 65.8 years, 25 men

No difference in baseline depression and BI between treatment and control group

Excluded: severe cardiac, hepatic and renal organic diseases, psychiatric disorders

Interventions

Treatment: paroxetine 20 mg daily plus routine stroke medication, nerve nutritional agents, acupuncture and rehabilitation

Control: routine stroke medication, nerve nutritional agents, acupuncture and rehabilitation

Duration of treatment: 12 weeks

Duration of follow‐up (post‐treatment to study end): 0 weeks

Outcomes

HAMD

BI

Death

Number completing the trial

AEs not reported

Funding source

No description of funding

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropouts: none

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Unclear risk

No obvious risks, baseline similar

Study characteristics

Methods

To investigate the effect of early antidepressant intervention on the acute depression and rehabilitation of neurological function after stroke

Participants

96 acute depression patients after stroke were selected and randomly divided into study group and control group. Stroke diagnosed according to the diagnostic criteria of stroke by the 4th Congress of Chinese Cerebrovascular Diseases, which requires both clinical and imaging criteria to be met. HAMD ≥ 17. Excluded patients with mental disorders. Range of disease: 2‐9 months

Interventions

The study group orally took the antidepressant ( citalopram) and the control group took placebo for 8 weeks

Outcomes

Depression (HAMD), neurological function (NIHSS), ADL (BI). Substance P and neuropeptide Y

Funding source

No information regarding funding

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Information not provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Information not provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

information not provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

information not provided

Selective reporting (reporting bias)

Unclear risk

Information not provided

Other bias

Unclear risk

No information provided e.g. on source of funding

Study characteristics

Methods

Parallel design

Aim: to treat depression and augment rehabilitation

Analysis: according to allocated treatment group

Participants

Location: China

Setting: inpatient

Treatment: 25 people

Control: 32 people

Whole group (including non‐depression group, depression control group and depression treatment group): 132 (mean age 62 ± 12 years, 79 men)

Stroke: ischaemic stroke or PICH, clinical diagnosis plus confirmation on brain imaging (not clear that a stroke lesion had to be present), clear consciousness

Depression diagnosis (at 2 weeks after stroke onset): psychiatric interview, DSM IV criteria

Excluded: major psychological trauma history in previous 1 year, severe mental retardation, severe impairment of lingual expression or comprehension, major complicated medical event in previous 1 year

Interventions

Treatment: fluoxetine 20 mg daily

Control: no fluoxetine

Duration of treatment: 6 months

Duration of follow‐up (post‐treatment to study end): 6 months

Outcomes

SSS

ADL

HAMD

Zung SDS

Zung SAS

No deaths, none left trial early

No data on AEs

Funding source

No description of funding

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

59 participants were diagnosed to have depression by symptoms but only 57 were included in the results table

Selective reporting (reporting bias)

High risk

No protocol, no report of the results of the self‐rating anxiety scale

Other bias

Unclear risk

No clear description of differences between the treatment and control group

Study characteristics

Methods

Randomised parallel‐group trial

Participants

Location: France

Setting: stroke units

Inclusion criteria: aged 18 to 85 years with FMMS of 55 or less, acute ischaemic stroke with hemiparesis or hemiplegia, 5 to 10 days after stroke onset, unclear if there had to be a visible lesion on brain imaging

Treatment: 59 people, mean ± SD age 66.4 ± 11.7 years; 63% men

Control: 59 people, mean ± SD age 62.9 ± 13.4 years; 59% men

Comparability of treatment groups: total FMMS score fluoxetine 17.1 compared with 13.4 in placebo
Previous stroke more common in the fluoxetine group; fluoxetine group had more diabetes

Exclusions: clinical depression or treatment with antidepressants, MADRS > 19, aphasia severe enough to mask detection/assessment of depression, pregnancy, patient on neuroleptics/benzodiazepines, owing to undergo carotid endarterectomy, other major diseases that would prevent follow‐up

Interventions

Treatment: fluoxetine 20 mg daily for 90 days

Control: identical capsules to active drug

Duration of treatment: 90 days

Duration of follow‐up (treatment end to study end): 0 days

Outcomes

Primary outcome: the mean change of FMMS score between inclusion (day 0) and day 90 after the start of the study drug

Secondary endpoints were NIHSS, mRS and MADRS measured at days 0, 30 and 90

Funding source

Funded by French national programme for clinical research: the sponsor had no involvement in study design, data collection, data analysis, data interpretation or writing the report

Notes

Recruitment 14 March 2005 to 9 June 2009. Authors state "no conflicts of interest"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Balanced by centre with an allocation based on a block size of 4 generated with a computer random‐number generator

Allocation concealment (selection bias)

Low risk

Sequentially‐numbered opaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Identical capsules for control arm

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All study site investigators and all investigators were masked to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropouts: 2 participants died (1 in each group) and 3 dropped out; not stated how missing outcome data were dealt with

Selective reporting (reporting bias)

Low risk

Trial protocol published on www.strokecentre.org/trials, all outcomes were reported

Other bias

Unclear risk

Note difference in baseline; particularly for the total FMMS score (17.1 in fluoxetine and 13.4 in the placebo): it is not clear what effect this had on results, so we have classified this as 'unclear risk'

Study characteristics

Methods

Parallel design

Analysis: per protocol: withdrawn because of AEs (2 treatment), all excluded from analysis

Participants

Location: Italy

Setting: unclear

Treatment: 18 people, mean ± SD age 68 ± 9 years, 44% men

Control: 17 people, mean ± SD age 68 ± 5.5 years, 44% men

Stroke criteria: ischaemic, unilateral MCA territory stroke, diagnosis via clinical signs and CT (100%), stroke 1 to 6 months prior to randomisation (average time 3 months)

Other inclusion criteria: unable to walk

Comparability of treatment groups: balanced

Exclusion: history of major affective disorders; alcohol abuse; or a history or evidence or both of severe heart, lung, kidney or liver diseases or mental deterioration

Interventions

Treatment: fluoxetine 20 mg daily

Control: matched placebo

Duration: treatment continued on average 74 ± 6 days, duration not reported for control group

Duration of follow‐up (treatment end to study end): 0

Outcomes

Depression: change in scores from baseline to end of treatment on HDRS

Additional: graded neurological scale (HSS), BI

Leaving the study early

Death

AEs including seizures ‐ unclear if these were reported systematically

Funding source

Funding source not stated

Notes

Dates of recruitment and conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description

Allocation concealment (selection bias)

Unclear risk

No description

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Examining neurologists blind to treatment".

Comment: Unclear if this refers to outcome assessors or the neurologist caring for the participant. However, placebo was 'matched' so this is low risk as the treating physician and the participants would have been blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

See above

Incomplete outcome data (attrition bias)
All outcomes

High risk

2/35 dropouts (5.7%), per‐protocol analysis

Selective reporting (reporting bias)

Low risk

Trial available, including results on www.strokecentre.org/trials: all specified outcome measures were reported

Other bias

Low risk

Baseline characteristics similar in the 2 groups

Study characteristics

Methods

Study type: interventional (clinical trial)

Allocation: randomised

Intervention model: parallel assignment

Masking: single (investigator)

Primary purpose: treatment

Participants

60 participants

Country: Nigeria

Setting: inpatient

At randomisation number allocated: N = 1500: fluoxetine (n = 750 ); placebo (n = 750 )

% male: fluoxetine (53.3%); placebo (43.3%)

Age: mean age: fluoxetine = 59 ± 11; placebo = 62 ± 9

Inclusion criteria

• 18 to 85 years of age

• Ischaemic stroke, unilateral, supra‐tentorial confirmed by neuroimaging

• Presentation within first 14 days of stroke onset

• NIHSS score ≤ 16

• Hemiparesis or hemiplegia

• FMMS ≤ 55

• Informed consent

Exclusion criteria

• Haemorrhagic stroke on CT

• Glasgow coma score < 8

• NIHSS score > 16

• Cardiovascular/metabolic/respiratory instability: hypertensive emergency or hypotension/acidosis or alkalosis/RR > 24 cycles per minute

• Previous central/peripheral nerve injury

• Current use of a medication likely to have an adverse interaction with fluoxetine

• Concurrent medications interacting with SSRI

• Substantial premorbid disability

• Depression (MADRS score > 19)

• Current use of antidepressant medication

• Pregnancy

Interventions

Experimental: 20 mg fluoxetine for 30 days plus standard treatment

Comparator: standard treatment

Outcomes

Primary outcome

• Changes in FMMS at day 14 and day 30

Secondary outcomes

• NIHSS at day 30

• mRS at day 30

Funding source

N o funding

Notes

PACTR201412000967245. Recruitment between January 2015 and May 2016. All authors declare no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Block randomization was used in the assignment of study participants. Permuted blocks of six (6) for two groups were drawn up. A random selection of possibilities was done using a list of random numbers generated with STATA 12."

Allocation concealment (selection bias)

Low risk

Quote: "Allocation concealment was done using sequentially numbered envelopes."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This was a single‐blind randomized controlled trial that compared motor recovery between 2 groups of stroke patients: those on fluoxetine 20mg daily + standard therapy; and the control group who received standard therapy only." Thus the participants would have known their treatment allocation

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

22/60 lost to follow‐up (presumably including the 7 in the intervention group and the 8 in the control group who died). 6 in fluoxetine group stopped treatment but were still included in the analysis. It is unclear what effect this would have had, hence the judgement about unclear risk of bias

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

Unclear risk

Insufficient information to to assess whether an important risk of bias exists

Study characteristics

Methods

Multicentre RCT

Study type: interventional (clinical trial)

Allocation: randomised

Intervention model: parallel assignment

Masking: quadruple (participant, care provider, investigator, outcomes assessor)

Primary purpose: treatment

Participants

1500 participants

Country: Sweden

Setting: inpatient

At randomisation number allocated: N = 1500: fluoxetine (n = 750 ); placebo (n = 750 )

% male: fluoxetine (62%); placebo (62%)

Age: mean age: fluoxetine = 70.6 ± 11.3; placebo = 71.0± 10.5

Subtype of stroke

• Total anterior circulation infarct: fluoxetine (27%); placebo (29%)

• Partial anterior circulation infarct: fluoxetine (46%); placebo (44%)

• Lacunar infarct: fluoxetine (15%); placebo (16%)

• Posterior circulation infarct: fluoxetine (10%); placebo (9%)

• Uncertain: fluoxetine (x2%); placebo (2%)

Inclusion criteria

• Age ≥ 18

• Informed consent can only be obtained from a patient who according to the trial investigator is mentally capable of decision‐making and who, after having received information and got answers to their questions, wants to participate in the trial

• Brain imaging is compatible with intracerebral haemorrhage or ischaemic stroke

• Randomisation can be performed between 2 and 15 days after stroke onset and by the research group at the person's local/emergency hospital

• Persisting focal neurological deficit is present at the time of randomisation severe enough to warrant treatment from the physicians and the patient's and relative's perspective

Exclusion criteria

• Subarachnoidal haemorrhage (except where secondary to a primary intracerebral haemorrhage)

• Unlikely to be available for follow‐up for the next 12 months e.g. no fixed home address

• Unable to speak Swedish and no close family member available to help with follow‐up forms

• Other life‐threatening illness (e.g. advanced cancer) that will make 12‐month survival unlikely

• History of epileptic seizures

• History of allergy or contraindications to fluoxetine

• Pregnant or breastfeeding

• Previous drug overdose or attempted suicide

• Already enrolled into a CTIMP

• Current or recent (within the last month) depression requiring treatment with an SSRI antidepressant

• Current use of medications which have serious interactions with fluoxetine

• Use of any MAOI during the last 5 weeks

Interventions

Fluoxetine (20 mg once daily) for 6 months with oral capsules

Outcomes

Outcomes collected at 6 months and 12 months

Primary outcome

• mRS

Secondary outcomes

• Death from all causes

• HRQoL (EQ5D‐5L)

• Depression and anxiety (MHI‐5)

• Level of fatigue (vitality subscale of the Health Questionnaire)

• Recovery from stroke (SIS)

• New diagnosis of depression since randomisation

• Adverse events (including participant‐completed diary)

• Health and social care utilisation

• Adherence to trial medication

• Motor function (NIHSS)

• Aphasia (NIHSS), aphasia (Norsk Grunntest for Afasi)

• Depression (MADRS + DSM‐IV/DSM‐V)

• Cognitive function (MoCA)

Funding source

The Swedish Research Council, the Swedish Heart‐Lung Foundation, the Swedish Brain Foundation, the Swedish Society of Medicine, King Gustav V and Queen Victoria’s Foundation of Freemasons, and the Swedish Stroke Association (STROKE‐Riksförbundet)

Notes

clinicaltrials.gov/ct2/show/NCT02683213. Recruitment between Oct 20, 2014, and June 28, 2019

BN has received honoraria for data monitoring committee work in the SOCRATES and THALES trials (AstraZeneca) and the NAVIGATE‐ESUS trial (Bayer). HW has received grants from the Swedish Medical Research Council (Vetenskapsrådet) during the conduct of the study; the grant was for the study that is presented inthe submitted manuscript. GJH has received grants from the National Health and Medical Research Council (NHMRC) of Australia, Vetenskapsrådet, and UK National Institute for Health Research Technology, during the conduct of the study; and personal fees from American Heart Association, outside of the submitted work. MD reports that the University of Edinburgh received some funding from the grants for EFFECTS (Vetenskapsrådet) in relation to its provision of a randomisation system. MLH has received grants from the NHMRC of Australia, outside of the submitted work. All other authors declare no competing interests

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A physician or nurse entered patients’ baseline data into a secure web‐based randomisation system. The system checked the data for completeness and consistency and allocated each patient an identification number and a treatment number. Patients were randomly assigned in a 1:1 ratio to either oral fluoxetine 20 mg once daily or placebo for 6 months."

Allocation concealment (selection bias)

Low risk

Quote: "secure web‐based randomisation system"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients, their families, health‐care personnel, investigators, outcomes assessors, and staff in the coordinating centre (Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Stockholm, Sweden), and the pharmacy were masked to treatment allocation. The placebo capsules were visually identical to the fluoxetine capsules, even when broken open. The success of the masking procedure was not assessed. An emergency unmasking system was available but was designed so that the coordinating centre and staff doing follow‐up continued to be masked throughout the study."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients, their families, health‐care personnel, investigators, outcomes assessors, and staff in the coordinating centre (Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Stockholm, Sweden), and the pharmacy were masked to treatment allocation"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 11 dropped out; 2 crossed over; the rest were included in the analysis

Selective reporting (reporting bias)

Low risk

All outcomes that were prespecified were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

Aim: to study the influence of Jieyu Huoxue decoction on rehabilitation of patients with depression after cerebral infarction

Participants

Country: China

4 groups: fluoxetine plus usual care, Jieyu Huoxue decoction plus usual care, usual care in people with depression, usual care in people with no depression

We are using data from 'fluoxetine plus usual care' versus 'usual care in people with depression'

Setting: mixed inpatient and outpatient

Stroke criteria: ischaemic stroke within 1 month of stroke onset, clinical diagnosis plus confirmation by imaging. Did not state whether a visible lesion was needed to make a diagnosis

Depression: psychiatric interview using DSM IV, Zung SDS ≥ 41

Included those with no previous psychiatric history

54 participants with post‐stroke depression were randomised

18 received fluoxetine plus usual care, 18 received usual care only and 18 received Jieyu Huoxue decoction

Of the 54 participants with depression randomised, mean age: 71.5 ± 6.7 years, 24 men

Excluded: previous stroke, previous depression, and severe cardiac, pulmonary, hepatic and renal diseases

Interventions

Treatment: fluoxetine 20 mg daily plus usual stroke care

Control: usual stroke care

Duration of treatment: 60 days

Duration of follow‐up (post‐treatment to study end): 0 weeks

Outcomes

Zung SDS

ADL: although score not referenced, so not used in analysis

MESSS

Reported side effects in fluoxetine group but not in the control group

Unclear how side effects were collected

Funding source

Funding source not stated

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not stated

Allocation concealment (selection bias)

Unclear risk

No description

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

8 participants dropped out (2 in fluoxetine group, 2 in the depression control group, 1 in the Jieyu Huoxue decoction, 3 in no‐depression control)

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Unclear risk

Baseline balanced

Study characteristics

Methods

Multicentre RCT

Study type: interventional (clinical trial)

Primary purpose: treatment

Participants

3127 participants

Country: UK

Setting: inpatient

At randomisation number allocated: N = 3127: fluoxetine (n = 1564); placebo (n = 1563)

% male: fluoxetine (62%); placebo (61%)

Age: mean age: fluoxetine = 71·2 ± 12.4; placebo = 71·5 ± 12.1

Subtype of stroke

• Total anterior circulation infarct: fluoxetine (20%); placebo (20%)

• Partial anterior circulation infarct: fluoxetine (36%); placebo (35%)

• Lacunar infarct: fluoxetine (20%); placebo (18%)

• Posterior circulation infarct: fluoxetine (12%); placebo (15%)

• Uncertain: fluoxetine (2%); placebo (2%)

Severity of stroke: NIHSS, Median (IQR) fluoxetine (6 (3 to 11)); placebo (6 (3 to 11))

Time since stroke onset: mean days: fluoxetine 6.9 ± 3.6; placebo 7.0 ± 3.6

Inclusion criteria

• Age > 18 years

• Brain imaging consistent with intracerebral haemorrhage or ischaemic stroke

• Randomisation can be performed between 2 and 15 days after stroke onset

• Persisting focal neurological deficit is present at the time of randomisation

Exclusion criteria

• SAH

• Unlikely to be available for follow up at 12 months

• Patient and/or carer unable to understand spoken or written English

• Other life‐threatening illness

• Pregnant or breast‐feeding or of child bearing age not taking contraception

• History of epileptic seizures

• Attempted suicide or self‐harm

• Allergy or contra indication to fluoxetine

• Taken a monoamine oxidase inhibitor in last 5 weeks

• Current or recent depression requiring treatment with selective serotonin reuptake inhibitor

• Already participating in a CTIMP

Interventions

Experimental: 20 mg orally once daily for 6 months

Comparator: matching placebo orally once daily for 6 months

Outcomes

Primary outcome

• mRS at 6 months

Secondary outcome measures

• Deaths from all causes at 6 and 12 months

• mRS at 12 months

• SIS

• Euroquol 5D‐5L

• MHI‐5

• Vitality subscale of SF36 (as an assessment of fatigue)

• Diagnosis of depression

• Other AEs

• Adherence to the trial medication

• Health and social care resources used during follow‐up

Funding source

MHRA approval granted. Start‐up phase funded by The Stroke Association. Main phase funded by NIHR

Notes

ISRCTN83290762. Recruitment 10 September 2012 to 31 March 2017. Authors declared no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned in a 1:1 ratio to receive fluoxetine or placebo, by use of a centralised randomization system."

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomly assigned in a 1:1 ratio to receive fluoxetine or placebo, by use of a centralised randomization system."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients, their families, and the health‐care team including the pharmacist, staff in the coordinating centre, and anyone involved in outcome assessments were all masked to treatment allocation by use of a placebo capsule that was visually identical to the fluoxetine capsules even when broken open."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients, their families, and the health‐care team including the pharmacist, staff in the coordinating centre, and anyone involved in outcome assessments were all masked to treatment allocation by use of a placebo capsule that was visually identical to the fluoxetine capsules even when broken open."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

For the primary outcome of mRS at 6 months data were available for fluoxetine n = 1553/1564 (99.3%) and placebo n = 1553/1563 (99.3%)

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported

Other bias

Low risk

The study appears to be free of other sources of bias

Study characteristics

Methods

Parallel design

Analysis: per protocol

Withdrawals: death (1 treatment), withdrawn owing to AEs (1 treatment, 2 control), all excluded from analysis

Participants

Location: Austria

Setting: inpatients

Treatment: 28 people, mean ± SD age 65 ± 14 years, 46% men

Control: 26 people, mean ± SD age 64 ± 14 years, 71% men

Stroke criteria: ischaemic stroke and PICH; diagnosis via clinical signs and CT (100%); stroke on average 11 days prior to randomisation

Depression criteria: psychiatric interviews, HDRS score > 15

Other entry criteria: not stated

Comparability of treatment groups: non‐significant trend towards more women and right‐sided strokes in treatment group

Exclusion criteria: MMSE < 20, more than mild communication deficit, diseases of the central nervous system and previous neurodegenerative or expansive neurological disorders

Interventions

Treatment: fluoxetine 20 mg daily, dose escalation at 4 weeks if HDRS score > 13

Control: matched placebo

Duration of treatment: 12 weeks

Duration of follow‐up (end of treatment to study end): 15 months

Outcomes

Depression: change in scores from baseline to end of treatment of HDRS, BDI, and CGI (item 1)

Proportion of responders (< 13 HDRS)

Additional: SSS

Death

AEs (selected data)

Unable to use: RS, BI, MMSE (data not presented at follow‐up)

AEs data on dizziness, nausea and cephalalgia (data not presented by group)

Funding source

The medication was supplied by Lannacher Heilmittel, Lannach, Austria

Notes

Recruitment 1 June 1998 to 31 Decmeber 1998. Conflicts of interest not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised randomisation, using random permutated block design

Allocation concealment (selection bias)

Low risk

Centralised concealment

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States blinded, used matching placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

States blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

4/54, per protocol analysis

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Unclear risk

Baseline balanced

All participants were randomly assigned to either fluoxetine or placebo treatment by the drug company independently of the research teams and the study centres

Study characteristics

Methods

Study type: interventional (clinical trial)

Primary purpose: treatment

Participants

274 participants

Country: China

Setting: outpatient

At randomisation number allocated: N = 274, citalopram (n = 91); placebo (n = 91); cognitive behavioural therapy (n = 92)

% male: 51.8%

Age: mean age, citalopram 66.0 ± 7.3 (n = 91); placebo 67.2 ± 9.6 (n = 91); cognitive behavioural therapy 64.9 ± 8.0 (n = 92)

Subtype of stroke: not available

Severity of stroke: not available

Time since stroke onset: acute ischaemic stroke within the previous 7 days

Inclusion criteria

• Age > 18

• First ever ischaemic stroke meeting World Health Organization (WHO) diagnostic criteria confirmed by MRI

• No history of depression

• No antidepressant use prior to the study

Exclusion criteria

• No consent

• Premorbid stroke related impairment

• BI < 10

Interventions

Experimental: citalopram 20 mg per day for a minimum of 3 months + general discussions

Comparator 1: placebo + general discussions

Comparator 2: placebo + cognitive behavioural therapy

Outcomes

• Depressive symptoms (17‐item HAMD), Bech‐Rafaelsen Melancholia Scale (MES)) at 3 months

• Drug side‐effects (Udvalg for Kliniske Undersogelser side‐effect scale at 2, 4, and 6 weeks, and 3 months

• Performance in ADL (BI) at 3 months

• Functional impairment (FIM scale) at 3 months

Funding source

Natural Science Foundation of China [81100243, 81171131, 81272564, 81272795, 81100893, 81172197, and 81372484], the Natural Science Foundation of Liaoning Province in China [No. L2013296], and Liaoning Science and Technology Plan Projects [No. 2011225020]

Notes

This trial was particular in that recruitment happened at 4 different time points: at 0 months, 3 months, 6 months, and 9 months from discharge. Inclusion criteria required that participants suffered from post‐stroke depression. Participants were invited to complete the BDI and those with a score > 10 were included, provided other criteria were met

Group 'placebo + general discussions' and 'citalopram + general discussions were included. No significant differences observed in the 2 included groups

Dates study conducted: participants enrolled between October 2011 and June 2013

Declarations of interest: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization into one of three intervention groups was undertaken by an independent researcher using computer‐generated random number sequences ..."

Allocation concealment (selection bias)

Low risk

Quote: "... that were prepared in advance and placed in consecutively numbered, sealed, opaque envelopes."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Study described as "single blind"

Quote: "The researcher successively opened the envelopes corresponding to different time periods and determined the intervention by patient number."

Quote: "The study therapists acted as clinical evaluators."

Quote: "The study therapists were asked not to divulge any treatment information to their patients."

Comment: Care providers, investigator and outcome assessors were all aware of allocation

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The study therapists acted as clinical evaluators."

Quote: "The study therapists were asked not to divulge any treatment information to their patients."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "in Group A [placebo + general discussions], one patient violated protocol in the second time period, one could no longer be reached, and one left the study owing to stroke recurrence in the third time period; in Group B [citalopram + general discussions], persistent side‐effects from the drugs led five patients to leave the study (two owing to orthostatic dizziness, one owing to palpitation, and two owing to constipation)"

Comment: Attrition reported for each intervention group and reasons given

Group A (placebo + general discussions) 3/91 = 3% attrition

Group B (citalopram + general discussions) 5/91 = 5% attrition

Overall = 4% attrition

Selective reporting (reporting bias)

Unclear risk

There is no study protocol available. Therefore insufficient information to judge high or low

Other bias

Low risk

The study appears to be free from other sources of bias

Study characteristics

Methods

Parallel group

Analysis: according to treatment group

Participants

Location: not stated

Setting: not stated

Stroke criteria: "documented diagnosis of stroke within 12 months prior to screening"

Mood: MADRS score > 17

Treatment: 112 people, age 64.3 ± 11.4 years, 61 men

Control: 117 people, 65.6 ± 10.5 years, 64 men

Excluded: concurrent psychiatric disorders, concurrent psychotropic pharmacotherapy, patients who posed a suicidal risk, patients with substance abuse/dependence, concurrent psychotropic pharmacotherapy, MMSE < 24, participating in another clinical trial, serious medical condition or clinically significant finding on screening or baseline evaluation that would preclude the administration of paroxetine and an intolerance to paroxetine

Interventions

Treatment: paroxetine 20 to 50 mg daily

Control: placebo (not stated whether matching)

Duration of treatment: 8 weeks

Duration of follow‐up (treatment to study end): 0 weeks

Outcomes

Change from baseline to endpoint in MADRS

Proportion of participants scoring < 8 on the MADRS total score at the endpoint (we used this in our analysis)

Changes from baseline to endpoint on the BI

Change from baseline to endpoint on RS score

Change from baseline to endpoint on the Clinical Global Improvement Severity of Illness Score (CGI‐S Proportion of responders based on CGI‐Global Improvement (CGI‐G) score (score of < 4) at endpoint

GI side effects reported, but unclear whether these are 'events' or 'participants', so we cannot use these data. It is not clear how the side effects were collected

Withdrawal from study

Funding source

Source of funding not stated, but we assume it was funded by GlaxoSmithKline

Notes

Study period 29 August 1998 to 15 October 1999. Conflicts of interest not stated. Study number PAR625. Date updated: 11 March 2005

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation method not described

Allocation concealment (selection bias)

Unclear risk

Allocation concealment: not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding not described, used placebo but not stated whether identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

20 in each group dropped out

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Unclear risk

Insufficient information to make clear judgement

Study characteristics

Methods

RCT

Study type: interventional (clinical trial)

Allocation: randomised

Intervention model: parallel assignment

Masking: double (participant, outcomes assessor)

Primary purpose: treatment

The study was designed as a double‐blind, randomized clinical trial in order to obtain evidence for using Shu‐Gan‐JieYu capsule as an integrative, anti‐depressive treatment for motor recovery in post‐stroke patients

Participants

254 participants

Country: China

Setting: inpatient

At randomisation number allocated: N = 254:

Group A (Shu‐Gan‐Jie‐Yu only (n = 64), Group B (fluoxetine n = 64), Group C (Shu‐Gan‐Jie‐Yu and fluoxetine (n = 64)), and Group D (placebo (n = 62))

% male: Group A (Shu‐Gan‐Jie‐Yu only (n = 68.5%), Group B (fluoxetine n = 64.2%), Group C (Shu‐Gan‐Jie‐Yu and fluoxetine (n = 67.3%)), and Group D (placebo (n = 61.0%))

Age: mean age:

Group A (Shu‐Gan‐Jie‐Yu only (58.36 ± 15.28), Group B (fluoxetine 56.68 ± 17.59), Group C (Shu‐Gan‐Jie‐Yu and fluoxetine (55.95 ± 19.66), and Group D (placebo (57.79 ± 17.54)

Inclusion criteria

• Age ≥ 18

• suffering from hemiparesis or hemiplegia as a result of a first‐time acute ischemic stroke within the past 24 hours

• initial FMMS score lower than 55

Exclusion criteria

• NIHSS score less than 5

• Prior disabilities, including aphasia, cognitive disorders, and motor disorders due to stroke, or any other neurodegenerative disease

• Pregnant or breastfeeding

• Currently taking antidepressants

• Recurrent suffering from acute stroke

• Met the recombinant tissue plasminogen activator (rtPA) treatment and treated by thrombolysis

• Contraindications for therapy, including renal insufficiency (glomerular filtration rate < 30 mL/min), abnormal liver function tests, hyponatremia, or a long QT interval on an electrocardiogram

Interventions

Group A (Shu‐Gan‐Jie‐Yu only), Group B (fluoxetine), Group C (Shu‐Gan‐Jie‐Yu and fluoxetine), and Group D (placebo)

Outcomes

mRS: categorised as (0&1), (2&3), (> 4)

Fugl‐Meyer: continuous

Funding source

Supported by a grant from The National Natural Science Foundation of China (81373619) and the Plateau Discipline of Neurology of Integrated Traditional Chinese and Western Medicine in Pudong New Area (PDZY‐2018‐0606)

Notes

No trila registration number. Recruitment from July 2015 to December 2018. The authors declare that they have no conflicts of interest

Please note: final per protocol number stated as 222, but Table 1 baseline only includes 219; Table 2 mRS n=291; Table 3 30 & 90 days n=222

Denominators change for each outcome – even different for mRS 90 day and Fugel‐Meyer 90 day

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Simple randomization method … computer‐generated schedule to assign the patients who met the criteria into one of four groups by block randomization, in a ratio of 1:1:1:1, without stratification"

Allocation concealment (selection bias)

Unclear risk

The method of allocation concealment is not described to allow a definite judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "All capsules looked identical ... in order to guarantee the consistency of capsule appearance. All of the patients were told the effects of the drugs ... could improve motor recovery even if they did not have a depressive disorder."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Three neurology residents who were blinded to the interventions served as eva‐ luators in the study. The evaluators obtained the patients’ FMMS and mRS scores at enrollment and follow‐up on day 30 and day 90 after the start of the intervention. They also recorded any adverse events observed during the study."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Final per protocol number stated as 222, but Table 1 baseline only includes 219; Table 2 mRS n = 291; Table 3 30 and 90 days n = 222. Denominators change for each outcome – and are different for mRS 90 day and Fugel‐Meyer 90 day

Selective reporting (reporting bias)

Unclear risk

No published protocol to cross check for selective reporting

Other bias

High risk

Non‐standard analysis of outcomes

Study characteristics

Methods

Parallel group, 3‐arm trial, comparing sertraline plus routine care versus routine care versus acupuncture plus routine care. We are using the sertraline plus routine care versus routine care in this review

Aim: to treat depression

Analysis: according to allocated treatment

Participants

Country: China

Setting: unknown

Stroke criteria: first ever stroke, clinical diagnosis plus relevant lesion on imaging, age ≥ 60 years old

Depression criteria: HAMD score ≥ 8, no depression prior to stroke

Treatment: 40 people, mean age 67.6 ± 12.43 years, 23 men

Control: 40 people, mean age 64.5 ± 12.07 years, 22 men

Exclusions: psychiatric disorders or family psychiatric disorders, severe cognitive impairment, global aphasia, sensory aphasia, apraxia, severe cardiac, hepatic, renal, lung or other severe somatic disorder, consciousness disturbance, severe deafness, family or patient unable to comply

Interventions

Treatment: sertraline 50 mg daily plus stroke care (acute, secondary prevention, rehabilitation and psychotherapy)

Control: stroke care (acute, secondary prevention, rehabilitation and psychotherapy)

Duration of treatment: 6 weeks

Duration of follow‐up: (treatment end to study end): 6 months

Outcomes

HAMD

NIHSS

FIM (reported cognition and mobility scores only)

SF‐36

AEs not reported

Funding source

Funded by a local scientific academic fund

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random‐number table

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor blind

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts, analysed by allocated treatment

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Low risk

No obvious risk, balance baseline

Study characteristics

Methods

Parallel group

Analysis: according to treatment allocation

Participants

Location: China

Setting: inpatient

Inclusion criteria: all pathological types of stroke, clinical diagnosis plus confirmation by imaging (did not state that a visible lesion was needed to make the diagnosis), first ever stroke

Depression diagnosis: 'HAMD scores'. Translation of paper: did not have to have depression at recruitment

Treatment: 36 people, mean age 70.8 ± 6.7 years, 25 men

Control: 35 people, mean age 70.4 ± 6.8 years, 23 men

Exclusion: psychiatric disorders, dysphasia, consciousness disturbance, agnosia, severe dementia

Interventions

Treatment: fluoxetine 20 mg daily plus usual stroke care

Control: usual stroke care

Duration of treatment: 8 weeks

Duration of follow‐up (treatment end to study end): 0

Outcomes

HAMD

SSS

No description of how side effects were collected

Funding source

Funded by local scientific academic fund

Notes

Reported that there were no AEs, so we have assumed no seizures or GI side effects

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Outcome assessors blind"

Incomplete outcome data (attrition bias)
All outcomes

High risk

13 dropped out after randomisation

Selective reporting (reporting bias)

Unclear risk

No protocol

Other bias

Low risk

Balanced baseline, no obvious risks

Study characteristics

Methods

Parallel design. 3 groups: paroxetine, paroxetine plus psychotherapy, control. We are using paroxetine and control data in this review

Analysis: according to treatment group

Participants

Location: China

Setting: inpatient

Stroke criteria: first ever stroke; ischaemic and haemorrhagic, timing: "acute", clinical diagnosis plus confirmation by imaging (though not clear whether a stroke lesion had to be present or not)

Mood criteria: meets ICD‐10 organic depression and organic anxiety diagnostic criteria on psychiatric interview, HAMD score ≥ 17 and HAMA score ≥ 14

Treatment: 27 people, mean age 62.4 ± 6.1 years, 14 men

Control: 27 people, mean age 63.2 ± 5.7 years, 16 men

Exclusion: previous psychiatric disorder, antidepressants and "nerve block agents" in recent 3 months, severe cognitive impairment, aphasia, severe cardiac, hepatic and renal function impairment, allergy to paroxetine, severe suicidal behaviour

Interventions

Treatment: paroxetine 20 mg plus routine stroke treatment

Control: routine stroke treatment

Duration of treatment: 6 weeks

Duration of follow‐up: end of treatment to study end: 0

Outcomes

SSS

BI

HAMD

HAMA

TESS

Also reported GI upset and dizziness. They did not list any seizures in the list of AEs, so we are assuming no seizures in either groups

Unclear how side effects were collected

Funding source

Funded by a local scientific academic fund

Notes

The authors mentioned using the SDS and the SAS for evaluation, but they did not report the results of SDS and SAS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts, analysed according to treatment group

Selective reporting (reporting bias)

High risk

No protocol, the authors mentioned using the SDS and the SAS for evaluation but they did not report the results

Other bias

Low risk

Balanced baseline

Study characteristics

Methods

Study type: interventional (clinical trial)

Primary purpose: prevention

Participants

374 participants

Country: China

Setting: inpatient

At randomisation numbers allocated: N = 300

Experimental group 1: fluoxetine immediately after enrolment n = 100; comparator group 1: fluoxetine 7 days after enrolment n = 100; comparator group 2: no fluoxetine n = 100

% male: unclear

Age: experimental, unclear; comparator 1, unclear; comparator 2, unclear

Subtype of stroke: unclear

Severity of stroke NIHSS score at baseline: unclear

Experimental: unclear

Comparator 1: unclear

Comparator 2: unclear

Time from stroke onset: within 1 week after onset of cerebral infarction

Inclusion criteria

• ICD‐10 diagnostic criteria for acute cerebral infarction

• Age 18 to 80 years

• First onset of stroke within 1 week

• NIHSS score > 2

• Stroke related impairment

• Informed consent by patients or legal representative

Exclusion criteria

• Coma

• Haemorrhagic stroke

• Previous neurological impairment

• Use of antidepressants over previous 3 months

• Use of benzodiapines over previous 2 weeks

• Self‐harm, suicidal ideation or need for antidepressants

• Abnormal liver enzymes or creatinine levels

• Gastrointestinal disorders affect drug absorption seriously

• Life‐threatening illness (e.g. malignancy)

• Allergic

• Mental health disorders

• Pregnant or breast feeding

• Allergic

• Enrolled in another interventional clinical research trial within previous 3 months

• Scheduled endovascular intervention

Withdrawal criteria

• Unblinding

• Serious adverse reactions e.g. anaphylactic shock

• Need for immediate stroke‐related surgery

• Complications

• Antidepressant use

• Self‐harm, suicidal intention, urgent need for antidepressants

• Withdrawal from the study

Interventions

Experimental: 20 mg of fluoxetine a day for 90 days and conventional therapy

Comparator: conventional therapy

Outcomes

Primary outcome at days 15, 90 and 180

• NIHSS score

Secondary outcome at days 90 and 180

• BI score

Funding source

This study was funded by Science and Technology Department of Guangdong, China (grant number: 2011B031800130), Science and Technology Innovation Committee of Shenzhen, China (grant number: 201101020), and Health and Family Planning Committee of Shenzhen, China (grant number: 201501009). It was registered on the Chinese Clinical Trial Registry (number: ChiCTR‐TRC‐12002078)

Notes

Dates study conducted: unclear. Either from June 2011 to December 2012 (ChiCTR‐TRC‐12002078) or from December 2015 to June 2016 (ChiCTR‐IPR ‐ 15007658)

Declarations of Interest: none reported

Trial registration detail (ChiCTR‐TRC‐12002078) does not match but rather matches ChiCTR‐IPR ‐ 15007658.

Baseline demographic and clinical characteristics for each group not presented, but rather the baseline demographic and clinical characteristics for those completing the trial (i.e. a subset of all those randomised at baseline) are presented

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Table of random numbers"

Allocation concealment (selection bias)

Unclear risk

Insufficient information on method of allocation concealment to judge high or low

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of high or low

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The evaluator was banned from participation in the treatment or from querying of the randomisation data."

Incomplete outcome data (attrition bias)
All outcomes

High risk

For the primary outcome of NIHSS score at 15, 90 and 180 days there was 8/187 (4%) lost to follow‐up in the experimental group; 16/187 (15%) in the comparator group. Twice as many participants in the comparator group (16/187(9%)) compared to the fluoxetine group (8/187 (4%)) were lost to follow‐up. Attrition and exclusions were not fully reported

> 5% lost to follow‐up

Selective reporting (reporting bias)

High risk

The trial registration number/protocol does not match the study design presented, but rather matches ChiCTR‐IPR ‐ 15007658

Other bias

High risk

The baseline data presented in table 1: comparison of data at baseline between control group and the treatment group are not true baseline characteristics (i.e. at randomisation). The data presented in table 1 are the baseline characteristics of all those completing the trial which is a subgroup of all participants randomised. We cannot tell if there is whether there was any baseline imbalance in important demographic or clinical characteristics

Study characteristics

Methods

Parallel design

Aim: to study effect of antidepressants on depressive symptoms and nervous function

Participants

Country: China

Setting: inpatient

Stroke criteria: all pathological stroke types, clinical diagnosis plus confirmation by imaging (though unclear whether a relevant lesion had to be visible), onset of stroke 0.5 to 2 months, no obvious aphasia

Depression: according to CCMD‐II‐R

Treatment: 42 people, mean age 61.4 ± 3.6 years, 32 men

Control: 30 people, mean age 60 ± 4.8 years, 23 men

Interventions

Treatment: fluoxetine 20 mg daily

Control: no other antidepressant

Duration of treatment: 8 weeks

Duration of follow‐up (end of treatment to study end): 0

Outcomes

HAMD

MESSS

However, these data were not usable, as they were reported as proportions above or below "decrement levels"

Reported side effects but unclear how this was done

None left the trial early

Funding source

Source of funding not stated

Notes

−

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk