role of antidepressants in post stroke recovery

François CHOLLET MD, PhD

Neurology Department: Stroke Unit

Toulouse University Hospital (CHU)

Neurosciences Institute of ToulouseCNRS , INSERM, University, CHU

Role of antidepressants in post stroke

recovery

CNRS , INSERM, University, CHU

Presenter Disclosure Information

François Chollet, MD, PhD

Role of antidepressants in post stroke recovery

Nothing to discloseNothing to disclose

Geneva Nov 24th 2016


recovery

• Recovery from stroke: worldwide major issue for public health

policies

• IV Thrombolysis with rTPa and Mechanical Thrombectomy • IV Thrombolysis with rTPa and Mechanical Thrombectomy

validated and registred treatment

– 20% patients only

– 40 % remain with a significant neurological deficit

• Spontaneous lesioned-brain reorganisation is a rationale basis

for spontaneous recovery of neurological functions

• Spontaneous lesioned brain reorganisation can be modulated

through external factors


recovery

• Spontaneous lesioned brain reorganisation can be

modulated through :

– Rehabilitation procedures

– Cortical stimulations (TDCS, rTMS…)

– Peripheral stimulations or inhibitions

• Stimulation of proprioceptive input

• Anesthetic block

– Monoaminergic drugs

• Amphetamines

• Antidepressants: SSRI, SNRI, Monoamine oxydase Inhibitors…

• But also: dopaminergic agents, piracetam, donepezil…


recovery

• Depression is also a major issue for stroke patients:

– mean prevalence of depression among in-patients in acute

or rehabilitation settings of 19.3% and 18.5% for major and

minor depression respectively (Robinson et al 2003)minor depression respectively (Robinson et al 2003)

– In out-patient studies, mean reported prevalence was

23.3% for major depression and 15% for minor depression (Robinson et al 2003)

– persistent depression in more than half (55%) of the

individuals identified as depressed during inpatient

rehabilitation post stroke (Farner et al 2010).


recovery

• The risk factors associated with increased risk for post-stroke

depression (PSD) include

– female sex,

– past history of depression or– past history of depression or

– psychiatric illness,

– Functional limitations, and

– Cognitive impairment.

• predictors of persistent depression include

– lower levels of pre-stroke social activity,

– greater severity of stroke and

– lower levels of function at baseline.


recovery

• Antidepressants in post stroke depression

– 1- Functional impairment and depression– 1- Functional impairment and depression

– 2- Antidepressants and treatment of post stroke depression

– 3- Antidepressants and stroke outcome in patients with depression

– 4- Antidepressants in prevention of poststroke depression

• Antidepressants in stroke patients without depression.


recovery

• Does post stroke depression reduce post stroke

recovery?

– mobility decline was experienced between 1 and 3 years post stroke – mobility decline was experienced between 1 and 3 years post stroke

by 21% of participant of a prospective cohort study (n=205) (Van de

Port et al. 2006) .

– Significant predictors of this decline in mobility status were

• level of activity,

• cognitive problems,

• fatigue and

• depression.


recovery

• Does post stroke depression reduce post

stroke recovery? :stroke recovery? :

– Co-occurrence of stroke and depression is associated with

greater physical limitations than either condition on its

own (Goodwin and Devanand 2008) .

– Depression post-stroke has a negative impact on functional

recovery


recovery

• Are Antidepressants active in post stroke

depression ?

– Interventions for treating depression after stroke (Hackett et – Interventions for treating depression after stroke (Hackett et

al; The Cochrane Database of Systematic Reviews 2010 Issue 1)

• “Antidepressant drugs may be useful in treating depression after

stroke, but also cause side effects. (…)

• These drugs should be used with caution in people with persistent

depressive symptoms after stroke, as little is known about the

risks, especially of seizures, falls, and delirium. (…)”


recovery• Are Antidepressants active in post stroke

depression ?

– Following have been shown to be active in treating stroke

depression

• Heterocyclic antidepressants• Heterocyclic antidepressants

• SSRI

• SNRI: reboxetine is effective in reducing retarded post-stroke

depression (Rampello et al 2005)


recovery

• Antidepressants and Stroke Outcome in Stroke

patients with Depression

– Early identification and treatment of post-stroke – Early identification and treatment of post-stroke

depression may serve to enhance functional recovery.

– improvement in depressive symptomatology has been

associated with reduced odds for dependency at 3

months post stroke (Schmid et al. 2011).


recovery

• Antidepressants and Stroke Outcome in Stroke

patients with Depression

Stroke recovery

after Treatment

of PSD with

antidepressants


recovery

• Antidepressants and Stroke Outcome in Stroke patients

with Depression:

– Despite negative studies

– There are arguments to think that pharmacologic treatment – There are arguments to think that pharmacologic treatment

of depression is associated with improved functional recovery

post-stroke.

– Interventions for treating depression after stroke (Hackett et al;

The Cochrane Database of Systematic Reviews 2010 Issue 1)

• “Antidepressant drugs may be useful in treating depression after

stroke, but also cause side effects. (…)

• This review of 16 trials, including 1655 participants, found that

antidepressant drugs may produce recovery or improve

depression symptoms. (…)”


recovery

• Can Antidepressants prevent the occurrence of depression in

stroke patients ?


recovery

• Can Antidepressants prevent the occurrence of depression

in stroke patients


recovery

• Antidepressants in post stroke depression

– 1- Functional impairment and depression– 1- Functional impairment and depression

– 2- Antidepressants and treatment of post stroke depression

– 3- Antidepressants and stroke outcome in patients with depression

– 4- Antidepressants in prevention of poststroke depression

• Antidepressants in stroke patients without depression.


recovery

• Antidepressants and Stroke Outcome in Stroke patients

without Depression:

– SNRI: reboxetine, maprotiline

– Heterocyclic: nortriptyline

– Monoamine oxydase inhibitors: moclobemide

– SSRI: fluoxetine, citalopram

Open fieldFew trialsOften small-sized trialsMotricty: main function addressedSSRIs mainly


recovery

double-blind

placebo-controlled crossover

study,

hemiparetic chronic stroke

patients (n = 10) received a single

dose of the noradrenaline reuptake

inhibitor reboxetine or placebo.

Baseline


recovery

Compared with placebo,

reboxetine ingestionreboxetine ingestion

was followed by an increase of

tapping speed and

grip strength in

the paretic but not in the

unaffected

hand.


recovery

90 acute stroke patients

with aphasia were randomized to either 600 mg moclobemide

or placebo daily for 6 months,

within 3 weeks of the onset of stroke.

Aphasia was assessed prior to treatment and

at 6 months, using Reinvang’s ‘Grunntest for afasi’

and the Amsterdam-Nijmegen-Everyday-Language-Test


recovery

“Compared to placebo, treatment with

moclobemide for 6 months did not enhance

the regression of aphasia following an acute stroke.”

Placebo-controlled trials of SSRIs in motor

recovery after ischaemic stroke


recovery

Twenty patients with unilateral stroke :

ten patients treated by citalopram (10mg

o.d) and

ten patients with placebo

in combination with physiotherapy

during one month


recovery

Patients treated by the serotonergic

drug,

compared to patients that received a

placebo,

showed a significant

improvement in neurological status as

measured by NIHSS

8 patients with chronic strokeStable motor deficitPlacebo-controlled cross over trialPlacebo-controlled cross over trial40 mg single dose Citalopram

Patients included

within 3 months after strokestroke

Non depressed

mean NIH : 6-7

positive

negative

-Acute ischemic stroke with

motor deficit

-Non depressed patients

-Fugl-Meyer Motor Scale

(FMMS) score ≤ 55

-randomisés entre J 5 et J10

Patients treated with antidepressants

had better recovery

from disability by one-year from

stroke

(ie 9 months after antidepressants

were stopped)were stopped)

than patients who did not received

antidepressant therapy.

This effect was independent of

depression

• prospective double-blinded study testing

one 20mg single dose of fluoxetinone 20mg single dose of fluoxetin

against placebo

• 8 patients with a pure motor stroke

• subcortical lesions

• capable to do repetitive flexion-extensions

with their finger

fluoxetine significantly

improved motor skills of the

affected side

A single dose of fluoxetine was

enough to modulate cerebral sensory-motor activation

Correlation with Motor Performance

Methylphenidate / Placebo - Active movement; paretic hand

( red: overactivation – blue: hypoactivation)

Anterior cingulumLesioned side« Healthy » side

P < 0.05hand

S1M1

Face S1M1

PMChand

S1M1

Single dose of

paroxetine

Stimulation Magnétique Trans Crânienne

• IRM fonctionnelle de repos

• Cohérence EEG


recovery

• Antidepressants in stroke patients without depression:

– SSRIs mainly

– heterogeneous clinical trials

– Most of the time small-sized trials

– Some are single dose trials– Some are single dose trials

– Addressing motricity recovery mainly

Most of the time positive trials

Limited side effects

Suggesting a direct effect on motor cortices excitability

Independent of depression

A 3-month treatment of 20mg o.d Fluoxetine showed positive motor

effect (FLAME)

Long term benefit suggested with citalopram

Ongoing large trials

role of antidepressants in post stroke recovery

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