Depression occurs in up to two-thirds of patients with stroke, and placebo-controlled trials have shown improvement in post-stroke depressive symptoms with antidepressant drug treatment Citation[1]. However, recent studies suggest that antidepressants could also improve outcome from stroke itself. At least three mechanisms may be involved: protection against acute ischemic neuronal injury, increased ischemia-induced neurogenesis and enhanced brain repair.
Neuroprotection
Antidepressants may have an acute neuroprotective effect in cerebral ischemia Citation[2]. The tertiary amine tricyclic antidepressant (TCA) clomipramine and the selective serotonin-reuptake inhibitor (SSRI) citalopram, given 5 min prior to transient forebrain ischemia in the gerbil, each reduced loss of hippocampal CA1 neurons by approximately 70% Citation[3]. The SSRI fluoxetine had a similar effect when given for 3 days pre-ischemia Citation[4]. The TCA nortriptyline, administered 30 min before and 12 h after middle cerebral artery occlusion (MCAO), reduced infarct volume by approximately 55% and improved motor outcome at 24 h in mice Citation[5]. Finally, fluoxetine, given 30 min to 9 h after MCAO, reduced infarct volume by up to 80% and yielded better performance on tests of motor, sensory, equilibrium and reflex function in rats at 24 h Citation[6]. These studies argue for an acute neuroprotective effect of multiple classes of antidepressants in cerebral ischemia.
Neurogenesis
Stroke in rodents Citation[7] and humans Citation[8] stimulates neurogenesis in the anterior subventricular zone (SVZ) and the subgranular zone of the hippocampal dentate gyrus. Neurons arising in the SVZ, but not hippocampus, migrate to the infarct site, where they assume features of mature neurons Citation[9]. Ischemia-induced neurogenesis in rodents appears to contribute to functional outcome, because outcome is worse when neuronal precursor cells are ablated Citation[10,11].
Antidepressants also stimulate neurogenesis. Rats treated for 2–4 weeks with fluoxetine, the norepinephrine-reuptake inhibitor reboxetine or the monoamine oxidase inhibitor tranylcypromine showed 30–200% increases in cell proliferation – measured by bromodeoxyuridine (BrdU) labeling – in the hippocampus; some of these cells went on to express mature neuronal markers Citation[12,13]. Antidepressants also stimulate SVZ neurogenesis. Treatment for 15 days with the TCA imipramine increased BrdU labeling of cells expressing a newborn neuronal marker by approximately 25% in rat SVZ Citation[14]. Both imipramine and fluoxetine, given for 3 weeks, reversed inhibition of SVZ neurogenesis by behavioral stress in mice Citation[15], and treatment for 2 weeks with the SSRI paroxetine increased BrdU labeling in SVZ by approximately 35% in rats Citation[16]. Nonpharmacological antidepressive treatments, including electroconvulsive therapy Citation[13], transcranial magnetic stimulation Citation[17] and exercise Citation[18], also enhance neurogenesis. Based partly on these observations, the therapeutic effect of antidepressants in some animal models of depression has been attributed to hippocampal neurogenesis Citation[19].
Mechanisms through which antidepressants might induce neurogenesis include altered monoaminergic (serotonin, norepinephrine or dopamine) neurotransmission and induction of growth factors. In rats treated with parachlorophenylalanine (which inhibits serotonin synthesis) or 5,7-dihydroxytryptamine (which damages serotonergic neurons), BrdU-labeled cells and cells expressing a newborn neuronal marker were depleted from the hippocampus and SVZ Citation[20]. This implies that serotonin promotes neurogenesis; thus, antidepressants that potentiate serotonergic transmission might do likewise. In another study, depletion of both serotonin and norepinephrine was required to inhibit hippocampal neurogenesis Citation[21]. Dopamine also appears to stimulate neurogenesis, as evidenced by increased BrdU labeling in the SVZ following administration of dopamine D2/D3 agonists Citation[22,23], and by depletion of SVZ cells that express a cell-proliferation marker after lesioning dopaminergic fibers in rats with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine Citation[23,24]. A neurogenesis-promoting effect of norepinephrine has also been demonstrated. BrdU labeling in rat hippocampus was reduced by the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride Citation[25] and by the presynaptic α2-adrenergic receptor antagonists clonidine and guanabenz, which inhibit norepinephrine release Citation[26]. In another study, the α2-adrenergic receptor antagonist dexefaroxan, which promotes norepinephrine synthesis and release, reduced apoptosis and enhanced survival of newborn neurons in rats Citation[27]. Enhancement of hippocampal neurogenesis by adrenergic stimulation may involve activation of postsynaptic β3-adrenergic receptors Citation[28]. To summarize, evidence exists to support a role for each of the monoamine neurotransmitter systems affected by antidepressants – serotonergic, dopaminergic and adrenergic – in neurogenesis.
Another potential mechanism for antidepressant-induced neurogenesis is induction of growth factors, several of which stimulate neurogenesis and have been proposed as mediators of monoamine neurotransmitter-induced neurogenesis specifically Citation[29]. Brain-derived neurotrophic factor Citation[30,31], FGF2 Citation[32] and VEGF Citation[33] all trigger neurogenesis in rat brain, and each improves outcome from experimental stroke Citation[34]. Administration of tranylcypromine, the TCA desipramine, the SSRI sertraline or the noradrenergic and specific serotonergic antidepressant mianserin for 3 weeks increased brain-derived neurotrophic factor expression in rat hippocampus Citation[35]. FGF2 levels in the cerebral cortex and hippocampus were increased in rats treated for 3 weeks with fluoxetine, desipramine or mianserin Citation[36]. Finally, fluoxetine and desipramine increased VEGF expression in the hippocampus and increased BrdU incorporation into newborn hippocampal neurons Citation[37].
If both ischemia and antidepressants stimulate neurogenesis, does antidepressant treatment provide benefit beyond that afforded by ischemia itself? In one study, fluoxetine given for up to 3 weeks following transient forebrain ischemia in rats yielded no further increase in BrdU labeling of hippocampal cells Citation[38]. However, others reported that survival of BrdU-labeled hippocampal cells was enhanced by 4 weeks of fluoxetine treatment, compared with transient MCAO alone Citation[39]. Fluoxetine also improved spatial cognitive performance, but not infarct volume. Imipramine administration for 2 weeks increased BrdU incorporation and survival of BrdU-labeled hippocampal cells in rats after transient forebrain ischemia Citation[40]. In summary, current data permit no definitive conclusion regarding the ability of antidepressants to potentate ischemia-induced neurogenesis.
Neurorepair
Some studies suggest that sympathomimetic drugs (e.g., amphetamines) promote, whereas GABAergic drugs (e.g., benzodiazepines) inhibit, long-term recovery from stroke Citation[41]. Desipramine enhanced, amitriptyline and fluoxetine had no effect on, and the serotonin 5-HT2A receptor antagonist trazodone impaired motor recovery after cortical lesions in rats Citation[42,43]. When fluoxetine was given to newborn rat pups for 1 week prior to cerebral hypoxia-ischemia, cognitive performance in adulthood was improved Citation[44]. Chronic administration of fluoxetine also enhanced visual function in adult rats after monocular visual deprivation, consistent with increased plasticity of visual cortex Citation[45].
Numerous clinical studies have evaluated the effects of antidepressants – typically given together with physical, occupational and speech therapy – in stroke. Most studies have focused on treatment of depression per se, but others have addressed either stroke symptoms or functional outcome measures. However, interpretation can be difficult because functional impairment in stroke may be influenced by mood as well as by neurological deficits Citation[46].
In one study, 46 patients unable to walk at 1–6 months after stroke were treated for 3 months with placebo, fluoxetine or the norepinephrine-reuptake inhibitor maprotiline Citation[47]. Patients who received fluoxetine showed the greatest improvement in activities of daily living (Barthel index) and gait, and constituted a disproportionate number of those with a good outcome, despite the fact that fluoxetine and maprotiline improved depressive symptoms to a similar extent. Another group of 18 depressed patients approximately 1 month post-stroke were given fluoxetine, trazodone or desipramine for 4 weeks Citation[48]. All groups showed similar improvement in depression (Hamilton Depression Scale) and there were no differences in neurological assessment (Fugl–Meyer scale), but function (Functional Independence Measure) improved most with fluoxetine and least with desipramine. Fluoxetine or nortriptyline, administered for 12 weeks beginning within 6 months of stroke, also improved executive function (Controlled Oral Word Association and Wisconsin Card Sorting Test Perseverative Errors) at 2 years, independent of depression, in a placebo-controlled study of 36 patients Citation[49].
The effect of antidepressants in post-stroke mortality was analyzed in 104 patients followed for 9 years Citation[50]. Patients enrolled within 6 months of stroke were treated for 12 weeks with placebo, nortriptyline or fluoxetine. Approximately 65% of placebo-treated but only 40% of antidepressant-treated patients died during the follow-up period, most due to cardiovascular disease or recurrent stroke. The effect of antidepressants on mortality was delayed, becoming apparent approximately 2 years post-treatment and becoming most pronounced at 6–9 years. A crossover study of a single dose of citalopram was conducted in eight patients at an average of 3 years post-stroke Citation[51]. Grip strength and dexterity (nine-hole peg test) were measured before and 2 h after citalopram, as well as following a physiotherapy session. Citalopram had no effect on grip strength but improved dexterity, compared with placebo. In a study of 20 patients, citalopram also improved neurological status (NIH Stroke Scale) 45–50 days post-stroke, when compared with placebo Citation[52]. The SSRI escitalopram was used in a study of 129 patients enrolled within 3 months after stroke and treated for 12 months Citation[53]. Compared with patients treated with placebo or problem-solving therapy, those given escitalopram showed greater improvement in tests of cognitive function, including verbal and visual memory (Repeatable Battery for the Assessment of Neuropsychological Status), independent of depression. By contrast, the monoamine oxidase inhibitor moclobemide, given for 6 months, was no more effective than placebo in eliciting recovery from aphasia among 90 patients treated within 3 weeks of stroke Citation[54].
Conclusion
Evidence exists for a beneficial effect of antidepressants of various classes on outcome from stroke, independent of their effect on depression. Variables that may influence efficacy, and which have not been systematically investigated to date, include type and location of stroke, post-stroke interval, choice of drug, duration of treatment and outcome measure. The mechanisms through which antidepressants influence stroke outcome are unknown, but possibilities include enhancement of monoaminergic neurotransmission, induction of growth factors and stimulation of neurogenesis. One study cited above suggests an additional possibility. Transcranial magnetic stimulation showed that citalopram reduced excitability of the intact (nonischemic) motor cortex in patients with stroke Citation[52]. This is notable because excessive transcallosal inhibition of the ischemic by the nonischemic hemisphere may impede stroke recovery Citation[55]. If this were the case, suppressing activity in the nonischemic motor cortex could be beneficial.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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