Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence

Abstract

BackgroundSeveral clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated.MethodsWe searched MEDLINE using the PubMed interface to identify evidence of SSRI mediated improvement of recovery from acute ischemic stroke and reviewed the literature on the potential underlying mechanisms of action.ResultsAmong identified clinical studies, a well‐designed randomized, double‐blind, and placebo‐controlled study (FLAME ‐ fluoxetine for motor recovery after acute ischemic stroke) demonstrated improved recovery of motor function in stroke patients receiving fluoxetine. The positive effects of SSRIs on stroke recovery were further supported by a meta‐analysis of 52 trials in a total of 4060 participants published by the Cochrane collaboration. Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic‐brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic‐brain regions, anti‐inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking.ConclusionIn addition to the need of comprehensive‐clinical evidence, further elucidation of the beneficial mechanisms whereby SSRIs may improve structural and functional recovery from ischemic‐brain damage is needed to form a basis for translation into clinical practice.

Cerebrovascular adaptations to cocaine-induced transient ischemic attacks in the rodent brain

“…Similarly, upregulation of platelet-derived growth factor (PDGF) after chronic cocaine was interpreted to reflect an increase in vessel permeability that might indirectly stimulate angiogenesis (30). Apart from ischemia, it is also plausible that the serotonin-enhancing effects of cocaine might have also contributed to angiogenesis for sustained administration of selective serotonin reuptake inhibitors (SSRI), which have been shown to improve recovery of stroke in animal models and in humans (31,32). Inasmuch as cocaine, like SSRI, blocks serotonin transporters (33,34), this effect could have accelerated the recovery associated with its vasoconstricting effects.…”

The neurophysiological effects of single-dose theophylline in patients with chronic stroke: A double-blind, placebo-controlled, randomized cross-over study

“…Given theophylline’s weak affinity for GABA A R at low concentrations, GABA A R antagonism is less likely to explain SICI reduction. Increasing glutamatergic, adrenergic, and serotoninergic signaling in the motor cortex are approaches currently being explored in preclinical and clinical stroke recovery studies (Cherry, Lenze, & Lang, 2014; Dhawan et al, 2011; Grade et al, 1998; Siepmann et al, 2015). …”

The risk of initiating fluoxetine for motor deficits after ischemic stroke in patients with bipolar disorder

“…Following the publication of FLAME and similar trials 2,3 , there is growing evidence that providers should consider prescribing a selective serotonin reuptake inhibitor for a patient who has experienced a stroke 4 . However, the psychiatric consequences or diagnostic contraindications of this therapy have not been discussed.…”