Methylphenidate and desipramine combined treatment improves PTSD symptomatology in a rat model

Abstract

Antidepressant medication constitutes the first line pharmacological treatment for posttraumatic stress disorder (PTSD), however, because many patients display no beneficial drug effects it has been suggested that combinations of antidepressants with additional drugs may be necessary. The defining symptoms of PTSD include re-experiencing, avoidance and hyperarousal. In addition, PTSD patients were shown to become easily distracted and often suffer from poor concentration together with indications of comorbidity with attention-deficit hyperactivity disorder (ADHD). Methylphenidate (MPH) is the most common and effective drug treatment for ADHD, thus we aimed to investigate the effects of MPH treatment, by itself or in combination with the antidepressants fluoxetine (FLU) or desipramine (DES). We modified an animal model of PTSD by exposing rats to chronic stress and evaluating the subsequent development of behavioral PTSD-like symptoms, as well as the effects on proinflammatory cytokines, which were implicated in PTSD. We report that while FLU or DES had a beneficial effect on avoidance and hyperarousal symptoms, MPH improved all three symptoms. Moreover, the combination of MPH with DES produced the most dramatic beneficial effects. Serum levels of interleukin-1β (IL-1β) and IL-6 were elevated in the PTSD-like group compared with the control group, and were decreased by MPH, FLU, DES or the combination drug treatments, with the combination of DES+MPH producing the most complete rescue of the inflammatory response. Considering the versatile symptoms of PTSD, our results suggest a new combined treatment for PTSD comprising the antidepressant DES and the psychostimulant MPH.

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury

“…If this is, indeed, the mechanism of action of MPH on reducing PTSD symptoms, then one might consider designing a future trial where MPH (vs placebo) is administered in conjunction with exposure therapy. But other animal models of PTSD also show benefits of MPH that may or may not involve facilitation of fear extinction (Aga-Mizrachi et al, 2014), pointing to the need to further explore mechanisms of action.…”

Immune signaling mechanisms of PTSD risk and symptom development: insights from animal models

“…Aga-Mizarachi et al investigated the effects of methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), on three core PTSD-like symptoms, including re-experiencing, avoidance, and hyperarousal [51]. In a stress paradigm consisting of repeated footshock exposures, chronic treatment with methylphenidate reverses the stress-related impairment in fear extinction (re-experiencing), decrease in locomotor activity (avoidance), and increase in startle response (hyperarousal).…”

“…In a stress paradigm consisting of repeated footshock exposures, chronic treatment with methylphenidate reverses the stress-related impairment in fear extinction (re-experiencing), decrease in locomotor activity (avoidance), and increase in startle response (hyperarousal). The effects of methylphenidate are enhanced when combined with desipramine, a noradrenergic reuptake inhibitor, and correlate with an attenuation of the stress-induced elevation of IL-1β and IL-6 serum levels [51], linking immune alterations and PTSD-like phenotype in vivo. In line with this study, a recent randomized placebo-controlled trial showed that methylphenidate improves PTSD symptoms in mixed head injury/PTSD patients [52], supporting the potential of this drug for treatment of PTSD.…”

Use of Stimulants and Performance Enhancers During and After Trauma Exposure in a Combat Veteran: A Possible Risk Factor for Posttraumatic Stress Symptoms

“…The study's authors conclude that stimulant use may contribute to the pathogenesis of PTSD. Other preclinical data and a small ( n =32) randomized controlled trial have found that psychostimulants may improve PTSD symptoms, possibly by enhancing learning, promoting a feeling of well-being, and targeting attention and concentration difficulties(14,18,19). Dopaminergic and serotonergic mechanisms may be implicated in the ameliorative effect of psychostimulants observed in these studies(14,19).…”

“…Other preclinical data and a small ( n =32) randomized controlled trial have found that psychostimulants may improve PTSD symptoms, possibly by enhancing learning, promoting a feeling of well-being, and targeting attention and concentration difficulties(14,18,19). Dopaminergic and serotonergic mechanisms may be implicated in the ameliorative effect of psychostimulants observed in these studies(14,19). It is likely that the relationship between stimulants and PTSD symptomatology may vary depending on timing, quantity, and duration of stimulant use during or after traumatic exposures as well as individual genetic and environmental factors(17).…”