Intermittent treatment with haloperidol or quetiapine does not disrupt motor and cognitive recovery after experimental brain trauma

Abstract

Traumatic brain injury (TBI)-induced agitation and aggression pose major obstacles to clinicians in the acute hospital and rehabilitation settings. Thus, management of these symptoms is crucial. Antipsychotic drugs (APDs) are a common treatment approach for alleviating these symptoms. However, previous preclinical TBI studies have indicated that daily and chronic administration of these drugs (e.g., haloperidol; HAL) can exacerbate cognitive and motor deficits. Quetiapine (QUE) is an atypical APD that differs from many typical APDs, such as HAL, in its relatively rapid dissociation from the D receptor. The goal of this study was to test the hypotheses that intermittent HAL and QUE would not hinder recovery of cognitive and motor function following TBI and that daily QUE would also not impair functional recovery, which would be in contrast to HAL. Seventy anesthetized male rats received either a controlled cortical impact or sham injury and were then randomly assigned to TBI and sham groups receiving HAL (0.5mg/kg) or QUE (10mg/kg) intraperitoneally once per day or once every other day and compared to each other and vehicle (VEH) controls. Motor function was assessed by beam balance/walk tests on post-operative days 1-5 and cognitive function was evaluated with a Morris water maze task on days 14-19. No differences were revealed among the sham groups in any task, and hence the data were pooled. No overall differences were detected among the TBI groups, regardless of treatment or administration paradigm [p>0.05], but all were impaired vs. SHAM controls [p<0.05]. The SHAM controls also performed significantly better in the cognitive test vs. all TBI groups [p<0.05]. Moreover, the TBI+continuous HAL group performed worse than the TBI+continuous VEH, TBI+continuous QUE, and TBI+intermittent QUE groups [p<0.05], which did not differ from one another. Overall, the data suggest that QUE does not exacerbate TBI-induced cognitive and motor deficits, which supports the hypothesis. QUE may prove useful as an alternative APD treatment for management of agitation and aggression after clinical TBI. HAL may also be safe, but only if used sparingly.

Brain Injury–Mediated Neuroinflammatory Response and Alzheimer’s Disease

“…Moreover, anti-inflammatory drugs are not effective against important inflammatory mediators or cells due to difficulties in drug delivery methods. Drug delivery to the CNS after TBI is complicated due to the BBB, blood-cerebrospinal-fluid barrier (BCSFB), and other problems (Weeks and others 2018). Intranasal drug delivery to the brain may improve the therapeutic effects (Drews and others 2019).…”

Comparable impediment of cognitive function in female and male rats subsequent to daily administration of haloperidol after traumatic brain injury

“…Fortunately, recent studies have emerged showing that APDs with different mechanisms of action do not impede recovery after TBI. Specifically, intermittent administration (i.e., once every other day for 3 weeks) of quetiapine did not hinder motor or cognitive performance after CCI injury in male rats (Weeks et al, 2016). Moreover, aripiprazole also did not hamper recovery at either of the doses provided, but did lead to enhanced spatial learning with the lowest dose (Phelps et al, 2017).…”

The Effects of Four Compounds That Act on the Dopaminergic and Serotonergic Systems on Working Memory in Animal Studies; A Literature Review

“…Another article investigated the effects of intermittent versus continuous haloperidol or quetiapine administration in a total number of 70 rats with previously induced traumatic brain injury. The study concluded that continuous, but not intermittent administration of haloperidol affected the acquisition phase of spatial learning, while quetiapine did not influence it significantly [ 34 ]. One study used haloperidol specifically to impair memory in mice (80 total subjects), and this effect was proved using the novel object-recognition test, where haloperidol-treated mice had significantly poorer results when compared to the control group.…”