Traumatic brain injury (TBI) survivors often suffer from agitated behaviors and will most likely receive pharmacological treatments. Choosing an optimal and safe treatment that will not interfere with neurological recovery remains controversial. By interfering with dopaminergic circuits, antipsychotics may impede processes important to cognitive recovery. Despite their frequent use, there have been no large randomized controlled studies of antipsychotics for the management of agitated behaviors during the acute TBI recovery period. We conducted a systematic review and meta-analysis of pre-clinical studies evaluating the effects of antipsychotics post-TBI on both cognitive and motor recovery. MEDLINE and Embase databases were searched up to August 2, 2023. Pre-clinical studies evaluating the effects of antipsychotics on cognitive and motor functions post-TBI were considered. Risk of bias was evaluated with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified 15 studies including a total of 1188 rodents, mostly conducted in male Sprague-Dawley rats using cortical impact injury. The analysis revealed no consistent effect of haloperidol on motor functions, but risperidone was associated with a significant impairment in motor function on day 5 post-injury (7.05 sec; 95% confidence interval [CI]: 1.47, 12.62; I2 = 92%). Other atypical antipsychotics did not result in impaired motor function. When evaluating cognitive function, haloperidol- (23.00 sec; 95% CI: 17.42–28.59; I2 = 7%) and risperidone-treated rats (24.27 sec; 95% CI: 16.18–32.36; I2 = 0%) were consistently impaired when compared to controls. In studies evaluating atypical antipsychotics, no impairments were observed. Clinicians should avoid the regular use of haloperidol and risperidone, and future human studies should be conducted with atypical antipsychotics.

Background Second-generation antipsychotics (SGAs) are increasingly being utilized in children and adolescents. Risperidone, one of the most commonly prescribed SGAs in this population, has been found to adversely affect cognitive function; however, limited knowledge exists regarding the impact of risperidone on the gut microbiome-brain axis. We hypothesized that the cognitive impairment induced by risperidone is mediated by alterations in the gut microbiome and its metabolites. Results In this study, we found that early-life risperidone exposure impaired cognition in mice, including deficits in behavior tests and hippocampal dendritic architecture. The risperidone-exposed mice also exhibited gut microbiota dysbiosis along with damage to the intestinal barrier. Fecal microbiota transplantation (FMT) from treated donors to recipients demonstrated the causal role of the gut microbiome in risperidone-induced cognitive deficits. Of note, risperidone increased the abundance of species Escherichia coli, Eggerthella lenta, Ruminococcus gnavus, Clostridium perfringens, Clostridium difficile, and Blautia hydrogenotrophica. These altered species are identified to encode 7α-HSDH, 3β/α-HSDH, TyrB, and porA, the key enzymes in secondary bile acid metabolism and tyrosine metabolism. Furthermore, a significant reduction in tauroursodeoxycholic acid (TUDCA, the metabolite of bile acid metabolism) and accumulation of p-cresol (the metabolite of tyrosine metabolism) were observed in the brains of mice exposed to risperidone. Mechanically, TUDCA prevented cognitive impairment and endoplasmic reticulum (ER) stress in the hippocampus induced by risperidone, while p-cresol induced neuronal ER stress. Knockout of protein tyrosine phosphatase 1B (PTP1B, ER stress-associated protein) in neurons ameliorated cognitive impairment and neurological damage induced by risperidone. Conclusions This study, for the first time, reveals that early risperidone exposure induces gut microbiome dysbiosis and disturbs the bile acids/tyrosine-PTP1B axis to impair cognitive function. These findings alert the risk of gut and neurological side effects of SGAs treatment and highlight that it is crucial to maintain gut homeostasis during the brain developmental phases of children and adolescents with SGAs exposure. Video Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s40168-026-02358-0.

First-generation antipsychotics (e.g., chlorpromazine, haloperidol, etc.), known as typical antipsychotics, were first introduced in the 1950s, and others were Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders. Together with mood stabilizers, they are also a mainstay in the treatment of bipolar disorder. Moreove Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis, that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on primary negative symptoms (such as apathy, lack of emotional…