岡田 剛史

Tramadol (TRA) overdose can induce severe hyperthermia associated with monoaminergic dysregulation, particularly serotonin toxicity, and may lead to fatal outcomes. Although supportive treatments such as hydration and external cooling are commonly used, effective pharmacological interventions are yet to be established. Here, we aimed to evaluate the effects of risperidone (RIS) and ambient temperature on TRA-induced hyperthermia and changes in central monoamines in a rat model. Male Wistar rats received intraperitoneal TRA (100 mg/kg) under ambient temperatures of 18 °C, 23 °C, or 28 °C. RIS (0.25 or 0.5 mg/kg) and various monoamine receptor antagonists were administered to assess pharmacological responses. Core body temperature and locomotor activity were continuously monitored via implantable sensors, and in vivo microdialysis was conducted in the anterior hypothalamus to quantify extracellular levels of serotonin (5-HT), norepinephrine (NA), and dopamine (DA). TRA significantly elevated 5-HT, NA, and DA levels in a temperature-dependent manner, with DA and NA being strongly affected by ambient temperature. RIS at 0.25 mg/kg effectively suppressed hyperthermia and reduced DA elevation, whereas the 0.5 mg/kg dose did not. 5-HT2A and D1 receptor antagonists replicated the hyperthermia-suppressive effect, whereas 5-HT1A, 5-HT2B/2C, and D2 antagonists did not. These findings suggest that RIS attenuates TRA-induced hyperthermia primarily via DA suppression through 5-HT2A and D1 receptor antagonism and that elevated environmental temperatures exacerbate monoaminergic dysfunction and hyperthermic outcomes. RIS may represent a potential therapeutic option for managing tramadol toxicity.

AIM: Constipation is one of the most common adverse effects in schizophrenia treatment, and it can sometimes cause severe gastrointestinal disease. However, the results of association studies between constipation and psychotropic medications in patients with schizophrenia are inconsistent. Therefore, we investigated the characteristics of psychotropic and laxative prescriptions at discharge in patients with schizophrenia to clarify the association between psychotropics and constipation. METHODS: We analyzed the data of 139 patients with schizophrenia with or without laxative prescriptions at discharge from eight institutions in 2020. RESULTS: Sixty-two patients were prescribed laxatives at discharge. The prescription of benzodiazepines in the laxative use group (66.1%) was significantly higher than that in the non-laxative use group (39.0%) (p = 1.4 × 10-3), and the mean number of benzodiazepines in the laxative use group (1.2 ± 1.1/day) was significantly higher than that in the non-laxative use group (0.7 ± 0.9/day) (p = 2.6 × 10-3). Multivariate logistic regression analyses revealed that benzodiazepine prescriptions were significantly associated with laxative usage (odds ratio, 3.059; 95% confidence interval, 1.523-6.144; p = 2.0 × 10-3). CONCLUSION: Benzodiazepines may be associated with constipation in patients with schizophrenia. Therefore, clinicians should be cautious when prescribing benzodiazepines for the treatment of schizophrenia.

Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication.