Katsutoshi Shioda

Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome

The serotonin (5-HT) syndrome is the most serious toxic interaction of antidepressants, but no pharmacotherapy has yet been established. In the present study, we created an animal model of the 5-HT syndrome by intraperitoneally injecting rats with clorgyline (2 mg/kg) and 5-hydroxy-L-tryptophan (5-HTP) (100 mg/kg) and evaluated the effectiveness of potent 5-HT(2A) receptor antagonists and GABA-enhancing drugs, including diazepam and chlormethiazole. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured by microdialysis. In the group pre-treated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min after administration. Pre-treatment with potent 5-HT(2A) receptor antagonists prevented the development of hyperthermia and death in the rats. Pre-treatment with diazepam, 10 and 20mg/kg, and chlormethiazole, 50 and 100mg/kg, attenuated the development of hyperthermia. Although neither of these drugs completely prevented the rats from dying, they prolonged their survival time. Regardless of the type of therapeutic agents, the concentration of 5-HT increased to about 1100-fold the pre-administration level. The NA levels in the saline group increased to about 16-fold the pre-administration levels, but the increase was significantly lower in the rats that survived as a result of drug therapy. These results suggest that GABA-mimetic drugs may be effective against the 5-HT syndrome, although they have a somewhat weaker effect than the potent 5-HT(2A) receptor blockers, and that not only is 5-HT activity increased in the brain in the 5-HT syndrome, but the NA system is also enhanced.

Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine.

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. The present study was undertaken to demonstrate that nervous systems other than the 5-HT system also participate in the pathophysiology of 5-HT syndrome. Concentrations of 5-HT, dopamine (DA) and glutamate in the hypothalamus were measured in two different 5-HT syndrome animal models using a microdialysis technique. The first model was induced by tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor (3.5 mg/kg) and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (10 mg/kg). The second model was induced by clorgyline, an MAO-A inhibitor (1.2 mg/kg) and 5-hydroxy-L-tryptophan, a precursor of 5-HT (5-HTP) (80 mg/kg). In the first model, the levels of 5-HT and DA increased by 40-fold and 44-fold, respectively, compared with the preadministration levels. In the second model, the concentrations of 5-HT increased by up to 140-fold, whereas DA levels increased by only 10-fold, of the preadministration levels. Although the level of glutamate in the second model barely changed, a delayed increase in the glutamate level was observed in the first model. These findings suggest that not only hyperactivity of the 5-HT system, but also hyperactivity of the DA system, are present in 5-HT syndrome, and that the glutamatergic system is influenced in some 5-HT syndrome cases in which the DA concentration markedly increases.

Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.

Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT1A receptor agonism as well as 5-HT2A and D2 receptor antagonism. We investigated the effect of perospirone in combination with fluoxetine on dopamine release in the rat medial prefrontal cortex using microdialysis. Perospirone and fluoxetine increased dopamine release to 270 and 210% of the baseline value, respectively. A combination of perospirone and fluoxetine markedly increased dopamine release to 800% of the baseline value. Pretreatment with a selective 5-HT1A receptor antagonist, WAY 100635, suppressed the increase in dopamine levels induced by the administration of perospirone and fluoxetine to 330% of the baseline value. These findings suggest that perospirone potentiates fluoxetine-induced dopamine increases in part via the action of the 5-HT1A receptor and may augment the effect of fluoxetine in treatment-resistant depression.

Neuroleptic malignant syndrome and serotonin syndrome.

This chapter is focused on drug-induced hyperthermia with special regard to use of antipsychotics and antidepressants for the treatment of schizophrenia and major depression, respectively. Neuroleptic malignant syndrome (NMS) develops during the use of neuroleptics, whereas serotonin syndrome is caused mainly by serotoninergic antidepressants. Although both syndromes show various symptoms, hyperthermia is the main clinical manifestation. In this review we describe the historical background, clinical manifestations, diagnosis, and differential diagnosis of these two syndromes based on our observations on the experimental and clinical data.

Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. Hyperthermia is the most serious symptom of this syndrome. Hyperthermia in 5-HT syndrome is reportedly the result of activation of 5-HT(2A) receptors. Mirtazapine is a novel antidepressant and a potent 5-HT(2) receptor antagonistic. Although mirtazapine has been reported to cause 5-HT syndrome, the pharmacological profile of mirtazapine suggests that it improves hyperthermia in 5-HT syndrome. In the present study, we evaluated whether mirtazapine attenuates hyperthermia in a rat model of 5-HT syndrome. This model was induced by administration of tranylcypromine, a nonselective monoamine oxidase inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor. Upon injection of these two drugs, the rectal temperature of the rats increased to over 40 degrees C. Pre- and post-administration of mirtazapine abolishes hyperthermia in this model of 5-HT syndrome. Post-administration of ritanserin, a 5-HT(2A) receptor antagonist, completely inhibited hyperthermia and pre-administration of WAY100635, a 5-HT(1A) receptor antagonist, significantly attenuated the ability of mirtazapine to abolish hyperthermia. The results of the present study suggest that mirtazapine inhibits hyperthermia in an animal model of 5-HT syndrome by blocking the activation of 5-HT(2A) receptors, and that it partly inhibits hyperthermia by activating the 5-HT(1A) receptors. The present study indicates that mirtazapine is unlikely to cause 5-HT syndrome and may be a useful drug for treating this condition.

Effect of risperidone on acute methamphetamine-induced hyperthermia in rats

The abuse of methamphetamine (METH) is popular in many parts of the world. The number of fatal cases related to METH-induced hyperthermia is increasing, but no definitive therapy has yet been found. In the present study, we investigated the ability of risperidone to attenuate acute METH-induced hyperthermia and the mechanism of its action. When administered before and after a single high METH dose (10 mg/kg), risperidone significantly suppressed acute METH-induced hyperthermia in a dose-dependent manner. The same effect was produced by dopamine-1 (DA(1)) and serotonin-2A (5-HT(2A)) receptor blockers, but not by D₂, 5-HT(1A), 5-HT(2B/2C), or 5-HT(2C) receptor blockers, demonstrating that risperidone suppressed METH-induced hyperthermia by blocking the D(1) and 5-HT(2A) receptors. A microdialysis study showed that when METH (10 mg/kg) was subcutaneously injected into rats, the levels of DA, 5-HT, glutamate, and the nitric oxide (NO) metabolites NOx (NO₂⁻+ NO₃⁻) in the anterior hypothalamus increased. Risperidone pretreatment significantly attenuated increases in the levels of DA, 5-HT, glutamate, and NOx. The present study indicates that risperidone may be an effective drug for treating METH-induced hyperthermia in humans and that METH influences the DA and 5-HT neuron systems as well as other neuron systems, including the glutamate and NO systems.

Risperidone attenuates the increase of extracellular nitric oxide and glutamate levels in serotonin syndrome animal models.

Serotonin (5-hydroxytryptamine; 5-HT) syndrome is a potentially life-threatening neurotoxic condition provoked by pharmacologically induced excess serotonergic activity. Several studies report that nitric oxide (NO) and glutamate play a role in psychostimulant-induced hyperthermia related to neurotoxicity. In the present study, the involvement of NO and glutamate, as well as the effect of risperidone, a potent 5-HT(2A) and D(2) (and a less potent D(1)) receptor antagonist, were investigated in animal models of 5-HT syndrome. Two 5-HT syndrome animal models were utilized. The first model was induced by administration of tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor, and fluoxetine, a selective 5-HT reuptake inhibitor. The second model was induced by the administration of clorgyline, an MAO-A inhibitor, and 5-hydroxy-l-tryptophan, a precursor of 5-HT. Changes in the level of NO metabolites and glutamate in the anterior hypothalamus were measured using microdialysis. In both models, NO metabolite levels significantly increased, and this increase was significantly attenuated by risperidone pretreatment. Extracellular levels of glutamate were increased only in the tranylcypromine and fluoxetine model, and this increase was significantly attenuated by risperidone pretreatment. These results indicate that NO and glutamate may be involved in the development of 5-HT syndrome and that risperidone may be effective against neurotransmitter abnormalities in 5-HT syndrome.

Differences in vulnerability to traumatic stress among patients with psychiatric disorders: One-year follow-up study after the Great East Japan Earthquake

The aim of this study was to evaluate differences in vulnerability to traumatic stress and the 1‐year course of post‐traumatic stress symptoms among patients with pre‐existing psychiatric disorders after the Great East Japan Earthquake.

Memantine attenuates 3,4-methylenedioxymethamphetamine-induced hyperthermia in rats.

3,4-Methylenedioxymethamphetamine (MDMA) is an illegal drug that can induce life-threatening hyperthermia. No effective pharmacological treatment for MDMA-induced hyperthermia has yet been established. We investigated the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist and an α-7 nicotinic acetylcholine receptor (nAChR) antagonist, on MDMA-induced hyperthermia in rats. Treatment of animals with memantine (10 or 20 mg/kg) either before or after MDMA (10 mg/kg) administration significantly decreased the peak body temperature. Results from our microdialysis study indicated that pretreatment with memantine (20 mg/kg) before MDMA administration had no effect on the MDMA-induced increase in serotonin (5-HT) and dopamine (DA) levels in the anterior hypothalamus. MDMA-induced hyperthermia was significantly suppressed by pretreatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg) and the competitive NMDA antagonist CGS 19755 (5 mg/kg), but not by the selective α-7 nAChR antagonist methyllycaconitine (6 or 10 mg/kg). These results indicate that the inhibitory effect of memantine on MDMA-induced hyperthermia may be due to its activity as an NMDA receptor antagonist and not as a result of a direct effect on the 5-HT or DA systems. The present study suggests that moderate doses of memantine may be useful for the treatment of MDMA-induced hyperthermia in humans.