Memantine, an NMDA antagonist, prevents the development of hyperthermia in an animal model for serotonin syndrome.

BACKGROUND: Serotonin (5-HT) syndrome is the most serious side effect of antidepressants. Although several drugs have been used for the treatment of 5-HT syndrome, a universal pharmacotherapy has not been established. NMDA receptor antagonists have been reported to have neuroprotective effects. In the present study, the efficacy of NMDA antagonists, including memantine and MK-801, and potent 5-HT (2A) antagonists, including risperidone and ketanserin, was evaluated in a 5-HT syndrome animal model. METHODS: 5-Hydroxy-l-tryptophan (100 mg/kg) and clorgyline (2 mg/kg) were administered intraperitoneally in rats to induce 5-HT syndrome. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured using a microdialysis technique. RESULTS: In the group pretreated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min of the drug's administration. The NA and 5-HT levels in the anterior hypothalamus increased to about 15- and 1100-fold of the pre-administration levels, respectively. Pretreatment with risperidone (0.5 mg/kg) and ketanserin (5 mg/kg) prevented the development of hyperthermia and the increase in the NA level. Memantine (10 mg/kg) and MK-801 (0.5 mg/kg) also prevented the development of hyperthermia and the increase in the NA level. These results suggest that NMDA antagonists, as well as potent 5-HT (2A) antagonists, may be effective drugs for the treatment of 5-HT syndrome. CONCLUSIONS: Since memantine is clinically well tolerated, this drug is a particularly promising therapeutic drug for 5-HT syndrome treatment.

Pitch perception shift: a rare side-effect of carbamazepine.

Carbamazepine-induced pitch perception shifts have rarely been described. Two cases of shifted pitch perception developing during medication with carbamazepine are described. Case 1 possessed absolute pitch. Her pitch perception shift disappeared with the discontinuance of carbamazepine. Case 2 did not have absolute pitch. Even though he experienced a pitch perception shift, he developed a tolerance to the shift. We concluded that carbamazepine was the cause of the pitch perception shift in the first case, while the second case probably became attuned to the change in pitch perception because he did not possess absolute pitch.

Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome.

The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and it often necessitates pharmacotherapy. In the present study, the efficacy of several drugs was evaluated in an animal model of the 5-HT syndrome. When 2 mg/kg of clorgyline, a type-A monoamine oxidase inhibiting antidepressant, and 100 mg/kg of 5-hydroxy-L-tryptophan, a precursor of 5-HT, were administered intraperitoneally to rats to induce the 5-HT syndrome, the rectal temperature of the rats increased to more than 40 degrees C, and all of the animals died by 90 min after the drug administration. The noradrenaline (NA) levels in the anterior hypothalamus, measured by microdialysis, increased to 15.9 times the preadministration level. Pretreatment with propranolol (10 mg/kg), a 5-HT(1A) receptor antagonist as well as a beta-blocker, and dantrolene (20 mg/kg), a peripheral muscle relaxant, did not prevent the death of the animals, even though these two drugs suppressed the increase in rectal temperature to some extent. Chlorpromazine and cyproheptadine prevented the lethality associated with the 5-HT syndrome only at high doses. By contrast, pretreatment with ritanserin (3 mg/kg) and pipamperone (20 mg/kg), both potent 5-HT(2A) receptor antagonists, completely prevented the increase in rectal temperature and death of the animals, and the hypothalamic NA levels in these two groups increased less than that in the other groups. These results suggest that potent 5-HT(2A) receptor antagonists are the most effective drugs for treatment of the 5-HT syndrome, and that NA hyperactivity occurs in the 5-HT syndrome.

Risperidone counteracts lethality in an animal model of the serotonin syndrome.

RATIONALE: The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and pharmacologic treatment should be offered in severe cases. OBJECTIVE: In the present study, the effects of risperidone, ketanserin, and haloperidol on an animal model of the serotonin (5-HT) syndrome were evaluated. METHODS: Intraperitoneal administration of 100 mg/kg 5-hydroxy-L-tryptophan (5-HTP) (a precursor of 5-HT) and 2 mg/kg clorgyline (a monoamine oxidase type-A inhibiting antidepressant) induced the 5-HT syndrome in rats. The rectal temperature of the rats was measured, and the microdialysis method was used to measure noradrenaline (NA) levels in the anterior hypothalamus. RESULTS: In the group pre-treated with saline, the NA concentration increased to 13 times the pre-administration level, rectal temperature increased to more than 40 degrees C, and all of the animals died 75 min later. In the group pre-treated with risperidone (0.5 mg/kg), the 5-HT syndrome was completely inhibited, and the NA level increased to 6.5 times the pre-administration level. Ketanserin, a selective 5-HT2A antagonist (5 mg/kg) also inhibited the 5-HT syndrome. In contrast, all of the rats in the group pre-treated with haloperidol (0.5 mg/kg) died earlier than in the saline group. CONCLUSIONS: These results suggest that strong 5-HT2A antagonists such as risperidone, but not dopamine D2 antagonists, counteract lethality due to 5-HT syndrome, and that not only does enhancement of 5-HT activity occur in the 5-HT syndrome, but NA activity also increases.

Electroconvulsive therapy for the treatment of neuroleptic malignant syndrome with psychotic symptoms: a report of five cases.

We report five cases of neuroleptic malignant syndrome (NMS) with psychotic symptoms treated with electroconvulsive therapy (ECT). Clinical response was observed after the first or the second session of ECT in every case, and the symptoms of NMS resolved by the third or fourth session. The mean time from the initial ECT to complete resolution was 6.0 days. No side effects from ECT were observed. Although the first treatment for NMS is pharmacotherapy using drugs such as dantrolene and bromocriptine, our results suggest that ECT is a useful therapeutic method for patients with NMS and psychotic symptoms.

Treatment of tardive dystonia with an antispastic agent.

Tardive dystonia is a difficult condition to treat. We describe the case of a patient with tardive dystonia that was unresponsive to various pharmacological and electroconvulsive therapies. The patient showed dramatic improvement after the administration of eperisone, a centrally acting muscle relaxant. Eperisone and tolperisone are beta-aminopropiophenone derivatives which are used clinically as antispastic agents. To date there have been no reports describing the effect of such muscle relaxants on tardive dystonia. The results of our study suggest that these muscle relaxants may be promising therapeutic drugs for the treatment of tardive dystonia.

Addition of carbamazepine to long-term treatment with neuroleptics may induce neuroleptic malignant syndrome.

BACKGROUND: Carbamazepine is an anticonvulsant, but also has an anti-manic effect, and recently it has been increasingly used in combination with neuroleptics. Nevertheless, there have been very few reports on the involvement of carbamazepine in the occurrence of neuroleptic malignant syndrome (NMS). METHODS: A case of NMS occurring after addition of carbamazepine to long-term neuroleptic administration is described. RESULTS: The patient had been treated with neuroleptics for about 30 years, and NMS developed when carbamazepine (400 mg/day) was added. CONCLUSIONS: This case suggests that clinicians should consider the risk of NMS when carbamazepine is administered to patients undergoing long-term treatment with neuroleptics.

A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone and amitriptyline and lithium.

We describe a patient treated with trazodone, amitriptyline and lithium carbonate who developed anxiety, restlessness, tremor, myoclonus, hyperreflexia, diaphoresis, rigidity and hyperthermia. The constellation of findings was diagnostic of serotonin syndrome. Although doses of trazodone and amitriptyline were relatively low, serotonin syndrome developed in this patient. It is suggested that the combination with lithium facilitated the effect of central serotonergic responses mediated by trazodone and amitriptyline.

Cerebrospinal fluid levels of monoamine metabolites and gamma-aminobutyric acid in neuroleptic malignant syndrome.

To investigate the pathophysiology of neuroleptic malignant syndrome (NMS), we measured various cerebrospinal fluid (CSF) parameters in 11 patients and compared them with 8 age-matched normal controls. Concentrations of homovanillic acid (HVA) were significantly decreased during the active phase of NMS. This finding indicates that the dopaminergic nervous system of the patients was in a state of hypofunction in this phase and supports the central dopamine blockade theory of NMS. Reduced CSF HVA levels were also found after recovery from NMS, suggesting that hypofunction of the dopaminergic system may continue subclinically. The levels of 5-HIAA were decreased in the active phase, but the change was not significant. Therefore, a relationship between the development of NMS and disturbances of serotonin metabolism remains unclear. The levels of noradrenaline and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol increased significantly during the active phase, but returned to normal after recovery. These results show the existence of sympathetic nervous system hyperactivity during the active phase of NMS. The levels of gamma-aminobutyric acid (GABA) were significantly lower in the patients than in the controls. These findings suggest that there is a GABAergic deficiency in NMS. Thus, our study indicates that, in addition to dopamine hypoactivity, disturbances in various neurotransmitter systems are involved in the pathophysiology of NMS.

Single photon emission computed tomography with 123I-IMP in three cases of the neuroleptic malignant syndrome.

Single photon emission computed tomography (SPECT) perfusion brain scans using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) were performed in three patients with the neuroleptic malignant syndrome (NMS). In two accumulation was increased in the left basal ganglia and decreased in the right on the early images during the active phase of NMS; this asymmetry was not seen after recovery. In the third patient two examinations were performed during the active phase; on the first, increased accumulation of 123I-IMP in the left basal ganglia was found on the early images, but on the second, increased accumulation of tracer was found in the right basal ganglia on the delayed images. These abnormalities disappeared after improvement of the NMS. These results suggest that a disturbance in the basal ganglia is related to the development of NMS.

Does dantrolene influence central dopamine and serotonin metabolism in the neuroleptic malignant syndrome? A retrospective study.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) were determined twice in nine cases of neuroleptic malignant syndrome (NMS) during the active phase. During the test period, three cases received no dantrolene and six cases received dantrolene prior to the second CSF examination. In the group not administered dantrolene, the levels of HVA and 5-HIAA were lower on the second examination compared to the first, suggesting that the levels of these substances decreased during the course of NMS. In the group receiving dantrolene, the levels of HVA and 5-HIAA increased after administration compared with the preadministration levels. In particular, a significant difference in the changes in HVA was demonstrated between the two groups. This suggests that dantrolene influences central dopaminergic metabolism in the active phase of NMS.

Neuroleptic malignant syndrome: a study of CSF monoamine metabolism.

In 8 cases of typical neuroleptic malignant syndrome (NMS), homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), noradrenaline (NA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels in the cerebrospinal fluid (CSF) were assayed during both the active phase of NMS and after recovery. Compared with levels in normal control subjects the levels of HVA were significantly lower in patients with active NMS. This finding supports the central dopamine blockade theory of NMS pathophysiology. In addition, the levels of HVA were significantly decreased after recovery, suggesting that there may be a decreased dopamine metabolism in patients susceptible to NMS. The levels of 5-HIAA in patients with active NMS and after recovery were also significantly lower than those in normal control group, suggesting a relationship between the development of NMS and a disturbance of serotonin metabolism. The levels of NA in patients with active NMS were significantly higher than in normal subjects, and were within normal range after recovery. The levels of MHPG had a tendency to increase in patients with active NMS, compared with levels during recovery. These findings are a result of increased sympathetic nervous system activity in patients with active NMS; however, they are also observed in other disorders and may well reflect the physical stress caused by NMS.