Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.

Mirtazapine has a low affinity for 5-HT(1A) receptors but shows 5-HT(1A)-agonistic-like effects in behavioral pharmacology test. However, there is to date no clear evidence that mirtazapine enhances 5-HT(1A) neurotransmission. The object of the present study was to assess the effects of mirtazapine on dialysate levels of dopamine and 5-HT in the medial frontal cortex of freely moving rats and to determine whether this drug could modulate 5-HT(1A) neurotransmission. In vivo microdialysis was used to study the effects of mirtazapine on extracellular dopamine and 5-HT levels, and the effect of the 5-HT(1A) antagonist WAY100,356 on extracellular dopamine level increased by mirtazapine in the rat prefrontal cortex. Mirtazapine (4-16 mg/kg, i.p.) produced a dose-dependent increase in extracellular dopamine levels in the medial prefrontal cortex (mPFC) of freely moving rats without modifying those of 5-HT. In the presence of the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-cyclohexane-carboxamide (WAY100,635; 0.3 mg/kg; i.p.), the influence of mirtazapine on cortical levels of dopamine was markedly attenuated. These results indicate that mirtazapine induces the enhancement of the output of cortical dopamine mediated via blockade of alpha(2)-adrenergic receptors and facilitation of post-synaptic 5-HT(1A) function.

[A clinical study of emergent anxiety in neuroleptic-naïve, first-episode schizophrenia patients following treatment with risperidone].

Risperidone (RIS) alone was administered to patients with neuroleptic-naïve, first-episode schizophrenia who visited the outpatient clinic of the Department of Psychiatry, Jikei University School of Medicine Hospital between April 1998 and December 2001, and the effectiveness of the drug in alleviating anxiety symptoms was prospectively examined. The study population comprised 42 patients (24 males and 18 females). Their mean age at first visit was 26.0 +/- 6.5 years, DUP (Duration of Untreated Psychosis) was 41.1 +/- 60.0 weeks, and the mean total BPRS (Brief Psychiatric Rating Scale) score at first visit was 60.5 +/- 8.5 points. The rating "effective" (a total BPRS score improvement at week 8 of 50% or more) was given to 32 out of the 42 patients (76.2%). Among these 32 patients, a 25% improvement in the PANSS (Positive and Negative Syndrome Scale) positive scale was achieved at 1. 53 +/- 0.72 weeks and a 50% improvement at 2.93 +/- 2.10 weeks, suggesting early onset of the effects of RIS. The present study focused on the anxiety complained of by some of the patients in whom treatment was rated as effective (increase of 2 points in anxiety BPRS score), dividing these patients into an anxiety group and a non-anxiety group. The anxiety group comprised 17 patients (53.1%). The anxiety observed during the course of treatment with RIS tended to develop early after the disappearance of positive symptoms. A comparison of demographic factors and GAF between the two groups revealed a significant difference in mean age at first visit, DUP and GAF score, the anxiety group tending to be younger, to have shorter DUP and to have social dysfunction compared to the non-anxiety group. Although it cannot be concluded that these anxiety symptoms are characteristic of risperidone, the effect of chemotherapy with other atypical antipsychotic drugs remains as an interesting theme for future investigation.

Possible alteration of tryptophan metabolism following repeated administration of sertraline in the rat brain.

The levels of tryptophan and the serotonin (5-HT) turnover were examined in various brain regions of rats after single or repeated treatment with the selective 5-HT uptake inhibitor, sertraline. A single administration of sertraline (10mg/kg, i.p.) increased tryptophan and 5-HT levels in all the brain regions investigated. The levels of 5-hydroxyindolacetic acid (5-HIAA) decreased in various brain regions. The 5-HIAA/5-HT ratio as turnover index was significantly decreased by a single administration of sertraline in all the brain regions investigated. Daily treatment with sertraline (10mg/kg) for 21 days did not affect tryptophan and 5-HT levels in various brain regions 1h after last injection. The 5-HT turnover was not changed in any of the brain regions investigated by a repeated administration of sertraline. In conclusion, the data show that the increase in tryptophan levels and the decrease in 5-HT turnover in rat brain are attenuated by repeated treatment of sertraline.

[Case of prolonged recovery from serotonin syndrome caused by paroxetine].

We report a case of serotonin syndrome in a patient being treated with paroxetine for depression. Despite prompt discontinuation of medication, his serotonin syndrome continued for 10 days before full consciousness was restored. The patient was a 48-year-old male with chief complaints of hypobulia and suicidal thoughts. He consulted as a psychiatric outpatient, and oral paroxetine 20 mg/day, etizolam 1.0 mg/day, and brotizolam 0.25 mg/day were immediately started. Upsurge of feeling and disinhibition state were noted the following day, then on treatment day 6 his condition deteriorated to substupor state and he was admitted for further treatment. On admission, change of mental condition (consciousness disturbance), perspiration, hyperreflexia, myoclonus and tremor were seen, and serotonin syndrome caused by paroxetine was suspected. Paroxetine was thus discontinued, and under intravenous drip his condition gradually improved. However, it was not until the 10th hospital day that he became fully alert. In examinations, no infectious, metabolic or organic diseases were detected. The patient's condition often improves with in 24 hours of discontinuation of the causative medication in serotonin syndrome. Symptoms continued for 10 days in this patient, however, perhaps because paroxetine was administered for 6 days before discontinuation. In addition, interaction with other medications may have occurred. Therefore, when serotonin syndrome is suspected, prompt discontinuation of the suspected causative medication, followed by close monitoring of the pharmacokinetics is warranted.