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The effects of several antidepressants, amitriptyline, citalopram, desipramine, fluoxetine, maprotiline, mianserin, nialamide, nomifensine, tranylcypromine and viloxazine, on the accumulation of cyclic AMP and inositol monophosphates were studied in rat cerebral cortical slices. The two enzymatic systems were stimulated either by adrenergic agonists or by forskolin. Cyclic AMP and inositol monophosphates (IPs) formed were determined by a double label method. In vitro all drugs, except inhibitors of monoamine oxidase, nialamide and tranylcypromine, inhibited alpha 1-agonist-mediated production but did not modify the cyclic AMP accumulation. Otherwise, chronic desipramine but not citalopram administration decreased the accumulation of cyclic AMP (-39%) elicited by beta-adrenoceptor agonists; no change was observed in inositol phosphate metabolism after administration of these two drugs. These data support previous investigations showing a decrease in cyclic AMP production after chronic treatment with norepinephrine uptake blockers but do not confirm the hypothesis of a modification of alpha 1-adrenoceptor-stimulated inositol phosphate metabolism.

The authors investigated the mechanism of action of the antidepressant serotonin (5-HT) reuptake blocker citalopram in the rat by means of an in vivo electrophysiologic paradigm. In control animals, the acute intravenous administration of citalopram reduced the firing rate of dorsal raphe nucleus serotonergic neurons with an ED50 of 230 micrograms/kg. Rats were treated with citalopram (20 mg/kg/day i.p.) for 2, 7, and 14 days. Two-day treatment was accompanied by a marked reduction of the firing activity of serotonergic neurons; there was a partial recovery after 7 days of treatment, and a complete one following 14-day citalopram administration. The response of serotonergic neurons to intravenously administered lysergic acid diethylamide (LSD), a somatodendritic 5-HT autoreceptor agonist, was reduced in rats treated with citalopram for 14 days, suggesting that such a treatment reduces the sensitivity of the somatodendritic autoreceptor. Fourteen-day citalopram treatment also markedly enhanced the efficacy of the stimulation of the afferent serotonergic pathway in suppressing the firing activity of postsynaptic CA3 dorsal hippocampus pyramidal neurons. This enhanced efficacy of serotonergic synaptic transmission was not the result of an increased sensitivity of postsynaptic neurons to serotonin, as the effect of the direct microiontophoretic application of serotonin onto these same neurons was not modified. That serotonin reuptake blockade per se was responsible for this enhancement could also be ruled out, as the acute intravenous administration of citalopram (1 mg/kg) in control rats failed to enhance the efficacy of the stimulation. To determine an involvement of the 5-HT terminal autoreceptor, methiothepin (1 mg/kg), a terminal autoreceptor antagonist, was injected intravenously in control and citalopram-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

In this multicenter study, the clinical efficacy of citalopram was investigated in 98 patients with moderate AD/SDAT or VD using a combined double-blind and open technique with placebo and citalopram. Analyses were made for each diagnosis after four weeks of double-blind treatment. Patients with AD/SDAT treated with citalopram showed a significant improvement in emotional bluntness, confusion, irritability, anxiety, fear/panic, depressed mood and restlessness. Those improvements were not found after treatment with placebo. There were no significant improvements in patients with VD. No improvements were recorded in motor or cognitive impairment. Citalopram provoked few and comparatively mild side-effects. None of the changes observed during the double-blind withdrawal period were identified as withdrawal symptoms or rebound phenomena.

The present study investigated the effect of repeated treatment with the antidepressant drugs imipramine, amitryptyline, citalopram and mianserin (10 mg/kg PO, twice daily for 14 days) on levels of thyrotropin-releasing hormone (TRH) in several brain structures (cerebral cortex, amygdala + pyriform cortex, hippocampus, nucleus accumbens, striatum and hypothalamus) of the rat. Amitriptyline caused a marked increase in the TRH content in the striatum and nucleus accumbens. Citalopram and mianserin produced a smaller but significant increase in the TRH content in the striatum only, while imipramine did not significantly affect the TRH concentrations in any of the brain structures. None of the antidepressant drugs administered acutely significantly affected the TRH concentrations in the nucleus accumbens or the striatum. These results indicate that changes in brain TRH induced by antidepressant drugs are not related to their therapeutic activity.

It has been known that many antidepressant drugs which have serotonin (5-HT) antagonistic activities and 5-HT antagonists can induce the reduction of 5-HT2 receptor binding by their acute or successive administration. We investigated the effects of repeated treatment with 5-HT agonists on 5-HT2 receptors in rat cerebral cortex. We used citalopram as selective 5-HT uptake inhibitor, 5-hydroxytryptophan as 5-HT precursor, and 5-methoxy-N,N'-dimethyltryptamine as 5-HT2 agonist. The 5-HT2 receptor density was decreased by repeated treatment with these respective drugs. So it may be supposed that the reduction of 5-HT2 receptor binding is induced not only by 5-HT antagonists but also by 5-HT agonists.

A repeated oral treatment (twice daily, for 21 consecutive days) with 10 mg/kg of antidepressants imipramine, amitriptyline, citalopram, mianserin affects the level of testosterone and its metabolites (5 alpha-dihydrotestosterone and estradiol-17 beta) in the serum and brain structures (cerebral cortex, hypothalamus). Citalopram and mianserin increased significantly the serum testosterone concentration, while imipramine and amitriptyline reduced the concentration of 5 alpha-dihydrotestosterone. In the cerebral cortex a reduction in 5 alpha-dihydrotestosterone after imipramine, and in the hypothalamus a decrease in testosterone level after amitriptyline were observed. None of the investigated drugs influenced estradiol-17 beta concentration in the serum or in the brain.

The effect of acute (single dose) and repeated (twice daily, for 21 days) administration of imipramine, amitriptyline, citalopram, mianserin and rolipram (the latter drug in a dose of 5 mg/kg po, all the other drugs in a dose of 10 mg/kg po) on drinking induced by isoprenaline (50 micrograms intracerebroventricularly (icv), 2 h after the single dose, 2 and 72 h after the last does of the antidepressants) was studied in rats. It was found that repeated, but not acute, treatment with imipramine, amitriptyline and rolipram significantly reduced the response to isoprenaline. The effect of amitriptyline and rolipram was observed 2 and 72 h after their last administration, while that of imipramine only 72 h after its last dose. Citalopram and mianserin were ineffective after both acute and repeated administration.