Paroxetine is a highly potent and selective inhibitor of serotonin reuptake, with in vitro potency greater than that of fluoxetine, fluvoxamine, and sertraline. It has little affinity for a wide variety of neurotransmitter receptors, including catecholaminergic or histaminergic systems, in marked contrast to the tricyclic antidepressants. Paroxetine undergoes first-pass metabolism that is partially saturable to give metabolites that are pharmacologically inactive in vivo, unlike those of fluoxetine or sertraline.

The novel antidepressant drug tianeptine had an antidepressant-like effect on a rat model of depression based on the deficit in open field activity observed on the day after 2 h immobilization. Thus, tianeptine (10 mg/kg ip) given 2 h after the end of the immobilization period led to the deficit being opposed. Similar results were obtained using rats previously given 10 mg/kg of the drug per day for 13 days and a final dose 2 h after the end of immobilization. Other workers have found that tianeptine attenuates stress-induced activation of the hypothalamo-pituitary-adrenal axis. Possible relationships between these findings are discussed together with the paradoxical co-existence of the antidepressant properties of tianeptine with its ability to decrease the availability of 5-HT to receptors.

Stress-induced stimulation of corticotropic function involves the activation of hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which can be measured by improved methods of neuroendocrine investigation. The antiserotoninergic tricyclic antidepressant, tianeptine, reduces the corticotropic response to stress, as shown by a reduction in hypothalamo-hypophyseal portal CRH and AVP levels.

The effect of paroxetine on symptoms of anxiety associated with depression were assessed by meta-analysis of data on the use of paroxetine (n = 2963), active control (n = 1151), and placebo (n = 554) in six-week clinical trials. Paroxetine significantly reduced psychic anxiety by comparison with placebo from week 1 and was more effective than active control from week 2. Paroxetine improved somatic anxiety from week 4 of treatment. There was no association between antidepressant therapy and the emergence of anxiety symptoms in patients with little or no baseline anxiety. Paroxetine resolved baseline symptoms of agitation from week 1 of treatment, and both paroxetine and active control prevented the emergence of agitation. There was no difference between placebo and antidepressant therapy in the frequency of adverse events indicative of increased arousal. The results indicate the utility of paroxetine in depressed patients presenting with associated anxiety symptoms.

The effect of the antidepressant agent, tianeptine, on the hypothalamo-pituitary-adrenal (HPA) axis was studied in adult male rats under basal and stressed conditions. Chronic treatment with tianeptine (10 mg/kg; 2 weeks; twice a day) induced a significant decrease of hypothalamic CRF (–12%) and pituitary ACTH concentrations (–21%), suggesting that tianeptine reduces the activity of hypothalamic CRF neurons and pituitary corticotrophs. The possible effect of tianeptine in the neuroendocrine response to stress was thus investigated. Rats were submitted to restraint stress for 30 min; under these conditions ACTH and corticosterone levels were considerably increased. A single injection of tianeptine was found to significantly reduce stress-evoked elevations of plasma ACTH and corticosterone. Time-course experiments, consisting of administering tianeptine 1–3 h before immobilization stress, revealed that the maximum inhibitory effect of tianeptine occurs about 2 h after injection of the antidepressant. Administration of various doses of tianeptine (from 2.5 to 20 mg/kg) showed that the effect of the drug was dose-dependent; the maximum effective dose being 10 mg/kg. Taken together, these data indicate that tianeptine may exert original ‘anti-stress’ activity.