The data presented represent cardiovascular parameters collected from one site of a larger, multicenter, double-blind, placebo-controlled, 6-week outpatient efficacy study of the serotonin uptake inhibitor fluvoxamine in depressed outpatients.
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This study investigated the involvement of NMDA receptors and the L-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl(2), 30 and 10-30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl(2) in the FST was prevented by pre-treatment of animals with guanosine 5'-monophosphate (GMP), ascorbic acid, L-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with D-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl(2)+MK-801 was not different from the result obtained with ZnCl(2) or MK-801 alone, but ZnCl(2)+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl(2) prevented the anti-immobility effect of MK-801, ketamine, GMP, L-arginine or N(G)-nitro-L-arginine (L-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the L-arginine-NO pathway.
The reported incidence of sexual dysfunction associated with antidepressant medication varies from 1.9% to 92%. The majority of studies reporting incidences were not systematically conducted.
The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.
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Light is a powerful modulator of higher-order cognitive processes such as mood but it remains unclear which neural circuits mediate the impact of light on affective behavior. We found that light deprivation produces a depressive-like behavioral state that is reversed by activation of direct retinal signals to the serotonergic dorsal raphe nucleus (DRN) in a manner equivalent to treatment with the selective serotonin reuptake inhibitor fluoxetine. Surprisingly, the DRN-projecting retinal ganglion cells (RGCs) are indistinguishable from the classic alpha/Y-like RGC type that contributes to image-forming visual pathways. Silencing RGC firing or specific immunotoxin ablation of DRN-projecting RGCs increased depressive-like behavior and reduced serotonin levels in the DRN. Serotonin has a key role in the pathophysiology of depression, and these results demonstrate that retino-raphe signals modulate DRN serotonergic tone and affective behavior.
The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol.
All classical anxiolytics raise the thresholds of septal-elicited hippocampal RSA overall, but do so mostly at 7.7 Hz (130 ms). The novel anxiolytic/antidepressant buspirone shows partial similarity with classical anxiolytics on septal driving thresholds. These effects of both the classical and novel anxiolytics are unchanged by long-term administration. The present experiment tested whether the tricyclic antidepressant imipramine and the monoamine oxidase inhibitor antidepressant phenelzine share these common effects of classical and novel anxiolytics with long-term administration. Rats, implanted with septal stimulating electrodes and subicular recording electrodes, received 15 mg/kg imipramine (twice per day) and 2 mg/kg phenelzine (once per day) for 28 days. Chronic administration of imipramine mimicked the documented effects of anxiolytics while chronic administration of phenelzine produced essentially opposite effects to the effects of anxiolytics on septal driving of RSA. Since both acute and chronic administration of imipramine but not phenelzine also produce similar effects to anxiolytics on the frequency of reticular-elicited hippocampal RSA, we suggest that (1) imipramine has a separate anxiolytic action, in addition to its antidepressant action; and (2) phenelzine may have no central anxiolytic action despite its capacity to relieve somatic symptoms in atypical depression.
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Baseline attendance, CBT plus imipramine, SAD, and AD were significant predictors of treatment response and accounted for 51% of the variance in outcome. Specifically, a higher rate of attendance at baseline and receiving imipramine predicted a better response to treatment whereas the presence of SAD and AD predicted a poorer response to treatment. The relationship between sociodemographic variables and treatment outcome was also evaluated. Age and socioeconomic status were unrelated to school attendance after treatment. Males had significantly higher rates of attendance after treatment than females.
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The acute and chronic administration of antidepressants (amitriptyline, imipramine, befol) to rats led to the sympathetic influences of a cardiointervalogram as reduced cardiointervals and its increased amplitude and tension index. Imipramine was found to be effective in eliminating disadaptational abnormalities in cardiac performance, which promoted REM-sleep deprivation.
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Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.
This study investigated the effect of tricyclic and atypical antidepressants on adenosine triphosphate (ATP) dependent calcium uptake by the endoplasmic reticulum of lysed synaptosomes from rat brain cortex. Tricyclic antidepressants (imipramine, desipramine, clomipramine, amitriptyline) exhibited no effect in the lower range (0.06 to 2 microM) of drug concentrations, and a concentration-dependent inhibition of calcium uptake in the upper range (6 to 200 microM). A concentration-dependent inhibition was observed for atypical antidepressants (mianserin, desmethylmianserin, venlafaxine, desmethylvenlafaxine, fluoxetine) in both the lower and the upper range of drug concentrations. Since no stimulation of calcium uptake was observed in either concentration range, it appears that the tricyclic and atypical antidepressants tested are not capable of normalizing, through their effect on the endoplasmic reticulum, an overactive calcium signal. which is possibly implicated in the etiology of affective disorders. Also, although only marginal inhibition of calcium uptake is expected at brain concentrations of tricyclics and mianserin-desmethylmianserin that are likely to be encountered during clinical use, a more substantial inhibition could occur with fluoxetine.
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Male rats were injected with imipramine (0-30 mg/kg) and subsequently tested in the forced-swim test in either fresh water or water soiled by other rats, which presumably contains an alarm substance. Imipramine did not affect the behavior of rats in fresh water. More than half the animals given the combination of imipramine (30 mg/kg) and stress from alarm substance had clonic convulsions. Adrenalectomy did not affect this relationship. This is the first study demonstrating the potential of an alarm substance for inducing convulsions.
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Antidepressant drugs are thought to counteract effects of hypercortisolemia, frequently associated with depression, by lowering cortisol level and by modifying the function of glucocorticoid receptors (GR). Indeed, classical antidepressants inhibit corticosteroid-induced gene transcription in cell cultures. The aim of the present study was to investigate effects of new generation antidepressant drugs on GR function in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). It has been found that reboxetine (at 10 and 30 microM), venlafaxine, citalopram and mirtazapine (at 30 microM), but not milnacipran, in statistically significant manner inhibited corticosterone-induced gene transcription. However, the effects of new generation antidepressant drugs were weaker than those evoked by imipramine, which was active already at 3 microM concentration. Further studies on the mechanism of antidepressant action on GR function revealed that protein kinase C, but not mitogen-activated protein kinases (MAPK), glycogen synthase kinase (GSK-3) and protein kinase B (PKB, Akt) play a role in this phenomenon.
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Even though cultural, biological and health service factors influence the tolerance and acceptability of psychotropic drugs in different settings, there is a lack of data on the use of antidepressants in primary care settings from India. The aim of this study was to examine the tolerance of 3 models of antidepressants treatments (fluoxetine 20 mg; imipramine 75 mg; imipramine 150 mg) for common mental disorders in attenders at a primary care clinic in Goa. The study design was a randomized trial. A total of 61 adult subjects with a common mental disorder were recruited and randomized to one of the 3 groups. Subjects were reviewed at 2 and 6 weeks. The main outcome measures were discontinuation rates. The key findings are that while discontinuation rates are higher in subjects on imipramine 150 mg as compared to the other groups, the majority of subjects in all groups discontinued their medication. The commonest reasons for discontinuation are anticholingeric and hypotensive side effects.
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The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants.