Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline. Major depression and its response to sertraline in primary care vs. psychiatric office practice patients. Results of an open-label trial in Argentina. Rx drugs

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Eur J Pharmacol. 1999 Jan 8;364(2-3):123-32.
Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression.

Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmond A, Leonard BE.

Department of Pharmacology, National University of Ireland, Galway.

The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the 'open-field' test. Examination of the onset of the antidepressant effect in the 'open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT1A receptor and alpha2-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9932714&dopt=Abstract

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Eur J Pharmacol. 1999 Jan 8;364(2-3):147-50.
Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline.

Millan MJ, Gobert A, Girardon S, Dekeyne A.

Department of Psychopharmacology, Institut de Recherches Servier, Croissy-sur-Seine, Paris, France.

Citalopram (2.5 mg/kg, i.p.) increased (+145-+180%) extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) in the frontal cortex, nucleus accumbens and striatum of freely-moving rats, whereas dopamine and noradrenaline were unaffected. At this dose, employing a two-lever, food-reinforced, drug discrimination procedure, citalopram generated reliable recognition and fully (> 80%) generalized to itself with an Effective Dose50 (ED50) of 0.1 mg/kg, s.c. Two further selective 5-HT reuptake inhibitors, sertraline and paroxetine, fully generalized with ED50s of 0.01 and 0.04 mg/kg, s.c., respectively. In contrast, the anxiolytic, diazepam (0.63), and the antipsychotic, clozapine (2.5), did not (< or = 20%) generalize. In conclusion, the selective 5-HT reuptake inhibitor, citalopram, elicits a pharmacologically-specific discriminative stimulus in rats at a dose selectively elevating extracellular concentrations of 5-HT.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9932717&dopt=Abstract

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Psychosomatics. 1999 Jan-Feb;40(1):70-5.
Major depression and its response to sertraline in primary care vs. psychiatric office practice patients. Results of an open-label trial in Argentina.

Lyketsos CG, Taragano F, Treisman GJ, Paz J.

Neuropsychiatry and Memory Group, Johns Hopkins University, Baltimore, MD, USA.

Great strides have been achieved in recent years in the detection and treatment of major depressive disorder (MDD) in primary care settings. Little is known about the types or patients with MDD seen in primary care as compared with those seen in psychiatric office practice. Few studies have compared clinical outcomes after treatment with antidepressants in these two settings. In Argentina, the authors conducted an open-label treatment study of MDD patients in primary care (n = 469) and psychiatric office practice (n = 299). The patients were compared on baseline sociodemographic and clinical variables. These same patients were treated with sertraline 50-100 mg per day for 8 weeks. At baseline, the patients in psychiatric office practice were younger, more likely to abuse alcohol, less likely to have comorbid medical disorders, and more likely to have failed a prior treatment for depression during the current episode. The two groups did not differ significantly on depression severity or in depressive symptom profile on the Hamilton Depression Rating Scale (Ham-D). After 8 weeks of treatment, mean Ham-D scores were reduced comparably in both groups, from about 25 to about 10. Rates of adverse events were 14%-29%, depending on the follow-up interval. Adherence with treatment was high in both groups (over 95%). The patients in primary care and psychiatry office practice are similar in several ways. Significant reductions in depressive symptoms are possible in both settings, in large numbers of patients, by using doses of sertraline in the 50-100 mg range.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9989124&dopt=Abstract

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