Rapid down regulation of beta-adrenoceptors by co-administration of desipramine and fluoxetine.
ABSTRACT Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.
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ABSTRACT: Major depressive disorder (MDD) is a highly prevalent disease, frequently characterized by recurrent or chronic course, and by comorbidity with other medical illnesses. The lifetime prevalence of MDD ranges up to 17% in the general population, and it almost doubles in patients with diabetes (9–27%), stroke (22–50%), or cancer (18–39%). Moreover, MDD worsens the prognosis, quality of life, and treatment compliance of patients with comorbid medical illnesses. Similar to what is observed with other comorbid illnesses, MDD worsens the outcome of kidney disease patients by increasing both morbidity and mortality. Treatment of depressive symptoms in renal failure patients increases medication acceptability and therefore potentially improves the overall patient outcome. The issue of the safety of antidepressant treatment in subjects with renal failure is frequently counterbalanced by the risks associated with depression comorbidity, provided that antidepressants with a low volume of distribution and low protein binding are prescribed, and most important, at low initial doses. Screening for CYP isoenzyme interactions with current medications is also recommended before starting antidepressant treatment.Seminars in Dialysis 03/2005; 18(2). DOI:10.1111/j.1525-139X.2005.18217.x · 2.07 Impact Factor
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ABSTRACT: The objective of this study was to compare the onset, rate of antidepressant (AD) response, and treatment outcome of depressed patients treated for 5 weeks with either the concomitant administration of the tricyclic AD desipramine (DMI) and lithium carbonate (Lithium) or with DMI alone.In this double-blind, placebo-controlled study, 31 nonpsychotic, mild to moderately depressed outpatients (DSM-III-R unipolar or bipolar major depression) were randomly assigned to 5 weeks of treatment with DMI plus Lithium (N = 16) or DMI plus placebo (N = 15). Drug dosages were adjusted to achieve therapeutic plasma levels. Clinical state was rated weekly by the Hamilton Rating Scale for Depression, the Clinical Global Impression Scale, a Visual Analogue Self-Report Scale, and an adverse-effect form. Twenty-seven patients completed the study, 12 in the DMI-Lithium group and 15 in the DMI-placebo group. Four patients dropped out due to adverse events, all from the DMI-Lithium group. Both groups responded well to treatment, without a significant difference between them in the rate of response or final outcome. Sixty-seven percent (10/15) of the patients taking DMI only and 75% (9/12) of the patients taking DMI plus Lithium met our response criteria. The combination of DMI and Lithium was associated with significantly more adverse effects than DMI alone. Concurrent treatment with Lithium did not demonstrate an enhancement of either DMI's efficacy or its onset of action in these patients, suggesting that this strategy may not confer any additional benefit compared with DMI alone in mild to moderately depressed patients who are not preselected for nonresponse to an AD during their current depressive episode. (J Clin Psychopharmacol 1997;17:44-48).Journal of Clinical Psychopharmacology 02/1997; 17(1):44-48. DOI:10.1097/00004714-199702000-00008 · 3.76 Impact Factor
Article: Fast-Acting Antidepressants[Show abstract] [Hide abstract]
ABSTRACT: Preclinical studies suggest that downregulation of β-adrenoceptors in the CNS in animals can be achieved with short term administration of high doses of antidepressants. Similarly, the function of the serotonergic system has been shown in preclinical studies to undergo rapid changes during antidepressant administration. However, the relevance of these observations to clinical antidepressant effects remains speculative. While manipulation of these 2 neurotransmitter systems has provided the rationale for several strategies for ‘rapid onset’ antidepressants, other neurotransmitter systems are undoubtedly involved in the mechanism of action. Dopaminergic, peptidergic and glucocorticoid receptors may provide a new focus for the rapid onset of antidepressant action. Nevertheless, some clinical studies with existing agents suggest that antidepressant responses in patients are evident within 1 week of the commencement of treatment. The limiting step in achieving such a rapid onset may be the drug doses required. Intolerance to the adverse effects precludes the use of the high doses needed. There is, therefore, a need to develop drugs with less troublesome adverse effects in order to test the hypothesis that high therapeutic doses of antidepressants may lead to a rapid clinical response.CNS Drugs 08/1994; 2(2). DOI:10.2165/00023210-199402020-00005 · 4.38 Impact Factor