Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior.
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Phylogenetically, the serotonergic system is one of the oldest transmitter systems in the brain. Combining a complex and widespread innervation of most cortical and subcortical structures, with over a dozen receptor subtypes, there is a diversity of signaling opportunities and functional roles that explain the association of serotonin with many different types of psychopathological conditions. The role of the serotonergic system in mood disorders and in the predisposition for suicidal behavior are reviewed in this paper. Effects on the serotonergic system underlie the antidepressant action of many types of medications and must be integrated into a neurobiological model of mood disorders. (+info)
Hyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na+1.
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Extracts of Hypericum perforatum (St. John's Wort) are widely used for the treatment of depressive disorders and are unspecific inhibitors of the neuronal uptake of several neurotransmitters. Previous studies have shown that hyperforin represents the reuptake inhibiting constituent. To characterize the mechanism of serotonin reuptake inhibition, kinetic analyses in synaptosomes of mouse brain were performed. Michaelis-Menten kinetics revealed that hyperforin (2 microM) induces a decrease in V(max) by more than 50% while only slightly decreasing K(m), indicating mainly noncompetitive inhibition. By contrast, citalopram (1 nM) leads to an elevation of K(m) without changing V(max). Monensin, a Na(+)/H(+) exchanger, showed similar properties as hyperforin (decrease of V(max) without changing K(m)). Compared with classical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, hyperforin is only a weak inhibitor of [(3)H]paroxetine binding relative to its effects on serotonin uptake. As monensin decreases serotonin uptake by increasing Na(+)/H(+) exchange, we compared the effects of hyperforin and monensin on the free intracellular sodium concentration ([Na(+)](i)) in platelets by measuring 1,3-benzenedicarboxylic acid, 4,4'-[1,4,10-trioxa-7, 13-diazacyclopentadecan-7,13-diylbis(5-methoxy-6, 2-benzofurandiyl)]bis-, tetraammonium salt (SBFI/AM) fluorescence. Both drugs elevated [Na(+)](i) over basal levels, with a maximal [Na(+)](i) of 69 +/- 16.1 mM (50 microM hyperforin) and 140 +/- 9.1 mM (10 microM monensin). Citalopram at concentrations relevant for [(3)H]serotonin uptake inhibition had no effect on [Na(+)](i). Although the mode of action of hyperforin seems to be associated with elevated [Na(+)](i) similar to those levels found with monensin, the molecular mechanism might be different, as even at high concentrations, hyperforin does not elevate free intracellular sodium concentration ([Na(+)](i)) up to the extracellular level, as monensin does. Hyperforin represents the first substance with a known preclinical antidepressant profile that inhibits serotonin uptake by elevating [Na(+)](i). (+info)
Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus.
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Recent evidence suggests that a novel serotonin receptor 5-HT7 localized in the hypothalamus downregulates in response to treatment with the antidepressant fluoxetine (Sleight et al. 1995). This receptor has also been implicated in the regulation of circadian rhythms (Lovenberg et al. 1993). Here, we show that several agents administered in a profile consistent with activity at the 5-HT7 receptor produce significant functional Fos immunoreactivity in the suprachiasmatic nucleus (SCN), an effect reduced upon chronic exposure. Furthermore, binding studies demonstrate that chronic administration of Fos-inducing agents produces a neuroadaptive downregulation of the 5-HT7 receptor in the hypothalamus. The current studies extend the previous observations to include several pharmacologically distinct antidepressants. In addition, these studies provide further evidence to support the role of the 5-HT7 receptor in the mechanism of antidepressant action and in the regulation of circadian rhythms controlled by the SCN. (+info)
Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial.
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OBJECTIVES: To evaluate two different methods of improving adherence to antidepressant drugs. DESIGN: Factorial randomised controlled single blind trial of treatment leaflet, drug counselling, both, or treatment as usual. SETTING: Primary care in Wessex PARTICIPANTS: 250 patients starting treatment with tricyclic antidepressants. MAIN OUTCOME MEASURES: Adherence to drug treatment (by confidential self report and electronic monitor); depressive symptoms and health status. RESULTS: 66 (63%) patients continued with drugs to 12 weeks in the counselled group compared with 42 (39%) of those who did not receiving counselling (odds ratio 2.7, 95% confidence interval 1.6 to 4.8; number needed to treat=4). Treatment leaflets had no significant effect on adherence. No differences in depressive symptoms were found between treatment groups overall, although a significant improvement was found in patients with major depressive disorder receiving drug doses of at least 75 mg (depression score 4 (SD 3.7) counselling v 5.9 (SD 5.0) no counselling, P=0.038). CONCLUSIONS: Counselling about drug treatment significantly improved adherence, but clinical benefit was seen only in patients with major depressive disorder receiving doses >/=75 mg. Further research is required to evaluate the effect of this approach in combination with appropriate targeting of treatment and advice about dosage. (+info)
Multifaceted shared care intervention for late life depression in residential care: randomised controlled trial.
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OBJECTIVE: To evaluate the effectiveness of a population based, multifaceted shared care intervention for late life depression in residential care. DESIGN: Randomised controlled trial, with control and intervention groups studied one after the other and blind follow up after 9.5 months. SETTING: Population of residential facility in Sydney living in self care units and hostels. PARTICIPANTS: 220 depressed residents aged >/=65 without severe cognitive impairment. INTERVENTION: The shared care intervention included: (a) multidisciplinary consultation and collaboration, (b) training of general practitioners and carers in detection and management of depression, and (c) depression related health education and activity programmes for residents. The control group received routine care. MAIN OUTCOME MEASURE: Geriatric depression scale. RESULTS: Intention to treat analysis was used. There was significantly more movement to "less depressed" levels of depression at follow up in the intervention than control group (Mantel-Haenszel stratification test, P=0.0125). Multiple linear regression analysis found a significant intervention effect after controlling for possible confounders, with the intervention group showing an average improvement of 1.87 points on the geriatric depression scale compared with the control group (95% confidence interval 0.76 to 2.97, P=0.0011). CONCLUSIONS: The outcome of depression among elderly people in residential care can be improved by multidisciplinary collaboration, by enhancing the clinical skills of general practitioners and care staff, and by providing depression related health education and activity programmes for residents. (+info)
5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders.
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Lithium ion is widely used to treat depressive patients, often as an initial helper for antidepressant drugs or as a mood stabilizer; however, the toxicity of the drug raises serious problems, because the toxic doses of lithium are quite close to the therapeutic ones. Thus, precise characterization of the target(s) involved in the therapeutic activity of lithium is of importance. The present work, carried out at molecular, cellular, and in vivo levels, demonstrates that 5-HT1B receptor constitutes a molecular target for lithium. Several reasons suggest that this interaction is more likely related to the therapeutic properties of lithium than to its undesirable effects. First, the observed biochemical and functional interaction occurs at concentrations that precisely correspond to effective therapeutic doses of lithium. Second, 5-HT1B receptors are well characterized as controlling the activity of the serotonergic system, which is known to be involved in affective disorders and the mechanism of action of various antidepressants. These findings represent progress in our knowledge of the mechanism of action of lithium that may facilitate clinical use of the ion and also open new directions in the research of antidepressant therapies. (+info)
Awareness, diagnosis, and treatment of depression.
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OBJECTIVES: To review recent findings on the epidemiology, burden, diagnosis, comorbidity, and treatment of depression, particularly in general medical settings; to delineate barriers to the recognition, diagnosis, and optimal management of depression in general medical settings; and to summarize efforts under way to reduce some of these barriers. DESIGN: MEDLINE searches were conducted to identify scientific articles published during the previous 10 years addressing depression in general medical settings and epidemiology, co-occurring conditions, diagnosis, costs, outcomes, and treatment. Articles relevant to the objective were selected and summarized. CONCLUSIONS: Depression occurs commonly, causing suffering, functional impairment, increased risk of suicide, added health care costs, and productivity losses. Effective treatments are available both when depression occurs alone and when it co-occurs with general medical illnesses. Many cases of depression seen in general medical settings are suitable for treatment within those settings. About half of all cases of depression in primary care settings are recognized, although subsequent treatments often fall short of existing practice guidelines. When treatments of documented efficacy are used, short-term patient outcomes are generally good. Barriers to diagnosing and treating depression include stigma; patient somatization and denial; physician knowledge and skill deficits; limited time; lack of availability of providers and treatments; limitations of third-party coverage; and restrictions on specialist, drug, and psychotherapeutic care. Public and professional education efforts, destigmatization, and improvement in access to mental health care are all needed to reduce these barriers. (+info)
Depression without sadness: alternative presentations of depression in late life.
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Older adults often deny feeling sad while exhibiting other characteristics of depression. Elderly patients with depression who do not present with sadness often have unexplained somatic complaints and exhibit a sense of hopelessness. Anxiety and anhedonia (a general loss of ability to feel pleasure) are also encountered frequently. Other features that may indicate underlying depression include slowness of movement and lack of interest in personal care. A screening device, such as the Center for Epidemiologic Studies--Depression Scale, Revised (CES-D-R), may identify depression in suspicious cases. When this condition is identified, treatment should generally include the use of an antidepressant medication, usually a selective serotonin reuptake inhibitor. (+info)