Chronic Antidepressant Treatment Prevents Accumulation of Gsalpha in Cholesterol-Rich, Cytoskeletal-Associated, Plasma Membrane Domains (Lipid Rafts).

Donati RJ, Rasenick MM.

[1] 1Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA [2] 2Basic and Health Science Department, Illinois College of Optometry, Chicago, IL, USA.

Previous studies demonstrated that Gsalpha migrates from a Triton X-100 (TTX-100) insoluble membrane domain to a TTX-100 soluble membrane domain in response to chronic treatment with the antidepressants desipramine and fluoxetine. Antidepressant treatment also causes a Gsalpha redistribution in cells as seen by confocal microscopy. The current studies have focused on examining the possibility that the association between Gsalpha and the plasma membrane and/or cytoskeleton is altered in response to antidepressant treatment, and that this is relevant to both Gsalpha redistribution and the increased coupling between Gsalpha and adenylyl cyclase seen after chronic antidepressant treatment. Chronic treatment of C6 cells with two fuctionally and structurally distinct antidepressants, desipramine and fluoxetine, decreased the Gsalpha content of TTX-100 insoluble membrane domains by as much as 60%, while the inactive fluoxetine analog LY368514 had no effect. Disruption of these membrane domains with the cholesterol chelator methyl-beta-cyclodextrin altered the localization of many proteins involved in the cAMP signaling cascade, but only Gsalpha localization was altered by antidepressant treatment. In addition, microtubule disruption with colchicine elicited the movement of Gsalpha out of detergent-resistant membrane domains in a manner identical to that seen with antidepressant treatment. The data presented here further substantiate the role of Gsalpha as a major player in antidepressant-induced modification of neuronal signaling and also raise the possibility that an interaction between Gsalpha and the cytoskeleton is involved in this process.Neuropsychopharmacology advance online publication, 23 February 2005; doi:10.1038/sj.npp.1300697.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15726116&dopt=Abstract antidepressant




Antidepressant-induced sweating.

Marcy TR, Britton ML.

Department of Pharmacy: Clinical and Administrative Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

OBJECTIVE: To report a case of excessive sweating probably caused by paroxetine, review the literature on antidepressant-induced sweating, and provide recommendations for the management of antidepressant-induced sweating. CASE SUMMARY: A 59-year-old white female presented to a pharmacist-staffed pharmacotherapy clinic with episodes of excessive sweating. The episodes occurred primarily on her head and back of the neck. Other etiologies were ruled out and paroxetine was discontinued. Paroxetine had been initiated at least 7 months prior to the reporting of symptoms. Sweating symptoms gradually improved until resolution 5 weeks following discontinuation of paroxetine. The Naranjo probability scale indicated a causal relationship is probable. DISCUSSION: Excessive sweating has been associated with antidepressants including tricyclic antidepressants, selective serotonin-reuptake inhibitors, and venlafaxine. In some patients, these symptoms require therapeutic intervention such as dose reduction, antidepressant substitution, antidepressant discontinuation, or addition of an agent to control sweating. Agents that have been reported successful in controlling the sweating include benztropine and cyproheptadine. CONCLUSIONS: We recommend a patient-specific approach for the management of antidepressant-induced sweating. First, consider dose reduction or a trial off antidepressant medication. In patients in whom this is inappropriate or ineffective, substitution of another antidepressant should be considered. If episodes of excessive sweating persist, consider treatment of sweating symptoms with benztropine or cyproheptadine in the absence of contraindications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728327&dopt=Abstract antidepressant




Suboptimal antidepressant use in the elderly.

Wang PS, Schneeweiss S, Brookhart MA, Glynn RJ, Mogun H, Patrick AR, Avorn J.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02120, USA. pwang rics.bwh.harvard.edu

Ongoing changes in available agents and health care delivery systems have made it imperative to study the quality of antidepressant use in vulnerable and traditionally underserved elderly. We conducted a retrospective cohort study among 12,130 new antidepressant users aged > or =65 years with a recent diagnosis of depression in the Pennsylvania Pharmaceutical Assistance Contract for the Elderly Program from January 1, 1994, to December 31, 1999. Additional use information was available through Medicare data. Potentially hazardous antidepressant regimens were defined as use of highly anticholinergic agents or daily dosages in excess of geriatric prescribing guidelines. Low-intensity regimens were defined by lower than recommended daily dosages, too-short durations of therapy, or lack of follow-up. Of all elderly antidepressant users, 43.3% were taking suboptimal regimens. Potentially hazardous regimens were used by 11.9%, including 7.3% taking highly anticholinergic agents and 5.3% using excessively high daily dosages. Low-intensity regimens were used by 34.8% of patients, including 7.6% with excessively low daily dosages, 19.3% with short durations of therapy, and 14.8% with inadequate follow-up. Potentially hazardous regimens were associated with ages 65 to 74 years, nursing home residence, cancer diagnoses, less comorbidity, use of other psychiatric medications, making more physician visits, and earlier calendar years. Low-intensity regimens were associated with ages > or =85 years, nonwhite race, greater comorbidity, fewer physician visits or inpatient days in the baseline 6 months, and not using other psychiatric medications. Suboptimal antidepressant use remains common in the elderly, especially the use of inadequately intensive regimens. Interventions are needed to improve the quality and outcomes of antidepressant use in this vulnerable population.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15738742&dopt=Abstract antidepressant




Orphan comparisons and indirect meta-analysis: a case study on antidepressant efficacy in dysthymia comparing tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors by using general linear models.

Ballesteros J.

Dpto de Neurociencias, Psicologia Medica y Psiquiatria, Universidad del Pais Vasco, UPV/EHU, Facultad de Medicina y Odontologia, Leioa, Spain. onpbaroj lg.ehu.es

Direct comparisons of the efficacy of competing interventions are not always available in the literature. This situation leads to the presence of clinically relevant "orphan comparisons" of therapeutic interventions which have never been compared head-to-head. To overcome this limitation, simple methods for indirect meta-analysis have been suggested. Nevertheless, their results are prone to bias when more than 1 indirect comparison is tested because of the likely duplication of data for some comparisons. In contrast, general linear models can be used to extend simple indirect meta-analysis beyond 1 indirect comparison by fitting to incomplete data using maximum likelihood within the framework of multitreatment comparisons. This study presents a tutorial application of general linear models to the comparative efficacy of several antidepressants in dysthymia (tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors. Working with previously published data comparing the efficacy of antidepressants with placebo, it is shown that tricyclic antidepressants and selective serotonin reuptake inhibitors present similar efficacy (odds ratio = 1.19, P = 0.37; relative risk = 1.10, P = 0.24; risk difference = 0.03, P = 0.53), whereas monoamine oxidase inhibitors outperform both tricyclic antidepressants and selective serotonin reuptake inhibitors, at least for some effect scales (odds ratio = 1.57, P = 0.05; relative risk = 1.25, P = 0.05; risk difference = 0.09, P = 0.08). This finding, which is an instance of a relevant orphan comparison and could not be obtained otherwise, could motivate the conduct of clinical trials or focused systematic reviews to support or refute its importance through appropriate head-to-head comparisons.

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[Efficacy of atypical antipsychotics in depressive syndromes.]

[Article in French]

Quintin P, Thomas P.

Lilly France, 13 rue Pages, 92158 Suresnes cedex, France. quintin_philippe lilly.com

Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15738862&dopt=Abstract antidepressant




Do antidepressants reduce the burden imposed by depression on employers?

Greener MJ, Guest JF.

CATALYST Health Economics Consultants, Northwood, Middlesex HA6 1BN, UK.

The ability to perform paid or unpaid work is integral to an individual's quality of life. Therefore, we performed a systematic literature review to examine the impact of depression and its treatment on occupational outcomes. This review found absenteeism from work to be markedly higher among depressed employees and productivity to be dramatically undermined by some symptoms of depression. Gaps in the published literature point to the need for future economic and clinical analyses to include work-related outcomes. Published studies showed that antidepressants can enhance work-related outcomes by alleviating affective symptoms. However, the pharmacological properties of antidepressants may produce differential effects that influence work-related outcomes in other ways. For example, TCAs, but not SSRIs, produce sedation and impair cognitive function in ways that could undermine work-related outcomes. Formal analyses are required to quantify whether the improved social functioning, motivation and vigilance that may be associated with some newer antidepressants translate into improved work-related outcomes. Although few published studies have directly quantified the cost benefit of managing depression and associated lost productivity, existing studies that directly assessed work-related outcomes have suggested that treating depression is cost effective. Gaps in the published literature imply that the impact of depression and antidepressants on occupational outcomes has been understudied. This reflects, in part, the fact that antidepressant studies lasting 4 or 6 weeks are unlikely to capture the impact of treatment on work-related measures. In addition, the current evidence base is fraught with other methodological limitations. The effect of depression on non-paid employment also requires further assessment. In conclusion, the efficacy of antidepressants on work-related outcomes should be measured in clinical trials that have an adequate design and a suitable follow-up period, and included in health technology assessments. Until such studies are available, the evidence base supporting the use of antidepressants will remain incomplete.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15740179&dopt=Abstract antidepressant




Trends in use of antidepressants, lithium, and anticonvulsants in Kaiser Permanente-insured youths, 1994-2003.

Hunkeler EM, Fireman B, Lee J, Diamond R, Hamilton J, He CX, Dea R, Nowell WB, Hargreaves WA.

Kaiser Permanente, Division of Research, Oakland, California 94612, USA. emh dor.kaiser.org

In view of the current controversy regarding the use of antidepressants in children and adolescents, we examined trends from 1994 to 2003 in the use of antidepressants, lithium, and anticonvulsants by enrollees, aged 5-17 years, of Kaiser Permanente in Northern California. We found that the use of antidepressants more than doubled from 9.4 per 1000 enrollees to 21.3 per 1000. Most of this increase is associated with selective serotonin reuptake inhibitors (SSRIs), which increased from 4.6 to 14.5 per 1000. The use of tricyclic antidepressants (TCAs) decreased markedly, while the increase of other newer antidepressants rose from 1.3 to 6.5 per 1000. The use of anticonvulsants nearly doubled, from 3.5 to 6.9 per 1000, while lithium use was relatively stable at a rate of nearly 1 per 1000. Use of SSRIs, newer antidepressants, and anticonvulsants increased in boys as well as girls in each of three age groups: 5-9, 10-14, and 15-17 years. An increasing percentage of the antidepressant users had a diagnosis of depression, and an increasing percentage of anticonvulsant users had a diagnosis of bipolar disorder. Although the safety and efficacy of antidepressants in youths needs to be more firmly established, these findings may reflect progress in the diagnosis and treatment of mental illness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15741783&dopt=Abstract antidepressant




African-American and white caregivers of older adults with dementia: differences in depressive symptomatology and psychotropic drug use.

Sleath B, Thorpe J, Landerman LR, Doyle M, Clipp E.

School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. bsleath email.unc.edu

OBJECTIVES: To examine relationships between race and psychotropic drug use (antidepressant, antianxiety, sedative/hypnotic agents) in informal caregivers with symptoms of depression who provide care for elderly relatives with progressive dementia. Whether racial differences in medication use relate to racial differences on predisposing, enabling, and need factors associated with use of these agents was also examined. DESIGN: National survey. SETTING: Community-based population of informal caregivers of elderly male U.S. veterans with dementia living throughout the 48 contiguous states and Puerto Rico. PARTICIPANTS: Two thousand thirty-two African-American and white female caregivers of elderly male veterans diagnosed with probable Alzheimer's disease or vascular dementia. MEASUREMENTS: Depressive symptoms were measured using a modified version of the Center for Epidemiological Studies Depression Scale. Antidepressant, antianxiety, and sedative/hypnotic agents were indexed using the Veterans Affairs medication classification system. RESULTS: Of caregivers with depressive symptoms, 19% used antidepressants, 23% antianxiety agents, and 2% sedative/hypnotics. African-American caregivers with depressive symptoms were significantly less likely than whites with depressive symptoms to be using antidepressants and antianxiety medications. Caregivers who reported higher levels of social support and more physician visits during the previous 6 months were significantly more likely than others to be taking antidepressants. CONCLUSION: This study found that 81% of caregivers with depressive symptoms were not taking antidepressant medication and that African-American caregivers were less likely than whites to be taking antidepressants. Results suggest that routine screening for depression in dementia caregivers may identify unmet needs for antidepressant therapy. Particular care should be taken to ensure that African-American caregivers are made aware of the potential benefits of such therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15743280&dopt=Abstract antidepressant