Depression in Ontario: under-treatment and factors related to antidepressant use.

Parikh SV, Lesage AD, Kennedy SH, Goering PN.

Mood Disorders Program, Clarke Institute of Psychiatry and the University of Toronto, ON, Canada. parikhs cs.clarke-inst.on.ca

Our study examines how depression is treated in Ontario, with particular examination of the correlates of antidepressant utilization using a broad model of individual (clinical), demographic, and health system determinants of treatment. From a community epidemiologic survey, a sample of 333 individuals with major depression in the past year was identified. More than half received no treatment (untreated n = 170, 51.1%), while 74 (22.2%) received treatment without medication, 29 (8.7%) received treatment mainly with anxiolytics, and only 60 (18.0%) were treated with antidepressants. All four groups had similar rates of alcohol and substance abuse. Disability and comorbid anxiety were common, with the least in the untreated group and the most in the antidepressant group. Increased use of antidepressants was associated with psychiatrist contact, while family physicians treated a substantial minority primarily with anxiolytics. Under a universal health care system, no differential access to antidepressants was found in terms of demographic characteristics. Clinical severity and contact with a psychiatrist correlate with antidepressant treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10357019&dopt=Abstract antidepressant




SSRI antidepressant use patterns and their relation to clinical global impression scores: a naturalistic study.

Hylan TR, Meneades L, Crown WH, Sacristan JA, Gilaberte I, Montejo AL.

Global Health Economics Research, Eli Lilly and Company, Indianapolis, IN 46285, USA. hylant lilly.com

BACKGROUND: A cascade of events follows initial antidepressant selection which includes the subsequent antidepressant use pattern, resultant clinical outcomes, and associated health care expenditures. PURPOSE: The purpose of this study using data from a clinical practice setting was to test whether the pattern of antidepressant use was correlated with patients' treatment response as measured by the score on the Clinical Global Impression-Improvement scale. DATA AND METHODS: A retrospective dataset of patients who initiated therapy on fluoxetine, fluvoxamine, paroxetine, or sertraline in a primary care setting in Spain was used. A Cox proportional hazard analysis was used to predict the likelihood of treatment response based upon the pattern of initial antidepressant use, while minimizing the influence of other factors. RESULTS: After controlling for other observed baseline characteristics including initial disease severity, (a) patients who remained on their initial antidepressant therapy for at least 2 months with no switching, augmentation, or upward dose titration were 1.63 times more likely to experience a treatment response than patients who had an adjustment to therapy; and (b) patients who initiated therapy on sertraline were 0.46 times as likely to experience a treatment response as patients who initiated therapy on the most common study antidepressant, fluoxetine. CONCLUSION: The pattern of antidepressant use is an important determinant of treatment response among patients initiating therapy on the newer antidepressants in clinical practice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10357024&dopt=Abstract antidepressant




Relationship between antidepressant partial and nonresponse and subsequent response to antidepressant augmentation.

Joffe RT, Levitt AJ.

Department of Psychiatry, McMaster University, Hamilton, ON, Canada.

OBJECTIVE: To evaluate the relationship between the degree of antidepressant nonresponse and subsequent response to lithium and triiodothyronine (T3) augmentation. METHOD: This is a retrospective analysis of data combined from two previous controlled studies of lithium and triiodothyronine augmentation of tricyclic antidepressants. RESULTS: There was no difference in the rate of augmentation response between partial and nonresponders to tricyclic antidepressant treatment. CONCLUSIONS: Augmentation response does not appear to be related to the degree of nonresponse to the preceding antidepressant trial.

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Selective serotonin reuptake inhibitors have broadened the utilisation of antidepressant treatment in accordance with recommendations. Findings from a Swedish prescription database.

Isacsson G, Boethius G, Henriksson S, Jones JK, Bergman U.

Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden. Goran.Isacsson cnsf.ki.se

BACKGROUND: With the advent of the selective serotonin reuptake inhibitors (SSRIs), the use of antidepressants has increased drastically in Sweden. The use of tricyclic antidepressants (TCAs) has, however, decreased. METHODS: We surveyed a prescription database in the Swedish county of Jamtland and compared prescription patterns for patients prescribed SSRIs with those prescribed TCAs. RESULTS: The incidence of treatments of antidepressants increased from 0.76% to 1.33% during the period 1991-1996. There were no significant differences between SSRIs and TCAs with regard to patients having only one prescription dispensed within three months from the index prescription, or patients who switched class of antidepressant. Only a minority of the treatments were continued for at least six months, but significantly more SSRI than TCA treatments (42% and 27%). A second treatment period suggesting recurrence was three-times more common in the TCA group than in the SSRI group. CONCLUSION: Provided that the increased use of SSRIs is mainly for depression, these drugs appear, despite a lower efficacy in severe depression, to have enabled a broader utilisation of antidepressants with regard to incidence, dosage and duration, in accordance with recommendations. Further analyses of this phenomenon relative to diagnostic criteria and outcome measures are required.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10363662&dopt=Abstract antidepressant




Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat.

Cryan JF, McGrath C, Leonard BE, Norman TR.

Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.

5-HT1A receptor antagonists have recently been shown to accelerate the effects of some antidepressant drugs in clinical trials. In this study we investigate the effects of combining a full antagonist at the 5-HT1A receptor, WAY 100635 (0.2 mg/kg, SC) with the selective serotonin reuptake inhibitor (SSRI) paroxetine (5 mg/kg. SC) in the olfactory bulbectomized (OB) rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in the open-field apparatus, following 3, 7, and 14 days of treatment. Further to the OB study, we simultaneously studied adaptive changes in 5-HT1A receptor function, utilizing alterations in the hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT. Paroxetine, in combination with WAY 100635, attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days, with a full reversal evident following 7 days, whereas paroxetine, although attenuating the hypothermic effects in OB group by day 7, only reversed it fully after 14 days. Paroxetine alone and in combination with the antagonist reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an "antidepressant" response in this model. However, there was no significant attenuation at any of the earlier time points. This further demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioral syndrome is insensitive to the potential faster onset of antidepressant action induced by 5-HT1A receptor antagonists. Nonetheless, WAY 100635, unlike previous studies with pindolol, did not interfere with the effects of the antidepressant in the model. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT faster than paroxetine alone, further emphasizes the role of the 5-HT1A receptor in the mechanism of action of antidepressants, and as a target for the development of faster acting antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10371664&dopt=Abstract antidepressant




Evidence of a possible role of altered angiotensin function in the treatment, but not etiology, of depression.

Gard PR, Mandy A, Sutcliffe MA.

Faculty of Health, University of Brighton, Moulsecoomb, United Kingdom.

BACKGROUND: Angiotensin-converting enzyme inhibitors are reportedly effective in the treatment of depression; furthermore, antidepressants decrease angiotensin function. It appears therefore that reduced angiotensin function may be important in the treatment of depression. The aims of this study were to elucidate the actions of antidepressants on angiotensin receptors; to investigate the antidepressant potential of an angiotensin antagonist; and to study angiotensin receptors in depressed puerperal women. METHODS: The effects of antidepressant drugs on angiotensin receptors and the relationship between mood and platelet receptors in puerperal women were investigated using radioligand binding. The antidepressant potential of the angiotensin antagonist losartan was assessed using the mouse forced swim test. RESULTS: Desipramine, but neither fluoxetine nor tranylcypromine, displaced angiotensin from its receptor; however, there was no significant relationship between receptor number and depressed mood. In the forced swim test losartan was shown to possess antidepressant like activity. CONCLUSIONS: These findings indicate that antidepressants differ in the mechanism by which they reduce angiotensin function, but the link between antidepressants and angiotensin is reiterated by the demonstration that losartan possesses antidepressant like activity. There is, however, no evidence of abnormal angiotensin receptors in women with depressed mood postpartum.

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5-HT1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats.

Moser PC, Sanger DJ.

Synthelabo Recherche, Bagneux, France. pmoser bagneux.synthelabo.fr

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT1A receptors using the forced swim test in rats using both (+/-)-pindolol and the selective 5-HT1A receptor antagonist WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125-1 mg/kg s.c.), used as a reference for 5-HT1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01-0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (+/-)-pindolol (1-16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10-80 mg/kg p.o.) and befloxatone (0.03-1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (+/-)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (+/-)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10395092&dopt=Abstract antidepressant




The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions.

Daniel WA, Wojcikowski J.

Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, Krakow, 31-343, Poland.

The purpose of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slices of various rat tissues as a system with intact lysosomes. Thioridazine and antidepressants (5 microM) were incubated separately or jointly with the tissue slices in the absence or presence of "lysosomal inhibitors," i.e., ammonium chloride or monensin. The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is as important as phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive interactions between thioridazine and the investigated antidepressants at the level of cellular distribution. Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal inhibitors. In general, the observed interactions between thioridazine and antidepressants occurred only in those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) but were not observed in the presence of ammonium chloride. The above finding provides evidence that the interactions proceeded at the level of lysosomal trapping. In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those tissues were not the site of such an interaction. Since the organs and tissues involved in the distributive interactions constitute a major part of the organism and take up most of the total drug in the body, the interactions occurring in them may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the heart and muscles. An in vivo study into the thioridazine-imipramine interaction showed that joint administration of the drugs under study (10 mg/kg ip) increased drug concentration ratios of lysosome-poor tissue/plasma and lysosome-poor/lysosome-rich tissue. Considering serious side effects of thioridazine and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine-antidepressant combinations studied should be approached with respect to the appropriate dose adjustment. Copyright 1999 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10406926&dopt=Abstract antidepressant