Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care.

Hippisley-Cox J, Pringle M, Hammersley V, Crown N, Wynn A, Meal A, Coupland C.

Division of General Practice, University of Nottingham, Nottingham NG7 2RD. julia.hippisley-cox nottingham.ac.uk

OBJECTIVES: To determine whether antidepressants are a risk factor for ischaemic heart disease and to compare the risk for different subgroups of antidepressants and individual antidepressants. DESIGN: Case-control study. SETTING: Nine general practices recruited from the Trent Focus Collaborative Research Network. PARTICIPANTS: 933 men and women with ischaemic heart disease matched by age, sex, and practice to 5516 controls. MAIN OUTCOME MEASURE: Adjusted odds ratio for ischaemic heart disease calculated by logistic regression. RESULTS: Odds ratios for ischaemic heart disease were significantly raised for patients who had ever received a prescription for tricyclic antidepressants even after diabetes, hypertension, smoking, body mass index, and use of selective serotonin reuptake inhibitors had been adjusted for (1.56; 95% confidence interval 1.18 to 2.05). Patients who had ever taken dosulepin (dothiepin) had a significantly raised odds ratio for ischaemic heart disease after adjustment for confounding factors and use of other antidepressants (1.67, 1.17 to 2.36). There was no significant increase in the odds ratios for amitriptyline, lofepramine, and selective serotonin reuptake inhibitors in multivariate analysis. Increasing maximum doses of dosulepin were associated with increasing odds ratios for ischaemic heart disease. Similarly, there was a significant positive trend associated with increasing numbers of prescriptions of dosulepin (adjusted odds ratio 1.52 for 1 prescription, 1.39 for 2-3, and 1.96 for >/=4, P<0.002). CONCLUSION: There is good evidence for an association between dosulepin and subsequent ischaemic heart disease and for a dose-response relation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11566831&dopt=Abstract antidepressant




Antidepressant drug treatments induce glial cell line-derived neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells.

Hisaoka K, Nishida A, Koda T, Miyata M, Zensho H, Morinobu S, Ohta M, Yamawaki S.

Department of Psychiatry and Neuroscience, Institute of Clinical Research, National Kure Medical Center, Kure, Japan. hisaokak kure-nh.go.jp

Modulation of neurotrophic factors to protect neurons from damage is proposed as a novel mechanism for the action of antidepressants. However, the effect of antidepressants on modulation of glial cell line-derived neurotrophic factor (GDNF), which has potent and widespread effects, remains unknown. Here, we demonstrated that long-term use of antidepressant treatment significantly increased GDNF mRNA expression and GDNF release in time- and concentration-dependent manners in rat C6 glioblastoma cells. Amitriptyline treatment also increased GDNF mRNA expression in rat astrocytes. GDNF release continued for 24 h following withdrawal of amitriptyline. Furthermore, following treatment with antidepressants belonging to several different classes (amitriptyline, clomipramine, mianserin, fluoxetine and paroxetine) significantly increased GDNF release, but which did not occur after treatment with non-antidepressant psychotropic drugs (haloperidol, diazepam and diphenhydramine). Amitriptyline-induced GDNF release was inhibited by U0126 (10 microM), a mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89 (1 microM), a protein kinase A inhibitor, calphostin C (100 nM), a protein kinase C inhibitor and PD 169316 (10 microM), a p38 mitogen-activated protein kinase inhibitor. These results suggested that amitriptyline-induced GDNF synthesis and release occurred at the transcriptional level, and may be regulated by MEK/MAPK signalling. The enhanced and prolonged induction of GDNF by antidepressants could promote neuronal survival, and protect neurons from the damaging effects of stress. This may contribute to explain therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11595754&dopt=Abstract antidepressant




Compliance with antidepressants in a primary care setting, 2: the influence of gender and type of impairment.

Demyttenaere K, Enzlin P, Dewe W, Boulanger B, De Bie J, De Troyer W, Mesters P.

Department of Psychiatry, University Hospital Gasthuisberg, Leuven, Belgium. koen.demytteneare mrd.kuleuven.ac.be

BACKGROUND: DSM-IV diagnosis of major depressive disorder includes a requirement that symptoms result in significant clinical distress or impairment. This criterion is difficult to assess and is often overlooked. This study examines the use of the Sheehan Disability Scale as a possible method of assessing impairment, as well as the relationship between functioning and discontinuation of antidepressant medication. METHOD: Patients (N = 272) receiving antidepressant therapy due to an episode of major depressive disorder were asked to complete an antidepressant compliance questionnaire. Patients were telephoned monthly while they continued on antidepressant therapy, up to 6 months. During each call, the Sheehan Disability Scale was administered. RESULTS: Of patients referred to this study, 94.8% met DSM-IV criteria of at least 5 symptoms of major depressive disorder. Most patients had initial scores ranging from 5 to 8 on all 3 Sheehan disability subscales (occupational, social, and family functioning); 72% of patients had at least moderate impairment (scores > or = 4) on all 3 subscales. After 8 weeks of treatment, 42% of patients had scores < 4 on all 3 subscales (recovery); after 24 weeks, 64% of patients had scores < 4 on all 3 subscales. Dropout risk in men was related to improvement in occupational, social, and family functioning, whereas dropout risk in women was related only to improvement in family functioning. CONCLUSION: The Sheehan Disability Scale can be valuable in assessing impairment and thus in correctly diagnosing major depressive disorder. We suggest that scores of 4 or more (moderate impairment) on all 3 subscales indicate sufficient impairment for a strict diagnosis of major depressive disorder. Functional symptoms continued to improve for up to 24 weeks on antidepressant therapy, suggesting 6 months or more of therapy is necessary for maximum functional improvement. Premature discontinuation of antidepressant therapy is more likely to occur in women who experience significant improvement in family functioning or men who experience significant improvement in any functional area.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11599646&dopt=Abstract antidepressant




Patient perspectives on once-weekly fluoxetine.

Judge R.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Ind 46285, USA.

BACKGROUND: Continuation therapy is recommended for 4 to 9 months following remission of symptoms of major depressive disorder. Long-term maintenance therapy is recommended for patients with severe, recurrent symptoms. However, most patients do not complete an adequate course of therapy. We investigated patient perceptions of antidepressant dosing to determine whether weekly dosing could provide an additional tool to help more patients remain compliant with antidepressant treatment. METHOD: Physicians were asked to complete an anonymous patient profile for 7 patients currently receiving antidepressant treatment and to give those patients a questionnaire that the patients could submit anonymously. In addition, clinically depressed patients in the United States and in France were surveyed by telephone. RESULTS: Patients surveyed by questionnaire agreed most strongly with statements indicating that they would like their doctor to involve them in the choice of antidepressant medication, that they did not want others to know they were taking antidepressant medication, and that they disliked the idea of taking daily medication. Patients in the telephone survey agreed most strongly with statements indicating that they considered once-weekly dosing more convenient than daily dosing, that they believed taking 1 pill a week would make them feel less dependent on pills, and that they perceived more advantages than disadvantages in taking 1 pill a week. CONCLUSION: Weekly antidepressant treatment may provide an effective tool in helping patients with depression. Positive patient perceptions of weekly dosing suggest that some patients may remain on continuation or maintenance therapy longer when they have the option of weekly dosing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11599651&dopt=Abstract antidepressant




[Changes in antidepressants consumption in the health area of Zamora from 1996 to 1999]

[Article in Spanish]

Diaz Madero A, Lopez Ferreras A, Ruiz-Clavijo Diez M, Vargas Aragon M.

Gerencia de Atencion Primaria de Zamora. Farmaceutico de Atencion Primaria, 49007 Zamora. adiaz gapza11.insalud.es

OBJECTIVE: To describe the evolution of antidepressants outside hospital consumption (therapeutic subgroup N06A) in the health area of Zamora since 1996 to 1999, and also to rate the impact of the most recently marketed drugs introduction. DESIGN: Retrospective observational study. SETTING: Primary care. METHODOLOGY: All antidepressants containers dispensed in Zamora with prescription of the Seguridad Social in the 1996-1999 period are obtained from SIFAR (Pharmacy Management Informatic System), computing defined daily doses per 1000 inhabitants day (DHD) for each drug. RESULTS: An increase of 47% in antidepressants whole consumption is observed, progressively since 1996 to 1999: 18.91 DHD (1996); 22.09 DHD (1997); 24.67 DHD (1998); 27.85 DHD (1999).ISRS (88%) and heterocyclics (56%) increase in this period, whereas IMAO (71%) and tricyclic antidepressants (14%) decrease. CONCLUSION: Antidepressant whole consumption experiments an outstanding increase in the area of Zamora. Recently marketed drugs utilisation increases as well, superseding classical antidepressants. The five most used drugs in 1999 were, in decreasing order, paroxetine, fluoxetine, sertraline, citalopram and venlafaxine. These last three ones got the most outstanding rise in the reviewed period.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11602104&dopt=Abstract antidepressant




Species-scanning mutagenesis of the serotonin transporter reveals residues essential in selective, high-affinity recognition of antidepressants.

Mortensen OV, Kristensen AS, Wiborg O.

Laboratory of Molecular Neurobiology, Department of Biological Psychiatry, Psychiatric University Hospital, Risskov, Denmark.

The serotonin transporter (SERT) is a high-affinity sodium/chloride-dependent neurotransmitter transporter responsible for reuptake of serotonin from the extracellular space. SERT is a selective target of several clinically important antidepressants. In a cross-species analysis comparing human and bovine SERTs, the kinetic parameters for serotonin uptake were found to be similar, however, the pharmacological profiles of the two transporters differ. Following transient expression in COS-1 cells, IC(50) values were determined for several antidepressants and psychostimulants. The potencies of the antidepressants citalopram, fluoxetine, paroxetine and imipramine were several-fold higher at hSERT compared with bSERT. No species selectivity was observed for the antidepressants fluvoxamine, and sertraline or for the psychostimulants cocaine, the cocaine analogue beta-carbomethoxy-3beta-(4-iodophenyl)tropane, or for 3,4-methylenedioxymethamphetamine (MDMA). Analysis of six hSERT/bSERT chimeras and subsequent species-scanning mutagenesis of each isoform revealed methionine-180, tyrosine-495, and phenylalanine-513 to be responsible for the increase in citalopram and paroxetine potencies at hSERT and methionine-180 and phenylalanine-513 to confer species selectivity at hSERT for fluoxetine and imipramine. Results were obtained by doing the forward, bovine to human, mutations and confirmed by doing the reverse mutations. Citalopram analogues were used to define the roles of methionine-180, tyrosine-495, and phenylalanine-513 and to reveal molecular interactions with individual functional groups of citalopram. We suggest that methionine-180 interacts with the heterocyclic nucleus of citalopram or stabilizes the binding pocket and phenylalanine-513 to be a steric blocker of antidepressant recognition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11677251&dopt=Abstract antidepressant




Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Jensen JB, Mork A, Mikkelsen JD.

Department of Neurobiology, H. Lundbeck A/S, Copenhagen, Denmark. jbj azign.com

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11679057&dopt=Abstract antidepressant




Deaths from antidepressants in England and Wales 1993-1997: analysis of a new national database.

Shah R, Uren Z, Baker A, Majeed A.

Sutton Hospital, Surrey.

BACKGROUND: The prescription of antidepressants has increased substantially over the last 10 years. It is therefore timely to examine trends in mortality associated with overdoses of antidepressants and to compare the relative mortality associated with different antidepressants. METHODS: Data were derived from a newly developed national database of deaths from overdose and poisoning in England and Wales between 1993 and 1997. Age and sex specific death rates associated with overdose and poisoning with antidepressants were calculated together with numbers of deaths per 100,000 prescriptions of individual antidepressants. RESULTS: Twenty per cent (2,503) of all deaths from overdose or poisoning were antidepressant related. The number of deaths increased by 18% between 1993 and 1997. Ninety-five per cent of deaths from antidepressants were associated with tricyclic antidepressants, particularly dothiepin and amitriptyline. Tricyclic antidepressants were associated with 5.3 deaths per 100,000 prescriptions, 4.4 for monoamine oxidase inhibitors and 0.4 for selective serotonin reuptake inhibitors. Annual death rates were highest in men aged 30-44 years (18.2 per million) and women aged 45-59 years (14.8). Death rates from antidepressants were 2.5 times higher in the most deprived fifth than in the least deprived fifth of enumeration districts. CONCLUSIONS: Antidepressants are an important cause of death from poisoning and overdose. SSRIs and newer antidepressants are associated with <10% of the risk of death than the older antidepressants. There is a strong association between area deprivation and deaths from antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11681546&dopt=Abstract antidepressant