Antinociceptive efficacy of antidepressants: assessment of five antidepressants and four monoamine receptors in rats.

Otsuka N, Kiuchi Y, Yokogawa F, Masuda Y, Oguchi K, Hosoyamada A.

Department of Anesthesiology, School of Medicine, Showa University, Tokyo, Japan.

PURPOSE: For assessment of the antinociceptive potency of antidepressants, we compared the antinociceptive effects of serotonin selective reuptake inhibitors (SSRIs) and classical tricyclic antidepressants (TCAs) in rats. We also attempted to elucidate the monoamine receptor subtypes predominantly involved in the antinociceptive effect of antidepressants. METHODS: Male Wistar rats received SSRIs (sertraline, fluvoxamine, and citalopram) or TCAs (imipramine and desipramine) intraperitoneally, and the reaction time until pain response in the hot plate test and licking time in the formalin test were measured 60 min later. We also observed the effects of prazosin (an alpha(1) antagonist), WB-4101 (a selective alpha(1A) antagonist), yohimbine (an alpha(2) antagonist), WAY-100635 (a selective 5-HT(1A) antagonist), and ketanserin (a 5-HT(2) antagonist), which were simultaneously administered with imipramine or desipramine, on the antidepressant-induced antinociceptive effect in the formalin test. RESULTS: In the hot plate test, desipramine, 20 mg.kg(-1), but not imipramine or sertraline, produced a significant increase in reaction time. In the formalin test, desipramine and imipramine produced significant reductions in the licking time at over 5 mg.kg(-1) and at over 10 mg.kg(-1), respectively. These reductions were nearly complete at 20 mg.kg(-1). On the other hand, both SSRIs induced significant reductions in the licking time only at 20 mg.kg(-1). Prazosin, WB-4101, and ketanserin significantly antagonized the antinociceptive effect of 10 mg.kg(-1) of imipramine. However, imipramine-induced antinociception was not affected by yohimbine and WAY-100635. Prazosin and ketanserin also significantly suppressed antinociception by 5 mg.kg(-1) of desipramine. CONCLUSION: These findings suggest that classical TCAs are likely to have a therapeutic advantage over SSRIs for pain control. In addition, it is likely that central alpha(1) adrenoceptors and 5-HT(2) receptors are predominantly involved in imipramine- and desipramine-induced antinociception.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14566514&dopt=Abstract antidepressant




Incidence and determinants of antidepressant drug use in migraine patients.

Rahimtoola H, Buurma H, Tijssen CC, Leufkens HG, Egberts AC.

Department. of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands. apo.notekraker zorggroep-almere.nl

The purpose of this retrospective, follow-up study was to characterise the use of antidepressant medication in a defined migraine population and evaluate the determinants thereof. Data was obtained from the PHARMO-RLS prescription database. Our migraine population (2,517 people) included patients having commenced specific migraine drugs, ergotamine or sumatriptan, for the first time from January 1 1992 to December 31 1998. The corresponding date was termed the 'index date'. Non-migraine patients, those not having used any medication specific for migraine, were selected and equally matched (n=2,517). The cumulative incidence of initiating antidepressant treatment was estimated during two-year observation periods prior to and after the index date. Several demographic and comedication characteristics were assessed as potential determinants of antidepressant drug use within the migraine population. Other determinants included usage patterns ("therapeutic intensity") of ergotamine and sumatriptan, defined as the absolute number of Defined Daily Doses (DDDs) dispensed per patient during one year prior to initiation of antidepressant therapy. A total of 300 migraine patients (11.9%) and 213 non-migraine patients (8.5%) had initiated antidepressant treatment in the two-year period prior to or in the two-year period after the index date (RR adj 1.4; 95% CI 1.2-1.7). The cumulative incidence of initiation of antidepressant treatment for the migraine population was 3.0% per year prior to and 3.2% per year after the initiation of specific migraine analgesia. The concomitant use of benzodiazepines (RR adj 4.7; 95% CI 3.5-6.3), migraine prophylactic medication (RR adj 2.1; 95% CI 1.6-2.8) and heavy therapeutic intensity use of specific migraine analgesia, defined as >/=150 DDDs per year were highly predictive of antidepressant drug use within the migraine population.In conclusion, compared to the non-migraine population, the initiation of antidepressant treatment was only slightly higher in the migraine population. A number of determinants within the latter were found to be strongly associated with antidepressant drug use, the nature of which most likely reflects an increased severity of migraine whereby therapeutic needs are higher.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14571153&dopt=Abstract antidepressant




Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants.

Gumilar F, Arias HR, Spitzmaul G, Bouzat C.

Instituto de Investigaciones Bioquimicas de Bahia Blanca, Universidad Nacional del Sur, CONICET, Camino La Carrindanga Km 7, B8000FWB Bahia Blanca, Argentina.

In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR.Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 muM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-(3)H (N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14573389&dopt=Abstract antidepressant




Antidepressant drug treatment induces Arc gene expression in the rat brain.

Pei Q, Zetterstrom TS, Sprakes M, Tordera R, Sharp T.

University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK. qi.pei pharm.ox.ac.uk

The mechanism underlying the therapeutic effect of antidepressants is not known but neuroadaptive processes akin to long-term potentiation have been postulated. Arc (Activity-regulated, cytoskeletal-associated protein) is an effector immediate early gene implicated in LTP and other forms of neuroplasticity. Recent data show that Arc expression is regulated by brain 5-hydroxytryptamine neurones, a target of many antidepressants. Here in situ hybridisation and immunohistochemistry were used to examine whether Arc expression in rat brain is altered by antidepressant drug treatment. Repeated administration of the monoamine reuptake inhibitors paroxetine, venlafaxine or desipramine induced region-specific increases in Arc mRNA. These increases were greatest in regions of the cortex (frontal and parietal cortex) and hippocampus (CA1 layer) and absent in the caudate putamen. Repeated treatment with the monoamine oxidase inhibitor, tranylcypromine, increased Arc mRNA in a similar fashion to the monoamine reuptake inhibitors. The antidepressant drugs also increased the number of Arc-immunoreactive cells in the parietal cortex. Acute antidepressant injection, and repeated administration of the antipsychotic drug chlorpromazine, produced either limited or no changes in Arc mRNA. The data suggest that chronic treatment with antidepressant drugs induces Arc gene expression in specific regions across the rat forebrain. Up-regulation of Arc expression may be part of the process by which antidepressant drugs achieve long-term changes in synaptic function in the brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14580947&dopt=Abstract antidepressant




Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients.

Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC.

Hospital Pharmacy Midden-Brabant, St Elisabeth Hospital and TweeSteden Hospital, Tilburg, The Netherlands.

BACKGROUND: Several reports of various bleeding problems associated with the use of serotonergic antidepressants have been published. However, no information concerning the effect of these drugs on perioperative blood loss and blood transfusion requirements during orthopedic surgery is available. The objective of this study was to determine the association between use of serotonergic antidepressants and perioperative blood loss and transfusion in orthopedic surgical patients. METHODS: A retrospective follow-up study, using routinely collected hospital and pharmacy data, was conducted among all orthopedic patients undergoing surgery from January 1, 1999, through December 31, 2000. The actual blood transfusion requirements and blood loss during surgery were assessed. Patients were divided into 3 groups for comparison: users of serotonergic antidepressants, users of nonserotonergic antidepressants, and nonusers of antidepressants. The Medical Ethics Committee approved the study protocol, and informed consent was obtained from all patients or their legal relatives. RESULTS: A total of 520 subjects with evaluable data participated in the study. The risk of blood transfusion almost quadrupled for the serotonergic antidepressant group as compared with the nonusers (adjusted odds ratio, 3.71; 95% confidence interval, 1.35-10.18). Patients using nonserotonergic antidepressants had no increased risk (odds ratio, 0.74; 95% confidence interval, 0.10-5.95). CONCLUSIONS: Use of serotonergic antidepressants is associated with an increased risk of bleeding and subsequent need for blood transfusion during orthopedic surgery. The bleeding could be attributed to inhibition of serotonin-mediated platelet activation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14581256&dopt=Abstract antidepressant




Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania.

De Luca V, Mundo E, Trakalo J, Wong GW, Kennedy JL.

Neurogenetics Section, Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

The involvement of the multi-drug-resistant 1 P-glycoprotein gene (MDR1 P-gp) in the transport of antidepressants across the blood-brain barrier makes it a good candidate for the prediction of antidepressant response and side effects. We investigated the role of the MDR1 P-gp gene in predicting the induction of mania in bipolar patients (BP) treated with proserotonergic drugs. Participants met the DSM-IV criteria for BP or BPII and had at least one depressive episode treated with proserotonergic antidepressants. The first group (n=26) included patients with at least one DSM-IV manic/hypomanic episode developed during antidepressant treatment; the second group (N=29) included patients with no antidepressant-induced switches. The common polymorphism of the MDR1 was genotyped for both groups and comparison was made with respect to the presence/absence of induced mania between the two groups. No association between antidepressant-induced mania and the MDR1 alleles or genotypes was found (chi2=1.85, 2 df, P=0.39; chi2=0.13, 1 df, P=0.72).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14583799&dopt=Abstract antidepressant




Antidepressant poisoning deaths in New Zealand for 2001.

Reith D, Fountain J, Tilyard M, McDowell R.

Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand. david.reith stonebow.otago.ac.nz

AIM: To compare the rates of death per volume of drug dispensed for antidepressants in New Zealand. METHODS: Deaths from antidepressant poisonings were identified from the reports of coronial inquiries for New Zealand in 2001. Prescriptions for antidepressant medications were identified from the PharmHouse database from 1 January 2001 to 31 December 2001. The rates of deaths (95% CI) per prescription, tablet/capsule or defined daily dose were calculated for individual antidepressants and classes of antidepressant. RESULTS: There were 200 poisoning deaths recorded in the database for New Zealand in 2001. Antidepressants were involved in 41 deaths, and death was attributed to an antidepressant in 23 cases. There were 5.52 (95% CI 3.85-7.68) deaths per 100 000 prescriptions for tricyclic antidepressants (TCAs) and 2.51 (1.57-3.79) deaths per 100 000 prescriptions for selective serotonin reuptake inhibitors (SSRIs). There was marked variability in rates of death per volume of drug dispensed between individual antidepressants. CONCLUSIONS: SSRIs have lower rates of death per volume of drug dispensed than TCAs and there is also variation in these rates within these classes of drugs. Toxicity in overdose should be considered when prescribing antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14583804&dopt=Abstract antidepressant




The utility of mandatory depression screening of dementia patients in nursing homes.

Cohen CI, Hyland K, Kimhy D.

Division of Geriatric Psychiatry, State University of New York Downstate Medical Center, Hillside Hospital, 450 Clarkson Avenue, Box 1203, Brooklyn, NY 11203, USA. cohen_c hscbklyn.edu

OBJECTIVE: Current methods for enhancing the recognition and treatment of depression in nursing home patients have been unsuccessful. This study examines the process, outcome, and impact of instituting a mandatory depression screening program for depressed dementia patients in nursing homes. METHOD: The experimental and comparison groups each consisted of two nursing homes of 519 and 363 patients, respectively. Two of the experimental group and one of the comparison group homes were more traditionally staffed facilities; one of the comparison group homes had an enriched staff of psychologists. The Cornell Scale for Depression in Dementia was administered to the residents with dementia. In the experimental group, the patients who scored > or =5 were referred for psychiatric assessment. RESULTS: In the experimental group, 100% of the referred dementia patients who met screening criteria for depression were seen by a psychiatrist. This resulted in a significant increase in the percentage of individuals given antidepressants. This was greater than the percentage of patients receiving antidepressants in the "typical" comparison group home but not the "staff-enriched" comparison group home. White patients were significantly more likely to receive antidepressants; however, screening significantly increased the proportion of depressed nonwhites receiving antidepressants. At the 12-week follow-up, there was a significant difference in scores between patients receiving antidepressants in each group. CONCLUSIONS: Mandatory depression screening can significantly increase the proportion of depressed dementia patients receiving antidepressants, lead to dose adjustments, diminish potential ethnic biases in treatment, and affect the depressive symptoms of treated individuals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14594749&dopt=Abstract antidepressant