Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?

Schreiber S, Bleich A, Pick CG.

Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Israel.

The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies as far as mild to moderate depression is involved. However, it seems that some antidepressants are more effective than others in the treatment of severe types of depression (i.e., delusional depression and refractory depression). Following studies regarding the antinociceptive mechanisms of various antidepressants, we speculate that the involvement of the opioid system in the antidepressants' mechanism of action may be necessary, in order to prove effective in the treatment of severe depression. Among the antidepressants of the newer generations, that involvement occurs only with venlafaxine (a presynaptic drug which blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine) and with mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-auto- and hetero-adrenoreceptors). When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11931344&dopt=Abstract antidepressant




Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.

Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS.

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, USA.

Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11943826&dopt=Abstract antidepressant




cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs.

Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA.

Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11943827&dopt=Abstract antidepressant




Counseling versus antidepressant therapy for the treatment of mild to moderate depression in primary care: economic analysis.

Miller P, Chilvers C, Dewey M, Fielding K, Gretton V, Palmer B, Weller D, Churchill R, Williams I, Bedi N, Duggan C, Lee A, Harrison G.

Trent Institute for Health Services Research, School of Community Health Sciences, University of Nottingham, Queens Medical Centre, UK. paul.miller nottingham.ac.uk

OBJECTIVE: To compare the cost-effectiveness of generic psychological therapy (counseling) with routinely prescribed antidepressant drugs in a naturalistic general practice setting for a follow-up period of 12 months. METHODs: Economic analysis alongside a randomized clinical trial with patient preference arm. Comparison of depression-related health service costs at 12 months. Cost-effectiveness analysis of bootstrapped trial data using net monetary benefits and acceptability curves. RESULTS: No significant difference between the mean observed costs of patients randomized to antidepressants or to counseling (342 pounds sterling vs 302 pounds sterling , p = .56 [t test]). If decision makers are not willing to pay more for additional benefits (value placed on extra patient with good outcome, denoted by K, is zero), then we find little difference between the treatment modalities in terms of cost-effectiveness. If decision makers do place value on additional benefit (K > 0 pounds sterling), then the antidepressant group becomes more likely to be cost-effective. This likelihood is in excess of 90% where decision makers are prepared to pay an additional 2,000 pounds sterling or more per additional patient with a good global outcome. The mean values for incremental net monetary benefits (INMB) from antidepressants are substantial for higher values of K (INMB = 406 pounds sterling when K = 2,500 pounds sterling). CONCLUSION: For a small proportion of patients, the counseling intervention (as specified in this trial) is a dominant cost-effective strategy. For a larger proportion of patients, the antidepressant intervention (as specified in this trial) is the dominant cost-effective strategy. For the remaining group of patients, cost-effectiveness depends on the value of K. Since we cannot observe K, acceptability curves are a useful way to inform decision makers.

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[Tricyclic antidepressants dosage and depressed elderly inpatients: a retrospective pharmaco-epidemiologic study]

[Article in French]

Ballon N, Siobud-Dorocant E, Even C, Slama F, Dardennes R.

Service de Psychiatrie et de Psychologie Medicale, CHU de Fort de France, Martinique.

It is recommended to reduce by one half the dosages of tricyclic antidepressants for patients over 65 years of age, in order to avert the occurrence of side-effects. The question we studied was: is it rightful to prescribe tricyclic antidepressants at half-dose to hospitalized elderly people? It is important, for the following reasons, to specify the rules of prescription of tricyclics in elderly patients: 1) The elderly population is on the increase; 2) There is a high prevalence of depression in elderly patients; 3) Depression exposes the elderly person to an increased risk of suicide; 4) Depression influences the prognosis of associated organic disorders 5) Recourse to tricyclic antidepressants is often necessary within this population group because of treatment resistant forms of depression which impose the use of different families of antidepressants and thus resort to tricyclics despite their lower tolerance. OBJECTIVES AND METHODS: The aim of our study is to evaluate whether the half doses of tricyclics recommended for an elderly person are sufficient in the case of an hospitalized patient. In order to provide some answer to this question, we have carried out a retrospective study. We have studied a sample of patients over-65, hospitalized at the Clinique des Maladies Mentales et de l'Encephale, over a period of two years, with a ICD 10 diagnosis of moderate or severe intensity major depressive episode, and treated effectively with return to the euthymia. Creatinemia was prescribed systematically to each patient on entry. Only patients with normal renal function were retained. Laboratory norms are between 45 and 120 micromol/liter. The routine practice of imipraminic blood dosages allowed the comparison of blood levels obtained among patients treated with posologies inferior or equal to 75 mg/day imipraminic, to those treated with more than 75 mg/day imipraminic for a least a week. The percentage observed were compared using the Khi2 test with Yates correction. We retained the blood concentrations of the mother molecule for tertiary amines (imipramine, clomipramine and amitriptyline). The samples were taken after at least seven days of treatment at the same dose, and twelve to thirteen hours after the last taking. The maxima of blood levels were respectively: desipramine 200 ng/ml, clomipramine 258 ng/ml, imipramine 163 ng/ml, amitriptyline 129 ng/ml. Research for evidence in favor of toxicity (fall, delirium, convulsion, reduction of dosage before discharge), was done through revision of patients' clinical files. RESULTS: The test group consisted of 87 individuals. The average age was 71.3 years (SD: 5.09). Mean creatinemia was 83.73 mmol/l (SD: 26.89). The population thus selected divided into 4 groups: 61 (70.1%) were given imipraminics, 10 (11.5%) serotonin recapture inhibitors, 11 (12.7%) other antidepressants essentially of mianserine and 5 (5.7%) treatment by electroconvulsivotherapy. The imipraminics prescribed were desipramine, imipramine, clomipramine and amitriptyline. Among the 61 patients treated with imipramine, blood level dosage was practised on 48 patients (79%). Two subgroup were distinguished: 13 (21%) received dosages inferior ou equal to 75 mg/day and 48 (79%) superior to 75 mg/day. The mean dosage found in the sub-group of patients treated with dosages superior to 75 mg/day was 140 mg/day (SD: 30). The subgroup treated with dosages superior to 75 mg/day was more frequently monitored than the subgroup receiving dosages inferior or equal to 75 mg/day, respectively 40/48 (83%), and 8/13 (62%). This difference is statistically nonsignificant (p > 0.10). The analysis of dosages used showed that:--among the dosages effected upon patients receiving doses inferior or equal to 75 mg/day, 1 (12.5%) exceeded the maximal value of therapeutic range.--Among the dosages effected upon patients receiving dosages superior to 75 mg/day, 9 (22%) exceeded the maximal value of the therapeutic range. The difference is statistically significant (p < 0.001). On revision of clinical files, no patient presented any element that might lead one to suspect toxicity such as defined in "Objectives and Methods". CONCLUSION: In our study, patients were hospitalized and so benefited from closer observation than one can expect in outpatients. In this particular context, the dosages used are close to those advocated for the general population. With the elderly subject, the systematic prescription of half-dose tricyclics runs the risk of infratherapeutic dosage. It is thus preferable to resort to blood level dosage and to look for a maximum dose tolerance before concluding ineffectuality. This allows one to monitor whether the blood levels obtained are included in the therapeutic range; to avoid toxic doses and to check weak compliance in the elderly patient. Our findings do not oppose the use, for the elderly hospitalized depressive, of doses of imipraminics close to those of a young subject. To confirm these results it would be desirable to carry out o prospective study, including a systematised evaluation of adverse effects and a comparison of clinical effectiveness for parallel groups of elderly patients receiving different doses of imipraminic antidepressants.

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Antidepressant-like effects of aniracetam in aged rats and its mode of action.

Nakamura K, Tanaka Y.

CNS Supporting Laboratory, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. kazuo.nakamura roche.com

RATIONALE: Aniracetam has been reported to be efficacious for treating poststroke depression, but no studies that basically examined the antidepressive effects have been made. OBJECTIVE: We aimed to test the antidepressant-like property of aniracetam in rats and to clarify the mechanisms of action through the interaction studies with some receptor antagonists. METHODS: Antidepressant-like effects of aniracetam and various classes of compounds including different antidepressants were examined in a forced swim test with young (9 weeks old) and aged (25-30 months old) rats. Rats were exposed to a 5-min swim in a test session on day 2 following a 15-min swim in a training session on day 1, and immobility time during the period on day 2 was measured. The test compounds were administered subacutely (three doses over 2 days) or acutely (0.5 h before the testing). RESULTS: Standard antidepressants except for tandospirone significantly reduced immobility time in both young and aged rats. Aniracetam (10-100 mg/kg PO) failed to decrease immobility time in young rats, but it (100 mg/kg PO) significantly shortened immobility in aged rats, the effects of which were mainly mimicked by combined treatment of the metabolites, 2-pyrrolidinone and N-anisoyl-GABA. The effects of aniracetam was reversed completely by mecamylamine (10 mg/kg IP) or haloperidol (0.1 mg/kg IP) and slightly by ketanserin (1 m/kg IP) but was potentiated by scopolamine (0.03 mg/kg IP). CONCLUSIONS: These results indicate that aniracetam acts more effective when the forced swim stress-induced immobility is accompanied with brain dysfunction that occurs with aging. The antidepressant-like activity of aniracetam, which is probably due to the combined effects of 2-pyrrolidinone and N-anisoyl-GABA, may be mediated by mainly facilitating dopaminergic transmission (dopamine release and dopamine D2 receptor activation) through nicotinic acetylcholine receptor stimulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11702095&dopt=Abstract antidepressant




Retrospective analysis of the health-care costs of bupropion sustained release in comparison with other antidepressants.

Poret AW, Neslusan C, Ricci JF, Wang S, Khan ZM, Kwong JW.

GlaxoSmithKline, Health Outcomes Department, Research Triangle Park, NC, USA. Amy.white medstat.com

OBJECTIVE: The objective of this study was to evaluate the health care costs associated with the treatment of a new episode of depression with bupropion sustained release (SR) rather than with other antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], and serotonin norepinephrine reuptake inhibitors [SNRIs]). METHODS: This was a retrospective cohort study based on the private-pay, fee-for-service 1997 and 1998 MEDSTAT MarketScan databases. Individuals were included if they were 18 years of age or older, had an initial prescription for an antidepressant under study with an index prescription date between July 1997 and June 1998, and had a claim for a diagnosis of depression diagnosis within 30 days of the index date. All patients' claims from six months before and after receiving their index antidepressant prescription were examined. Total, outpatient, and pharmacy costs were compared among antidepressant groups using an intent-to-treat analysis with exponential regression models and bootstrapped 95% confidence intervals. RESULTS: A total of 1771 patients were included in the study cohort. The mean age was 41.6 years, and 69.5% of subjects were female. Most patients (75%) continued with the index antidepressant during the 6-month follow-up period. Although the drug acquisition cost was lowest for TCAs, total costs were significantly higher for patients treated with TCAs than for those treated with bupropion SR (p < .05). In comparison with bupropion SR, patients initiating therapy with sertraline had significantly higher mental health payments (p < .05). CONCLUSIONS: Initiating treatment of depression with bupropion SR was associated with lower total mental health care costs compared with TCAs and with sertraline. This study reaffirms that formulary and medical decision-makers should consider the overall impact of antidepressant treatment, including but not limited to drug acquisition costs, other health care costs, and drug efficacy and safety.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705126&dopt=Abstract antidepressant




Long-term costs of treatment for depression: impact of drug selection and guideline adherence.

Crown WH, Treglia M, Meneades L, White A.

MEDSTAT Group, Inc., Cambridge, MA, USA.

OBJECTIVES: This paper examines three processes: SSRI antidepressant choice, adherence to treatment guidelines, and long-term health care expenditures associated with antidepressant treatment for patients with a diagnosis of depression. METHODS: Patient records were abstracted from a medical claims database covering employer-provided health care plans. Treatment episodes required a 6-month antidepressant-free prior period; initial treatment with sertraline, paroxetine or fluoxetine; and data on direct medical costs over the 24 months following the initial prescription. The multivariate model of drug selection, patient adherence to antidepressant use guidelines, and cost was subjected to specification testing to rule out the possibility that nonrandom initial antidepressant selection might lead to sample selection bias. Further tests indicated that the results were free of bias due to a possible correlation between antidepressant selection and use of the medication, or because of the endogeneity of use patterns in the process driving cost. However, there was evidence of unobserved variables correlated with both achieving guideline adherent use and expenditures, which might have led to sample selection bias. RESULTS: Subjects who met the study criteria included 796 initiating therapy with sertraline, 352 with paroxetine, and 882 with fluoxetine. Fluoxetine patients were significantly more likely than sertraline or paroxetine patients to achieve a use pattern that was consistent with guidelines for treating depressive disorder (p < .05). There were no statistically significant differences between the three treatment cohorts in total direct health care expenditures over the 2-year period (p < .05), and depression-related expenditures, other mental health expenditures, and non-mental health care expenditures did not show significant differences across the treatments (p < .05). Natural logged values of antidepressant drug expenditures were predicted to be highest for fluoxetine, followed by sertraline, then paroxetine (p < .01). Predicted log values of mental health expenditures were lower for sertraline relative to fluoxetine. CONCLUSIONS: Fluoxetine patients had the highest likelihood of using antidepressant medication according to treatment guidelines that were developed to assure quality care. This benefit was achieved without incurring greater total health care expenditures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705297&dopt=Abstract antidepressant