Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

The validity of the depression rating scales in discriminating between citalopram and placebo in depression recurrence in the maintenance therapy of elderly unipolar patients with major depression.

The World Federation of Societies of Biological Psychiatry guidelines for treatment of unipolar major depression has recommended three depression rating scales for evaluating outcome: The Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Bech-Rafaelsen Melancholia Scale (MES). In this study we evaluated the ability of these scales to differentiate between citalopram and placebo in the recurrence prevention of unipolar depression. The study is a psychometric reexamination of a trial on the efficacy of citalopram versus placebo in the maintenance therapy of elderly patients with unipolar depression. Internal validity (the Cronbach coefficient alpha, the Loevinger coefficient of homogeneity, and factor analysis) of the three scales has been examined to evaluate their unidimensionality. In the outcome analysis for depression recurrence, the conventional cutoff scores of the three scales are used. In total, 60 patients received citalopram and 61 patients received placebo in the maintenance phase of 48 weeks. The results showed that the internal validity was higher for MES and MADRS than for HAM-D. Using the MADRS, 67.2 % of the patients on placebo and 31.6 % of the patients on citalopram developed a depression recurrence (ratio 2.12); using HAM-D17, 42.6 % on placebo and 13.3 % on citalopram developed a depression recurrence (ratio 3.20); and using the MES, 34.4 % on placebo and 11.7 % on citalopram developed a depression recurrence (ratio 2.94). The conventional cutoff scores of HAM-D17 and MES for depression recurrence indicated a ratio between citalopram and placebo of around 3, while the conventional cutoff scores of MADRS for depression recurrence indicated a ratio of only around 2. In future trials on the recurrence prevention of unipolar depression, a cutoff score of 25 rather than 22 on the MADRS is recommended.

Combined treatment with imipramine and mianserin. A controlled pilot study.

The effect of imipramine plus mianserin and imipramine plus a placebo was compared in 40 depressed patients with a median age of 60 years. The imipramine dosage was flexible to give a plasma concentration around 200 nmol/l and mianserin was given at a fixed dosage of 30 mg daily. After six weeks of treatment the results showed that the scores on the Hamilton Depression Scale as well as on the Melancholia Scale were significantly more improved in the imipramine-plus-minaserin group than in the group of patients receiving imipramine alone (P less than 0.01). In terms of percentage of improvement (a reduction of baseline rating scores of 50% or more) 77% of the imipramine-plus-mianserin group had improved, compared with 27% of the imipramine group. The combination of imipramine and mianserin was well tolerated both as regards clinical side-effects and laboratory tests.

Effects of treatment with a lithium-imipramine combination on components of adenylate cyclase in the cerebral cortex of the rat.

This study was aimed at investigating the effects of treatment with a lithium-imipramine combination on the activity of adenylate cyclase in membranes from the cerebral cortex of the rat. Treatment with (1) lithium for 2 weeks, yielding a level of lithium in serum of 0.54 +/- 0.12 mmol/l, (2) imipramine for 4 weeks (10 mg/kg i.p. twice per day) and (3) a combination of the two drugs reduced isoprenaline-induced stimulation of adenylate cyclase by GTP, with a greater decrement with the combined treatment. None of the treatments exerted any effect on the activity of the enzyme stimulated by GTP alone. Lithium ex vivo inhibited the calcium (Ca2+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but imipramine ex vivo did not affect the activity of adenylate cyclase, stimulated by these activators. The lithium-imipramine treatment reduced Ca2(+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but this was not different from that observed in the lithium-treated group. In conclusion, the beta-adrenoceptor-stimulated adenylate cyclase was affected markedly by administration of lithium and imipramine together. In contrast to lithium ex vivo, imipramine ex vivo did not impair the activity of either the guanine nucleotide regulatory protein or the catalytic subunit, since no change in activity was observed in the presence of beta,gamma-imidoguanosine-5' triphosphate (Gpp(NH)p) or Ca2+. Furthermore, lithium ex vivo exerted its post-receptor effects on the adenylate cyclase, independent of imipramine. The decrement in activity of beta-adrenergic adenylate cyclase, induced by administration of the two drugs together may partly be involved in the therapeutic action of the augmentation of antidepressants by lithium in refractory depression.

Sexual dysfunction in male and female patients with epilepsy: a study of 86 outpatients.

Sexual dysfunction is a well-known complication of chronic somatic illness. Eighty-six consecutive epileptic outpatients, 38 men and 48 women, without accompanying disorders, were studied. The frequency and symptoms of sexual dysfunction were compared with results from previous studies using identical sexological methodology. The previous studies were of diabetic patients and healthy controls. Eight percent of the epileptic men reported a sexual dysfunction compared to 44% of the diabetics and 13% of the controls. Epileptic women, diabetic women, and controls showed no significant differences in sexual dysfunction (29%, 28%, and 25%, respectively). In both sexes, the sexual function measured by frequencies of coitus and masturbation was normal. Most patients had good control of epileptic attacks on a treatment of monotherapy. Hormonal status was generally within normal limits in both men and women; only a few minor differences were found and they showed no correlation with sexual dysfunction. Psychologically and socially the patients did not differ appreciably from normals, and they exhibited a high degree of disease acceptance. This study, using a biopsychosocial approach in understanding sexual dysfunctions, is in contrast with previous, mainly uncontrolled, studies of epileptic patients that reported high frequencies of "hyposexuality" in males. We conclude that epilepsy does not necessarily increase the risk of sexual dysfunction in male or female.

Enhanced histamine- and beta-adrenoceptor-mediated cyclic AMP formation in leukocytes from patients with endogenous depression.

Beta-adrenoceptor-mediated cyclic AMP formation was found to be increased in leukocytes from manic-depressive patients during untreated depression when compared with euthymic patients treated with antidepressants. The difference was dependent on the stimulation used (isoprenaline or a combination of noradrenaline and phentolamine) and was only significant when the combination was used. Histamine-stimulated cyclic AMP formation in leukocytes was enhanced in patients with untreated depression, both when compared with euthymic patients suffering from manic-depressive illness, with or without treatment with antidepressant drugs, and also when compared with control persons without any known psychiatric disease. Although at variance with the results of some other studies on the same topic, the results of the present study indicate that changes in receptor function in leukocytes may be a state-dependent marker in depressive illness.

Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics.

Seventeen hospitalized patients (age 39-66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40-637 nmol/l for imipramine, 49-1148 nmol/l for desipramine and 89-1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548-910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50-400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.

Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism.

Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean +/- SD) 713 +/- 132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50-400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.

Characterization of human platelet beta-adrenoceptors.

The widespread use of beta-adrenoceptor antagonists against hypertension, angina pectoris and migraine or as a preventive treatment after myocardial infarction has encouraged us to investigate the effects of these drugs on platelet function. The aim of this study was to examine whether beta-blocking drugs interfere with platelet beta- adrenoceptors and whether this dependency is related to their selectivity for beta-adrenoceptor subtypes. Beta-adrenoceptor stimulation of human platelets with isoprenaline increased cyclic AMP (cAMP), which is known to inhibit platelet aggregation. Furthermore, our studies showed that cAMP formation in vitro was stimulated by non-selective and beta 2-selective agonists, but not by the predominant beta 1-agonist prenalterol. Isoprenaline- stimulated cAMP formation was blocked by the non- selective beta-adrenoceptor antagonists propranolol, timolol, and alprenolol, while the beta 1-selective antagonists atenolol and metoprolol had no influence on an isoprenaline-induced cAMP formation. Receptor binding studies using (3H)-dihydroalprenolol revealed an IC50 value for propranolol of 85 nM, while metoprolol only displaced the bound (3H)-dihydroalprenolol at far higher concentrations (IC50, 20 microM). We conclude that the human platelet beta-adrenoceptors are mainly of the beta 2- subtype and that beta-adrenoceptor antagonists, especially the non-selective antagonists interfere with platelet function assessed as platelet cAMP formation.

3,4-O-diacetylisoproterenol. Preparation, structure proof, and beta-receptor effect.

Direct acetylation of isoproterenol by selective O-acetylation using CH3COCl/CF3COOH was shown to lead to the formation of 2-(3,4-diacetoxyphenyl)-2-chloro-N-isopropyl-1-ethanamine and not to 3,4-O-diacetylisoproterenol. The latter was prepared by reduction of 3,4-diacetoxy(2-isopropylamino)acetophenone and its structure confirmed by IR, 1H, 13C NMR, mass spectral, and elemental analysis. The two compounds were tested for activity on beta-receptors. Efficacy and affinity on beta 1-receptors were found identical with the effect of isoproterenol. So was efficacy on beta2-receptors, while affinity was lower for the chloro compounds than for isoproterenol and diacetylisoproterenol which exhibited identical affinity.

The effect of lithium in vitro and in vivo on dopamine-sensitive adenylate cyclase activity in dopaminergic areas of the rat brain.

Lithium (5 and 20 mM) was found to inhibit the dopamine-stimulated cyclic AMP formation in homogenates from rat striatum and olfactory tubercle, leaving basal and fluoride-stimulated activities unaffected. The inhibition of dopamine-stimulated adenylate cyclase was non-competitive and dose-dependent. However, in rats treated with lithium for four weeks, no alterations were found in basal, fluoride- and dopamine-stimulated adenylate cyclase activities. It is suggested that lithium interferes with hormonal stimulation of adenylate cyclase activity by an interaction with the process regulating the transfer of the receptor-hormone stimulus to the adenylate cyclase enzyme.

Forskolin-stimulated adenylate cyclase activity in rat cerebral cortex following chronic treatment with psychotropic drugs.

Rats were treated with lithium, imipramine, reserpine, and lithium combined with imipramine or reserpine. Lithium was given in the diet (40 mmol/kg) resulting in a serum-Li+ level of 0.5-0.6 mmol/l. Other drugs were dissolved in 0.9% saline and given intraperitoneally once or twice daily. After 3 weeks of treatment, forskolin-stimulated adenylate cyclase activity was measured in cerebral cortex homogenates. Reserpine did not affect the forskolin stimulation, while both imipramine and lithium caused a decrease in this activity. The combined treatments lithium-imipramine and lithium-reserpine also exhibited a clear decrease in forskolin stimulation, but the effect of concomitant lithium and imipramine treatment did not differ from the effect seen after any of the treatments alone. The unstimulated activity was unaltered by all treatments. The inhibition of lithium and imipramine on the forskolin stimulation indicates an interference of these two drugs with the forskolin-mediated activation of the adenylate cyclase.

No change in rat cerebral cortex calmodulin content following chronic treatment with lithium, reserpine, imipramine, and lithium combined with reserpine or imipramine.

Rats were treated 2-3 weeks with lithium, reserpine, imipramine, and combinations of lithium with reserpine or imipramine. Lithium was given in the diet, while the other drugs were dissolved in 0.9% saline and given intraperitoneally twice daily. The control and lithium groups received only vehicle injections. Twenty-four hours after the last injection the rats were decapitated and the cerebral cortex dissected. The tissue was sliced and the noradrenaline-stimulated cyclic AMP accumulation determined or the tissue was homogenized and centrifuged at 10,000 X g for 30 min. and the calmodulin content determined in the pellet and the supernatant. Reserpine treatment was found to cause an 50% increase in the noradrenaline-stimulated cyclic AMP accumulation, while treatment with imipramine and the combination lithium-imipramine decreased the noradrenaline-stimulated cyclic AMP accumulation by 40%. The tissue content of calmodulin was, however, found unaltered by all treatments.

Characterization of the beta-adrenergic receptor on the human platelet: a beta 2-subtype.

The human platelet beta-adrenergic receptor was characterized by using the ability of different drugs to stimulate the adenylate cyclase activity and the effects of various beta-antagonists to block the isoprenaline-stimulated adenylate cyclase activity. Isoprenaline was found 10 times more potent than adrenaline and 1000 times more potent than noradrenaline in stimulating the adenylate cyclase activity in these cells. Isoprenaline-stimulated activity was blocked by the non-selective beta-antagonists propranolol and alprenolol and by the beta 2-selective antagonist IPS 339 and prenalterol. Metoprolol, a beta 1-selective blocker, was without effect on the isoprenaline-stimulated adenylate cyclase activity. We conclude from our findings that the beta-adrenergic receptor type on the human platelet is mainly of the beta 2-subtype.