Treatment with mirtazapine and venlafaxine increases noradrenaline excretion in depressed patients.

To the Editors: Depression is a risk factor for cardiovascular morbidity and mortality, but the precise pathophysiological mechanisms are not fully understood. An increased sympathetic tone in depressed patients may contribute to the increased risk for cardiac events in depressed patients. Prolonged sympathoadrenergic activation may lead to impaired health. High plasma and urine levels of noradrenaline (NA) have been found to be associated with reduced survival in otherwise healthy elderly as well as in patients with heart disease. Several mechanism have been discussed to explain the pathophysiological link between high NA levels and increased risk of mortality such as down-regulation of Q-receptors, hypertension, and metabolic disorders. Sympathetic activity may be assessed by measuring catecholamines and their metabolites in plasma or urine as well as indirectly, for example, by heart rate variability. With regard to NA excretion, several studies have shown increased sympathetic activity related to depression, to depressive symptoms in healthy subjects, and to depression in patients with coronary artery disease. Thus, disbalance of the autonomous nervous systemwith predominantly sympathoadrenergic tone may contribute to the cardiovascular risk of depressed patients. Interestingly, there is only limited information on the effect of antidepressants on NA excretion, and there are no studies on the effects of venlafaxine and mirtazapine on NA in plasma or urine. We conducted this study to test the hypothesis that mirtazapine and venlafaxine increase the sympathoadrenergic tone. We included 95 adult patients with unipolar major depressive episodes (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and a score of at least 18 points on the Hamilton Depression Rating Scale (HDRS, 21 items). Upon inclusion, they had either been untreated or were then kept off their psychiatric medication.We did not include patients who had been taking fluoxetine or long-acting injectable antipsychotics. We examined 65 female (52.2 T 16.2 years) and 30 male patients (45.6 T 14.5 years) along with 16 age-matched healthy volunteers (7 women and 9 men; age, 48.3 T 18.9 years). Patients were being treated on an inpatient basis and participated in all routine ward activities; healthy controls were not hospitalized but remained in their regular environment. Exclusion criteria were lifetime diagnosis of schizophrenia or bipolar disorder, current substance dependence, and all physical disorders and medications (eg, A-blocker) that may interfere with sympathetic activity or excretion of catecholamines (eg, impaired renal function). Semistandardized diagnostic interviews in healthy controls revealed no axis I disorder. Before enrollment, all subjects had provided written informed consent. The study had been approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. Patients were kept off psychiatric medication for a period of at least 6 days (week j1), after which they were treated with either venlafaxine or mirtazapine over a period of 4 weeks. Their assignment to either antidepressant treatment (arm) was at random. With the exception of lorazepam and zolpidem as needed, no additional psychotropic medication was allowed. Venlafaxine was dispensed at either 8:30 A.M. or at 2 time points (8:30 A.M. and 12:30 P.M.). Mirtazapine was dispensed at 12:30 P.M. Drugs were given in flexible doses with a minimum dose of 75 mg venlafaxine (final dosage, 150Y300 mg/d; mean, 202 T 57 mg/d) and 30 mg mirtazapine (final dosage, 30Y60 mg/d; mean, 46 T 9 mg/d). Psychopathologic assessment was conducted weekly (HDRS). Patients with less than 18 points on the HDRS at the end of the drug-free washout period or a drop of 10 or more points were excluded from the study (n = 8). Remission was defined as a final HDRS score of 7 or less. Patients and controls were instructed to void at 10 P.M. and to sample all urine after 10 P.M. , including the morning urine at 8 A.M. Urine was sampled on 10-mL hydrochloride to allow NA estimation. We collected one urine sample from controls and 2 samples from patients (baseline; day 28). Urine volume was measured, and aliquots were frozen at j20-C until analysis. After completion of the study, the samples were shipped in dry ice to the laboratory for quantification of NA concentration by means of a commercially available radioimmunoassay (Labor Diagnostika Nord, Nordhorn, Germany). Shortly, NAwas extracted from urine samples using a cis-diolspecific affinity gel fixed to the bottom of the wells of a microtiter plate and further acylated to N-acylnoradrenaline. After release, N-acylnoradrenaline was enzymatically converted (S-adenosylmethionine + catechol-3-O-methyl-transferase) to its respective O-methyl-derivative N-acylnormetanephrine. Final quantification took place by means of a manually performed conventional double antibody competitive radioimmunoassay. Between-run coefficient of variations were 8.9% at a concentration range of 18.6 to 117 Kg/L. We used repeated-measurement analysis of variance (ANOVA) (ANOVA-rm) to first analyze the effect of medication (mirtazapine vs venlafaxine) and then the effect of response (remitters vs nonremitters) separately before combining both factors for further analysis of treatment outcome. All withinand between-group comparisons were analyzed by using paired and unpaired t tests. Noradrenaline concentration multiplied with nighttime urine volume was used as excretion variable. As NA excretion showed no normal distribution, we used logarithmus naturalis-normalized values in all analyses but still reported the original values. All P values are 2-tailed. The level of significance was set at P G 0.05. Eight patients had to be excluded after the washout period (G18 HDRS or drop of Q10 points), leaving in 87 patients for the active treatment phase of the study. Fortytwo patients were treated with mirtazapine, and 45 patients were treated with venlafaxine. After exclusion of patients failing to meet study requirements due to missing or, in all likelihood, incomplete urine samples, and patients using Q-blockers, we analyzed 24 mirtazapine-treated patients (16 women and 8 men; age, 50.0 T 17.2 years; HDRS, 22.9 T 4.2) and 27 venlafaxinetreated patients (17 women and 10 men; age, 55.1 T 13.0 years; HDRS, 23.4 T 5.1). In mirtazapine-treated subjects, there was a significant decline in severity of depression (HDRS, day 28: 8.0 T 5.4) and 11 of 24 subjects were in complete remission at the end of the study period. Similarly, we found a significant decline in severity of depression in the venlafaxine-treated group of patients (HDRS, day 28: 8.9 T 6.6), with 13 of 27 patients considered to be in full remission at the end of the study. There was no statistically significant difference in sex distribution, age, or severity of depression between treatment groups; nor was there a difference between treatment groups and healthy controls (7 women, 54.6 T 12.6 years; 9 men, 43.4 T 17.2 years) regarding sex, age, or urine volume. Sex had no effect on NA excretion in either healthy controls Letters to the Editors Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012