Weight-gain independent effect of mirtazapine on fasting plasma lipids in healthy men.

Treatment with mirtazapine, a widely prescribed antidepressant, has been linked to weight gain and dyslipidemia. Whether dyslipidemia occurs secondary to increased appetite due to antidepressant treatment, or due to direct pharmacological effects of mirtazapine is unknown. The aim of this analysis is to complement our previously published results of the effect of mirtazapine on metabolism and energy substrate partitioning from a proof-of-concept, open-label clinical study (ClinicalTrials.gov NCT00878540) in 12 healthy males (20-25 years). We report the effect of a seven-day administration of mirtazapine 30 mg per day on weight and lipid metabolism in healthy men under highly standardized conditions with respect to diet, physical activity and day-night-rhythm and under continuous clinical observation. After a 7-day administration of mirtazapine 30 mg, we observed a statistically significant increase in triglyceride levels (mean change + 4.4 mg/dl; 95% CI [- 11.4; 2.6]; p = 0.044) as well as TG/HDL-C ratio (mean change + 0.2; 95% CI [- 0.4; 0.1]; p = 0.019) and a decrease in HDL-cholesterol (mean change - 4.3 mg/dl; 95% CI [2.1; 6.5]; p = 0.004), LDL-cholesterol (mean change - 8.7 mg/dl; 95% CI [3.8; 13.5]; p = 0.008), total cholesterol (mean change - 12.3 mg/dl; 95% CI [5.4; 19.1]; p = 0.005), and non-HDL-C (mean change - 8.0 mg/dl; 95% CI [1.9; 14.0]; p = 0.023). Notably, weight (mean change - 0.6 kg; 95% CI [0.4; 0.8]; p = 0.002) and BMI (mean change - 0.2; 95% CI [0.1; 0.2]; p = 0.002) significantly decreased. No change in waist circumference (mean change - 0.4 cm; 95% CI [- 2.1; 2.9]; p = 0.838) or waist-to-hip-ratio (mean change 0.0; 95% CI [- 0.0; 0.0]; p = 0.814) was observed. This is the first study showing unfavorable changes in lipid metabolism under mirtazapine in healthy individuals despite highly standardized conditions including dietary restriction, and despite the observation of a decrease of weight. Our findings support the hypothesis that mirtazapine has direct pharmacological effects on lipid metabolism. ClinicalTrials.gov: NCT00878540.

Effect of mirtazapine on metabolism and energy substrate partitioning in healthy men.

BACKGROUND: Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS: We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS: While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION: Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. CLINICALTRIALS: gov NCT00878540. FUNDING: Nothing to declare.

Mirtazapine provokes periodic leg movements during sleep in young healthy men.

STUDY OBJECTIVES: Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. DESIGN: Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. SETTING: Research institute. PARTICIPANTS: Twelve healthy young (20-25 years) men. INTERVENTIONS: Seven days of nightly intake (22:00) of 30 mg mirtazapine. MEASUREMENTS AND RESULTS: Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. CONCLUSIONS: Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels.

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.

Suppressive effect of mirtazapine on the HPA system in acutely depressed women seems to be transient and not related to antidepressant action.

Impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system is a consistent finding among patients with depression, which can be most sensitively detected with the combined dexamethasone (dex)/corticotrophin releasing hormone (CRH) test. The majority of patients with acute depression shows an exaggerated plasma corticotrophin (ACTH) and cortisol response to this test that normalizes gradually during successful antidepressant therapy. In contrast, persistently high HPA-responses to this challenge are prognostically less favorable. It has been recently questioned, whether this observation applies also to treatment with the atypical antidepressant mirtazapine, as patients treated with this drug showed a distinct attenuation of the endocrine response to the dex/CRH test already after 1 week of treatment. In the present study, we investigated whether the attenuating effect of mirtazapine on the HPA system is an acute pharmacological reaction disappearing after physiological adaptation or whether this effect is related to the antidepressant action of the drug. We examined plasma ACTH and cortisol responses to the dex/CRH test in acutely depressed inpatients treated either with mirtazapine (n=55) or a monoamine reuptake inhibitor (n=105) according to doctor's choice and compared the test results with healthy controls (n=40). Patients treated with monoamine reuptake inhibitors received either selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or the combined serotonin and noradrenalin reuptake inhibitor venlafaxine. We found increased plasma ACTH and cortisol responses to the dex/CRH test in depressed patients compared with healthy controls, but also significantly (p=.017) attenuated plasma cortisol secretion in the mirtazapine group compared to the group of monoamine reuptake inhibitor treated patients. This effect was not significant in male patients. Furthermore this effect was independent of the psychopathological state, but depended on treatment duration. Patient treatment with mirtazapine for up to 7 days resulted in dex/CRH test outcome that was indistinguishable from controls. This effect, however waned as it was not observable in patients treated for a longer period. These results suggest that short-term administration of mirtazapine has immediate but only transient suppressive effects on the HPA system predominantly in women. Our results confirm that dex/CRH tests can be used as predictors of clinical course also under mirtazapine treatment.

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project.

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.

Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression.

The clinical efficacy of a systemically administered drug acting on the central nervous system depends on its ability to pass the blood-brain barrier, which is regulated by transporter molecules such as ABCB1 (MDR1). Here we report that polymorphisms in the ABCB1 gene predict the response to antidepressant treatment in those depressed patients receiving drugs that have been identified as substrates of ABCB1 using abcb1ab double-knockout mice. Our results indicate that the combined consideration of both the medication's capacity to act as an ABCB1-transporter substrate and the patient's ABCB1 genotype are strong predictors for achieving a remission. This finding can be viewed as a further step into personalized antidepressant treatment.

Overweight and obesity affect treatment response in major depression.

BACKGROUND: Epidemiologic and clinical studies suggest comorbidity between major depressive disorder (MDD) and obesity. To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight. METHODS: Four hundred eight inpatients with MDD participated in the Munich Antidepressant Response Signature Study, designed to discover biomarkers and genotypes that are predictive for clinical outcome. Psychopathology and anthropometric parameters were monitored weekly in 230 patients. In subsamples, combined dexamethasone-corticotropin-releasing hormone and attention tests were conducted at admission and discharge. One thousand twenty-nine diagnosed matched controls served for morphometric comparisons. RESULTS: Patients with MDD had a significantly higher body mass index (BMI) compared with healthy controls. Patients with high BMI (> or =25) showed a significantly slower clinical response, less improvement in neuroendocrinology and attention, and less weight gain than did patients with normal BMI (18.5 < or = BMI < 25) during antidepressant treatment. CONCLUSIONS: Our findings suggest that overweight and obesity characterize a subgroup of MDD patients with unfavorable treatment outcome.

Huntington's disease transgenic mice are resistant to global cerebral ischemia.

Excitotoxicity plays a key role in ischemic neuronal death and is also one of the candidate mechanisms contributing to neurodegeneration in Huntington's disease (HD). Unexpectedly we have now found that transgenic mice expressing exon 1 of a mutant human HD gene (R6/1) are protected against global cerebral ischemia (GCI), installed by temporary bilateral occlusion of the carotid arteries. Whereas wild type mice showed a substantial neuronal damage in the hippocampus following 15, 20 and 60 min of GCI, transgenic mice were partially protected after 15 and 20 minutes of hypoxemia. This tolerance to ischemia is not blocked by pretreatment of mice with cycloheximide, an unspecific protein synthesis inhibitor. We conclude that this form of tolerance to ischemia in HD transgenic mice--although somewhat reminiscent of ischemic tolerance after ischemic preconditioning--is therefore independent of short term expression of endogenous neuroprotective proteins.