Mirtazapine Lowers Cortisol and Blocks the Stress Response

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Mirtazapine lowers cortisol and serotonin, responsible for its benefits in autism-spectrum disorder (ASD), major depressive disorder (MDD), generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD).

Mirtazapine lowers cortisol:

“…in all subjects, the cortisol (COR) concentrations were remarkably lower after mirtazapine compared to placebo…”

“Mirtazapine lowered afternoon cortisol from week 1 to 4.”

“Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects.”

Lowered cortisol alleviates symptoms of depression:

“Lowering the concentrations of free cortisol in depressed patients may be an important prerequisite to prevent glucocorticoid-related sequelae of depression.”

Venlafaxine (another antidepressant) does not lower cortisol:

“In contrast, during the course of the entire treatment period, venlafaxine did not attenuate saliva cortisol concentrations.”

Elevated cortisol rendered venlafaxine ineffective as an antidepressant:

“High baseline cortisol concentrations, on the other hand, were related to an unfavourable course during venlafaxine treatment and patients remitting during venlafaxine treatment had significantly lower afternoon cortisol concentrations in saliva, when compared to non-remitting patients.”

Mirtazapine’s ability to lower cortisol complements other antidepressants:

“Low-dose mirtazapine as add-on therapy has shown better efficacy, earlier onset of action and more number of responders and remitters as compared to conventional treatment in major depressive disorder (MDD).”

Even if ineffective as an antidepressant, mirtazapine lowers cortisol:

“Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment…tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders.”

Corticotropin-releasing hormone (CRH) triggers the release of adrenocorticotropin hormone (ACTH), which can raise cortisol.  Like CRH1 antagonists, mirtazapine blocks CRH and lowers cortisol:

“In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified.”

Mirtazapine’s inhibition of CRH blocks the entire stress response:

“Since the acute inhibition of COR secretion in the healthy volunteers was paralleled by a simultaneous decrease of ACTH release, central mechanisms (e.g., inhibition of hypothalamic corticotropin releasing hormone (CRH) output) are suggested to be responsible for the inhibitory effects of mirtazapine on COR secretion. Our results are of particular interest in the light of the hypercortisolism observed in depressed patients and new pharmacological approaches such as CRH1 receptor antagonists.”

Mirtazapine also lowers ACTH and prolactin:

“Two-sided t-tests for paired samples revealed significantly lower cortisol (COR) area under the curve (AUC), ACTH AUC, urinary free cortisol (UFC) and prolactin (PRL) AUC values after 15-mg mirtazapine compared to placebo…”

Mirtazapine has beneficial hormonal effects and can acutely control symptoms of stress.

Dr. Raymond Peat has briefly mentioned that it takes two weeks for the enzymatic machinery to adapt to a new stimulus in healthy individuals, and this appears with the brain’s conditioning to drugs imipramine and mirtazapine. Mirtazapine also has serotonergic and noradrenergic effects in the brain, and it can provoke aggression, but at least in the prefrontal cortex, it seems to lower noradrenaline.

The effect of repeated administration of imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, was studied on the stress-induced increase in the extracellular concentration of norepinephrine in the prefrontal cortex of freely moving rats. Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). <strong>Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output</strong>. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs. Link: https://www.ncbi.nlm.nih.gov/pubmed/11746735

References

Laakmann, G., Hennig, J., Baghai, T., & Schüle, C. (2003). Influence of mirtazapine on salivary cortisol in depressed patients. Neuropsychobiology, 47(1), 31–36. https://doi.org/6887.  Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2)-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1 receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified.

Laakmann, G., Schüle, C., Baghai, T., & Waldvogel, E. (1999). Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects. Psychoneuroendocrinology, 24(7), 769–784.  In the present study the effects of acute PO-administration of 15 mg mirtazapine on the growth hormone (GH), prolactin (PRL), and cortisol (COR) secretion were examined in eight physically and mentally healthy male subjects, compared to placebo. Mirtazapine is a new antidepressant agent which does not inhibit the reuptake of norepinephrine or serotonin but is an antagonist of presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors. After insertion of an i.v. catheter, blood samples were drawn 1 h prior to the administration of mirtazapine or placebo, at time of application, and during the time of 4 h after application in periods of 30 min. Plasma concentrations of GH, PRL, and COR were determined in each blood sample by double antibody RIA methods. The area under the curve (AUC) value was used as parameter for the GH, PRL, and COR response. With respect to GH and PRL secretion, mirtazapine did not show any effects in comparison with placebo. However, in all subjects, the COR concentrations were remarkably lower after mirtazapine compared to placebo, the difference being obvious in the mean value graphs 60 min after the application up to the end of the measurement period. The t-test for paired samples revealed a highly significant difference (P < 0.01) in COR-AUC-values between the mirtazapine group (mean COR-AUC: 1558.07 micrograms/100 ml x 240 min) and the placebo group (mean COR-AUC: 2698.86 micrograms/100 ml x 240 min). Further studies have to elucidate the question whether the demonstrated inhibition of COR secretion after application of 15 mg mirtazapine is caused by central or peripheral effects of this substance.

Matreja, P. S., Badyal, D. K., Deswal, R. S., & Sharma, A. (2012). Efficacy and safety of add on low-dose mirtazapine in depression. Indian Journal of Pharmacology, 44(2), 173–177. https://doi.org/10.4103/0253-7613.9384.  Objectives: Although antidepressant medications are effective, they have a delayed onset of effect. Mirtazapine, an atypical antidepressant is an important option for add-on therapy in major depression. There is insufficient data on mirtazapine in Indian population; hence this study was designed to study the add-on effect of low-dose mirtazapine with selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD) in Indian population.  Materials and Methods: In an open, randomized study, 60 patients were divided into two groups. In Group A (n=30) patients received conventional SSRIs for 6 weeks. In Group B (n=30) patients received conventional SSRIs with low-dose mirtazapine for 6 weeks. Patients were evaluated at baseline and then at 1, 2, 3, 4, 5, and 6 weeks.  Results: There was significant improvement in Hamilton Depression Rating Scale (HDRS), Montgomery and Asberg depression rating scale (MADRS) scores (P<0.05) in both groups. Mirtazapine in low dose as add on therapy showed improvement in scores, had earlier onset of action, and more number of responders and remitters as compared to conventional treatment (P<0.05). No serious adverse event was reported in either of the groups.  Conclusion: Low-dose mirtazapine as add-on therapy has shown better efficacy, earlier onset of action and more number of responders and remitters as compared to conventional treatment in MDD in Indian patients.

Scharnholz, B., Weber-Hamann, B., Lederbogen, F., Schilling, C., Gilles, M., Onken, V., … Deuschle, M. (2010). Antidepressant treatment with mirtazapine, but not venlafaxine, lowers cortisol concentrations in saliva: a randomised open trial. Psychiatry Research, 177(1–2), 109–113. https://doi.org/10.1016/j.psychres.2009.08.010.  Lowering the concentrations of free cortisol in depressed patients may be an important prerequisite to prevent glucocorticoid-related sequelae of depression. We tested the hypothesis that the hypothalamus-pituitary-adrenal (HPA) system-dampening effects of venlafaxine and mirtazapine differ. We compared the course of morning (08.00h) and afternoon saliva cortisol (16.00h) in 42 mirtazapine- and 45 venlafaxine-treated depressed patients during a 1-week wash-out and a 4-week treatment period in a randomised open trial. Mirtazapine lowered afternoon cortisol from week 1 to 4. In contrast, during the course of the entire treatment period, venlafaxine did not attenuate saliva cortisol concentrations. Treatment effects of mirtazapine on cortisol concentrations did not differ in remitters and non-remitters to treatment. High baseline cortisol concentrations, on the other hand, were related to an unfavourable course during venlafaxine treatment and patients remitting during venlafaxine treatment had significantly lower afternoon cortisol concentrations in saliva, when compared to non-remitting patients. Thus, mirtazapine and venlafaxine show different effects on HPA system activity as measured by saliva cortisol. This may be of relevance with regard to physical sequelae of depression.

Schüle, C., Baghai, T., Bidlingmaier, M., Strasburger, C., & Laakmann, G. (2002). Endocrinological effects of mirtazapine in healthy volunteers. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 26(7–8), 1253–1261.  OBJECTIVE: Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin (5-HT) but acts as an antagonist at presynaptic alpha2-receptors and at postsynaptic 5-HT2, 5-HT3 and histamine H1-receptors. In the present investigation, the influence of acute oral administration of 15-mg mirtazapine on the cortisol (COR), adrenocorticotropin (ACTH), growth hormone (GH) and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to placebo. METHODS: After insertion of an intravenous catheter, both the mean arterial blood pressure (MAP) and the heart rate were recorded and blood samples were drawn 1 h prior to the administration of mirtazapine or placebo (7:00 a.m.), at time of administration (8:00 a.m.) and during 5 h thereafter in periods of 30 min. Concentrations of COR, ACTH, GH and PRL were measured in each blood sample by double antibody radioimmunoassay and chemiluminescence immunoassay methods. The area under the curve (AUC; 0-300 min after mirtazapine or placebo administration) was used as parameter for the COR, ACTH, GH and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of administration of placebo or mirtazapine) up to 8:00 a.m. the day after. RESULTS: Two-sided t-tests for paired samples revealed significantly lower COR AUC, ACTH AUC, UFC and PRL AUC values after 15-mg mirtazapine compared to placebo, whereas no significant differences were found with respect to GH AUC, MAP and heart rate. CONCLUSIONS: Since the acute inhibition of COR secretion in the healthy volunteers was paralleled by a simultaneous decrease of ACTH release, central mechanisms (e.g., inhibition of hypothalamic corticotropin releasing hormone (CRH) output) are suggested to be responsible for the inhibitory effects of mirtazapine on COR secretion. Our results are of particular interest in the light of the hypercortisolism observed in depressed patients and new pharmacological approaches such as CRH1 receptor antagonists.

Schule, C., Baghai, T., Rackwitz, C., & Laakmann, G. (2003). Influence of mirtazapine on urinary free cortisol excretion in depressed patients. Psychiatry Research, 120(3), 257–264.  Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response.

Posey, D. J., Guenin, K. D., Kohn, A. E., Swiezy, N. B., & McDougle, C. J. (2001). A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. Journal of Child and Adolescent Psychopharmacology, 11(3), 267–277. https://doi.org/10.1089/10445460152595586

OBJECTIVE: The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs). METHODS: Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger’s disorder, 1 with Rett’s disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects’ primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist. RESULTS: Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders (“much improved” or “very much improved” on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation. CONCLUSIONS: Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs. 

Gambi, F., De Berardis, D., Campanella, D., Carano, A., Sepede, G., Salini, G., … Ferro, F. M. (2005). Mirtazapine treatment of generalized anxiety disorder: a fixed dose, open label study. Journal of Psychopharmacology (Oxford, England), 19(5), 483–487. https://doi.org/10.1177/0269881105056527

We investigated the efficacy of mirtazapine in the treatment of generalized anxiety disorder (GAD). Forty-four adult outpatients with GAD were treated openly with a fixed dose of mirtazapine (30 mg) for 12 weeks. The primary outcome measure was the change from baseline in total score on the Hamilton Rating Scale for Anxiety (HAM-A). The Clinical Global Impression of Improvement (CGI-I) was rated at the endpoint. Patients with a reduction of 50% or more on the HAM-A total score and a CGI-I score of 1 or 2 at endpoint were considered responders to treatment; remission was defined as a HAM-A score <or=7. At 12 weeks, response was achieved by 79.5% of the patients (n=35) and remission by 36.4% of patients (n=16). This study supports the notion that mirtazapine is an efficacious and well tolerated treatment for GAD. Limitations of the present study must be considered and further placebo-controlled trials are needed. 

Koran, L. M., Gamel, N. N., Choung, H. W., Smith, E. H., & Aboujaoude, E. N. (2005). Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation. The Journal of Clinical Psychiatry, 66(4), 515–520.

BACKGROUND: Many patients with obsessive-compulsive disorder (OCD) experience little response to standard treatment with serotonin reuptake inhibitors. Mirtazapine enhances serotonergic function by a mechanism distinct from reuptake inhibition. Because a pilot study suggested effectiveness of mirtazapine in OCD, we conducted a controlled trial. METHOD: We recruited 30 subjects, 15 treatmentnaive and 15 treatment-experienced, with DSM-IV OCD of > or =1 year’s duration and a Yale-Brown Obsessive Compulsive Scale (YBOCS) score of > or =20. In the 12-week, open-label phase, subjects received mirtazapine starting at 30 mg/day and titrated over 2 weeks as tolerated to 60 mg/day. At week 12, responders (YBOCS score decrease > 25%) were randomly assigned, double-blind, to continue mirtazapine or switch to placebo for 8 weeks, including a 1-week, double-blind taper week for placebo subjects. RESULTS: In the open-label phase, the mean +/-SD YBOCS score fell from 28.3 +/-3.7 to 20.3 +/-8.5 (paired samples t = 4.81, p < .0001). Four subjects (13.3%) discontinued for side effects. Sixteen subjects (53.3%) (8 treatmentnaive, 8 treatment-experienced) were responders and 15 agreed to randomization. Response was independent of comorbid mood disorders. In the 8-week, double-blind, placebo-controlled discontinuation phase, the mirtazapine group’s mean YBOCS score fell a mean +/-SD of 2.6 +/-8.7 points while the placebo group’s mean score rose a mean +/-SD of 9.1 +/-7.5 points (Mann Whitney U = 6.5, p = .005, 1-tailed). All other outcome measures were consistent with mirtazapine’s superiority versus placebo. CONCLUSION: Mirtazapine may be an effective pharmacotherapy for OCD. If our results are replicated, larger double-blind studies would be indicated.

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  1. no study is mentioned that indicates that mirtazapine has benefits in autism-spectrum disorders, genralized anxiety disorder and obsessive-compulsive disorder. How can you conclude that mirtazapine benefits in those disordes?

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