Mirtazapine Powerfully Lowers Cortisol

[DaveFoster]

Yes, progesterone ..going for blood tests and will see if I can up it. And aspirin, I have to be careful because of stomach burning/pain. It doesn't seem to help too much with pain...but maybe in long run it would help. Are there better drugs than Savella ? Looking forward to podcast . Will I find it here on forum?

Yeah, I'll post it. Judging from its side effects Savella is an unsafe drug with more in common with other serotonergic antidepressants. Anti-serotonin drugs like cyproheptadine, dyphenhydramine, and mirtazapine can improve symptoms.

For aspirin, you could get famotidine OTC or from your doctor and that will protect against the ulcers, as well as dissolving aspirin in hot water and adding glycine and/or baking soda. 1-2 grams before bed can greatly lessen pain the following day.

 

[kaybb]

Yeah, I'll post it. Judging from its side effects Savella is an unsafe drug with more in common with other serotonergic antidepressants. Anti-serotonin drugs like cyproheptadine, dyphenhydramine, and mirtazapine can improve symptoms.

For aspirin, you could get famotidine OTC or from your doctor and that will protect against the ulcers, as well as dissolving aspirin in hot water and adding glycine and/or baking soda. 1-2 grams before bed can greatly lessen pain the following day.

Thank you so much ...I will try it. I have appt. with Doctor so hopefully she will let me try the antiseronin and famotidine. She knows Ray Peat from her studies (she's close to 70) but wasn't too interested. I have another NP that would be willing to let me try some of these . Thanks so much !!

 

[klauban]

I don’t know if it is correlated to Mirtazapine or not, I don’t know.
But I have been using Mirtazapine for 8 years.
Over that period of time my morning Cortisol raised from high in the range to a few point OVER the range.
What I see here is they administered Mirtazapine at 8:AM , and saw COR lower 4 hours later.
That is , seems to me just normal , as I understand COR is at his highest at 8:AM end naturally goes down during day.
Second point is that I wonder if you take Mirtazapine at late evening, if COR does not come back with a vengeance. Effect that is also seen with ex Naltrexone that blocks endorfine , but result is a endorfine spike after Naltrexone looses its effect.
It is not really completely comparable as Naltrexone does not lower endorfine , but just blocks the endorfine receptor , giving you system a signal endorfine is to low, resulting in a spike.

But nevertheless, for a reason I do not know enough about, I can imagine that if Mirtazapine puts down COR output, afterward your system could try to restore what it reckons is the adequate COR level with a spike.
( As for the 24 urinary output, if it has been lowered for a few hours it can still be lower despite the spike afterwards , if the lowering is longer/stronger than the spike. ) ( My 24h free COR collect is also still just bellow the top of the the range, even if my morning readings are always to high )
Gives me the idea of taking a Mirtazapine in the very early morning before next COR test.

Have you had another check of your cortisol under Mirtazapine?
My cortisol is 1 standard dev. over the 97th percentile since 2010 in 2012 it was 97th. I completely resignated and am depressed.
Unfortunately, here in Germany the knowledge is appalling. I started Mirtazapine having read that it must lower cort. due to antagonism. It is so frustrating to read taht yours was not surpressed by it.
Unless, my cortisol is not controlled by medication ( fish oil etc is not enough), I will never be able to do anything again.
I can also induce striae b scratching my skin. However, it is pseudo-cushing due to depression or causing depression.
I also took steroids for 4 years in puberty due to medical malpractice. I think that changed my cortisol forever

 

[ddjd]

any dangers of using Mirtazapine?

 

[biohacker]

Forum member haidut has posted many studies that anti-serotonin drugs lower cortisol, and here's some more evidence that the antidepressant mirtazapine dose the same. Mirtazapine has mixed serotenergic properties, but Ray thinks it might be useful in some situations.

It's anti-serotonin and anti-cortisol effects clarifies its benefits in autism-spectrum disorders (ASD) and major depressive disorder (MDP), as well as some treatments for generalized anxiety disorders (GAD) and obsessive-compulsive disorder (OCD).

Haidut has already outlined the role of cortisol in depression:
Depression May Be Caused By Estrogen In Females And Cortisol In Males

Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects. - PubMed - NCBI

"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."

Ray has also spoken of the ability of the SSRI's to stimulate the adrenals to secrete cortisol, and he has endorsed a rapid tapering off of these drugs probably for that reason. Unlike venlafaxine (Effexor), mirtazapine (Remeron) lowers cortisol and can be safely tapered off very slowly without any fear of further physiological damage.

Antidepressant treatment with mirtazapine, but not venlafaxine, lowers cortisol concentrations in saliva: a randomised open trial. - PubMed - NCBI

"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."

Mirtazapine is often used as an adjunct to other antidepressants, and the association of high cortisol and unsucessful use of venlafaxine point to the necessity of opposing brain serotonin as well as cortisol. As a further hypothesis, unsuccessful "relapses" from antidepressant treatment remain common, and the cause could be caused by a lacking restoration of neuronal metabolism by certain antidepressants.

Efficacy and safety of add on low-dose mirtazapine in depression

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 patient

Mitochondrial dysfunction, oxidative stress, and major depressive disorder

"There is controversy about depression being a physical illness, in part because a reproducible, sensitive, and specific biologic marker is not available. However, there is evidence that mitochondrial dysfunction and oxidative stress may be associated with abnormal brain function and mood disorders, such as depression. This paper reviews selected human and animal studies providing evidence that intracellular mitochondrial metabolic dysfunction in specific brain regions is associated with major depressive disorder. This supports the hypothesis that chronic mitochondrial dysfunction in specific tissues may be associated with depression. Evaluation of mitochondrial dysfunction in specific tissues may broaden the perspective of depression beyond theories about neurotransmitters or receptor sites, and may explain the persistent signs and symptoms of depression."

Influence of mirtazapine on salivary cortisol in depressed patients. - PubMed - NCBI

"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."

Here's a follow-up to the previous study, which shows that mirtazapine tones down the pituitary to produce less ACTH and thus cortisol. Similar to cyproheptadine, mirtazapine should be able to counteract the effects of caffeine, and maybe even more effectively since mirtazapine lowers adrenaline more powerfully.

Endocrinological effects of mirtazapine in healthy volunteers. - PubMed - NCBI

"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."

Influence of mirtazapine on urinary free cortisol excretion in depressed patients. - PubMed - NCBI

"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."

I've taken 30 mg of Mirtazapine for 16 years. It's a fantastic med for me. I have a TBI that won't ever go away. I take it at night as it helps a bit with sleep, but probably not at that dose. I once experimented with 45 mg, but way too much adrenaline. 15 mg did very little for me. It and Welbutrin are the only antidepressants I ever recommend to people. I've gotten people off SSRI's and SNRI's, and they always thank me for that.