Prozac (Fluoxetine) and Other SSRIs Alter Cortisol and Cytokine Levels

[Lotus97]

There seems SSRIs initially raise cortisol, but lower cortisol in long-term treatment (?)

http://www.ncbi.nlm.nih.gov/pubmed/18805677

Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder.

Abstract
Major depressive disorder (MDD) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines. Previously it has been reported that administration of selective serotonin reuptake inhibitors (SSRI) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period. This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks. A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI. HDRS and BDI were administered over a year, and levels of interleukin IL-1beta, IL-10, IL-2, IFN-gamma, IL-4, IL-13, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. Before treatment we found high levels of cortisol, IL-4, IL-13 (Th2) and IL-10 in MDD patients when compared with healthy volunteers. At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1beta but without changes in cortisol. Towards the end of the treatment (W52) we observed a significant reduction (p<0.01) in cortisol levels, with an increment in IL-1beta and IFN-gamma and a decrease in Th2 cytokines. Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI.

http://www.ncbi.nlm.nih.gov/pubmed/22429479

Serum cortisol concentration in patients with major depression after treatment with fluoxetine.

Abstract

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels is characteristic of the pathophysiology of major depressive disorder (MDD). The aim of this study was to determine whether increased plasma cortisol levels appear in patients with major depression and if effective antidepressant treatment by fluoxetine leads to regulation of cortisol level. This aim was realized by describing and validation of methods of determining fluoxetine and cortisol in serum and searching for correlation between their concentrations in patients with endogenous depression, the therapeutic effect as assessed in Hamilton Depression Rating Scale (HDRS), age and sex of patients. Plasma cortisol and fluoxetine levels were measured using high performance liquid chromatography (HPLC) methods with applying Shimadzu chromatograph with UV detection. Plasma cortisol and fluoxetine levels were measured at time zero (before therapy) and after 6h, 24h, 2, 4, 6 and 8 weeks of fluoxetine administration in patients with major depression qualified for therapeutic drug monitoring (TDM). The study included 21 patients (14 women, 7 men; mean age 29-75 years) and 24 healthy comparison subjects. The patients had a mean score on the 21-item HDRS. As the effect of fluoxetine administration the decrease of the level of cortisol was observed in patients who responded to the therapy (the reduction of points in HDRS scale in at least 50%). The validation parameters of HPLC method of fluoxetine and cortisol determination indicate the possibility of applying them for determination of both: the level of concentration of the drug in therapeutic drug monitoring and the level of cortisol in serum of patients with endogenous depression.

This last article was posted in a forum from another website (I didn't write it)
http://survivingantidepressants.org/index.php?/topic/1147-cortisol-and-ssris/

Complication number one

There seems to be some evidence that people with depression have elevated or varying cortisol levels in some way due to depression (this is mentioned in the wikipedia article above) - so unpicking the effect of depression on cortisol and the SSRI alone on cortisol is going to be difficult.

Complication number two
Whilst SSRIs seem to be having some kind of interaction with cortisol. It appears they may suppress it or increase it and this may be dependent on the SSRI and how long it is taken for. It seems unclear in the longer term what effects of this increased or decreased cortisol levels might be or how acute these might be (because nobody seems to have done any studies ion this).

Citalopram and Escitalopram (Celexa, Lexapro) appear to increase cortisol levels initially see (1) and a number of studies referred to in (2). The dosage might make a difference, in one study 20mg of citalopram didn't have an effect but 40mg did (3).

A lot of the studies I've found seem to be around these two anti-depressants - I'm not sure [without doing a lot more work] what the impact on cortisol of other antidepressants might be. Some of the studies are about stressing rats - rather than about people (I haven't included links to those ones here).

However, there is some help from this study
see here (4) below - you may find this is locked behind a pay wall so may only be able to see the abstract.
This study reviews a number of studies that look at the HPA axis* and SSRIs. They review studies which have meassured cortisol levels, they find a number of studies (7) that have found supression of cortisol levels after a course of treatment by SSRIs - they list the following drugs, mirtazapine (Remeron, Avanza, Zispin), amitriptyline (Elavil, Tryptizol, Laroxyl, Sarotex, Lentizol), citalopram (Celexa, Cipramil), paroxetine (Aropax, Paxil, Seroxat, Sereupin), Sertraline (Zoloft and Lustral). They then list a further 20 studies that have found no change in cortisol due to anti-depressants treatment though they don't list which drugs this applies to.
[The overall study which is a meta-anlayis to look at if antidepressant treatment is effecting coritsol levels, looks not just at SSRIs, but also at tricyclics, lithuim and ECT and finds less than half the studies show reductions in levels of cortisol.]

{* From wikipeda - HPA axis The hypothalamic-pituitary-adrenal axis (HPA or HTPA axis), also known as the limbic-hypothalamic-pituitary-adrenal axis (LHPA axis) and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (or suprarenal) glands (small, conical organs on top of the kidneys) see furtherWikipedia - HPA}

A key problem is none of the studies are over the typical period someone takes an SSRI for - i.e 6 months plus (sometimes of course this is for years not months); they often look at a period of days or weeks, indeed a 4 week study called itself a long term study (2). The clinical trials are also generally with small numbers of patients.

A further issues seems to be that a majority of studies seem to be trying to work out whether cortisol levels can be used to assess how affective treatment is (4), rather than looking at whether the anti-depressants themselves might be raising or lowering cortisol levels and if this might be a problem of itself .

Complication number 3
Whether cortisol level increase or decrease as a result of taking SSRIs may depend on the individual as well as the SSRI.
One recent study seems to suggest that the impact on cortisol of SSRIs might also be affected by genetic differences
(5)

Changes in cortisol levels have not been found to be any predictor of treatment outcome in one small study [Note cortisol level do seem to change as a result of using an SSSRI in this case escitalopram] (A look at the full text of this {whihc you may find is stuck behind a pay wall for you} shows it was a small 8 week trial - 17 started - 12 completed. If I'm reading the results correctly the levels of cortisol seem to on average have increased within 90 minutes of takin escitlaloptam initially, overall it appears that for some in the trial levels of cortisol increase, for others it decreases).(6)

Concluding points

So it appears that SSRIs do interact with cortisol - but we can't really tell how or why, who will be effected, or which SSRIs and SNRIs are implicated in what way.

I find the lack of clear information on how SSRIs interact with cortisol over the long term very concerning - this seems like an area that needs way more research. I would conjecture that if SSRIs are influencing cortisol levels then this may explain some of the withdrawal effects that people experience. Also if some SSRIs are increasing cortisol, but others decreasing it, then swapping between an increasing type of cortisol SSRIS to a decreasing type of cortisol SSRI might lead to some rather difficult side effects (but if this also depends on individual factors this might be very difficult to predict).

It seems to me that IF taking SSRIs is suppressing cortisol this sounds disturbingly similar to some of the side-effects that people get when they take steroids - could it be that SSRI stimulate cortisol production so the body produces less naturally like steroids - and could it be this only happens to some people with particular genetic traits - if so shouldn't we be very cautious about how we use these drugs (as we now are with steroids...).

This area is (like many areas around anti-depressant withdrawal) crying out for some good quality research into the interactions between long term effects of SSRI use and SSRI withdrawal on cortisol.

However, if the interaction between cortisol and SSRIs is important for withdrawal, then in practical terms it probably just reinforces the slow taper advice on this site - since when reducing levels of corticosteroids it is also advised that you slow taper.
For example see the Mayo clinc advice on slow tapering the corticosteroid prednisone - Mayo clinic - corticosteroid tapering

Bright

References (Numbers noted above)

(1) BERARDELLI R et al (2010) Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans, Journal of endocrinological investigation, vol. 33, no9, pp. 657-662
http://cat.inist.fr/...cpsidt=23509222
(2) Knorr U, Vinberg M, Hansen A, Klose M, Feldt-Rasmussen U, et al. (2011) Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial. PLoS ONE 6(6)
http://www.plosone.o...al.pone.0021224
No evidence of decreases incortisol levels over a 4 week period on 10mg of escitalopram in healthy individuals who were relatives of those who have a major depressive disorder for which they were treated in hospital - they study was undertaken because it has been suggested that people with a major depression and those with a family history of depression have higher cortisol
"The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD)."
"Previous studies have shown that even healthy first-degree relatives to patients with major depressive disorder (MDD) have an abnormal HPA response to the DEX-CRH test, with an intermediary response when compared to healthy controls and patients with major depression [2]. Furthermore, salivary cortisol has been shown to be increased in individuals with a family history of MDD as compared to healthy individuals without a family history of MDD [3]–[5]. Intervention with a single dose of a selective serotonin re-uptake inhibitor (SSRI) has been found to increase serum corticosterone levels in rats [6], [7] and plasma corticosteroid levels in healthy humans [8]–[12]. In rats plasma levels of HPA-axis hormones, corticosterone and adrenocorticotropic hormone (ACTH), decreased after 15 days intervention with citalopram [13]"{Numbers refer to articles quoted as references to this study - see the wblink below if you want to look these up futher}
"The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age."

(3) Hawken et al (2006) Effects of oral racemic citalopram on neuroendocrine responses, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 30, Issue 4, June 2006, Pages 694-700
http://www.sciencedi...27858460600042X

(4) McKaya & Zakzanis (2010) The impact of treatment on HPA axis activity in unipolar major depression, Journal of Psychiatric Research, Volume 44, Issue 3, February 2010, Pages 183-192
http://www.sciencedi...022395609001757

(5) Klock et al (2011) Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs , Psychoneuroendocrinology, Volume 36, Issue 4, May 2011, Pages 484-494
http://www.sciencedi...306453010001939

(6) Papkostas et al (2010) 5HT1A-mediated stimulation of cortisol release in major depression: use of non-invasive cortisol measurements to predict clinical response, European Archives of Psychiatry and Clinical Neuroscience, Volume 260, Number 2, pp 175-180
http://www.springerl...33w8u177k16137/

 

[adreno]

SSRIs lowers cortisol in MDD because cortisol levels are high to begin with. In someone with low cortisol they would most likely increase it. So in a way they act to (at least partially) restore the HPA axis function.

 

[jimells]

This is very interesting. I've been subjected to more antidepressants than I can shake a stick at. Most of them seemed to help a little at first, then they made me much sicker. The idea that they may initially increase cortisol then reduce it could explain my reaction to these drugs, and is very troubling. It is truly outrageous that billions of these pills are handed out like candy, and the doctors have no idea what they are doing to the patients.

As for me, I refuse to take any more of these medications.

 

[Lotus97]

This is very interesting. I've been subjected to more antidepressants than I can shake a stick at. Most of them seemed to help a little at first, then they made me much sicker. The idea that they may initially increase cortisol then reduce it could explain my reaction to these drugs, and is very troubling. It is truly outrageous that billions of these pills are handed out like candy, and the doctors have no idea what they are doing to the patients.

As for me, I refuse to take any more of these medications.

I wouldn't recommend prescription medications except as a last resort, but for me many are necessary unfortunately. Treating the underlying condition and/or supplements would be a better option.

 

[Ema]

SSRIs lowers cortisol in MDD because cortisol levels are high to begin with. In someone with low cortisol they would most likely increase it. So in a way they act to (at least partially) restore the HPA axis function.

As someone with adrenal insufficiency, it has not been my experience at all that SSRIs and their ilk increase cortisol and restore the HPA axis function. I would say that those drugs were some of the worst I have ever taken in terms of exacerbating low cortisol symptoms. Cymbalta precipitated an adrenal crisis and nearly killed me.

In my experience, they work by increasing cortisol in the short term but then in people prone to HPA axis dysfunction, they stop working when the adrenals can no longer continue to increase cortisol production. Then all hell breaks loose and doctors generally try to treat this by simply adding in more meds rather than treating the underlying dysfunction. It's a recipe for disaster in many cases.

I think there is a place for antidepressant meds but I don't think that they should be handed out like candy the way they currently are. One of my doctors described them as using a sledgehammer to repair a fine watch. Sometimes it can be put back together and it works and other times you just end up with a mess of broken parts.

Ema

 

[caledonia]

I don't know about lowering cortisol during use, but when you try to withdraw, it raises cortisol like crazy. I have the lab tests to prove it. My cortisol went from nearly a flat line (one of the 4 worst results my naturopath had ever seen), to values 5 times higher than normal. It was literally off the top of the chart! All kinds of horrible mental and physical symptoms go along with this.

The solution is to taper extremely slowly to allow your brain and body time to adjust - I'm on a 3 year taper.

This is just one bad thing that anti-depressants do. The other biggie is that they affect the serotonin receptors in your bone marrow, which can cause osteoporosis. This is just the tip of the iceberg. Nobody should be on these things.

 

[Lotus97]

As I mentioned earlier in this thread, going off my antidepressants right now isn't an option for me, but I hope after treating my Lyme disease and doing methylation for awhile I could maybe taper off of them. caledonia Thanks for the heads-up about the spike in cortisol from tapering/discontinuing SSRIs. Anyone know anything about Elavil/amitriptyline (a tricyclic antidepressant) and cortisol? I take that for sleep, but not during the day

 

[adreno]

TCAs (including amitriptyline) lowers cortisol.

 

[jeffrez]

Cymbalta's an SNRI, more similar to the TCAs. Like Adreno said, the research findings typically have been that cortisol is high in major depression. SSRIs as well as TCAs are most often discussed in terms of normalizing HPAA function, at least relative to what it is during the depression.

 

[Lotus97]

It's true that prescription drugs can potentially cause a lot of problems, but it's important to note that supplements aren't without possible contraindications. For example, holy basil, chamomile, phosphatidylserine, Seriphos, skullcap, lemon balm/melissa, and ashwaghandha can all lower cortisol.

 

[Ema]

Cymbalta's an SNRI, more similar to the TCAs. Like Adreno said, the research findings typically have been that cortisol is high in major depression. SSRIs as well as TCAs are most often discussed in terms of normalizing HPAA function, at least relative to what it is during the depression.

The research is apparently inconsistent on whether or not cortisol is high in major depression.

http://www.ncbi.nlm.nih.gov/pubmed/19487626

I think it is safe to say that the HPA axis and cortisol in particular are affected (positively or negatively) by antidepressants but I think it is premature to say that levels of cortisol are typically one way or another at this point.

Ema

 

[Ema]

It's true that prescription drugs can potentially cause a lot of problems, but it's important to note that supplements aren't without possible contraindications. For example, holy basil, chamomile, phosphatidylserine, Seriphos, skullcap, lemon balm/melissa, and ashwaghandha can all lower cortisol.

I am still curious about whether or not the supplements that have been found to lower cortisol are actually adaptogens or if any of them really ONLY lower cortisol.

I have wanted to try phosphatidyl serine for a long time but have been put off for fear of lowering my already non-existent cortisol levels. But PS is supposedly great at re-sensitizing the POMC neurons of the hypothalamus and normalizing cortisol production which may be exactly what those of us with HPA axis dysfunction need. One of these days I will work up my courage and give it a shot. I'm not convinced it will lower cortisol in those who are already low.

Ashwagandha is also possibly adaptogenic. But in my experience, adaptogenic herbs seem to work best for those with high cortisol or high/low fluctuating cortisol patterns instead of all out low.

I think it would be really helpful to have more studies on these herbs to learn more about how they work. Of course, no one wants to pay for anything that can't be patented.

Ema

 

[Lotus97]

I am still curious about whether or not the supplements that have been found to lower cortisol are actually adaptogens or if any of them really ONLY lower cortisol.

I have wanted to try phosphatidyl serine for a long time but have been put off for fear of lowering my already non-existent cortisol levels. But PS is supposedly great at re-sensitizing the POMC neurons of the hypothalamus and normalizing cortisol production which may be exactly what those of us with HPA axis dysfunction need. One of these days I will work up my courage and give it a shot. I'm not convinced it will lower cortisol in those who are already low.

Ashwagandha is also possibly adaptogenic. But in my experience, adaptogenic herbs seem to work best for those with high cortisol or high/low fluctuating cortisol patterns instead of all out low.

I think it would be really helpful to have more studies on these herbs to learn more about how they work. Of course, no one wants to pay for anything that can't be patented.

Ema

I have the same questions about those supplements. I've done searches for adaptogens and cortisol and haven't really been able to find much in regards to studies, but maybe I'm not doing the right searches. Many adaptogens have other functions such as improving cognitive function and stimulating the immune system (could be a good thing or bad thing) and I don't believe all of them even lower cortisol.

I'm curious though - what's the effect of taking a supplement that lowers cortisol if you already have low cortisol? Does that cause an increase in norepinephrine and/or are there other symptoms? I'm not 100% sure if I even have low cortisol. Last time I was tested was 4 years ago and it was both high and low then. Since my health has gotten worse since then I assumed the natural progression was towards low cortisol, but I don't really know if that's true.

 

[jeffrez]

The research is apparently inconsistent on whether or not cortisol is high in major depression.

http://www.ncbi.nlm.nih.gov/pubmed/19487626

I think it is safe to say that the HPA axis and cortisol in particular are affected (positively or negatively) by antidepressants but I think it is premature to say that levels of cortisol are typically one way or another at this point.

Ema

Hmm, not really convinced, as almost everything in the abstract supports the idea of higher cortisol in MDD! And higher even in those who have remitted from MDD, which I believe is also the usual finding.

Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion.

Iow, antidepressant use tended to normalize HPAA functioning, lowering the significantly higher cortisol levels often found in MDD, and then increasing sensitivity of the HPAA to dexamethasone challenge, which would mean the HPAA is functioning more normally.
Even the conclusion acknowledges association between MDD and higher cortisol, and suggests higher cortisol could indicate a greater predisposition to MDD:

CONCLUSIONS:​

This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.

Curious: how do you read any of that as indicating conflicting data? I'd ask the authors the same thing, as their conclusion doesn't seem to follow their "context" section.