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Hochberg, 2003 Endocrine withdrawal syndromes.

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Barbarannamated

Although this article doesn't address antidepressant withdrawal (and horridly suggests their use to alleviate symptoms of endocrine withdrawal) I found the description of common withdrawal mechanisms (between endocrine and drugs of abuse) quite interesting.

 

Table 5 shows a few examples of serotonin, dopamine and GABA involvement in the endocrine system. This is a very simplified visual that could be referred to when long term neuroendocrine effects of psychotropics aren't acknowledged by docs.

 

This info is way over my head ~ perhaps someone else could find more useful info in full text.

 

Endocr Rev. 2003 Aug;24(4):523-38.

Endocrine withdrawal syndromes.

Hochberg Z, Pacak K, Chrousos GP.

 

Source

 

Division of Endocrinology (Z.H.), Meyer Children's Hospital, Haifa 31096, Israel.

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/12920153 Full text at http://edrv.endojournals.org/content/24/4/523.long#ref-166

 

Hypersecretion of endogenous hormones or chronic administration of high doses of the same hormones induces varying degrees of tolerance and dependence. Elimination of hormone hypersecretion or discontinuation of hormone therapy may result in a mixed picture of two syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome. Thus, hormones with completely different physiological effects may produce similar withdrawal syndromes, with symptoms and signs reminiscent of those observed with drugs of abuse, suggesting shared mechanisms. This review postulates a unified endocrine withdrawal syndrome, with changes in the hypothalamic-pituitary-adrenal axis and the central opioid peptide, in which noradrenergic and dopaminergic systems of the brain act as common links in its pathogenesis. Long-term adaptations to hormones may involve relatively persistent changes in molecular switches, including common intracellular signaling systems, from membrane receptors to transcription factors. The goals of therapy are to ease withdrawal symptoms and to expedite weaning of the patient from the hormonal excess state. Clinicians should resort to the fundamentals of tapering hormones down over time, even in the case of abrupt removal of a hormone-producing tumor. In addition, the prevention of stress and concurrent administration of antidepressants may ameliorate symptoms and signs of an endocrine withdrawal syndrome.

 

 

From the full text:

 

Endocrine Withdrawal Syndromes

Ze’ev Hochberg, Karel Pacak and George P. Chrousos

 

....

 

TABLE 5.

Mechanisms and time course for drugs of abuse and glucocorticoid withdrawal syndrome as a paradigm for the unified concept

 

Acute hormone excess state and corresponding hormone action     

Activation of receptor ---> ⇓ CRH

Activation of message cascade ---> ⇓ Vasopressin

Action on target proteins ---> ⇓ Central noradrenergic system (Minutes to hours)

Endocrine negative feedback ---> ⇑ Central dopaminergic system

Down regulation of receptor ---> ⇓ GABA and serotonin

Down regulation of message cascade ---> ⇓ POMC, Opioid peptides

 

Chronic hormone excess state ----> Tolerance, dependence    

Receptor adaptation—up-regulation ---> ⇑ Vasopressin

Message adaptation—up-regulation ---> ⇑ Central noradrenergic system (Days to years)

Transcription factors up-regulation ---> ⇓ Central dopaminergic system

Endocrine positive feedback ---> ⇑ GABA and serotonin

 

Withdrawal—short term ---> Perpetuation

Abrogation ---> ⇑ CRH ⇑ Central noradrenergic system ⇓ Central dopaminergic system (Hours to days) ⇓ POMC, opiates ⇑ Prostaglandins ⇑ IL-6

 

Withdrawal—long lasting ---> Sustained adaptation     

Stable changes in gene expression ---> ⇓ CRH

neurotransmission ---> ⇓ Central noradrenergic system

synaptic connections ---> ⇑ Central dopaminergic system (Days to years) ⇑ POMC ⇑ Glutamatergic system

Edited by Altostrata
added Pubmed citation

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Altostrata

Excellent find, Barb.

 

Correct -- a generic withdrawal syndrome, causing autonomic instability the symptoms of which may vary from individual to individual, fluctuate, and may have different emphases depending on the action of the original drug.

 

You can describe it in endocrinological terms as hypothalamic-pituitary-adrenal axis dysfunction or in neurological terms as autonomic dysfunction. All of the hormonal systems are networked. Mess with one and you mess with all the others.

 

(And thanks for posting in Journals in the standard format!)

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Skyler

WOW.. gotta digest that, LOL, or at least try. Echo Alto, great find. Botta Bimp, Botta Bump

 

When articles are this good, why oh why can't those who wrote the original scale it down a notch or two for us lesser mortals?

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Barbarannamated

Glad I could contribute even if I don't comprehend the content.

 

The complexity and interconnectedness of the neuroendocrine system demonstrated in the article is the take-home message for me. Impossible to alter one part without causing a cascade of events, some undefined, some irreversible.

 

I only wish the author did not suggest antidepressants to treat the depression of other withdrawals. Baffling!

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Barbarannamated

I just saw this link. Great discussion, Alto!

 

I disagree with his statement about GABA and serotonin being distinct and separate.

" I described benzodiazepine withdrawal. SSRIs affect serotonin reuptake; Benzodiazepines act at the GABA complex. They are about as related as the heart and the kidneys both having blood flowing through them!"

 

I think any attempt to say that oneneurotransmitter functions in a vacuum and has no effect on others is how we got into this mess to begin with. Always assume that messing with one neurotransmitter/hormone will have an unknown cascade effect.

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Altostrata

Well, he was working with a lot of mythology about neurotransmitters. The chemical imbalance theory set medicine back several decades.

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Altostrata

I find myself coming back to this paper over and over. Although the authors are struggling to associate particular symptoms with putative hormonal pathways, which believe is barking up the wrong tree (the right tree being a more generalized autonomic dysfunction), the overlap (see illustration below) of symptoms with what we know of antidepressant withdrawal syndrome is striking.

 

From the full text:

 

Endocrine Withdrawal Syndromes

Ze’ev Hochberg, Karel Pacak and George P. Chrousos

 

....

Thus, the mania, hypomania, and depression attributed to the withdrawal of anabolic steroid abuse in athletes has little to do with the symptoms and signs of testicular failure, because these symptoms occur in some patients with hypogonadism. Similarly, the syndrome that follows discontinuation of high-dose glucocorticoids or correction of hypercortisolism in Cushing’s syndrome bears similar but not identical symptoms and signs of adrenal insufficiency.

 

Interestingly, hormones with completely different physiological effects can produce similar withdrawal syndromes, whereas some of the clinical manifestations that are due to the chronic presence of high hormone levels or withdrawal syndromes are also observed with drugs of abuse. This review postulates that changes of the hypothalamic-pituitary-adrenal (HPA) axis and the central opioid peptide, noradrenergic and dopaminergic systems act as shared features in the pathogenesis of several endocrine withdrawal syndromes. The molecular and cellular bases of endocrine or drug-related addiction and withdrawal syndromes, however, are poorly understood. The best established molecular and cellular mechanisms of short- and long-term adaptation to hormones or allostasis induced by drugs of abuse is potentiation of G protein receptor coupling, up-regulation of cAMP, increased activities of protein kinases, and changes in the expression and activities of several transcription factors.

 

....

 

Figure 2 (showing only the A figure; the B figure attempts to associates hormonal mechanisms with the symptoms)

03_hochberg_endocrine_fig2_A.jpg

 

Withdrawal syndromes of several hormones share common symptoms and signs (A) and mechanisms (B). Many of these symptoms and signs are also manifestations of withdrawal syndromes after discontinuation of drugs of abuse....

 

 

Some of the withdrawal symptoms listed in chart are hard to see. Here they are:

 

Dark purple (overlap of everything but growth hormone): Drugs of abuse (I think they mean steroids)

  • flu-like
  • labile mood
  • depression
  • myalgias
  • fatigue
  • GI symptoms
  • insomnia
Light purple (overlap of estrogen and androgen:

  • hot flashes
  • autonomic hyperactivity
Red (overlap of androgen and growth hormone):

  • insomnia
Dull red (overlap of glucocorticoid and androgen):

  • orthostatic hypertension

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Altostrata

I posted this as a comment on an article by Sandy Steingard on MadinAmerica about supersensitivity psychosis following withdrawal from antipsychotics.

 

http://www.madinamerica.com/2013/03/optimal-use-of-neuroleptic-drugs-part-2/#comment-22001

 

I am wondering about the dopamine supersensitivity hypothesis.

 

What we are seeing when people withdraw from SSRIs and SNRIs too precipitously -- even when they had no withdrawal symptoms while tapering or for months afterwards -- is a recognizable supersensitivity to stress, evidenced by unprecedented symptoms described as anxiety surges, panic attacks, and a harsh sleeplessness over days or weeks.

 

Anxiety surges in the early morning are a common feature, an exaggeration of the diurnal cortisol peak that normally gets us ready to wake up and start our days.

 

As SSRIs and SNRIs have only an indirect effect on dopamine, it's unlikely that dopamine alone is the culprit for these tardive symptoms. Rather, they're due to a more generalized disruption of autonomic regulatory systems resulting in over-representation of alerting activity.

 

These psychiatric drug withdrawal symptoms have a lot in common with endocrine withdrawal symptoms, see

 

"....Interestingly, hormones with completely different physiological effects can produce similar withdrawal syndromes, whereas some of the clinical manifestations that are due to the chronic presence of high hormone levels or withdrawal syndromes are also observed with drugs of abuse. This review postulates that changes of the hypothalamic-pituitary-adrenal (HPA) axis and the central opioid peptide, noradrenergic and dopaminergic systems act as shared features in the pathogenesis of several endocrine withdrawal syndromes....."

 

They repeatedly advise slow tapering to avoid such symptoms.

 

Although the authors are struggling to associate particular symptoms with putative hormonal mechanisms, which I believe is barking up the wrong tree (the right tree being a more generalized autonomic disruption), the overlap of endocrine withdrawal symptoms with what we know of antidepressant withdrawal syndrome is striking (see Figure 2 in the paper http://edrv.endojournals.org/content/24/4/523/F2.large.jpg ).

 

In terms of autonomic disruption, there may be no real distinction between playing with levels of neurohormones and playing with endocrine hormones.

 

I suggest that the supersensitivity psychosis seen after even apparently uneventful withdrawal of antipsychotics is parallel to the stress hypersensitivities very frequently seen in SSRI and SNRI post-withdrawal syndromes, but expressed as "psychotic" symptoms reflecting the particular neurological variability of those who came in hearing voices, etc.

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btdt

I find myself coming back to this paper over and over. Although the authors are struggling to associate particular symptoms with putative hormonal pathways, which believe is barking up the wrong tree (the right tree being a more generalized autonomic dysfunction), the overlap (see illustration below) of symptoms with what we know of antidepressant withdrawal syndrome is striking.

 

From the full text:

 

Endocrine Withdrawal Syndromes

Ze’ev Hochberg, Karel Pacak and George P. Chrousos

 

....

Thus, the mania, hypomania, and depression attributed to the withdrawal of anabolic steroid abuse in athletes has little to do with the symptoms and signs of testicular failure, because these symptoms occur in some patients with hypogonadism. Similarly, the syndrome that follows discontinuation of high-dose glucocorticoids or correction of hypercortisolism in Cushing’s syndrome bears similar but not identical symptoms and signs of adrenal insufficiency.

 

Interestingly, hormones with completely different physiological effects can produce similar withdrawal syndromes, whereas some of the clinical manifestations that are due to the chronic presence of high hormone levels or withdrawal syndromes are also observed with drugs of abuse. This review postulates that changes of the hypothalamic-pituitary-adrenal (HPA) axis and the central opioid peptide, noradrenergic and dopaminergic systems act as shared features in the pathogenesis of several endocrine withdrawal syndromes. The molecular and cellular bases of endocrine or drug-related addiction and withdrawal syndromes, however, are poorly understood. The best established molecular and cellular mechanisms of short- and long-term adaptation to hormones or allostasis induced by drugs of abuse is potentiation of G protein receptor coupling, up-regulation of cAMP, increased activities of protein kinases, and changes in the expression and activities of several transcription factors.

 

....

 

Figure 2 (showing only the A figure; the B figure attempts to associates hormonal mechanisms with the symptoms)

Posted Image03_hochberg_endocrine_fig2_A.jpg

 

Withdrawal syndromes of several hormones share common symptoms and signs (A) and mechanisms (Posted Image. Many of these symptoms and signs are also manifestations of withdrawal syndromes after discontinuation of drugs of abuse....

 

Some of the withdrawal symptoms listed in chart are hard to see. Here they are:

 

Dark purple (overlap of everything but growth hormone): Drugs of abuse (I think they mean steroids)

[*]flu-like

[*]labile mood

[*]depression

[*]myalgias

[*]fatigue

[*]GI symptoms

[*]insomnia

Light purple (overlap of estrogen and androgen:

[*]hot flashes

[*]autonomic hyperactivity

Red (overlap of androgen and growth hormone):

[*]insomnia

Dull red (overlap of glucocorticoid and androgen):

[*]orthostatic hypertension

 

See this for the first time.  Thinking it completely true due to my personal experience.  I can't help but wonder Alto how the drug you take in very low doses helps this system heal... how does it relate? 

I am also wondering if it is almost time to take a chance and do something different... while I think about this can't help but think a failure one that would send me back to where I have been the past several years would be one I could not survive again...or would not choose to survive. 

Still I would like to know how it relates if you could spell it out for me please.  

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Altostrata

I used to take lamotrigine in very low doses of about 1mg-5mg. Lamotrigine mutes the glutamatergic chain of communication that results in release of anxiety hormones and stimulation of alerting. See http://survivingantidepressants.org/index.php?/topic/392-one-theory-of-antidepressant-withdrawal-syndrome/

 

The inappropriate release of alerting hormones (noradrenaline, cortisol) causes changes in the levels of other hormones. The whole organism goes slightly out-of-whack. This causes all kinds of hard-to-define symptoms.

 

For example, daytime levels of cortisol at night might reduce the night-time hormone vasopressin, which causes us to hold urine while sleeping, resulting in frequent night-time urination -- of which many people with withdrawal syndrome complain.

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PabloHoney825

This is an old post, but I thought I'd ask about chronic use of moderate doses of melatonin for years. I'm still trying to nail down what it causing my withdrawal. Say someone is using melatonin 10-15 mg for a couple of years and suddenly discontinues use. Could this in theory cause a sort of HPA dysregulation starting with the pituitary gland where melatonin and ACTH is produced? Does anyone know where I may find more information on this as I've been scouring the web with no success. 

 

Thanks 

 

 

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Barbarannamated
1 hour ago, PabloHoney825 said:

This is an old post, but I thought I'd ask about chronic use of moderate doses of melatonin for years. I'm still trying to nail down what it causing my withdrawal. Say someone is using melatonin 10-15 mg for a couple of years and suddenly discontinues use. Could this in theory cause a sort of HPA dysregulation starting with the pituitary gland where melatonin and ACTH is produced? Does anyone know where I may find more information on this as I've been scouring the web with no success. 

 

Thanks 

 

 

 

Melatonin is a hormone produced by the pineal gland.  The dosage you've been taking is on the high end. I think your suspicion may be correct, but I hope someone will offer more input. 

This thread might help:

 

Edited by Barbarannamated
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Altostrata

10-15mg melatonin is a very high dose. If you read this topic from the beginning, you'll see that for sleep, dosage starts at .25mg-.33mg.

 

I don't know what taking high dosages of melatonin does over time, we don't deal with that here.

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PabloHoney825

Thanks Altostrata. I realized exactly what you are saying after any potential damage has been done and after reading your helpful post on melatonin. I read through all 5 pages of replies too. 

 

I still believe my symptoms are from mirtazapine withdrawal (maybe Klonopin too). I'll stick to questions about those. Take care! 

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