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Andrews, 2015 Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

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Neurosci Biobehav Rev. 2015 Jan 24;51C:164-188. doi: 10.1016/j.neubiorev.2015.01.018. [Epub ahead of print]

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
Andrews PW1, Bharwani A2, Lee KR2, Fox M3, Thomson JA Jr4.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/25625874 Full text at https://www.researchgate.net/publication/270902371_Is_serotonin_an_upper_or_a_downer_The_evolution_of_the_serotonergic_system_and_its_role_in_depression_and_the_antidepressant_response(free registration required)

 

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

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This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

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Link to full text added.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

All postings © copyrighted.

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I thought this was a very interesting article.

1988-2012: Prozac @ 60mg (with a few stops and starts)

Fall 2012: Returned to 40mg after discontinuing and horrid withdrawal 

Fall 2013: 40mg Fluoxetine, added 150mg Wellbutrin to treat fatigue 

Winter 2014: Attempting to taper both (too fast)

April 2014: 9mg Fluoxetine + 37.5 Wellbutrin 

Summer 2014: 8 mg Fluoxetine + 0 Wellbutrin (way too fast a drop)

Late summer/Early Fall 2014: Debilitating Withdrawal symptoms 

Fall 2014 - Wellbutrin successfully kicked to the curb but…

Oct- Dec 2014: Panicked reinstatement of Fluoxetine ->30mg - held for 5yrs

Jan 2021: taper to 20mg Fluoxetine  then tapering by 1mg every 2-3 months

Fall 2022 - held at 10mg->December 2022: 9mg->Feb 2023: 8mg ->March 2023: brassmonkey slide begins: 7.8mg -> 7.6 -> 7.4->2 week hold (April)->7.2->7mg->6.8->2 week hold->6.6-> 1-month hold ->(June)-6.5->4-week hold-> (July)-6.4 (discontinued brassmonkey slide and slowed taper)-> (Aug)-6.2->(Sept)-6.0->(Oct)-5.9->(Nov)-5.8->(Dec)-5.7->wave!->(Jan)-5.8->(Feb)-6mg and holding.

 

My 2014 withdrawal experience: https://rxisk.org/antidepressant-withdrawal-a-prozac-story/

 

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For anyone who has a bead on the science of this, would those brain compensatory mechanisms include the business about SSRIs causing synapse growth, which I believe some now posit as the real reason for their efficacy? To the small extent that it exists, of course. And, would this possibly explain why I always felt fine for a while, usually a month or two, after I took my last dose, and then eventually massive depression would hit? I never could figure out why, if I did a long slow taper, I had no serious withdrawal symptoms while I was doing the taper. I would think this could explain it, since there would still be a need for compensation even during the taper, and then a month or two after it ended...all compensation gone. And I guess over time you'd become accustomed to the compensation...and it would take time to get used to not having it. Plenty of inference and speculation there, but it's the closest I've seen to a good explanation of the timing of it all. Any thoughts?

1994-2009 50-100 mg Zoloft (plus tried Effexor, Lexapro, Wellbutrin at times)
5/'09-7/'09 taper off Zoloft
7/'09-12/'09 no zoloft, rough times after ~ 2 mos.
1/'10-6/'10 50 mg zoloft
6/'10-1/'11 slow taper
2/'11-7/'11 off entirely, ok for 2-3 mos., then rough
7/'11-9/'11 50 mg
9/15/'11 - 11/15/'11 taper off
11/15/'11 - 2/'11 clean, doing well but with some PSSD
2/'11 - 6/'11 depression creeps back, fairly significant by May.

6/'14 (long time...!)  life is good, full recovery, at least in terms of SSRI addiction.  Still digging out from the social and professional hole that it all left me in, but despite the loss of far too many years to this business I'm basically doing pretty well.  Still some depression at times, even severe on occasion, but clearly related to past trauma and current circumstances, all things that I am continuing to work through and work on.  I'd say it took at least six months and perhaps a year to fully get back to normal (neuro-psychologically and sexually) after the last dose in 2011.

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ChanceLucky Newbie

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I've read this theory but don't get why the compensatory mechanisms would lead to a decrease in depression from baseline levels rather than just a return to baseline. Are the authors saying the brain not only compensates but somehow overcompensates?

-I was on an SSRI (most recently Celexa at 40mg/day) for about 15 years for anxiety. I tapered off over about 8 months and in 2015 and had worsened anxiety and well-being once off it. In the fall of 2015 (I believe) I did a low dose reinstatement and was doing better. I stayed on roughly 1 ml (2 mg) for a while but eventually lowered it to .5 ml and was on this for a long time.

-Around late mid May (2017) my anxiety was worse and I increased the Celexa to 1.5 ml. At first, I felt significantly better but I developed a hand tremor. I also was having some attention and concentration difficulties. In mid July (over about 2 weeks) I tapered off of the Celexa and was off it for about 2 1/2 weeks before I started to feel an intense increase in anxiety and my hand tremor returned.

-Aug 13, 2017 I did a low dose reinstatement of 0.5 ml a day and am currently still taking that. Initial response is good.

-Early September 2017 to present - hand tremor returns and attention and concentration are impaired. Feeling of unbalance/unsteadiness from using treadmill. Mild changes to sexual performance too.

-Sept 18, 2017: 0.4 ml Celexa. Everything is generally improving although hand tremor is worse. Attention, concentration, and anxiety are good.

-I am also on Wellbutrin (200 mg/day) for anxiety and take a Benadryl at night for sleep and allergies. Eventually I'd like to be off everything.

http://survivingantidepressants.org/index.php?/topic/9730-chancelucky-antidepressant-withdrawal-social-anxiety-pessimism/

 

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The compensatory mechanisms incidentally change all hormonal functioning, causing people to feel differently. Some people interpret this as beneficial, some react badly, and some don't feel any effect, in about equal proportions.

 

The ways "decrease in depression" are measured is very sloppy -- usually multiple-choice questionnaires or subjective reports -- and highly subject to observer bias and predisposition of subjects to believe the treatment is working as well as other aspects of the placebo effect.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

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nz11 Newbie

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....and some react with 'Stockholm syndrome' ...reacting due to a fear of isolation, a fear your life may be at risk and kindness on behalf of the hostage takers (doctors) resulting in an apparent insouciance or congenial conversation concealing deep unhappiness with the treatment or even alarm at side effects emerging on treatment.....

Doctors are not trained to manage 'Stockholm Syndrome' .

 

 and some react with spellbinding ...Breggin said 'because of medication spellbinding prescribers and clinicians cannot take patient reports at face value when they are doing well on medication.'

Thought for the day: Lets stand up, and let’s speak out , together. G Olsen

We have until the 14th. Feb 2018. 

URGENT REQUEST Please consider submitting  for the petition on Prescribed Drug Dependence and Withdrawal currently awaiting its third consideration at the Scottish Parliament. You don't even have to be from Scotland. By clicking on the link below you can read some of the previous submissions but be warned many of them are quite harrowing.

http://www.parliament.scot/GettingInvolved/Petitions/PE01651   

Please tell them about your problems taking and withdrawing from antidepressants and/or benzos.

Send by email to petitions@parliament.scot and quote PE01651 in the subject heading. Keep to a maximum of 3 sides of A4 and you can't name for legal reasons any doctor you have consulted. Tell them if you wish to remain anonymous. We need the numbers to help convince the committee members we are not isolated cases. You have until mid February. Thank you

Recovering paxil addict

None of the published articles shed light on what ssri's ... actually do or what their hazards might be. Healy 2013. 

This is so true, with anything you get on these drugs, dependance, tapering, withdrawal symptoms, side effects, just silent. And if there is something mentioned then their is a serious disconnect between what is said and reality! 

  "Every time I read of a multi-person shooting, I always presume that person had just started a SSRI or had just stopped."  Dr Mosher. Me too! 

Over two decades later, the number of antidepressant prescriptions a year is slightly more than the number of people in the Western world. Most (nine out of 10) prescriptions are for patients who faced difficulties on stopping, equating to about a tenth of the population. These patients are often advised to continue treatment because their difficulties indicate they need ongoing treatment, just as a person with diabetes needs insulin. Healy 2015

I believe the ssri era will soon stand as one of the most shameful in the history of medicine. Healy 2015

Let people help people ... in a natural, kind, non-addictive (and non-big pharma) way. J Broadley 2017

 

 

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ChanceLucky Newbie

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The compensatory mechanisms incidentally change all hormonal functioning, causing people to feel differently. Some people interpret this as beneficial, some react badly, and some don't feel any effect, in about equal proportions.

 

The ways "decrease in depression" are measured is very sloppy -- usually multiple-choice questionnaires or subjective reports -- and highly subject to observer bias and predisposition of subjects to believe the treatment is working as well as other aspects of the placebo effect.

So it's a combination of physiological compensation and cognitive processes (interpretations)? It's definitely plausible but the authors would have to explain this for their theory to make sense. (Or perhaps I missed the cognitive part since I only skimmed the article.)

I think randomized controlled trials would rule out the second explanation unless the double blinding fails (which could be the case).

-I was on an SSRI (most recently Celexa at 40mg/day) for about 15 years for anxiety. I tapered off over about 8 months and in 2015 and had worsened anxiety and well-being once off it. In the fall of 2015 (I believe) I did a low dose reinstatement and was doing better. I stayed on roughly 1 ml (2 mg) for a while but eventually lowered it to .5 ml and was on this for a long time.

-Around late mid May (2017) my anxiety was worse and I increased the Celexa to 1.5 ml. At first, I felt significantly better but I developed a hand tremor. I also was having some attention and concentration difficulties. In mid July (over about 2 weeks) I tapered off of the Celexa and was off it for about 2 1/2 weeks before I started to feel an intense increase in anxiety and my hand tremor returned.

-Aug 13, 2017 I did a low dose reinstatement of 0.5 ml a day and am currently still taking that. Initial response is good.

-Early September 2017 to present - hand tremor returns and attention and concentration are impaired. Feeling of unbalance/unsteadiness from using treadmill. Mild changes to sexual performance too.

-Sept 18, 2017: 0.4 ml Celexa. Everything is generally improving although hand tremor is worse. Attention, concentration, and anxiety are good.

-I am also on Wellbutrin (200 mg/day) for anxiety and take a Benadryl at night for sleep and allergies. Eventually I'd like to be off everything.

http://survivingantidepressants.org/index.php?/topic/9730-chancelucky-antidepressant-withdrawal-social-anxiety-pessimism/

 

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The published criticisms of randomized controlled trials in psychiatry, which are very extensive, include the probability of the failure of blinding. See the writings of Irving Kirsch, for example.

 

You may wish to read up on this and post journal articles in the Journals forum, following our format described here Before you start a topic in Journals.... (basically, copy and paste the abstract from PubMed).

 

Andrews, et al believe there is physiological compensation for the action of antidepressants, and this iatrogenic compensation is "perturbational" -- see Andrews, 2011 Blue again: Perturbational effects of antidepressants...

 

Reading the full text of these papers probably would answer most of your questions about them.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

All postings © copyrighted.

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