Serotonin - The 'chemical imbalance' myth

[panic_down_under]

The chemical imbalance hypothesis of anxiety and depression proposes that these disorders are caused by too little of a neurotransmitter, usually serotonin, in the brain which is corrected by antidepressant drugs. Its been known for more than two decades that the 'chemical imbalance/low brain serotonin' theory was deeply flawed, yet in continues to be promoted in the media, by pharmaceutical companies and even in medical journals.

Firstly, there have been a number of studies showing stress actually triggers an increase in brain serotonin levels in areas linked to anxiety and depression such as the amygdala, hippocampus, hypothalamus and nucleus caudatus, which should prevent that stress from triggering these disorders if the low brain serotonin levels hypothesis was correct. [1]

Serotonergic antidepressants do increase serotonin levels both in synapses and the brain overall within about 30 minutes of the first dose, and levels may remain elevated for some weeks before dropping back to baseline in most brain regions, and well below in regions associated with anxiety and depression.[2] The novel depression treatment ketamine also reduces serotonin concentrations (and increases dopamine). [2b]

The fact the quick initial boost in serotonin activity doesn't immediately alleviate anxiety and depression is the first clue there is more to these disorders than just a lack of serotonin.

An even stronger indicator serotonin isn't the factor responsible for the therapeutic effect is provided by the French antidepressant tianeptine (Stablon®), a Selective Serotonin Reuptake Enhancer/Accelerator. That is, it speeds up the removal of serotonin from the synapses, the direct opposite of what SSRIs (Selective Serotonin Reuptake Inhibitors) do. When taken with a SSRI class antidepressant the two drugs cancel each other out. [3] Yet, it is at least as effective as SSRIs such as Prozac®, which delay removal of the neurotransmitter. [4] Just as with the SSRIs and other antidepressants, tianeptine also promotes neurogenesis (see below) in the two hippocampi [5], demonstrating that increased/decreased serotonin activity isn't itself the critical factor in neurogenesis.

Further evidence against the hypothesis comes from rat models of depression. Rats bred to have a high genetic predisposition for depression have up to 8 times more serotonin in brain regions associated with clinical depression (and anxiety disorders) - the nucleus accumbens, prefrontal cortex, hippocampus, and hypothalamus - than controls. [6] Chronic antidepressant treatment reduces serotonin to levels found in normal rats, but the amount of serotonin in the brains of the controls remains unchanged. OTOH, mice with only trace amounts of brain serotonin because they lack a gene needed to effectively synthesize the neurotransmitter do not exhibit depressive behaviour either despite their brains containing less than 2% of the serotonin found in controls. [7] These low brain serotonin mice appear to be much less anxious than controls, though they tend to be more aggressive. [8]

Significantly elevated serotonin synthesis has now also been found in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex regions of human anxiety disorder patients compared with healthy controls. [9] Synthesis rates decreased following antidepressant treatment. [10]

How antidepressants work is still a matter of debate. It is thought they stimulate neurogenesis (see also) - the formation of new neurons in the two hippocampal regions of the brain by affecting glucocorticoid receptors, and encouraging increased nerve-fibre innervation between limbic structures and the frontal lobes which manifest consciousness. Reducing serotonin levels in central brain areas also seems to boost hippocampal neurogenesis [11], possibly by increasing the survival of new neurons. [12]

It wouldn't matter how antidepressants work, just as long as they do, except that the 'chemical imbalance' hypothesis is used to promote sales of the serotonin precursors L-Tryptophan and 5-HTP which not only can't work as advertised, but which, at least in the case of L-Tryptophan and possibly 5-HTP too, may cause harm through a contaminate, Peak-X. Peak-X is though to trigger the immune system disorder Eosinophilia-myalgia syndrome (EMS). L-Tryptophan linked EMS caused the deaths of 37 people in the late 1980s and permanently damaged the health of another 1,500+. See also: Notes on the Tryptophan Disaster.

Despite claims Peak-X contamination was confined to a few batches produced by one manufacturer, Simat et al, 1999 found markers for Peak-X in pharmaceutical grade L-Tryptophan on sale in Germany in 1998, some 10 years after the original EMS disaster. Peak-X has also been found in 5-HTP (Klarskov K, 2003; Klarskov K, 1999) and possibly implicated in at least 2 cases of EMS (Michelson D, 1994). The National Eosinophilia-Myalgia Syndrome Network website continues to report new cases of EMS linked to tryptophan and 5-HTP linked cases on a regular basis.

See also:

• The media and the chemical imbalance theory (PDF)

• The "Chemical Imbalance" Explanation for Depression: Origins, Lay Endorsement, and Clinical Implications (PDF)

• What has serotonin to do with depression?

• Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature

• From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder

References (Note 5-HT = 5-hydroxytryptamine = serotonin):

[1]
Moncrieff J, Cooper RE, Stockmann T, et al. (2022)
The serotonin theory of depression: a systematic umbrella review of the evidence.
Mol Psychiatry, (Full text)

Rex A1, Voigt JP, Fink H. (2005)
Anxiety but not arousal increases 5-hydroxytryptamine release in the rat ventral hippocampus in vivo.
Eur J Neurosci. Sep;22(5):1185-9 (Abstract

Devoino L, Alperina E, Podgornaya E, et al. (2004)
Regional changes of brain serotonin and its metabolite 5-hydroxyindolacetic Acid and development of immunosuppression in submissive mice.
Int J Neurosci. Sep;114(9):1049-62. (Abstract)

Devoino LV, Al'perina EL, Podgornaia EK, et al. (2002)
Distribution of serotonin and its metabolites in the brain structures and immunosuppression in submissive mice.
Ross Fiziol Zh Im I M Sechenova. 2002 Jan;88(1):106-12 (Abstract)

Funada M1, Hara C. (2001)
Differential effects of psychological stress on activation of the 5-hydroxytryptamine- and dopamine-containing neurons in the brain of freely moving rats.
Brain Res. May, 18;901(1-2):247-51. (Abstract)

Rueter LE, Fornal CA, Jacobs BL. (1997)
A critical review of 5-HT brain microdialysis and behavior.
Rev Neurosci. 1997 Apr-Jun;8(2):117-37. (Abstract)

Kudriavtseva NN, Amstislavskaia TG, Avgustinovich DF, et al. (1996)
The effect of the repeated experience of victories and defeats in social conflicts on the function of the brain serotoninergic system in male mice
Zh Vyssh Nerv Deiat Im I P Pavlova. Nov-Dec;46(6):1088-96. (Abstract)

Kawahara H1, Yoshida M, Yokoo H, et al. (1993)
Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis.
Neurosci Lett. Nov 12;162(1-2):81-4. (Abstract)

Adell A, Garcia-Marquez C, Armario A, Gelpi E. (1988)
Chronic stress increases serotonin and noradrenaline in rat brain and sensitizes their responses to a further acute stress.
J Neurochem. 1988 Jun;50(6):1678-81. (Abstract)

[2]
Frick A, Ahs F, Appel L, et al (2016)
Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.
Eur Neuropsychopharmacol. Nov;26(11):1775-1783 (Abstract)

Siesser WB, Sachs BD, Ramsey AJ, et al. (2013)
Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice.
ACS Chem Neurosci. Jan 16;4(1):84-8 (Abstract)

Bosker FJ, Tanke MAC, Jongsma ME, et al. (2010)
Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: Role of serotonin synthesis.
Neurochemistry International 2010 Dec;57(8):948-957. (Abstract)
See also: New Rat Study: SSRIs Markedly Deplete Brain Serotonin

Honig G, Jongsma ME, van der Hart MC, Tecott LH. (2009)
Chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain.
PLoS One. 2009 Aug 27;4(8):e6797. (Study)

Stenfors C, Yu H, Ross SB. (2001)
Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram.
Naunyn Schmiedebergs Arch Pharmacol, vol 363(2): p 222-32. (Abstract)

Moret C, Briley M. (1997)
Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.
J Neural Transm (Vienna) 104(2-3):147-60 (Abstract)

Trouvin JH, Gardier AM, Chanut E, et al. (1993)
Time course of brain serotonin metabolism after cessation of long-term fluoxetine treatment in the rat.
Life Sci, vol 52(18): p PL187-92. (Abstract)

Caccia S, Anelli M, Codegoni AM, Fracasso C, Garattini S. (1993)
The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.
Br J Pharmacol. 1993 Sep;110(1):355-9. (Abstract | Full text)

Caccia S, Fracasso C, Garattini S, Guiso G, Sarati S. (1992)
Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain.
Neuropharmacology. 1992 Apr;31(4):343-7. (Abstract)

Adell A, García-Marquez C, Armario A, Gelpí E. (1989)
Chronic administration of clomipramine prevents the increase in serotonin and noradrenaline induced by chronic stress.
Psychopharmacology (Berl). 99(1):22-6. (Abstract)

Hall TR, Urueña G, Figueroa HR. (1985)
Changes in mouse brain serotonin turnover following chronic imipramine administration.
Gen Pharmacol. 1985;16(1):55-9. (Abstract)

Carlsson A, Lindqvist M (1978)
Effects of antidepressant agents on the synthesis of brain monoamines.
J Neural Transm 43: 73–91 (Abstract)

[2b]
Tiger M, Veldman ER, Ekman CJ, etal. (2020)
A randomized placebo-controlled PET study of ketamine´s effect on serotonin 1B receptor binding in patients with SSRI-resistant depression
Transl Psychiatry. Jun 1;10(1):159 [Article | Full text]

[3]
Nowakowska E, Kus K, Chodera A, Rybakowski J. (2000)
Behavioural effects of fluoxetine and tianeptine, two antidepressants with opposite action mechanisms, in rats.
Arzneimittelforschung. Jan;50(1):5-10. (Abstract)

[4]
Novotny V, Faltus F. (2002)
Tianeptine and fluoxetine in major depression: a 6-week randomised double-blind study.
Hum Psychopharmacol. Aug;17(6):299-303. (Abstract)

Waintraub L, Septien L, Azoulay P. (2002)
Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine.
CNS Drugs. 16(1):65-75. (Abstract)

[5]
Liu W, Shu XJ, Chen FY, et al (2011)
Tianeptine reverses stress-induced asymmetrical hippocampal volume and N-acetylaspartate loss in rats: an in vivo study.
Psychiatry Res. 2011 Dec 30;194(3):385-92 (Abstract)

Kasper S, McEwen BS. (2008)
Neurobiological and clinical effects of the antidepressant tianeptine
CNS Drugs 22(1):15-26 [Abstract)

McEwen BS, Olie JP (2005)
Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine
Mol Psychiatry Jun;10(6):525 (Abstract | Full text)

Czéh B, Michaelis T, Watanabe T, et al. (2001)
Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.
Proc Natl Acad Sci U S A. Oct 23;98(22):12796-801 (Abstract)

[6]
Zangen A, Overstreet DH, Yadid G. (1997)
High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: normalization by chronic antidepressant treatment.
J Neurochem, vol 69(6): p 2477-83 [Abstract | Full text-PDF]

Stress elevates brain noradrenaline, aka norepinephrine and dopamine levels too:

Zangen A, Overstreet DH, Yadid G. (1999)
Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment.
Brain Res. Apr 10;824(2):243-50. [Abstract]

[7]
Angoa-Pérez M, Kane MJ, Briggs DI, Herrera-Mundo N, Sykes CE, et al. (2014)
Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype.
ACS Chem Neurosci. 15;5(10):908-19 (Abstract | Full text)

[8]
Mosienko V1, Bert B, Beis D, et al. (2012)
Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin.
Transl Psychiatry. 2012 May 29;2:e122 (Full text)

[9]
Frick A, Åhs F, Engman J, et al. (2015)
Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.
JAMA Psychiatry. Aug;72(8):794-802 (Full text)

[10]
Frick A, Åhs F, Appel L, et al (2016)
Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.
Eur Neuropsychopharmacol. 2016 Nov;26(11):1775-1783 (Abstract)

[11]
Song NN, Jia YF, Zhang L, et al. (2016)
Reducing central serotonin in adulthood promotes hippocampal neurogenesis.
Sci Rep. Feb 3;6:20338. (Abstract | Full text)

[12]
Diaz SL, Narboux-Nême N, Trowbridge S, et al. (2013)
Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin.
Eur J Neurosci. 2013 Sep;38(5):2650-8 (Abstract | Full text - PDF)


Last updated: Jan 29, 2022 (added, updated links) - © 2002-2022 IMW

[Shazamataz]

Interesting.

[Catherine S]

Although alot of people say antidepressants have quite few nasty side effects, there seems to be equally as many people who say they have helped them enormously. So would the success rates of them be just a placebo effect then?

ISB

[panic_down_under]

So would the success rates of them be just a placebo effect then?

Well, this is the argument pushed by psychologists, often supported by questionable studies. However, I find it interesting that behind the scenes their associations have for many decades been lobbying governments for prescribing rights. They have succeeded in some American states.

In one of his last books even Siggy Freud speculated drugs might become a better treatment option. After detailing the shortcomings of his psycho-analysis approach, which admittedly most now agree was/is nonsense, he wrote:

"Those who have been following our discussion only out of of therapeutic interest will perhaps turn away in contempt after this admission. But here we are concerned with therapy only in so far as it works by psychological means; and for the time being we have no other. The future may teach us to exercise a direct influence, by means of particular chemical substances, on the amounts of energy and their distribution in the mental apparatus. It may be there are other still undreamed-of possibilities of therapy. But for the moment we have nothing better at out disposal than the technique of psychoanalysis, and for that reason, in spite of its limitations, it should not be despised."

S. Freud, An Outline of Psycho-Analysis, WW Norton & Company, New York, 1949, p62

But to answer your question, no I don't believe it is the placebo effect because it is usually short-lived. I've been on antidepressants for nearly 30 years and know people who began taking them in the 1960s. In the first decade I tried several times to live without them but always relapsed between 6-18 months after stopping them. I've now been on my current drug continually for 20 years.

Which doesn't mean I think they are necessarily the best treatment. Frankly, antidepressants can be ornery meds which no one in their right minds would take (although apparently some do in the mistaken belief they can make themselves better than 'normal' - in fact they have no affect on those without a disorder except for side-effects). Nor do they work for everyone. IME, about a third get excellent results becoming essentially anxiety/depression free, another third derive enough benefit to make taking them worthwhile, though still experiencing some anxiety, or depression from time to time, and the remaining third would do better on M&Ms which at least taste good. The cognitive/behavioural/mindfulness therapies produce similar response rates.

Imho, if therapy is an option it should be the first treatment tried. Unfortunately, in much of the world it is about as accessible/affordable as airline tickets to the Moon.

[Catherine S]

Plus, going back to the seratonin 'myth' you first talked about, of the people who don't actually get much from the pills that are supposed to address the balance, there are natural plant based remedies out there that can boost seratonin levels without the nasty side effects. One lady on here recently told of how good she felt taking St John's Wort, but was told by her GP that she'd be better off on antidepressants instead, yet she feels so ill on them. I find that quite scary tbh. To be taken off something that is really helping in favour of prescribed meds.

ISB

[panic_down_under]

of the people who don't actually get much from the pills that are supposed to address the balance, there are natural plant based remedies out there that can boost seratonin levels without the nasty side effects.

But increased serotonin is not what you want. Stress increases brain serotonin levels and, as stated above, antidepressants reduce them. In some brain regions associated with anxiety and depression levels drop to half the baseline within a few weeks and then stay there as long as the med is taken (Trouvin JH, 1993). But this seems to be a side-effect of the therapeutic response, not its cause. Antidepressants work by stimulating the growth of new brain cells (neurogenesis) to replace cells killed, or prevented from growing by high brain stress hormone levels. The therapeutic response is produced by these new cells, not the meds directly.

One lady on here recently told of how good she felt taking St John's Wort,

Studies have shown St Johns Wort can be effective for mild to moderate anxiety and depression and one study hints it may also work by the same neurogenesis mechanism as antidepressants, however, these studies use standardised pharmaceutical grade SWJ extracts such as PM235, STW 3, STW3-VI, WS 5570, WS 5572, WS 5573 and ZE 117 which are available on prescription in Germany and some other European countries. The produce sold in health stores varies greatly in potency from zero to more than is claimed on the label. Potency may also vary from batch to batch.

[GlassPinata]

I had good success in treating my anxiety with Prozac, a SSRI. I took 20 ml per day for about a year.
I got off it because I was feeling better, and I couldn't deal with the side effects: weight gain, loss of sex drive, overly vivid and disturbing dreams.
I guess I thought I was just going through a rough patch after my son was born, and needed something to help me for a little while.
But now that I'm off it, My anxiety is back full force. :(

[panic_down_under]

But now that I'm off it, My anxiety is back full force. :(

For some anxiety disorders (also depression) are chronic conditions which wax and wane but never completely go away although remissions lasting years do occur. At present there is no cure, meds and therapy are only treatments.

[beatroon]

So - if people feel the benefit of anti-depressants (and lots seem to, myself included, although I take mine for anxiety) - what is the reason for this, if the suspected serotonin imbalance isn't it? Is it that they work in some other way (not placebic) that we don't yet understand - i.e. That they have some weird unexpected side effect yet to be identified?

Sorry if I'm missing something in the responses above, but this is so interesting, I'd like to understand it more.

[panic_down_under]

So - if people feel the benefit of anti-depressants (and lots seem to, myself included, although I take mine for anxiety) - what is the reason for this, if the suspected serotonin imbalance isn't it? Is it that they work in some other way (not placebic) that we don't yet understand

Antidepressants (also therapy) work by stimulating the growth of new brain cells (neurogenesis) to replace cells killed, or prevented from growing by high brain stress hormone levels. The therapeutic response is produced by these new cells and the strengthened interconnects forged, not the meds directly.

The changes in brain serotonin (&/or noradrenaline/norepinephrine with some SNRIs, TCAs) levels is likely a side-effect of neurogenesis, not the thing driving it.