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)
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)
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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)
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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
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