Serotonin Depression Notes

1.Discuss the possible role of serotonin in the causes and treatment of depression

Role of serotonin In cause of depression

Serotonin hypothesis: Proposed by Alec Coppen - Diminished activity of 5-HT pathways plays a causal role in pathophysiology of depression

Evidence:

-Coppen et al-1978: To show there was diminished activity of 5-HT in the CNS pathways – serotonergic transport in human platlets is used as a model due to similarities of processes in the central serotonergic neurons- Kinetic analysis using low substrate concentrations and measuring initial uptake rate have shown that uptake of 5-HT into platelets of depressed patients is decreased

-Changes in platelet uptake may be secondary and possibly compensatory to depression and chemical and hormonal changes

-Reduced CSF concentrations of 5-HIAA-major metabolite of 5-HT in drug free depressed patients, reduced concentrations in post-mortem brain tissue/suicidal patients, decreased plasma tryptophan concentrations

-Cowen et al: 1989 showed that there was decreased plasma tryptophan levels in major depression- need other risk factors

-Tryptophan depletion- lower plasma and brain tryptophan by administering an amino acid mixture free of 5-HT precursor tryptophan- in healthy volunteers, lowering tryptophan doesn’t produce changes in mood- this suggests that lowering brain 5-HT is not sufficient to cause clinical depressive symptomatology (is this evidence against serotonin as not the major causative agent?). But in recovered depressed patients withdrawn from medication tryptophan depletion causes transient and striking return of depressive symptomatology

-Suggests that patients with risk factors for depression- lowering brain 5-HT function causes clinical depressive symptomatology

-The same finding is found when catecholamines are depleted with a-methyl-para tyrosine-this shows recovered recovred depressed patients are psychologically vulnerable to both 5-H and Catecholamine deficiency

-Brain imaging techniques- ligand imaging with PET and single photon emission tomography- enables direct investigation of 5-HT receptors in living human brain- these data have provided consistent and convincing evidence that binding density of 5-H1a receptors show widespread decrease in depressed patients

-5-HT genes and depression: Depression in twins and families have shown moderate to high heritability

-5HTT gene is one of the most intensively investigated genetic risk factors. first degree relatives of those with bipolar disorder have 2-3 times higher rates than those without.

-Also carriers of the short allele of 5-HT have greater risk of depression, increased anxiety related behaviour. Theories include that more serotonin in the synapse during early development increases predisposition to depression

Theories against serotonin

-Other studies showed unequivocally that unmedicated depressed patients have abnormalities in aspects of brain 5-HT activity but there caveats that makes it difficult to link these changes with depression- many of the reported abnormalities are present even when patients are recovered from depression which suggests that 5-HT may be markers of vulnerability indicating that people with abnormal brain 5-HT function are more linkely to become depressed-perhaps when exposed to psychosocial stress

-Bhagwagar et al: 2002- showed that brain serotonin function in depression is impaired through neuroendocrine studies

-Citalopram highly selective 5-HT reuptake inhibitor so when administered intravenously produces dose related increase in prolactin and cortisol.

-People with depression- have a blunted response to citaloprmm- the increase in prolactin and cortisol secretion is not seen

-Nature of impairment in brain 5-HT pathways that is responsible for blunted endocrine response to presynaptic 5-HT challenge in acute depression could be due to decreased numbers of post synaptic 5-HT1a and 2a receptors- these abnormalities contribute to decreased functional responses to 5-HT challenge identified by neuroendocrine tests

-People who recovered from depression also had blunted prolactin response to citalopram

The impaired prolactin response to citalopram in recovered subjects could be a consequence of having been depressed, rather than a marker of vulnerability

Serotonin mediated treatment

-SSRIs don’t produce elevation In mood in healthy volunteers- suggests...

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