SSRIs Lower Platelet And Plasma Serotonin?

alywest

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Serotonin (aka 5HT) receptors are a complex thing, and that's putting it mildly. I have been looking at serotonin in platelets as it has been implicated as a biomarker for autism, which is an area of particular interest to me because of my son. While researching I came across some interesting, and seemingly backwards, research that mostly took place in the 90's and early 2000's. The first thing that stood out to me was a study from Canada in 2007 that showed that paroxetine (also known as Paxil) DECREASED platelet associated serotonin in responders only. The funny thing is that the researchers called it "severe reduction." They include a chart which shows the "normal" levels of platelet serotonin, then the levels of platelet serotonin in depressed people (which is below that of healthy persons), and all the women who responded well to treatment with paroxetine were well below the "depression" threshold. In fact, the three people who didn't respond to treatment were still within the "depression" range of the platelet serotonin chart.


Platelet serotonin levels support depression scores for women with postpartum depression


Platelet serotonin levels in patients with depression before paroxetine treatment or nonresponsive to their initial paroxetine regimen were reduced to 50% of normal levels. Treatment-induced severe reduction of platelet-associated serotonin only occurred in responsive patients. Mean platelet serotonin levels were significantly lower in responders (17.3%, standard deviation [SD] 4%), compared with nonresponders (33.4%, SD 8%; p < 0.001).


Further, there seem to be some discrepancies between the studies in relation to densities of 5HT(2A) receptor sites on platelets in depressed subjects vs. healthy, although they are studying different types of mental illness (ie. schizophrenia vs. bipolar, etc.) However, one study pointed out the inverse relationship between density of platelet receptors and overall serotonin synthesis, but in this study the higher density of receptor sites was actually induced by a 5HT(2A) antagonist (M100907).


5-HT2A receptor antagonist M100907 reduces serotonin synthesis: An autoradiographic study


"In this study, we quantitatively evaluated the effects of the administration of a specific 5-HT2A receptor antagonist, M100907, using the α-MTrp autoradiographic method on regional 5-HT synthesis rates in the rat brain. The (serotonin) synthesis rates in the M100907 treatment group was, overall, significantly lower than in the control group and 5-HT synthesis rates were reduced on average by 24 ± 15% (Table 1). Significant decreases of 5-HT synthesis rates were seen in the cortices, anterior olfactory nucleus, accumbens nucleus, caudate putamen (Table 1), where there is an enriched density of 5-HT2A receptors in the rat brain [29]. This suggests a relationship between density of 5-HT2A receptors and reduction of serotonin synthesis (the trend exist showing higher reduction for regions with higher densities of receptors). Because 5-HT2A receptors are postsynaptic influence on 5-HT synthesis is most likely through postsynaptic loops and/or modulated by other neuro-transmitters (e.g., dopamine; many 5-HT2A receptors are found on dopaminergic neurons; [47]). The action through 5-HT2A receptors is probably also related to 5-HT dopamine interaction because blocade of 5-HT2A receptors on dopaminergic neurons could result in higher release of dopamine which could influence 5-HT synthesis [35]. The tryptophan hydroxylase (TPH) is “mostly” expressed in the cell bodies found in raphe nuclei (e.g., [36]), but there is also substantial evidence that TPH is present in the serotonergic terminals [62,18,59], and that the synthesis of 5-HT is occurring in those terminals (e.g., [49,33,11,51]).



Another study showed that patients with unipolar depression had significantly decreased paroxetine binding sites (5-HTT), however fluoxetine and clomipramine both lowered the amount of binding sites even further, resulting also in lower plasma and platelet serotonin levels, which was apparent in responders to treatment:


Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: Effects of clomipramine and fluoxetine

Jean‐Claude Alvarez PharmD, PhD

Nathalie Gluck MD

Isabelle Arnulf MD


In patients with depression versus matched control subjects, platelet [3H]paroxetine binding sites were found to be significantly decreased (2.10 ± 0.70 versus 3.88 ± 0.77 fmol/109 platelets; P = .0001), platelet serotonin (5‐HT) content was found to be significantly decreased (1.90 ± 1.52 versus 2.74 ± 1.12 nmol/109 platelets; P = .001), and platelet inositol triphosphate levels were found to be significantly increased (2.85 ± 0.70 versus 1.85 ± 0.77 fmol/109 platelets; P = .0001). No significant difference between patients and control subjects was found for platelet [3H]‐lysergic acid diethylamide ([3H]LSD) binding sites, aggregation tests with 5‐HT or adenosine diphosphate and plasma 5‐HT levels. Treatment with both clomipramine and fluoxetine gradually further reduced the density of platelet [3H]paroxetine binding sites and induced a dramatic decrease in platelet and plasma 5‐HT levels. With clomipramine, the decreased blood 5‐HT levels are associated with increased platelet [3H]LSD binding sites and aggregation responses. After 12 weeks, nonresponders to both treatments had platelet inositol triphosphate levels that were still increased (2.81 ± 0.75 fmol/109 platelets) when responders levels were not different from those of control subjects (1.41 ± 0.45 versus 1.70 ± 0.25 fmol/109 platelets).

Drug‐free patients with depression had simultaneously decreased 5‐HT transporter (5‐HTT) sites and overstimulated phosphoinositide signaling systems. Clomipramine and fluoxetine treatments, which further decreased the density of 5‐HTT sites, allowed platelet inositol triphosphate levels to return to normal values only in responders.




5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.


The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively.

Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.
 

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