Tremor In Parkinson Disease (PD) Is Due To High Serotonin

Discussion in 'Scientific Studies' started by haidut, Feb 15, 2018.

  1. haidut

    haidut Member

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    The non-motor signs/symptoms of PD (tremor, drooling, slurred speech, etc) have long been thought to be directly due to dopamine deficiency due to the death of the nigrostriatal dopamine neurons. The common treatment for those signs/symptoms and the motor symptoms as well is usually a dopamine agonist of some sort, or L-DOPA.
    This study shows that the tremor signs are possibly due to decreased availability of the serotonin transporter (SERT). Lower SERT availability results in elevated intracellular serotonin levels. The commonly prescribed SSRI drugs are SERT inhibitors and sadly they are being prescribed quite often to people with PD. Given that dopamine and dopamine agonists are inhibitors of TPH, they tend to lower serotonin levels, which explains their benefit for PD. If high serotonin is indeed a major cause of dysfunction/pathology in PD then increased salt, protein (which lowers brain serotonin) and keeping endotoxin (and thus serotonin) low could also have pronounced benefit for PD.

    Progression of tremor in early stages of Parkinson’s disease: a clinical and neuroimaging study | Brain | Oxford Academic
    Resting Tremor Most Common in Early Parkinson Disease
    "...At baseline and follow-up, the severity of resting tremor was found to be inversely correlated with raphe serotonin transporter availability in tremor-predominant patients (constancy P <.05, tremor index P <.05 [baseline] vs amplitude P <.05, constancy P <.05, tremor index P <.05 [follow-up]). Greater severity of tremor was associated with significantly higher raphe dysfunction severity (constancy P <.01, tremor index P <.05 [baseline] vs amplitude P <.01, constancy P <.001, tremor index P <.001 [follow-up]). In addition, acute dopaminergic therapy was associated with a smaller improvement in resting tremor amplitude in patients with lower raphe/putamen uptake (P <.01)."

    Interestingly enough, this is not the only study that has found serotonin (levels of neuronal activity) excess in PD patients. However, given the widespread use of SSRI in virtually all patients with a neurodegenerative disorder, I doubt that we will see the serotonin angle addressed any time soon.
    Clinical correlates of raphe serotonergic dysfunction in early Parkinson’s disease | Brain | Oxford Academic
    Increased excitability in serotonin neurons in the dorsal raphe nucleus in the 6-OHDA mouse model of Parkinson's disease. - PubMed - NCBI
    The role of the dorsal raphe nucleus in the development, expression and treatment of LID in hemiparkinsonian rats
     
  2. jamies33

    jamies33 Member

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    Is cyproheptadine the best purely serotonin blocking drug?
     
  3. Koveras

    Koveras Member

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    I was researching cerebral palsy recently and found some evidence that serotonin was involved in the hypertonicity and spasticity there as well.

    Dopaminergic agents underexplored but potentially beneficial.

    I think the doctors sometimes prescribe SSRIs...

    J Neurotrauma. 2018 Jan 16. doi: 10.1089/neu.2017.5400. [Epub ahead of print]
    Effects of treadmill training combined with serotonergic interventions on spasticity after contusive spinal cord injury.
    Ryu Y1, Ogata T2, Nagao M3, Sawada Y4, Nishimura R5, Fujita N6.

    Spasticity usually emerges during the course of recovery from spinal cord injury (SCI). While medications and physical rehabilitation are prescribed to alleviate spastic symptoms, the insufficiency of their effects remains an important problem to be addressed. Given the challenges associated with increasing the dose of medication, we supposed that a combination therapy with medication and physical rehabilitation can be effective. Therefore, we examined the effects of treadmill training (TMT) along with serotonergic medication using a spastic rat model after contusive injury. Spasticity-strong SCI rats were selected 4 weeks after SCI, and received combinatorial interventions for 2 weeks, i.e., either only TMT, TMT with fluoxetine (a selective serotonin re-uptake inhibitor), TMT with cyproheptadine (a 5-HT2 receptor antagonist), only fluoxetine, or only cyproheptadine. We performed the swimming test to quantify the frequency of spastic behaviors. We also evaluated hind limb locomotor functions every week. At the end of the intervention, we examined the Hoffman reflex from the plantar muscle and the immunoreactivity of the 5-HT2A receptor in spinal cord tissues. While the TMT group and cyproheptadine-treated groups showed decreased spastic behaviors and reduction in spinal hyperreflexia, the fluoxetine-treated group showed the opposite effect, even with TMT. Moreover, TMT suppressed the expression of the 5-HT2A receptor in the lumbar spinal motor neurons, while cyproheptadine treatment did not change it. We did not observe any differences in locomotor functions between the groups. Taken together, our findings indicate that TMT and cyproheptadine significantly alleviated spastic symptoms, but did not show synergistic or additive effects.

    J Neurochem. 2015 Feb;132(4):394-402. doi: 10.1111/jnc.12997. Epub 2015 Jan 23.
    Elevated spinal monoamine neurotransmitters after antenatal hypoxia-ischemia in rabbit cerebral palsy model.
    Drobyshevsky A1, Takada SH, Luo K, Derrick M, Yu L, Quinlan KA, Vasquez-Vivar J, Nogueira MI, Tan S.

    We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic-ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic-ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non-hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits' cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5-HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non-hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic-ischemic brain injury. Following prenatal hypoxia-ischemia, newborn rabbits exhibit elevated levels of serotonin in the spinal cord that were linked to muscle hypertonia. Serotonergic terminal density was also increased in hypertonic newborns' spinal cord. Intrathecal administration of the non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic newborns only. Elevated spinal serotonin thus suggests a novel pathophysiological mechanism of hypertonia in cerebral palsy.

    PM R. 2013 Dec;5(12):1077-80. doi: 10.1016/j.pmrj.2013.07.002.
    Deleterious cognitive and motoric effects of haloperidol in an adolescent with cerebral palsy: a case report.
    Mortimer D1, Gelfius CD2, Potts MA3.

    This case report describes a 15-year-old male patient with spastic diplegic cerebral palsy, Gross Motor Function Classification System Level III, who developed severe new cognitive and motoric impairments after the administration of haloperidol. He received this dopamine antagonist and typical antipsychotic medication for an acute postoperative episode of agitation. He improved when he received the dopamine agonists amantadine and carbidopa/levodopa. This case suggests that dopamine blockade may be deleterious for individuals with cerebral palsy. Potential explanations for the events observed in this case are also presented.


    Rev Neurol (Paris). 2000 Apr;156(4):380-3.
    [Akinetic mutism and progressive supranuclear palsy-like syndrome after the shunt of an obstructive hydrocephalus. Successful treatment with bromocriptine: 2 cases].
    [Article in French]
    Aidi S1, Elalaoui-Faris M, Benabdeljlil M, Benomar A, Chaoui M, Chkili T.

    Two cases of obstructive hydrocephalus who suffered multiple shunt failures and shunt revisions are presented. The patients developed after the neurochirurgical treatment a clinical syndrome of akinetic mutism followed by a Progressive Supranuclear Palsy-like (PSP) syndrome. The akinetic mutism and the PSP-like syndrome were remarkably improved with bromocriptine.
     
  4. OP
    haidut

    haidut Member

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    I don't know what you mean by the best but there are very few non-selective serotonin antagonists out there. Cyproheptadine is one of them, metergoline and ritanserin are the other two I know of. There are other partial antagonists like bromocriptine, lisuride, methyserdie, pergolide, etc but they seem to be mixed antagonist/agonist so may cause issues in some cases. Tianeptine is thought to be a SERT enhancer, so could be a good alternative to try.
     
  5. OP
    haidut

    haidut Member

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    Wow, I am beginning to wonder if there is any CNS pathology where serotonin is not involved. I guess it should not be surprising given how powerfully it inhibits metabolism everywhere.
     
  6. aguilaroja

    aguilaroja Member

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    Excuse the preaching to the choir.

    There has been insistence for years on proposing SSRI’s to boost serotonin to “relieve” Parkinsonian symptoms. You’d think that decades of evidence for high serotonin for causing tremor would be a clue.

    Many sorts of tremors seem to start with SSRI use (and with supplementing Tryptophan & 5HT), then subside with SSRI (&Trp) discontinuation. Visiting friends and family, I have pointed this out to doctors, including neurology movement specialists, who literally deny what they see.

    Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism
    “SSRI administration in PD patients may result in worsening of motor symptoms, at least in part, by exacerbating existing DA depletions through 5-HT2A/2C-mediated modulation of DA neurotransmission.”

    Sertraline-induced Hemichorea. - PubMed - NCBI
    “enhanced serotonergic transmission in the ventral tegmental area or nigrostriatum may be involved in sertraline-induced hemichorea.”

    Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studi... - PubMed - NCBI
    “Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements”

    Serotonergic modulation of nicotine-induced kinetic tremor in mice. - PubMed - NCBI
    “The 5-HT1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT1A antagonist).”

    Escitalopram-induced Parkinsonism. - PubMed - NCBI
    Two weeks after the initiation of escitalopram, the patient started complaining of tremor, rigidity, slowness of movement, use of small steps when walking difficulty to rise when seated, disturbance of speech and along with the development of a mask-like facial expression.”
    Escitalopram - Wikipedia
    “Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest selectivity for the serotonin transporter (SERT)”

    Serotonin toxicity: a short review of the literature and two case reports involving citalopram. - PubMed - NCBI
    “The serotonin toxicity is often described as a clinical triad of mental-status changes (agitation and excitement with confusion), autonomic hyperactivity (diaphoresis, fever, tachycardia, and tachypnea), neuromuscular abnormalities (tremor, clonus, myoclonus, and hyperreflexia) and, in the advanced stage, spasticity; not all of these findings are consistently present.”

    Effects and side effects associated with the non-nutritional use of tryptophan by humans. - PubMed - NCBI
    “…occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants).”

    A boy with tremor, diaphoresis, and altered behavior. - PubMed - NCBI
    “the clinical diagnosis of serotonin toxicity was corroborated when the pill exposure was identified as sertraline, a selective serotonin reuptake inhibitor.”
     
  7. OP
    haidut

    haidut Member

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    Thanks...and add to that evidence that serotonin is involved in demyelination of nerves as well as motor neuron dysfunction (ALS) and we basically see it is involved in most major classes of CNS pathologies. Interestingly, I think there are studies showing serotonin is involved in both ischemic and hemorrhaging strokes even though it would be expected to only contribute to the former. So, truly a neurotoxin when chronically elevated and it keeps getting promoted as panacea while Pfizer quietly runs its trials with terguride...
     
  8. Soren

    Soren Member

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    This might explain why Thiamine has a beneficial effect on PD as thiamine deficiency has been shown to impede expulsion of brain serotonin. Perhaps it has some kind of effect on SERT levels. I posted a study on this in another thread about PD awhile back, quoted below.

     
  9. OP
    haidut

    haidut Member

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    This is actually very interesting, as I also noticed extra thiamine produces signs of lower serotonin - clear vision, excellent cognition, calm, composed, etc. If you find anything on exogenous/extra thiamine's effects on serotonin please share.
     
  10. Koveras

    Koveras Member

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    Neurology. 1978 Jul;28(7):691-8.
    Thiamine deficiency: selective impairment of the cerebellar serotonergic system.
    Plaitakis A, Nicklas WJ, Berl S.
    To explore the role of thiamine deficiency in synaptic transmission, the high-affinity uptake and release systems for putative neurotransmitters were studied in synaptosomal preparations isolated from the telencephalon, hypothalamus, and cerebellum of rats made thiamine deficient by diet or pyrithiamine. There was significant decrease in the uptake of serotonin by the synaptosomal preparations of the cerebellum. Although thiamine and its phosphorylated forms added in vitro did not restore the decreased serotonin uptake, the administration of the vitamin in vivo resulted in a significant reversibility of the inhibition of serotonin uptake, coinciding with dramatic clinical improvement. The study supports the possibility of an important serotonergic innervation of the cerebellum and suggests a selective involvement of this system in the pathogenesis of some of the neurologic manifestations of thiamine deficiency.

    Although there was also this one...

    I think you just posted something about the context around agonists/antagonists being important..

    Effect of thiamine on serotonin levels in magnesium-deficient animals
    YoshinoriItokawa1 ChikakoTanaka2 MiekoKimura3
    To clarify the relationship between thiamine metabolism and peripheral vasodilation symptoms seen in the early stages of dietary magnesium deficiency, various synthetic diets were administered to rats. After a 4-wk period of thiamine excess and magnesium-deficient diet, blood serotonin levels increased significantly. A thiamine-deficient and magnesium-deficient diet revealed no elevation of blood serotonin. Serotonin in stomach and intestine increased in the excess-thiamine, magnesium-deficient group. Blood magnesium concentration decreased markedly in thiamine-supplemented, magnesium-deficient groups but not in the thiamine-deficient magnesium-deficient group. A possible explanation of the mechanism is presented.
     
  11. OP
    haidut

    haidut Member

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    Thanks. Don't these two studies sort of contradict each other though? I guess the second one was a special case of magnesium deficiency but still - in the first one extra thiamine increased serotonin uptake while in the second one blood serotonin increased (decreased uptake).
     
  12. Koveras

    Koveras Member

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    Exactly, why I threw in the reference to this post of yours

     
  13. Soren

    Soren Member

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    So these imply that without sufficient magnesium Thiamine increases serotonin levels. Something important to note for anyone taking high doses of thiamine.

    Sorry for stating the obvious but I am surprised by the results of these studies.
     
  14. No_Energy

    No_Energy Member

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    dlt. Sorry, can't find the function to delete the post. maybe there isn't one.
     
  15. Sheila

    Sheila Member

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    Dear All
    Thank you for these postings. I have a special interest in 'what goes wrong and why' when using higher thiamine levels and also (but largely unrelated) interest in understanding the system wide effects of cerebral palsy, so your postings here are greatly valued. The latter is very poorly understood and even more poorly managed clinically.
    I have seen the 'wired' response to cyproheptadine at low (1mg) and higher doses when one would imagine it would help to calm CNS-challenged patients (those with CNS pathologies), although I appreciate all systems are different. I always try to understand the mechanisms here so any light that can be shed on the 'boundaries' of use for useful agents such as thiamine and cypro are helpful, thanks.
    I have certainly observed increased spasticity/irritation/jerky movements in children whose guts are irritated which would point to increased serotonin I think and their thinking, for those that can communicate, becomes much harder for them.
    Thanks again - any more you have, especially @Koveras (since you have been researching here) would be most gratefully received.
    Sincerely,
    Sheila
     
  16. No_Energy

    No_Energy Member

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  17. No_Energy

    No_Energy Member

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    @haidut, great posts, thanks
    maybe you have more on this but,

    I suppose Tianeptine SSRE mechanism has been called into question. It was based on older study, considered to have some technical limitations . More recent studies showed tianeptine affinity for the serotonin transporter is actually low, and serotonin extracelular levels weren't altered by tianeptine use.

    "At that time, this finding was hypothesized to be the consequence of a 5-HT re-uptake enhancement. It has been demonstrated that tianeptine also reduced both the number of transporter sites and their mRNA levels in the dorsal raphe nucleus (88). However, any facilitatory influence of tianeptine upon 5-HT re-uptake may be exerted indirectly rather than directly at 5-HT transporters, for which its affinity is low.Further, the validity of older data has been contested on the basis of technical limitations that could not be circumvented at that time (89). More recent investigations have shown that acute and long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) inextracellular levels of 5-HT in cortico limbic structures of conscious rats (89,90) "

    Tianeptine effects seem more likely related to its actions on the glutamatergic system, (µ-opioid agonist athigher dosages).

    "From an electrophysiological point of view, sustained administration of tianeptine did not modify the spontaneous firing rate of serotonergic neurons in the dorsal raphe, nor did it modify the activity of postsynaptic 5-HT1A receptors nor the effectiveness of the terminal 5-HT autoreceptor antagonist in increasing the efficacy of the stimulation of the 5-HT pathway, despite prolonged treatment (90). Thus, the role of 5-HT in the mechanism of antidepressant efficacy of tianeptine is doubtful."
     
  18. OP
    haidut

    haidut Member

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    Thanks, I saw the studies questioning tianeptine as a SSRE, but there are isolated case studies where it helped with flushing from carcinoid syndrome and diarrhea, which are clearly serotonin driven. So, you are right - we probably do not know its full mechanism of action but based on what I have seen it certainly has an effect on serotonin, because it acts synergistically with sodium (salt) and the SERT is a sodium dependent protein.
     
  19. dfspcc20

    dfspcc20 Member

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    @haidut thanks!
    I did find some references to serotonin reduction possibly helping with intention tremor, and possibly being involved with essential tremors, both of which I'm mildly afflicted by.

    Intention tremor - Wikipedia
    "Another neurotransmitter targeted by drugs that has been found to alleviate intention tremors is serotonin. The agonist buspirone hydrochloride, which decreases serotonin's function in the central nervous system, has been viewed as an effective treatment of intention tremors.[1]"

    ^ Referenced link does not work for me, though.

    Essential Tremor: What We Can Learn from Current Pharmacotherapy

    "There is no known monoaminergic (norepinephrine, dopamine, histamine, serotonin) drug that benefits tremor. Serotonin re-uptake inhibitors often cause or worsen tremor. "

    Besides whole blood serotonin and prolactin, remind me what other blood tests are good surrogates for serotonin? I don't think I have any of the obvious symptoms of high serotonin, and low doses of cyproheptadine don't seem to impact the tremors for me.
     
  20. OP
    haidut

    haidut Member

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    I think NO and TNF-a, as well as NF-kB are all very tightly correlated with serotonin. Not sure if doctors will be willing to order these tests but you can try convincing them.
     
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