Physiology, Serotonin

Article Author:
Omar Bamalan
Article Editor:
Yasir Al Khalili
Updated:
8/10/2019 8:25:44 AM
PubMed Link:
Physiology, Serotonin

Introduction

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter that's of integral physiological importance for our body's systems as it regulates most of our (behaviors, mood, memory, etc.).[1] It is utilized as the main treatment for many psychiatric and neurological cases as a class of 5-HT elevating drugs called antidepressants which work on disorders such as Major depressive disorder, dysthymia, post-traumatic stress disorder, bulimia nervosa, obsessive-compulsive disorder, anxiety, aggressive behavior, premenstrual dysphoric disorder, panic disorders, social phobia, bipolar disorder, atypical depression and migraines.[2][3][4]

There was a noticed pattern of disrupted 5-HT levels in the areas of concentration in the CNS and peripherally in the plasma, which might have contributed to pathogenesis in most cases.[5][6] There is no consensus over the fact that 5-HT is the only main neurotransmitter involved in initiating the pathophysiological mechanism of neuropsychiatric disorders.[7][8] However, the potency of antidepressants which effect 5-HT levels has been proven, leading to elevation centrally and peripherally.[9][10][11] Consequently, restoring the homeostatic balance of 5-HT levels will increase the chances of good prognosis.

Issues of Concern

The serotonergic pathway's pre-synaptic axons terminals will start the formation of 5-HT through tryptophan hydroxylase utilizing tryptophan. Although, it is thought to be mainly in the CNS (raphe nuclei), maintaining cortical functions such as perception, memory, mood. It's also found in different sites (e.g., enterochromaffin cells, platelets, etc.), regulating its tone, functionality, and blood supply.[12][13][14] Then the release of 5-HT in the synaptic cleft, where it majorly has a receptor-dependent effect as through one pathway will cause adrenergic responses (e.g., mydriasis, increased heart, and respiratory rates, etc.), which in observation are adrenergic outcomes. Thus, different serotonergic and adrenergic receptor subtypes might show distinctive molecular affinities and actions.[15]

In the post-synaptic end, metabotropic G-protein receptors with high 5-HT affinity will initiate second messenger cascades. The cascades' visceral effect differs based on the receptor subtype. The metabotropic receptors (HTR1/2) alongside its different subtypes, has an effect of decreasing cyclic-AMP (CAMP), through the coupling of Gi/o protein alpha subunit (GNAI) in which the activity of adenylate cyclase (ADCY) will be inhibited.[16] On the other hand, (HTR4/6/7) cascades work on a coupling of Gs protein alpha (GNAS) which stimulates ADCY, and that leads to increased CAMP.[17] The only Ionotropic receptors (HTR3) will maintain electrolytic gradients.[18] The electrolytes gradient difference between sodium influx and potassium efflux will depolarize the membrane and facilitate the need for a physiological outcome. Therefore, the outcome has its basis on the visceral function in response to such induced gradient of CAMP.[19][20]

Moreover, as 5-HT plays a role in increasing CAMP concentration a partial function will be the downregulation of the innate immune system.[21][22] That plays a role in preventing symptoms from occurring in some hypersensitive pathologies such as asthma.[23][24]

Additionally, as 5-HT is a neurotransmitter there are few things to note down in regulating its function.

  • 5-HT receptors agonist/partial agonist (e.g. zolmitriptan): as we have different receptors, the postsynaptic receptors' concentration differs in certain viscera where it will either depolarize or hyperpolarize the cells. That plays a role in regulating the function of the receiving cells as either stimulatory or inhibitory effect. Therefore, maximizing the receptor's functionality will give us the needed outcome.[25][26][27]
  • Selective serotonin reuptake inhibitors (SSRI) (e.g. fluoxetine): predominantly used in the neuropsychiatric field of disorders. The SSRI's work by blocking the major 5-HT down-regulating, pre-synaptic reuptake channels (e.g. SLC6A4), resulting in increasing the 5-HT concentration. Consequentially, re-setting the abnormal feedback loop of the patient.[28][20]
  • Monoaminoxidase inhibitors (MAOI) (e.g. selegiline): Monoaminoxidase is one of 5-HT's degrading enzymes to maintain a balanced outcome. The reversible or irreversible inhibition of such enzymes will result in less degradation of 5-HT and other adrenergic neurotransmitters within the synaptic cleft (e.g. norepinephrine).[29]
  • Tricyclic anti-depressant (TCA) (e.g. imipramine): pre-synaptically, it blocks 5-HT and norepinephrine reuptake channels. Post-synaptically, it blocks cholinergic and histamine receptors. As a result, increasing the concentration of 5-HT.[30]

Similarly, there is also a range of different legal and illegal drug groups (e.g. SNRIs or ecstasy) that will work on elevating 5-HT concentration.

Cellular

Most patients would prefer to take the drug orally taken as a pill (PO). The other methods can be by applying dermal patches, through nasal route, intraperitoneal (IP) not clinically used, intramuscularly (IM) and intravenously (IV), each route has a different half-life, efficacy, and potency of the type of drug administered. Furthermore, in IV administration, one needs to be careful and monitor BP alongside vital signs and cardiac activity to prevent sudden deterioration.[31][32] Also, in (IM) injections applied for local vasoconstricting effect would cause the induction of pain in patients rather than alleviating it.[33] Intraperitoneal (IP) frequent administration has shown a correlation with disrupting thyroidal hormones function and concentration and other physiological functions, which is why it is not used clinically, only on experimental rats.[34][35][34] Although we have different forms of delivering 5-HT related drugs, we need to understand which route the patient is more comfortable with, which shows the needed efficacy to tackle the pathology.  

Development

5-HT has known and undiscovered functions; moreover, the adverse effects might range from mostly they are mild symptoms but can increase in severity. These adverse effects can present as hyperhidrosis, mydriasis, hypertension, nausea, dry mouth, constipation, rash, paranesthesia, akathisia, headaches, orthostatic hypotension, increased bleeding time, hyponatremia, insomnia, agitation, anxiety, extrapyramidal side effects, and sexual dysfunction.[36][37][38][39][40] The underaged patients might experience abnormal and/or suicidal thoughts; however, treatment continuation in neuropsychiatric disorders is of necessity.[41] Also, long term administration may induce the pathogenesis of carcinoid heart disease.[42][43]

The effects are further triaged based on hospitals' coding system to either minor, mild, or major (toxicity), has been made to elaborate more on how to approach and treat it. There has been increasing evidence that most patients are not adherent with their drug course, due to the evolving side effects that are relieved mostly by abstinence.[44][45]

Organ Systems Involved

  • Patients on an anticoagulant (e.g., warfarin) course.[46]
  • Contraceptives intake, as their mechanism of action, will antagonize catecholamines.[47][48]
  • Cardiac arrhythmic patients as 5-HT will increase the myocytes intracellular calcium, which will increase its contractility rate leading predominantly to abnormal and sometimes life-threatening arrhythmias (e.g., atrial fibrillation, ventricular tachycardia, etc.).[49][50]
  • Pregnant females: as the levels of drug will increase in the mother's serum supplying the embryo, which affects the embryo's neurodevelopmental pathways as 5-HT plays a major role in the process. Moreover, in lactating patients, there is not enough evidence suggesting continuation or termination; thus, adverse effects are yet not recorded.[51][52][53]
  • Epileptic patients: 5-HT is a major pathophysiological factor in epilepsy.[54][55][56]
  • Hypertensive patients: the serotonergic vasoconstricting action will lead to disrupted feedback and regulation of blood pressure, which causes fluctuations in blood pressure.[14][57][58]
  • Patients with ocular disorders (e.g., glaucoma).[59][60][61]

Function

Utilization of any drugs elevating or depleting 5-HT concentration peripherally or centrally need to be dosed appropriately and patient-oriented not fixed-doses administration. A room for dose changing while checking for tolerance is of therapeutic benefit.[62][63] The maintenance of serum-serotonin-level (SSL) at a range in between 101 to 283 nanograms per milliliter (ng/mL) is within normal levels. On the one hand, an increase in SSL above normal ranges can lead to cardiac arrhythmias.[1] Abrupt bone metabolic regulation by causing a decrease in the bone mineral density and abnormal regulation of metabolic processes such as lipolysis and gluconeogenesis.[64][65][66] On the other hand, a decrease in SSL generally correlates with depressive disorders and many neuropsychiatric disorders.[67][68] Thus, the true nature of pathogenesis is still not fully understood. Clinically, frequent checks of vital signs, cardiac rhythm, blood analysis, and the continuous checkups on patients for the appearance of any signs of toxicity or minor side effects.[69][70] Contrarily, if the patient after the drug's onset of action time has passed and there are no signs of the patient's evaluation improving, that might suggest an increase in dose to reach the needed concentration. Additionally, tryptophan plasma levels have shown to play a major indicator of decreased or increased SSL and its concentration centrally.[71][72]

Mechanism

Serotonin syndrome or toxicity (ST) is a combination of hyper-serotonergic visceral presentation. Toxicity can present when a patient receives a combination of 5-HT elevating drugs or in an overdose.[73][70] The spectrum of clinical manifestations can be life-threating, thus manageable signs and symptoms appear first, which help in early recognition. The signs and symptoms may develop 24-hours after administration as the drug's pharmacokinetic and pharmacodynamic processes take place. The diagnostic mechanism of ST is mostly dependent on a thorough history and physical examination while having increased emphasis on integrating Sternbach, Radomski, and Hunter's criteria of diagnosis.[70] The predominant diagnostic mechanism is having the presentation dependent on three parts, which are the neuromuscular, autonomic, and mental manifestations: 

Neuromuscular:

  • Tremor
  • Hyperreflexia
  • Myoclonus
  • Babinski sign
  • hypertonia

Autonomic:

  • Mydriasis
  • Diaphoresis
  • Tachycardia
  • Tachypnea
  • Hyperthermia
  • Vomiting
  • Arrhythmias

Mental[74][75][76][77]:

  • Agitation
  • Excitement
  • Insomnia
  • Confusion
  • Anxiety

Consequently, a presence in abnormalities within these three domain will confirm the diagnosis of ST. 

Related Testing

The multidisciplinary approach to deal with serotonin toxicity (ST) is crucial. The confirmation of the diagnosis also requires the combination of nurses, doctors, and toxicologists' investigatory methods. Nonetheless, blood analysis must be done to check for the appropriate plan of care to understand where the patient is standing and to alleviate patient's toxicity. Furthermore, health practitioners should be updated with the new edits to the diagnostic criterion of ST as the integration of Sternbach, Radomski, and Hunter's methods have shown optimum results so far. The presentation will require the triage nurse or doctor to understand the level of severity at which the patient's manifestations has reached. The next step is to manage to symptoms and try to get some history either from the patient if alert or family if possible. There is a need to contact the psychiatric ward for consultation if the patient has a file within the hospital and getting their feedback on whether it is a suicidal attempt or a part of a specific neuropsychiatric disorder the patient is facing. Therefore, formulating patient's data between nurses, doctors, toxicologists, pharmacists, and psychiatrists is the optimal path to early recognize ST and to treat it accordingly.  

Clinical Significance

The treatment of serotonin toxicity is mainly dependent on decreasing the dosages of the serotonergic agonist(s) taken by the patient. The maintenance of the patient's vital sign, continuous cardiac monitoring, and sedation by benzodiazepines are required; moreover, controlling the patient's hyperthermia by IV cold fluid and antipyretics is essential to prevent further autonomic and neuromuscular disruption.[78][79] Eventually, a serotonin antagonist might be necessary. Cyproheptadine is the first-line choice and is considered as an antidote, though caution is advisable as there are reports of prolonged sedation and transient hypotension.[80] The resolution of mild to moderate cases can be within 24 hours, as early recognition and management is key to improved prognosis.[81]


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