Introduction
Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter with an integral physiological role in the human body; it is involved in regulating various activities (e.g., behavior, mood, memory).[1] In addition, it is utilized as a primary target of treatment for many psychiatric and neurological disorders (e.g., major depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, anxiety disorders).[2][3][4]
These treatments target 5-HT (either by increasing the neurotransmitter's concentration or maximizing the receptors' potentiality), which contributes to partial alleviation of such disorders' pathophysiological underlying schema. There is experimental evidence demonstrating reduced central nervous system (CNS) and plasma serotonin levels in patients with major depressive disorder and low mood, in general.[5][6] This results in significant post-therapeutic outcomes in patients' clinical and social status.[7][8][9]
There is no consensus on whether serotonin should be the only factor studied extensively regarding these pathologies as they commonly manifest in multifactorial pathophysiology.[10][11] Hence, their algorithm of management may include several psychological interventions (e.g., cognitive behavioral therapy, psychoanalysis) and adjunctive therapies, which lay on a spectrum of pharmacological (e.g., anxiolytics, sedatives, antipsychotics) and non-pharmacological (e.g., acupuncture, cupping, physiotherapies, exercises) therapies.
Cellular
The synthesis of serotonin begins with the essential amino acid tryptophan, which is utilized by tryptophan hydroxylase yielding 5-hydroxy-L-tryptophan, which is then processed through Aromatic L-amino acid decarboxylase forming 5-HT. Although it was thought to be mainly in the CNS raphe nuclei maintaining cortical functions, it is also found in other systems (e.g., enterochromaffin cells, platelets and the coagulation cascade, blood vessels), in which 5-HT has a different mechanism of action, type of receptors' predominance and resultants.[12][13][14]
The release of 5-HT in the synaptic cleft, which has a receptor-dependent effect, will cause an adrenergic-like response that is physical (e.g., mydriasis, increased heart, respiratory rate, and blood pressure) and neuropsychiatric (e.g., agitation, hallucinations, delirium). However, different therapies that target serotonergic and adrenergic receptor subtypes independently might show a distinctive molecular affinity to various subtypes, which is receptor and site-dependent (i.e., demonstrating experimentally that there might be cross-reactivity between the two families of receptors).[15]
In the post-synaptic membrane, metabotropic G-protein receptors with high 5-HT affinity initiate second messenger cascades. The cascades' visceral effect differs based on the receptor subtype. The metabotropic receptors (HTR1/2), alongside its different subtypes, decreases cyclic-adenosine monophosphate (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 by coupling Gs protein alpha (GNAS), which stimulates ADCY, leading to increased CAMP, while the ionotropic receptors (HTR3) maintain electrolytic gradients in the gastrointestinal tract and seem to be contributing to chemotherapy-induced nausea and vomiting.[17][18] In addition, the electrolyte gradient difference between sodium influx and potassium efflux will depolarize the membrane, leading to inter-neuronal synaptic modulation and possible aversion to dysregulation and neuropsychiatric manifestations.[19][20]
The mechanism of 5-HT, increasing CAMP concentration, can work on downregulation of the innate immune system, which correlates with psychological wellbeing (5-HT levels dependent) and several disorders' pathophysiology (e.g., asthma exacerbations, atopic dermatitis), that has an element of hypersensitivity with possible emotional triggers.[21][22][23][24]
Function
Various drug classes affect the serotonergic system in the CNS and peripherally, with distinct utility and side effects. There are several classes:
Selective Serotonin Reuptake Inhibitors (SSRI) (e.g., citalopram, fluoxetine)
These are the first line of medications in moderate to severe anxiety disorders and depressive disorders; they can also be used in other neuropsychiatric disorders (e.g., eating disorders, obsessive and compulsive disorders) as adjunctive therapies. Furthermore, the mechanism of action is by blocking the major 5-HT down-regulating pre-synaptic reuptake channels (e.g., SLC6A4), increasing 5-HT concentration. Consequently, resetting the abnormal feedback loop of the patient's inter-neuronal synapses, targeting the hypothesized pathophysiology of low 5-HT concentration in patients' CNS and serum.[42][20]
Side effects include headache, agitation or mild irritability, dyssomnia or sleepiness, nausea or constipation, dizziness, and sexual dysfunction (e.g., delayed ejaculation, absence of orgasm, decreased sense of pleasure). Hence, the patient education session should be thorough, covering several areas (check your facility's protocol). The starting dose will be sub-therapeutic for 1 to 2 weeks and then increase to the therapeutic dose. The reason is to decrease the severity and likelihood of experiencing any side effects mentioned above, which can be transiently experienced in the first two weeks. Secondly, the mood will be regulated in approximately four weeks, but that is not an indication to stop taking the medication.
Therefore, Patients that abruptly stop their medications without notifying the provider after 6 to 8 weeks of intake might have manifestations of serotonin discontinuation syndrome (i.e., increased anxiety similar to the pre-treatment levels or higher, myalgia and malaise, flu-like state, brain zaps which are an electricity-like sensation on their head), that is associated with low half-life SSRIs (e.g., paroxetine, fluvoxamine). The management is to reinitiate the treatment, and the symptoms will resolve in 1 to 3 days. On the other side, the risk of serotonin syndrome (check clinical significance section) is increased if a drug holiday period of 2 to 4 weeks is not taken between shifting from SSRIs to monoaminoxidase inhibitors.
Several studies have analyzed the association between initiation of SSRIs and suicidality.[12][13] The hypothesized mechanism is that treating the neuronal dysregulation goes through phases; the first is gaining back lost energy and not the mood. Hence, the suicidal thoughts might still be in their realm, and they have not acted upon because it requires effort, and now they have the energy. In addition, there is a group of psychiatric side effects, such as activation syndrome (i.e., a group of psychiatric manifestations of insomnia, irritability, akathisia, agitation, or mania, which is observed at an unknown rate in patients after SSRI initiation) and several others (e.g., anxiety, apathy, tremors), that seem to have a clinical correlation.[13]
Monoaminoxidase Inhibitors (MAOI) (e.g., phenelzine, selegiline)
MAOIs are a class used in resistant depressive disorders and anxiety disorders that fail to respond to SSRIs. The mechanism of action is by antagonism of monoaminoxidase, as it is one of the enzymes that degrade 5-HT. They cause both reversible and irreversible antagonism of this enzyme, which will result in less degradation of 5-HT and other adrenergic neurotransmitters within the synaptic cleft (e.g., norepinephrine, dopamine), alleviating the clinical manifestations.[43] The side effects profile includes sweating, tremors, sedation, postural hypotension, atropine-like effects (e.g., blurry vision, dry mouth, urinary retention), and mild agitation.
The patients should understand that it takes 2 to 4 weeks for the drug to work, and there must be a drug holiday from SSRIs before the shift to MAOIs; once started, there will be a list of medications they cannot take (e.g., amphetamine, pseudoephedrine, john wart herb), as it has a wide range of drug-drug interactions leading to serotonin syndrome. Nonetheless, certain types of food and drinks should also be avoided (e.g., cheese, alcohol, pickles), as they contain quantities of tyramine which induces the release of norepinephrine, leading to a Hypertensive crisis.[14]
Tricyclic Anti-depressant (TCA) (e.g., desipramine, imipramine)
This class was the first line of drugs for depressive and anxiety disorders; however, currently, it is used in resistant or atypical cases, secondary to its side effects profile. The mechanism of action is by pre-synaptically blocking 5-HT and norepinephrine reuptake channels while post-synaptically blocking cholinergic and histamine receptors. As a result, the concentration of 5-HT is increased, alongside its effect on the other receptors' functionality, which sets the mechanism of each group of receptors' possible side effects.[44]
The side effects are:
- Sedation and increase in weight (antihistamine)
- Atropine-like effect (anti-cholinergic)
- Refractory tachycardia with or without hypotension, arrhythmia (e.g., supraventricular tachycardia, ventricular tachycardia) (norepinephrine agonism)
Therefore, patients should be educated that it takes around two weeks to work and that the physician should consult the list of side effects and drugs before initiation to prevent any drug interactions. There is a possibility of overdosing either intentionally (suicidal attempt) or secondary to the class's narrow therapeutic index. After hemodynamic stabilization, the management of an overdose is by activated charcoal (if in less than 2 hours), sodium bicarbonate, and benzodiazepines, while monitoring the patient's urinalysis and electrocardiogram (ECG).
5-HT Receptors Agonist/Partial Agonist (e.g., zolmitriptan)
This class is used in migraine episodes' management, and contraindication must be ruled out before initiation (e.g., uncommon migraine, hypertension, ischemic heart disease). The mechanism of action is by affecting different cortical nuclei, as post-synaptic 5-HT receptors when activated, may cause an excitatory or inhibitory effect on the post-synaptic cell. Therefore, maximizing the receptor's functionality in serotonin-deficient disorders will optimize the function of the systems requiring this neurotransmitter.[39][40][41] The possible side effects are dizziness, nausea, elevated blood pressure, and nasal irritation (the usual route of intake). Similarly, a range of illegal drug groups (e.g., ecstasy) will elevate 5-HT concentration.
Pathophysiology
Serotonin syndrome (SS) or toxicity (ST) is a combination of hyper-serotonergic stimulation on CNS and visceral organs, resulting from a patient receiving a combination of 5-HT elevating drugs or an overdose.[45][46] The spectrum of clinical manifestations can be life-threatening; thus, recognizing the manageable signs and symptoms that appear first is crucial to preventing deterioration. The signs and symptoms may develop 24 hours after administration as the drug's pharmacokinetics and pharmacodynamic processes occur. The diagnostic criterion of SS mostly depends on a thorough history and physical examination while considering Sternbach, Radomski, and Hunter's criteria for diagnosis.[46] However, if a patient's prior history of an anti-depressant's initiation, suicidality, or ingesting other drugs with a possible drug-drug interactions with multisystemic manifestations, then SS should be ruled out.
The predominant diagnostic criteria consider the patients' presentation depends on symptoms or signs reflecting the neuromuscular, autonomic, and mental manifestations of SS.[47][48][49][50] These include:
Neuromuscular
- Tremor
- Hyperreflexia
- Myoclonus
- Babinski sign
- hypertonia
Autonomic
- Mydriasis
- Diaphoresis
- Tachycardia
- Tachypnea
- Hyperthermia
- Vomiting
- Arrhythmias
Neurological
- Agitation
- Excitement
- Insomnia
- Confusion
- Anxiety
The severity assessment is based on the type and extent of manifestations, formulating a mild, moderate, and severe SS spectrum. The mild presentation (e.g., nervousness, insomnia, tremors), the moderate (e.g., hyperreflexia with or without clonus, agitation, horizontal nystagmus), and severe might lead to stupor, coma, and rarely death.[15]
Clinical Significance
The management of serotonin syndrome mainly depends on decreasing the dose of the offending serotonergic agonist(s) taken by the patient. The maintenance of the patient's vital signs, continuous cardiac monitoring, and sedation by benzodiazepines are required; moreover, controlling the patient's hyperthermia by intravenous (IV) cold fluid and antipyretics is essential to prevent further autonomic and neuromuscular disruption.[61][62] Eventually, a serotonin antagonist might be necessary; cyproheptadine is the first-line choice and is considered an antidote, though caution is advisable as there are reports of prolonged sedation and transient hypotension.[63] The resolution of mild to moderate cases can be within 24 hours, and early recognition and management are key to improving prognosis.[64]
The drugs that elevate or deplete 5-HT concentration peripherally or centrally need to be dosed appropriately and in a patient-oriented manner, as dose titration following initiation of therapy and monitoring patient symptoms is of therapeutic benefit.[51][52] The goal of therapy is to maintain serum serotonin level (SSL) at a range between 101 to 283 nanograms per milliliter (ng/mL). Clinically, frequent checks of vital signs, cardiac rhythm, blood analysis, and regular review of signs of toxicity or minor side effects are prudent, given the risk of toxicity, particularly if the serotonergic drug has recently been added to the patient's regimen.[53][46] Conversely, if the patient's hypo-serotonergic symptoms have not improved, a dose increase may be required. Additionally, tryptophan plasma levels have been demonstrated as a significant indicator of decreased or increased serum serotonin level and its concentration.[54][55]
The usual route patients take serotonergic drugs is oral as a pill preparation; while alternative methods are available, including dermal patches, nasal spray, intramuscular (IM), and IV solutions, it is important to note that each route has a different half-life, efficacy, and potency of the type of drug administered. Furthermore, in IV administration, one must be careful and monitor blood pressure alongside other vital signs and cardiac activity to prevent sudden deterioration.[56][57] Moreover, IM injections applied for local vasoconstricting effects may cause local irritation, swelling, and pain.[58] Lastly, intraperitoneal (IP) administration is used in experimental research in mice and has shown a correlation with disrupting thyroid hormone function.[59][60]
Physiology, Serotonin