Serotonin & Antiserotonin Drugs

Serotonin (5-hydroxytryptamine, 5-HT) is a key autacoid acting as a neurotransmitter, vasoactive amine and gut regulator. This chapter consolidates its synthesis, the bewildering family of 5-HT receptors, the major agonists and antagonists, and the two clinical scenarios examiners love: carcinoid syndrome and serotonin syndrome.

Synthesis, storage and metabolism

5-HT is synthesised from the essential amino acid L-tryptophan in a two-step pathway:

Tryptophan → (tryptophan hydroxylase) → 5-hydroxytryptophan (5-HTP) → (aromatic L-amino acid decarboxylase / DOPA decarboxylase) → 5-HT

• Tryptophan hydroxylase is the rate-limiting enzyme and requires tetrahydrobiopterin (BH4) as cofactor; it is NOT saturated under normal conditions, so serotonin synthesis depends on dietary tryptophan availability.
• The decarboxylase step uses pyridoxal phosphate (vitamin B6) and is the same enzyme that converts L-DOPA to dopamine.
• About 90% of total body serotonin resides in the enterochromaffin (EC) cells of the gut; the remainder is in platelets (which take up but cannot synthesise it) and CNS raphe neurons.
• 5-HT is stored in vesicles via VMAT and released by exocytosis. Action is terminated by reuptake through the serotonin transporter (SERT) — the target of SSRIs.
• Degradation: 5-HT → (monoamine oxidase, MAO-A) → 5-hydroxyindole acetaldehyde → 5-hydroxyindoleacetic acid (5-HIAA), excreted in urine. Urinary 5-HIAA is the key diagnostic metabolite for carcinoid.

High-yield: Tryptophan hydroxylase is rate-limiting; MAO (chiefly MAO-A) degrades serotonin to 5-HIAA, the urinary marker measured in carcinoid syndrome.

5-HT receptor subtypes

There are seven families (5-HT1 to 5-HT7). All are G-protein coupled EXCEPT 5-HT3, which is a ligand-gated cation channel (ionotropic) — a classic single-best-answer fact.

Receptor	Type / coupling	Key location	Main effect	Clinically relevant drug
5-HT1A	Gi (↓cAMP)	Raphe (autoreceptor), hippocampus	Anxiolysis, hyperpolarisation	Buspirone (partial agonist)
5-HT1B/1D	Gi	Cranial vessels, trigeminal nerve	Vasoconstriction, ↓CGRP release	Triptans (agonist), ergots
5-HT2A	Gq (↑IP3/DAG)	Smooth muscle, platelets, cortex	Vasoconstriction, aggregation, hallucination	Atypical antipsychotics, ketanserin (antag)
5-HT2B	Gq	Cardiac valves, pulmonary vessels	Fibrosis, valvulopathy	(Off-target: fenfluramine, ergots, methysergide)
5-HT2C	Gq	Choroid plexus, hypothalamus	Appetite suppression	Lorcaserin (agonist)
5-HT3	Ligand-gated cation channel	Area postrema/CTZ, vagal afferents, gut	Emesis, gut secretion/motility	Ondansetron (antag)
5-HT4	Gs (↑cAMP)	GI myenteric plexus	Prokinetic (↑ACh release)	Prucalopride, cisapride (agonist)
5-HT7	Gs	CNS, vessels	Mood, circadian, vasodilation	Lurasidone, vortioxetine

High-yield: 5-HT3 = ionotropic ligand-gated channel; every other 5-HT receptor is GPCR. 5-HT4 agonists are prokinetic, while 5-HT3 antagonists are antiemetic.

Serotonin agonists — drug by drug

Triptans (sumatriptan and the "-triptans")

• Mechanism: selective 5-HT1B/1D agonists. 5-HT1B mediates cranial vasoconstriction; 5-HT1D inhibits trigeminal release of CGRP and other vasoactive peptides, reducing neurogenic inflammation.
• Use: acute migraine and cluster headache (NOT prophylaxis).
• Sumatriptan: poor oral bioavailability (~15%), available subcutaneous/intranasal; short half-life (~2 h). Newer agents (naratriptan, frovatriptan) have longer half-lives.
• Adverse: chest tightness/"triptan sensations", coronary vasospasm.
• Contraindications: ischaemic heart disease, Prinzmetal angina, uncontrolled hypertension, recent ergot use (within 24 h) and concurrent MAO inhibitors.

High-yield: Triptans (5-HT1B/1D agonists) abort acute migraine; contraindicated in coronary artery disease. Do NOT combine with ergot alkaloids within 24 hours (additive vasospasm).

Ergot alkaloids (ergotamine, dihydroergotamine, methysergide)

• Mixed/partial agonist–antagonist at 5-HT, alpha-adrenergic and dopamine receptors — "dirty" drugs.
• Ergotamine: acute migraine (now largely replaced by triptans). Ergometrine/methylergometrine: postpartum haemorrhage (uterotonic).
• Methysergide: migraine prophylaxis but causes retroperitoneal, pleural and endocardial fibrosis (5-HT2B mediated) — limited use, drug holidays required.
• Toxicity = ergotism: intense vasoconstriction → gangrene of extremities ("St. Anthony's fire"), and oxytocic uterine contraction.

Other agonists

• Buspirone: 5-HT1A partial agonist — non-sedating anxiolytic for generalised anxiety disorder; delayed onset (1–2 weeks), no dependence.
• Cisapride / prucalopride / mosapride: 5-HT4 agonists, prokinetics. Cisapride withdrawn in many markets due to QT prolongation and torsades.
• Tegaserod: 5-HT4 agonist for IBS with constipation.
• Lorcaserin: 5-HT2C agonist (anti-obesity; withdrawn over cancer concern).
• Fenfluramine/dexfenfluramine: serotonin releasers — withdrawn after causing valvular heart disease and pulmonary hypertension (5-HT2B).

Serotonin antagonists (antiserotonin drugs)

Drug	Receptor blocked	Principal use	Notable point
Ondansetron, granisetron, palonosetron	5-HT3	Chemotherapy/radiation & post-op nausea	Palonosetron longest acting; can prolong QT
Cyproheptadine	5-HT2 + H1 (antihistamine)	Carcinoid diarrhoea, cold urticaria, appetite stimulation, serotonin syndrome antidote	Also weak anticholinergic
Ketanserin	5-HT2A (+ alpha-1)	Hypertension (limited)	Research/antihypertensive
Methysergide	5-HT2 (partial agonist)	Migraine prophylaxis	Fibrosis risk
Clozapine, olanzapine, risperidone	5-HT2A + D2	Atypical antipsychosis	5-HT2A block → fewer EPS
Mirtazapine	5-HT2/5-HT3 + alpha-2	Depression	Appetite gain, sedation
Pizotifen	5-HT2	Migraine prophylaxis	Antihistaminic

Ondansetron — the exam favourite

• Selective 5-HT3 antagonist acting on vagal afferents and the chemoreceptor trigger zone (area postrema).
• Indication of choice for chemotherapy-induced nausea/vomiting (CINV), especially highly emetogenic regimens (cisplatin), and post-operative nausea/vomiting (PONV).
• Most effective against the acute (first 24 h) phase of CINV; for delayed CINV add an NK1 antagonist (aprepitant) and dexamethasone.
• Adverse: headache, constipation, QT prolongation (avoid with other QT-prolonging drugs).

High-yield: First-line antiemetic for cisplatin chemotherapy = 5-HT3 antagonist (ondansetron) + dexamethasone + NK1 antagonist (aprepitant).

Cyproheptadine

• Combined 5-HT2 and H1 receptor antagonist with antimuscarinic action.
• Uses: appetite stimulation, cold-induced urticaria, control of carcinoid diarrhoea, and most importantly the specific antidote for serotonin syndrome.

Carcinoid syndrome (excess serotonin)

Carcinoid tumours are neuroendocrine tumours of EC cells, commonly in the terminal ileum/appendix, secreting serotonin and other vasoactive amines.

• The classic syndrome appears only after hepatic metastasis (because the liver normally inactivates serotonin draining via the portal vein; metastatic deposits release serotonin into systemic circulation).
• Clinical triad/features: episodic flushing, secretory diarrhoea, bronchospasm/wheeze, and right-sided valvular heart disease (tricuspid regurgitation, pulmonary stenosis — left side spared because lung MAO degrades serotonin). Niacin deficiency (pellagra) can occur as tryptophan is diverted to serotonin.

Diagnostic approach:

1. Urinary 5-HIAA (24-hour) — investigation of choice; avoid serotonin-rich foods (banana, pineapple, walnuts) before the test.
2. Serum chromogranin A (sensitive marker). 3 Octreotide (somatostatin receptor) scan / Ga-68 DOTATATE PET for localisation; CT/MRI for metastases.

Management:

• Octreotide / lanreotide (somatostatin analogues) — drug of choice for symptom control of flushing and diarrhoea.
• Telotristat ethyl — tryptophan hydroxylase inhibitor; reduces serotonin synthesis for refractory diarrhoea.
• Cyproheptadine for diarrhoea; surgical resection where feasible.
• For carcinoid crisis (severe hypotension during anaesthesia/manipulation): IV octreotide.

High-yield: Carcinoid → right-heart valve disease (TR/PS); urinary 5-HIAA is diagnostic; octreotide is the drug of choice. Left heart spared due to pulmonary MAO.

High-yield mnemonic — Carcinoid "FDB-R": Flushing, Diarrhoea, Bronchospasm, Right-sided valvular lesions.

Serotonin syndrome (the toxic excess)

A potentially fatal hyperserotonergic state from drug combinations that raise synaptic serotonin.

Precipitating combinations (most tested):

• SSRI/SNRI + MAO inhibitor (classic, most dangerous)
• SSRI + tramadol, pethidine (meperidine), fentanyl
• SSRI + linezolid (a reversible MAO inhibitor) or methylene blue
• SSRI + triptans, St. John's wort, dextromethorphan, ondansetron
• MDMA/amphetamines, lithium added to serotonergic agents

Clinical triad (Hunter criteria basis):

1. Neuromuscular hyperactivity — clonus (especially inducible/ocular), hyperreflexia, tremor, rigidity (lower limb > upper).
2. Autonomic instability — hyperthermia, tachycardia, diaphoresis, mydriasis, diarrhoea.
3. Altered mental status — agitation, confusion.

Feature	Serotonin syndrome	Neuroleptic malignant syndrome (NMS)
Offending drug	Serotonergic (SSRI, MAOI)	Dopamine blocker / withdrawal of DA agonist
Onset	Rapid (<24 h)	Slow (days)
Neuromuscular	Clonus, hyperreflexia	Lead-pipe rigidity, bradyreflexia
Pupils	Mydriasis	Normal
Bowel sounds	Hyperactive	Normal/decreased
Antidote	Cyproheptadine	Dantrolene, bromocriptine

Management flow: Stop offending drug → supportive cooling + IV fluids + benzodiazepines (control agitation/rigidity) → cyproheptadine (5-HT2A antagonist) if no response → consider intubation/paralysis for severe hyperthermia.

High-yield: Serotonin syndrome = clonus + hyperreflexia + hyperthermia, onset within hours; specific antidote is cyproheptadine. The classic precipitant is SSRI + MAOI, and linezolid + SSRI is a frequently asked combination.

Drugs acting on serotonin reuptake / metabolism

• SSRIs (fluoxetine, sertraline, paroxetine, etc.): block SERT → ↑ synaptic 5-HT; first-line for depression/anxiety/OCD. Discontinuation syndrome with abrupt stop (paroxetine worst).
• SNRIs (venlafaxine, duloxetine): serotonin + noradrenaline reuptake inhibition.
• MAO inhibitors block degradation; with serotonergic agents → syndrome (above) and with tyramine-rich food → hypertensive crisis ("cheese reaction").
• Vortioxetine: SERT inhibition plus 5-HT3 antagonism and 5-HT1A agonism ("multimodal").

Key differentials & decision points

• Flushing differential: carcinoid vs phaeochromocytoma (catecholamine, hypertension, metanephrines) vs mastocytosis (tryptase, urticaria pigmentosa) vs menopause/medications.
• Antiemetic choice: motion sickness → antimuscarinic/antihistaminic (hyoscine); CINV → 5-HT3 antagonist; gastroparesis/prokinesis → 5-HT4 agonist or metoclopramide; vertigo → antihistamine.
• Migraine acute vs prophylaxis: triptans/NSAIDs for acute attack; beta-blockers, topiramate, amitriptyline, CGRP antibodies for prophylaxis (NOT triptans).

Recently asked / exam angle

• "Which 5-HT receptor is a ligand-gated ion channel?" → 5-HT3.
• Mechanism of sumatriptan → 5-HT1B/1D agonist; contraindicated in ischaemic heart disease.
• Drug of choice for cisplatin-induced acute vomiting → ondansetron (5-HT3 antagonist), combined with dexamethasone ± aprepitant.
• Antidote for serotonin syndrome → cyproheptadine.
• Urinary marker in carcinoid → 5-HIAA; valvular lesion → right-sided (TR/PS).
• Rate-limiting enzyme in serotonin synthesis → tryptophan hydroxylase.
• Drug combination precipitating serotonin syndrome → SSRI + MAOI / SSRI + tramadol / SSRI + linezolid.
• 5-HT4 agonist used as prokinetic → prucalopride/cisapride; cisapride → QT prolongation.
• Methysergide / ergot adverse effect → retroperitoneal & cardiac valvular fibrosis (5-HT2B).
• Buspirone mechanism → 5-HT1A partial agonist for GAD.

Rapid revision

1. Tryptophan hydroxylase = rate-limiting enzyme; needs BH4.
2. 90% of body serotonin is in gut EC cells; platelets store but don't synthesise.
3. MAO-A degrades 5-HT to 5-HIAA (urinary carcinoid marker).
4. 5-HT3 is the only ionotropic 5-HT receptor; all others are GPCRs.
5. Triptans = 5-HT1B/1D agonists for acute migraine; avoid in CAD and with ergots.
6. Ondansetron = 5-HT3 antagonist acting on CTZ/vagal afferents; best for acute CINV; causes QT prolongation, headache, constipation.
7. Cyproheptadine blocks 5-HT2 + H1; antidote for serotonin syndrome and used in carcinoid diarrhoea.
8. Carcinoid → flushing, diarrhoea, bronchospasm, right-sided valve disease; appears after liver metastasis; treat with octreotide.
9. Serotonin syndrome = clonus + hyperreflexia + hyperthermia within hours; classic trigger SSRI + MAOI; antidote cyproheptadine.
10. NMS differs by lead-pipe rigidity, bradyreflexia, slow onset; antidote dantrolene/bromocriptine.
11. 5-HT4 agonists (prucalopride, cisapride) are prokinetics; cisapride → torsades.
12. Methysergide/ergots → fibrosis and ergotism (gangrene); buspirone = 5-HT1A partial agonist anxiolytic.