• Information
  1. Overview
  2. 5HT-1 Receptors
  3. 5HT-2 Receptors
  4. 5HT-3 Receptors
  5. 5HT-4 Receptors
  6. Additional 5HT Receptors
  7. Additional Serotonin Enhancing Agents
  8. Additional Serotonin Blocking Agents
  9. Serotonin Syndrome
  10. Neonatal Effects of Serotonin Reuptake Inhibitors

A. Overview

1. Six distinct families of serotonin (5-hydroxytrypamine, 5HT) receptors:
   1. 5HT1, 5HT2, 5HT3, 5HT4, 5HT6, 5HT7
   2. Subtypes of 5HT1 and 5HT2 exist
   3. Isoforms of multiple receptors including 5HT4
   4. All told, 14 distinct serotonin receptors
2. All receptor coupled to G proteins except 5HT-3R
   1. Except 5HT-3R, all are 7 transmembrane proteins
   2. 5HT-3R is a 4 transmembrane gated ion channel protein
3. Key Organ Systems Producing and Metabolizing Serotonin
   1. Enterochromaffin Cells - in gastrointestinal tract, produce a great deal of 5HT
   2. Platelets - uptake, storage and release of 5HT; platelets cannot synthesize 5HT
   3. Major catabolism by monoamine oxidase (MAO)
   4. Minor catabolism by sulfation and O- or N-methylation
   5. Clearance of intact 5HT by uptake in neurons and platelets (via Na+ coupled transporter)
4. Key Organ Systems regulated by Serotonin
   1. Cardiovascular (CV)
   2. Gastrointestinal (GI)
   3. Central Nervous System (CNS)
5. CV Effects
   1. Vasoconstriction
   2. Increased platelet aggregation (synergizes with collagen)
   3. Direct constrictor effects on vascular smooth muscle
   4. Possible role in vasospastic disease (such as atypical angina, Raynaud's)
   5. Positive inotropic and chronotropic actions on heart
   6. Can also activate Bezold-Jarisch reflex (extreme bradycardia, hypotension)
   7. Overexposure to serotonin can lead to valve abnormalities, ? pulmonary hypertension
6. GI Tract
   1. 5HT from enterochromaffin cells enter portal vein
   2. Major metabolism by MAO A (MAO-A) in liver
   3. Unmetabolized MAO-A is removed by endothelium in lung capillaries
   4. Effects on GI variable depending on receptor expression
   5. In general, gut motility (peristalsis) and secretion are stimulated
7. CNS
   1. Sleep
   2. Cognition
   3. Appetite
   4. Motor activity
   5. Sensory Perception
   6. Sexual Behavior
   7. Hormone Secretion
   8. Temperature Regulation
   9. Addiction behavior, particularly alcohol [1]
   10. Fourteen of the 15 cloned HT receptors are expressed in CNS
   11. Overexposure of neurons to serotonin can lead to cell death

B. 5HT-1 Receptors

1. Five members currently known
2. Interact with inhibitor G protein (Gi)
   1. Inhibits adenylyl cyclase (AdCyc) activity
   2. Pertussis toxin-sensitive Gi/Go family of G proteins
3. All 5HT-1 R are intronless
4. 5HT-1A R
   1. Also activates receptor operated K+ channel and blocks VG Ca2+ channel
   2. Found in raphe nuclei of brainstem
   3. Functions as somatodendritic autoreceptor on cell bodies of serotonergic neurons
   4. Buspirone (Buspar®) and ipsaperone are partial agonists for anxiety and depression
   5. Eltoprazine has 5HT-1A and 5HT-1B agonist activity
5. 5HT-1B R
   1. Autoreceptor activity, gated K+ channels
   2. Found in subiculum and substantia nigra
   3. Found in cranial vessels where these mediate vasoconstriction
6. HT-1D R
   1. Autoreceptor on axon terminals, inhibits 5HT release
   2. Substantia nigra and basal ganglia
   3. May regulate rate of dopamine-containing cells and release of dopamine
   4. Found in cranial vessels where these mediate vasoconstriction
7. HT-1F R
   1. No effect on cerebral or coronary blood vessels
   2. Likely involved in migraine etiology
   3. LY334370 is an HT-1F R agonist with antimigraine efficacy in humans [15]
   4. LY334370 does not cause vasoconstriction, so mechanism of action in migraine unclear
8. Triptans (Antimigraine Agents) [17,20,29]
   1. Selective agonists primarily for 5HT-1B and -1D R
   2. Also bind to 5HT-1F
   3. 5HT-1B agonism can lead to coronary artery (as well as cerebral) vasoconstriction
   4. Contraindicated in patients with cerebrovascular or coronary artery disease (CAD)
   5. However, these agents are safe in many patients with minimal CAD [18]
   6. First generation Sumatriptan (Imitrex®) and others
   7. Second generation with improved onset of action and oral bioavailability
   8. Eletriptan, rizatriptan, almotriptan provide highest success rates for migraines

C. 5HT-2 Receptors

1. Three subtypes of 5HT-2R
2. Linked to phospholipase C with generation of DAG and PIP2
3. Couple to pertussis toxin-insensitive G proteins (eg. Gq)
4. HT-2A R
   1. Coupling to various G proteins is tissue dependent
   2. Broadly distrubuted in CNS, mainly prefrontal cortex, claustrum
   3. Found on platelets
   4. Gastrointestinal Tract
   5. Receptor polymorphisms linked to anorexia nervosa, OCD, but not to bulimia [3,4]
5. 5HT-2B R
   1. Stomach fundus
   2. Vascular beds, particularly pulmonary
   3. Thusfar not found in CNS
   4. Drugs with 5HT-2B R agonist activity associated with valvular fibroplasia [42,43]
   5. Some association of 5HT-2B R agonists with pulmonary hypertension
   6. Drugs with 5-HT2B R agonist activity include dexfenfluramine, fenfluramine, ergot- derived migraine drugs, methsergide, pergolide and cabergoline
6. 5HT-2C R
   1. High density in choroid plexus (tissue which makes cerebrospinal fluid)
   2. Some data suggest receptor may act to transmit growth signals
7. Antagonists
   1. 5HT-2A/C blockers include methysergide, risperidone, (ketanserin)
   2. These drugs are used for migraine, schizophrenia, (hypertension)

D. 5HT-3 Receptors

1. Only monoamine neurotransmitter which acts as an ion channel
2. Activation mediates depolarization by gating of cations
3. Found on parasympathetic terminals in GI tract
   1. Vagal Afferents
   2. Splanchnic Afferents
4. Found in CNS
   1. Nucleus tractus solitarii and area postrema
   2. Involved in emetic responses, including nausea
5. 5HT-3R Antagonists
   1. Very potent agents for blocking emetic response
   2. Used in chemotherapy [25] and peri- or post-operative [32] emesis
   3. Ondansetron (Zofran®): 24-32mg bolus IV, or in 8-12mg divided doses, or continuous infusion, or oral 24mg po 30 minutes before chemotherapy, or 8mg bid
   4. Granisetron (Kytril®): 3mg iv or 10µg/kg iv q24°, or 1mg bid po or 2mg qd po [4]
   5. Dolasetron (Anzemet®): 100mg iv or 1.8mg/kg once; oral 100mg once [5]
   6. Palanosetron (Aloxi®): 0.25mg IV x 1 dose only; very long half-life
   7. Tropisetron (Vavoban®) under development
6. Irritable Bowel Syndrome (IBS) [6]
   1. Alosetron (Lotronex®), an 5HT-3R antagonist, has shown efficacy in diarrhea type IBS [26]
   2. Improves diarrhea predominant IBS, mainly in women
   3. Initiate therapy at 1mg po qd and gradually increase to 1mg po bid as tolerated
   4. Caution as this agent has been linked with colonic ischemia and severe constipation [26]
   5. Additional serotonin (5HT) receptor modulators are being investigated [23]
7. 5HT-3 Receptors in Alcoholism [1]
   1. Densely distributed 5HT-3R found in limbic system
   2. These neurons can regulate release of dopamine, involved in "addiction"
   3. Urge to drink can be ameliorated by ondansetron, a 5-HT3 receptor antagonist
   4. Ondansetron 4µg/kg bid is an effective treatment for early onset alcoholism
8. No subtypes have been cloned to date
9. Unknown if polymorphisms exist

E. 5HT-4 Receptors

1. Activate AdCyc through Gs protein
2. CNS
   1. Neurons of superior and inferior colliculi
   2. Hippocampus
3. Gastrointestinal Tract
   1. Myenteric plexus
   2. Smooth muscle and secretory cells
   3. Stimulates secretion and peristalsis
   4. May reduce visceral pain sensation
4. Cisapride (Propulsid®)
   1. Cisapride stimulates gut motility and increases lower esophageal sphincter tone
   2. Withdrawn from market due to QTc prolongation
   3. Available for compassionate use for gastric hypomotility, other motility disorders
5. Tegaserod (Zelnorm®) [13,14]
   1. Prokinetic 5-HT4 agonist approved for cIBS
   2. Increases GI motility and reduces visceral (pain) sensation
   3. Dose is 6mg po bid before meals
   4. Main side effect is diarrhea; possible increase gallstones and ovarian cysts

F. Additional 5HT Receptors

1. 5HT-5R
   1. At least two subtypes (A and B)
   2. Subtype A found in hippocampus
   3. Signal Transduction ?
2. 5HT-6R
   1. Activation of AdCyc
   2. Found in corpus striatum (CNS)
   3. May play key role in clozapine's antischizophrenia actions
3. 5HT-7R
   1. Activation of AdCyc
   2. Found in hypothalamus and intestine
   3. May play key role in clozapine's antischizophrenia actions

G. Additional Serotonin Enhancing Agents [47]

1. Selective Serotonin Reuptake Inhibitors (SSRI) [5,7,33]
   1. Inhibit presynaptic reaccumulation of neuronally released 5HT
   2. Specifically, these agents block the 5HT transporters
   3. Thereby increase the effective levels of serotonin in brain
   4. Action potentiated by coadminstration of 5HT precursor, tryptophan
   5. Agents include fluoxetine (Prozac®), paroxetine (Paxil®), sertraline (Zoloft®)
   6. Fluvoxamine (Luvox®), citalopram (Celexa®), escitalopram (Lexapro®) [27]
   7. Used for treatment of depression, anxiety, and obsessive-compulsive disorder (OCD) [31]
   8. Paroxetine, sertraline and fluoxetine have similar effectiveness for depression [16]
   9. Also effective in mixed chronic pain and possibly tension headaches
   10. Effective for treatment of premenstrual syndrome (used intermittently or chronically) [8]
   11. Fluoxetine is approved as Sarafem® for premenstrual dysphoric disorder [11]
   12. Fluoxetine (flexible dosing) clearly of benefit versus placebo in fibromyalgia [21]
   13. Fluoxetine of no benefit as maintenance therapy in anorexia after weight regain [41]
   14. Paroxetine controlled release (Paxil® CR) effective for menopausal hot flashes [30]
   15. Fluvoxamine (Luvox® and Luvox® CR) approved for OCD and social anxiety disorder (SAD) in adults [48]
   16. Sertraline, citalopram, escitalopram have no meaningful CYP inhibition activity
   17. Fluvoxamine inhibits CYP 3A4, 2C19, and 1A2 (similar to fluoxetine)
   18. Paroxetine has an intermediate CYP inhibition profile compared with others
   19. Black-box warning for use in adolescents due to increased suicide risk with at least some SSRIs, particularly paroxetine [31]
   20. Overall, however, benefits clearly outweigh risks of SSRIs and related antidepressants in pediatric populations including MDD, OCD, anxiety disorders [46]
2. Mixed Serotonin - Norepinephrine (NE) Reuptake Inhibitors (SNRI) [35,36]
   1. Venlafaxine (Effexor®) is best studied SNRI and effective in depression and anxiety
   2. Venlafaxine may be more effective than SSRIs for initial therapy of depression [35]
   3. Clomipramine also blocks both 5HT and NE reuptake
   4. Venlafaxine 75mg qd reduces menopause-associated hot flashes in >60% of patients [10]
   5. Duloxetine approved for neuropathic pain, depression and anxiety
3. Duloxetine (Cymbalta®) [36,37]
   1. Selective serotonin and norepinephrine reuptake inhibitor (SNRI)
   2. Approved (60mg qd po; up to 60mg po bid) for diabetic neuropathic pain
   3. Also approved for depression 30mg po bid or 60mg qd
   4. ~50% of patients had >50% reduction in pain in 24 hours and reduction in other pain drugs
   5. Open label extension showed efficacy out to 52 weeks
   6. Nausea (22%), dizziness (14%), somnolence (15%), consiptation (11%) main side effects
   7. Erectile dysfunction occurs in some patients
   8. Abrupt withdrawal leads to irritability, headache, vomiting, insomnia
4. Buspirone (Buspar® and others)
   1. 5HT-1A partial agonist
   2. Also has weak dopamine D2 blocking activity
   3. alpha1 and alpha2 adrenergic activity necessitates slow up-titration of dose
   4. Used for anxiety and depression
   5. Very well tolerated with slow onset (4-8 weeks) of action
   6. Initial dose 5mg po tid or 7.5mg bid, increase every 3-5 days
   7. Maximum 20mg tid or 30mg bid; may be combined with other agents
5. Trazodone (Desyryl®) [5]
   1. Metabolized to m-chlorphenylpiperazine (mCPP), which is active agent
   2. Activation mainly at 5HT-1B and 5HT2A/C receptors
   3. Weak antidepressant, relatively strong sleep inducer (sedative)
   4. Priapism occurs in about 1:1000 men taking trazodone
6. Nefazodone (Serzone®) [5]
   1. Atypical antidepressant activity, blocks 5HT functions and NE reuptake
   2. Sedation is prominant
   3. Low incidence of impotence
7. MAO Inhibitors (MAO-I) [5,40]
   1. Phenelzine (Nardil®) and tranylcypromine (Parnate®) block NE, 5HT, dopamine reuptake
   2. Used for depression (third line)
   3. Selegiline (Eldepryl®) - mild 5HT reuptake blocker, mainly DA reuptake inhibitor
   4. Selegiline transdermal (Emsam®) appears better tolerated than oral (6mg/24 hr patch)
   5. Used as adjunctive therapy for Parkinson's Disease and in resistant major depression
8. Tricyclic Antidepressants (TCA) [5]
   1. The tertiary amine TCAs have NE and 5HT reuptake blocking effects
   2. The secondary amine TCAs block mainly NE (and some dopamine) reuptake
   3. Tertiary amines have marked side effects and are not recommended first line
9. Amphetamine-like Anorexic Agents
   1. Sibutramine (Meridia®) is the only approved serotonergic obesity agent available in USA
   2. Fenfluramine (Pondimin®) and Dexfenfluramine (Redux®) removed from market
   3. Mechanism of action not clearly understood
   4. Stimulates serotonin release peripherally
   5. This appears to lead to marked depletion of brain 5HT levels
   6. May have serotonin-selective neurotoxic action as well
10. Lysergic Acid Diethylamide (LSD)
    1. Ergot derivative, nonselective 5HT agonist
    2. Key effects on HT-1 and HT2A/C receptors

H. Additional Serotonin Blocking Agents

1. Ergot Alkaloids
   1. Most are non-specific for various 5HT receptor subtypes
   2. Metergoline binds preferentially to 5HT-2 R
   3. Dihydroergotamine (DHE) is used for acute migraine treatment
   4. Can cause significant cardiac ischemia in patients with heart disease [18]
   5. Cause potent peripheral vasoconstriction that can lead to ischemia [19]
   6. Ischemia leading to gangrene due to ergotism was called Saint Anthony's fire
2. Methysergide (Sansert®)
   1. Ergot derivative, third line therapy for migraine prophylaxis
   2. Blocks 5HT-2A/C R but possibly has partial agonist activity
   3. Weak vasoconstrictor and moderately inhibits gut motlity
   4. May be used adjunctively to block the symptoms of Carcinoid Syndrome (5HT mediated)
   5. Main serious side effect is retroperitoneal fibrosis
3. Ketanserin (Sufrexal®)
   1. Not available in USA at present
   2. Blocks 5HT-2A > 5HT-2C receptors
   3. High affinity blocker of a-adrenergic receptors
   4. Mild blocking of platelet aggregation
   5. Used for hypertension
4. Olanzapine (Zyprexa®) [12]
   1. Thienobenzodiazepine, binds similar receptors as clozapine
   2. Also binds and blocks serotonin (5HT)-2, -6, and -7 receptors
   3. Blocks H1 histamine receptors
   4. Affinity for alpha1 adrenergic receptors as well
   5. Effective similar to or greater than risperdone or haliperidol
   6. Starting dose is 5-10mg daily, up to 15mg per day po
5. Quetiapine (Seroquel®) [13]
   1. Dibenzothiazepine, similar receptor binding to olanzapine
   2. Appears to be well tolerated in the elderly
   3. Cataracts reported in dogs (not in humans), so biannual ophthalmology exams requested
   4. Initial dose 25mg qd or bid, increase to 100mg po tid or 200mg po bid
   5. Maximum dose is 800mg per day
   6. Metabolized through CYP3A4, so caution with inhibitors of this pathway
6. Clozapine (Clozaril®)
   1. Blocks 5HT-2A/C R and also blocks 5HT-6 and -7 R
   2. Polymorphisms at 5HT-2A/C R show some correlation with activity
   3. Potent antischizophrenic activity with reduced incidence of extrapyramidal reactions
   4. Neutropenia occurs in ~1% of persons, severe in up to 0.1%
   5. Weekly or biweekly neutrophil count monitoring is required
7. Risperidone (Resperdal®)
   1. Combined 5HT-2A/C R and Dopamine D2 R blocker
   2. Extrapyramidal side effects are common
   3. Not quite as effective as clozapine for schizophrenia, but no risk of neutropenia
   4. Dose 3mg bid or 6mg qd
   5. Effective in pediatric autistic disorders with serious behavioral problems [24]
8. Ziprasidone (Geodon®) [14]
   1. Benzisothiazolyl piperazine
   2. Combined D2 and 5HT-2 antagonist
   3. Serotonin receptor agonist and reuptake inhibitor
   4. Histamine H1 receptor antagonist
   5. Norepinephrine reuptake inhibitor
   6. Efficacy as good as older agents and olanzapine
   7. Mild QT prolongation (no arrhythmias reported)
   8. Extrapyramidal symptoms 5% of patients
   9. Little weight gain
   10. Dose 20mg bid with food, may increase to 80mg bid maximum
9. Cyproheptadine (Periactin®)
   1. Blocks 5HT-2A R but also blocks Histamine H1 R
   2. Weak anticholinergic activity
   3. May be used to counter sexual side effects of SSRIs
   4. Third line symptomatic treatment for mild extrapyramidal reactions

I. Serotonin Syndrome [33,34]

1. Rare, potentially fatal syndrome due to 5-HT excess
   1. Post-synaptic activation of 5-HT2A receptors are primarily implicated
   2. Activation of post-synaptic 5-HT1A receptors also plays a role
2. Syndrome Triad
   1. Mental status (cognitive-behavioral) changes
   2. Neuromuscular excitability (usually rigidity)
   3. Autonomic instability (usually hyperactivity)
3. Overview of Drugs Implicated
   1. Occurs in ~15% of patients who overdose on SSRIs
   2. Usually due to combinations of SSRIs and MAO inhibitors
4. Onset of symptoms within 2 hours in 50% and 24 hours in 75% of cases
5. Symptoms
   1. Altered mental status
   2. Agitation, tremor
   3. Fever
   4. Hyperreflexia, myoclonus
   5. Incoordination, ataxia
   6. Diaphoresis, shivering
   7. Gastrointestinal disturbances
   8. Life-threatening complications uncommon: coagulopathies, cytopenias, seizures, rhabdomyolysis, renal failure, acidosis, multiorgan failure, respiratory failure
6. Caution with drugs with "unsuspected" MAO inhibitor activity added to SSRIs
   1. Isoniazid (INH)
   2. Linezolid (Zyvox®)
7. Caution with drugs with serotonergic activity added to SSRIs
   1. Dextromethorphan
   2. Tramadol (Ultram®)
   3. St. John's Wort
   4. MDMA ("Ecstasy")
8. Differential Diagnosis [34]
   1. Serotonin Syndrome
   2. Anticholinergic Agent Overdose
   3. Neuroleptic Malignant Syndrome
   4. Malignant Hyperthermia
9. Treatment
   1. Discontinuation of serotonergic agent
   2. Benzodiazepines
   3. Cardiorespiratory abnormalities may benefit from 5-HT2A antagonists
   4. Cyproheptidine (5-HT2A antagonist) given as 12mg initially, then 2mg q2 hours as needed
   5. Parenteral chlorpromazine 50-100mg may also be used to block 5-HT2A receptors
   6. Hypertension should be controlled with short-acting agents such as nitroprusside, esmolol
   7. Hyperthermic patients (>41.1°C) should receive aggressive therapy and intubation
   8. Initiate neuromuscular blockade with nondepolarizing agent such as vecuronium
   9. Avoid succinylcholine because of arrhythmia risk and hyperkalemia
   10. Propranolol, bromocriptine, dantrolene are not recommended

J. Neonatal Effects of Serotonin Reuptake Inhibitors

1. SSRI's that cause withdrawal syndrome may do so on fetus in pregnant women [9,38]
   1. Exposure in utero in 3rd trimester can cause a neonatal serotonin syndrome
   2. Neonatal 5HT syndrome includes CNS signs, motor, respiratory, gastrointestinal signs that are usually gone by age of 2 weeks
2. Questionable Association of SSRI's with Birth Defects
   1. Increased risk of persistent pulmonary hypertension of newborn reported [39]
   2. Exposure of fetus after 20th week gestation associated with 6X increased risk
   3. SSRI use before the 20th week or use of other antidepressants had no increase in risk
   4. Larger assessments of risks of SSRI's in first trimester show no overall increased risk of heart defects [44,45]
   5. Paroxetine and sertraline associated with some defects, but very rare [44,45]
   6. Possible increase in craniosynostosis, omphalocele, anencephaly, with small absolute risks and conflicting data [44,45]
3. Paroxetine (Paxil®) associated with neonatal convulsions; less so with other SSRIs [9]
4. Cautiously manage use of SSRI's, particularly paroxetine, in pregnant women

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