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  • Serotonin is used throughout the body in multiple physiological roles.

  • 90% of all serotonin in human body in the GI tract.

  • 8% in blood platelets.

  • 2% in CNS.

  • Neurons in brain make their own; none from body crosses Blood Brain Barrier (BBB).


  • Tryptophan 5 hydroxytryptophan 5 hydroxytryptophan 5hydroxytryptamine(5HT) 1.Tryptophan hydroxylase (rate limiting step) High serotonin levels within neuron do not inhibit enzyme synthesis-serotonin just builds up. Rate of enzyme activity can be modulated by second messengers involving cAMP.

  • Also, can be modulated by Oxygen levels in blood; more oxygen, more synthesis of serotonin.

  • 2.5-hydroxytryptophan( 5HTP) decarboxylase:

  • Production of enzyme and use to make serotonin very rapid.

  • Can't manipulate serotonin by manipulating this enzyme.

  • N.B. Release of serotonin is Ca++ dependant, Ca++ must come into trigger release.

Deactivation and Breakdown

  • Action terminated by active re-uptake process into neurons and ganglia.

  • Then broken down by MAO.

  • MAO breaks down 5HT into several things.

  • 5-hydrozindoleacetic acid (5HIAA) is a metabolite that is often used to index activity in system; measured in CSF( cerebrospinal fluid).


  • 7 major types;3 of relevance to current set of medications:

  • 5HT1 “slow inhibition”: through G proteins, reduce adenylyl cyclase activity; exists as postsynaptic and presynaptic receptors.

  • 5HT2 “slow excitation": through G proteins, increase K+ & Ca++ influx.CNS has mostly 5HT1A (found in prefrontal cortex).

  • 5HT3 “Fast excitation”: ion-coupled to Na+;some modulation also of Ca++ channels in the area of postrema,trigger vomiting.

Serotonin Pathways in Brain

Serotonin Pathways in Brain

  • Serotonin is released as neurotransmitter but also released non-synoptically through some axon terminals.

  • Neurotransmitter pathways can be consolidated into 3 major paths.

  • All paths emerge from same set of neurons in the Raphe region of the brainstem, a group of nuclei along midline of midbrain,pons and medulla.

1.Caudal pathway (from Raphe nuclei to medulla and spinal cord)

  • Uses mainly 5HT1 receptors " slow excitation”.

  • Causes contraction or uterine muscles cramps.

  • Causes some contraction of blood vessel walls" blood pressure”.

  • Causes mild motor neuron excitation.

  • Stimulates release of endorphins that then inhibit pain messages.

  • 5HT3 receptors in area postrema trigger vomiting.

2.Middle pathway (from Raphe neurons to cerebral cortex and basal ganglia)

  • Goes to cortex along with NE axons.

  • Goes to basal ganglia along with DA & ACh neurons.

  • 5HT2 “slow excitation” receptors.

  • Serotonin induces positive mood and affect cortex.

  • “This is the system where SSRIs work by inhibiting the transporter protein necessary for serotonin reuptake”.

3.Rostral pathway: (from Raphe nuclei to 5 areas)

  • Uses 5HT1 “slow inhibition” &5HT2 “slow excitation”

  • A. Raphe nuclei within): within Raphe,there are autoreceptors(5HT1-self inhibit)

  • B. Raphe to sensory cortex: Sensory cortex-particularly visual perception-5HT2 relevant to hallucinogens(LSD,psilocybin mushrooms)

  • C. Raphe to limbic system: Limbic system “Pleasure & anxiety” slow inhibition at 5HT1 receptors.

  • D. Raphe to hypothalamus and thalamus: Uses 5HT1 receptors in thermoregulation. Ecstasy causes hyperthermia through here.

  • E. Raphe to suprachiasmatic nucleus: Uses 5 HT1. Important in sleep/wakefulness. Serotonin induces sleep-inject into brain-sleep occurs. Inhibit serotonin (by PCPA,inhibits Tryptophan hydroxylase and production of serotonin); no sleep and there is an increase in activity. But other neurotransmitter are also important in sleep.

CNS Relevant diseases

  • Depression

  • Anxiety

  • Possible some interactive role in Schizophrenia

  • Ecstasy “empathogen”

  • High levels of Amphetamine

  • LSD and psilocybin mushroom hallucinogens

  • Migraine headache(5HT1 agonists cause constriction of intracranial blood vessels; may block endogenous inflammatory agents)

Drugs used to treat depressive disorders:

  • MAO inhibitors.

  • Tricyclic antidepressants

  • SSRIs “selective serotonin reuptake inhibitors”

  • Other serotonergic drugs

Sedopram tablets

  • Product knowledge


  • Sedopram (citalopram HBr) is an orally administered selective serotonin re-uptake inhibitor (SSRIs) with a chemical structure unrelated to that of other SSRI’s or of tricyclic, tetracyclic or other available antidepressant agent.


  • The mechanism of action of citalopram HBr as inhibitor of CNS neuronal re-uptake of serotonin (5HT).

  • Citalopram is a highly selective serotonin re-uptake inhibitor (SSRI) with minimal effects on norepinephrine(NE) and dopamine (DA) neuronal re-uptake.

  • Citalopram has no or very low affinity for 5HT 1A,5HT 2A,dopamine D1& D2,alpha 1;alpha 2 & beta adrenergic, histamine H1,gamma amino-butyric acid (GABA), muscarinic cholinergic and benzodiazepine receptors.


  • Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram(DDCT), citalopram-N-oxide & deaminated propionic acid derivative.

  • Citalopram is at least 8 times more potent than its metabolites.

  • Biotransformation of citalopram is mainly hepatic.

  • Approximately 20 % is excreted by renal clearance.

Population and Subgroups

  • 20 mg is the recommended dose for most elderly patients.

  • No sex difference and no adjustment of dose on the basis of gender is recommended.

  • In hepatic patients;20 mg is the recommended dose for most hepatically impaired patients.

  • No adjustment of dosage for mild to moderate renal function impairment patients is recommended.

Drug-Drug interactions

  • Citalopram has interaction with ketoconazole, itraconzole, macrolide antibiotics and omeprazole.

  • Citalopram can be combined with many other medications as TCAs.


  • Hyponatremia: In few cases of hyponatremia & inappropriate antidiuretic hormone secretion may occur.

  • Activation of Mania/Hypomania was reported in 0.2% in one trial; so citalopram should be used cautiously in patients with a history of mania.

  • Seizures occurred in 0.3% of patients treated with citalopram. Like other antidepressants; citalopram should be introduced with care to patients with history of seizure disorder.

  • Patients should be advised to notify their physician if they become pregnant or intended to become pregnant during therapy.

  • Patients should be advised to notify their physician if they are breast feeling an infant.


  • The product dose not interfere with cognitive and motor performance as Sedopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance.

  • Sedopram is not associated with the development of clinically significant ECG abnormalities or with orthostatic changes or weight changes.

  • There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which equivalent to 20 times the maximum recommended human daily dose.

  • When citalopram was administered orally to male & female rats fertility was decreased at doses>/=32mg/kg/day,approximately 5 times the maximum recommended human dose.

Adverse reactions: GIT disorders:

  • Comparison of the GIT adverse reactions between the Citalopram (n=1063)and the placebo (n=446)

Adverse reactions:

Adverse reaction:

Adverse reaction:

Dose and administration:

  • Initial treatment:

  • Should be administered at an initial dose of 20 mg once daily, generally with an increase to a dose of 40 mg/day. Dose increases should usually occur in increments of 20 mg at intervals of no less than one week up to 60 mg.

  • Sedopram should be administered once daily, in the morning or evening with or without food.

Dose and administration:

  • Maintenance treatment: in two studies show that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment(32 weeks total).

  • In dose of citalopram (20-40 mg/day) during maintenance treatment and if adverse reactions are bothersome; a decrease in dose to 20 mg/day can be considered.

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