Question 9(p.2)

Compare and contrast the mechanism of action and side effects of tricyclic antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors.

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College Answer

Good answers were in tabular format.
The antidepressant action is similar for each agent. Initial increase in 5HT and NA, followed
in 2-3 weeks by a down regulation or change in efficiency of 5HT transmission. The agents
produce elevated neurotransmitters via different mechanisms, either reuptake blockade or
enzyme inhibition. MAOIs can be competitive or non-competitive. Mention of the different
neurotransmitters affected by each agent was required.
A description of significant side effects at therapeutic doses, and in overdose was expected
with explanations provided. These should have included - the anticholinergic effects and
cardiotoxicity of TCAs, postural hypotension, the catecholamine, pethidine and tyramine
related complications of MAOIs, and serotonin syndrome with SSRI/MAOI use and or
overdose. More marks were gained for mention that side effect profiles can be beneficial e.g.
analgesic properties of TCAs, sedation with TCAs/ SSRIs and energizing benefits of
SSRIs/SNRIs. SSRI’s safety and efficacy have markedly reduced the use of MAOIs and to a
lesser extent TCA’s..
Syllabus G2f2d
Reference: Stoelting p 398-407
Katzung p 476-487.


Specific mechanism of action

TCAs act by at least five different mechanisms:

  • Inhibition of synaptic serotonin uptake
  • Inhibition of synaptic noradrenaline uptake 
  • Inhibition of post-synaptic α-adrenoceptors
  • Inhibition of histamine receptors and muscarinic acetylcholine receptors

SSRIs inhibit SERT, the serotonin reuptake protein. This increases the availability of serotonin in the synapse. According to the monoamine hypothesis of mood regulation, the increase in serotonin  

MAOIs inhibit the activity of monoamine oxidase, which is responsible for the catabolism of monoamines like dopamine, noradrenaline and serotonin
Common mechanism of action
  • All of these mechanisms ultimately lead to the increase in synaptic concentrations of the affected monoamines, which - according to the monoamine hypothesis of mood regulation - should reverse the monoamine depletion which is supposed to be at the root of depression.
Common side effects
  • All of these drugs can continue to the development of serotonin syndrome
Side effects
  • Antihistamine effects (sedation)
  • Anti-adrenergic effects (postural hypotension)
  • Anticholinergic effects (constipation, urinary retention, xerostomia, delirium),
  • Sodium channel blockade in overdose
Agitation, diarrhoea, loss or gain of weight, vertigo, sexual dysfunction,  risk of increased suicidality Hypertensive crises, hepatotoxicity, seizures, hypoglycaemia, mania, psychosis. Dangerous pharmacodynamic interactions with other antidepressants and monoaminergic drugs, as well as foods that act as catecholamine precursors


Alvano, Sebastian A., and Luis M. Zieher. "An updated classification of antidepressants: A proposal to simplify treatment." Personalized Medicine in Psychiatry 19 (2020): 100042.

Bauer, M., et al. "WFSBP Task Force on Unipolar Depressive Disorders. Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines." Int J Psychiatry Clin Pract 21 (2017): 166-76.

Frieling, Helge, and Stefan Bleich. "Tranylcypromine." European archives of psychiatry and clinical neuroscience 256.5 (2006): 268-273.

Norman, T. R., G. D. Burrows, and K. P. Maguire. "Pharmacokinetics of tricyclic antidepressants." Recent Advances in Neuropsycho-Pharmacology. Pergamon, 1981. 339-350.

Hiemke, Christoph, and Sebastian Härtter. "Pharmacokinetics of selective serotonin reuptake inhibitors." Pharmacology & therapeutics 85.1 (2000): 11-28.