MAOIs

MAOIs were the first class of antidepressants to be developed. They are effective but their use
requires dietary restrictions and avoiding some other medicines, therefore have largely been
replaced by other safer antidepressants. MAOIs are mostly used as a last resort in cases where
other antidepressants have failed.

Mechanism of action: MAOIs work by inhibiting the activity of Monoamine Oxidase.

Monoamine oxidase are enzymes that metabolize neurotransmitters norepinephrine, serotonin
and dopamine.

Types: There are two types of MAOs: MAO-A and MAO-B. MAO-A metabolizes serotonin and
norepinephrine-the neurotransmitters most closely associated with depression. MAO-B
metabolizes dopamine and trace amines, including phenethylamine. Tyramine is metabolized
by both MAO-A and MAO-B. Inhibition of MAO-B is not effective as an antidepressant because
it has no direct effect on serotonin and norepinephrine metabolism. Brain MAO-A must be
inhibited for an antidepressant effect to occur. Reversible inhibitors of monoamine oxidase A
(RIMAs) are a subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme.

Reversiblity: The early MAOIs covalently bound to the monoamine oxidase enzymes, thus
inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was
blocked until the cell made new enzymes. The enzymes turn over approximately every two
weeks. A few newer MAOIs are reversible, meaning that they are able to detach from the
enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is
governed by the concentrations of the substrate and the MAOI.

TCA

They are named after their chemical structure, which contains three rings of atoms. Tetracyclic
antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of
antidepressant compounds.

Mechanism of action: Like reuptake inhibitors, tricyclics seem to block the reabsorption of
serotonin and norepinephrine back into nerve cells after these chemicals are released into a
synapse.

TCAs do not evenly inhibit reuptake of these neurotransmitters. Some drugs preferentially
inhibit serotonin reuptake, and some norepinephrine reuptake.

They differ in their propensity to cause certain side effects.

SSRIs
SSRIs inhibit reuptake of serotonin by the presynaptic neuron, therefore increasing the levels of
serotonin in the synaptic cleft.

 ADs are used for MDD and dysthymia

 serotonergic agents are also approved for the treatment of anxiety disorders, such as OCD,
GAD and PTSD.
 Both tricyclics and serotonin reuptake inhibitors have been found useful in treating certain
chronic pain disorders (e.g., diabetic neuropathy, fibromyalgia).
 Occasionally, some ADs are used in treating schizoaffective disorder, somatoform disorders,
some personality disorders, eating disorders, chronic insomnia, and benzodiazepine
withdrawal states.
 Agitated, disinhibited, or depressed patients with dementia may also benefit from certain
ADs.
 Neurotropic effects of ADs, such as their ability to increase brain-derived neurotrophic factor
(BDNF).
 ADs, like nearly all psychotropics, undergo extensive metabolism in the family of enzymes
known as the cytochrome P450 (CYP) system.
 TCA. 3 types of side effecrs. Cardiac/autonomic (dizziness, orthostatic hypotension,
tachycardia), anticholinergic (dry mouth, blurred vision, constipation, urinary retention,
confusion, memory impairment), neurobehavioral (memory impairment, tremors, motor
issues, EPS). Other side effects are sedation, weight gain, and sexual dysfunction.
 The SSRIs are less likely to cause anticholinergic and cardiac/autonomic side effects than are
the TCAs; however, SSRIs are associated with frequent gastrointestinal (GI) side effects
(nausea, diarrhea), headache, sexual dysfunction, insomnia, psychomotor agitation, and
occasional EPS.
 Combining MAOIs with SSRI may cause serotonin syndrome. Sign of serotonin syndrome:
headache, fever, diarrhea, confusion, high BP and rapid heartbeat. Severe serotonin
syndrome: high fever, seizures, unconsciousness.
 For treatment-resistant depression, add another AD with a different mechanism of action
(MOA). Another approach is to add lithium to a SSRI or a TCA.
 When depression is accompanied by psychosis, the addition of an antipsychotic agent is
usually necessary.
 In elderly populations, the choice of AD is strongly influenced by comorbid medical
conditions (e.g., cardiac disease) and the risk of drug–drug interactions. The elderly require
special precautions when TCAs are used. The elderly are especially sensitive to the
anticholinergic and cardiovascular side effects of all TCAs and must be monitored carefully
for orthostatic hypotension, heart abnormalities, and cognitive side effects. TCAs are not
suitable for elderly with heart disease and dementia.
 Only fluoxetine is FDA approved for children and it has been shown to be effective for
treating major depression in both children and adolescents in double-blind, placebo-controlled
studies.
 For post-partum depression: TCAs have been considered first-line therapy, but SSRIs,
especially fluoxetine, have also been utilized. Specialconcerns may arise when AD-treated
mothers are breastfeeding, though this rarely poses major risks to the infant.
 MAOI side effects: dizziness, drowsiness, insomnia, headache, nausea, diarrhea constipation,
low BP, weight gain, sexual dysfunction. MAOI can cause hypertensive crisis, so avoid
tyramine containing foods like aged cheese, cured meats.
 Most antidepressants are generally safe, but the FDA requires that all antidepressants carry
black box warnings, the strictest warnings for prescriptions. In some cases, children, teenagers
and young adults under 25 may have an increase in suicidal thoughts or behavior when taking
antidepressants, especially in the first few weeks after starting or when the dose is changed.