Answer the following for a Blog Summary:

• Using your textbooks, draw up a classification of the drugs that are used as antidepressants.

MAOIs: Mono-amine inhibitors ex. Phenelzine, Selegiline, Tranylcypromine.

TCAs: Tricyclic antidepressants ex. Amitriptyline, Clomipramine, Imipramine.

TCAs are further subdivided into: 

• Tertiary amine: Amitriptyline, Imipramine, Trimipramine, Chlorimipramine, Dothiepine etc.
• Secondary amine: Nortriptyline ,Desimipramine etc.

SNRI: Serotonin, Norepinephrine re-uptake inhibitors ex. Duloxetine, Venlafaxine

SSRIs: Serotonin re-uptake inhibitors ex. Escitalopram, Citalopram, Fluoxetine, Paroxetine, Sertraline

Circadian rhythm regulators: Agomelatine

Serotonin receptor modulators: Trazodone, Vortioxetine

Tetracyclic & Unicyclic Ads: Manserin, Mirtazapine, Bupropion.

• What do the existing drugs all have in common regarding their mechanisms of action?

They all promote mono-amine activity by increasing noradrenaline and serotonin concentrations at the central synapse through either re-uptake inhibition, degradation inhibition or blockade of pre-synaptic alpha2 auto receptors.

• How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?

Onset of action is very slow (14-21 days or more). The actual anti depressive effects can only be seen after about 6 - 8 weeks since the mono amine regulation in the brain is altered either through re-uptake inhibition, degradation inhibition or the blockade of alpha 2 auto receptors.

• How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of: efficacy, side effects, safety?

Effectivity:

All AD need approximately 6 – 8 weeks with sufficient dosages before AD effects can be observed.

TAD requires titrations to the minimum effective dose whils SSRIs can usually be used immediately.

TCA’s

Side effects of TCAs:

• Sedation
• Sympathomimetic: tremors, insomnia
• Anticholinergic: disturbed vision, dry mouth constipation, urinary retention, confusion 
• CVS: orthostatic hypotension, dysrhythmias 
• Psychosis, precipitates mania 
• Convulsions
• Metabolic /endocrine: weight gain, sexual disturbances 

TAD safety: An overdose in TCAs is very dangerous. 10x daily dose can be fatal. Common symptoms of overdose include; Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory collapse, hyperpyrexia, dysrhythmia. In severe cases it can lead to Coma, Convulsions, Cardiotoxicity. TADs should also not be used with MAOIs as it can cause serotonin syndrome.

SSRI’s:

Side effects of SSRIs:

• Insomnia, tremors, GIT disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS (needles ‘n pins, restless legs), withdrawal syndrome. 
• ↓ appetite, overweight patients = lose weight. 
• Non-sedating
• Acute ↑ 5-HT synaptic activity = acute anxiety, later 5-HT reduces again. 

Safety: SSRIs unlike TCA’s do not bind aggressively to histamine, muscarinic or other receptor. It allosterically inhibits the transporter by binding to the SERT receptor at a site other than the serotonin binding site. These drugs must be discontinued for at least 4 weeks or longer before an MAOI can be administered to remove the risk of serotonin syndrome. Fluoxetine is the only AD approved for use in children. It also has the longest half-life of all the SSRIs. A combination of SSRIs with carbamazepine can also lead to toxicities.

SSRIs are the preferred Ads along with newer drugs because they have a better side-effect profile, safer in acute overdose and SSRI’s can suppress appetite, overweight patients may lose weight. 

• What is the action of mirtazapine?

Is a NaSSA: NA & specific serotonin anti-depressant
Blockade of α2, 5-HT2A & 5-HT3. Also block H1, α1 and indirect stimulation of 5-HT1A. 

Blockade of the inhibitory α2 R’s advance both NA (auto receptors) & 5-HT release (on the heteroreceptors). 

Indirect stimulation of 5-HT1A: anxiolytic 

Blockade 5-HT3: anxiolytic, ̄nausea 

Blockade 5-HT2: anti-depressive effects 

• What is the action of venlafaxine?

Blocks both 5-HT - and NA re-uptake, more potent for 5- HT than for NA. Moderately selective blockade of SERT and NET. Venlafaxine is a weak inhibitor of NET.

• What is the action of agomelatine?

Antagonist: 5-HT2c , Agonist: Melatonergic R’s – MT1 & MT2. The blockade of 5-HT2c receptors causes a disinhibition of DA & NE release in the frontal cortex =éDA and NA release. This promotes the anti-depressive effect. Melatonin is a by-product of 5-HT. It is responsible for the regulation of biological clock mechanism. Melatonin repairs the malfunctioning rhythms caused due to depression. Depression influences melatonin release.