Classification of drugs used as ADs: 

• MAO inhibitors (MAOIs)

• Tricyclic antidepressants (TCAs) 

• Heterocyclic antidepressants (tetracyclics and unicyclics) 

• 5-HT-NA reuptake inhibitors (SNRIs) 

• 5-HT receptor antagonists 

• Selective 5-HT reuptake inhibitors (SSRIs) 

• Selective NA reuptake inhibitors (NARIs) 

• Circadian rhythm regulators 

What do the existing drugs all have in common regarding their MoA? 

Antidepressants (ADs) relieve depression by potentiation/increase of the NA and/or 5-HT neurotransmitter action within the CNS. Thus, the majority of these drugs ↑ [NA] & [5-HT] at the central synapses, b.m.o: 

• Reuptake inhibition 

• Degradation/metabolism inhibition 

• Antagonism of pre-synaptic alpha-2 receptors 

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

Even though acute, chemical changes in monoamines in the brain already occur within hours after antidepressant administration, a clinical (anti-depressive) response may only be observed after about 3-5 weeks. This may be attributed to multipotent actions on numerous monoaminergic receptors due to the non-specific increase in 5-HT/NA. 

Recent studies on the matter provide an analogous explanation of why ADs do not provide clinical improvements immediately. The reason provided is that ADs do not target the 5-HT molecule transporters directly, even though multiple ADs (ex some SSRIs) directly bind to 5-HT transporters, this direct binding is not the main underlying MoA. The suggested main MoA is thus that ADs target our DNA – specifically genes that code for 5-HT transporters. ADs ↓ activity of these genes, that then causes less 5-HT molecules to be readily available in the brain for release. There are multiple active 5-HT transporter molecules present in the brain before AD administration, thus it takes a few weeks before this gene suppression gives rise to a noticeable effect on 5-HT within the brain. This is the argued explanation for the delayed clinical response of ADs. 

How do the TADs and the selective serotonin reuptake inhibitors (SSRIs) differ in respect of efficacy, side effects & safety? 

	TDAs	SSRIs
Efficacy	TADs act by inhibiting certain transporters in the brain that carry NA & 5-HT into neurons. This transition allows more of these NTs to be available for other neuronal use and is thought to be the mechanism for improving symptoms of depression. These drugs are non-selective since they act on many receptors throughout the body, although they do have more of an effect on NA levels than 5-HT.	SSRIs cause more 5-HT to be available for neuronal use, through highly selective inhibition of 5-HT transporters. SSRIs can also cause more NA to be available (b.m.o same action), but not as much as TADs. These drugs have a more selective action than TADs, their higher selectivity for receptors also cause them to produce fewer side effects.
Side effects	TADs can cause several SEs since they affect many receptors throughout the body. Specific SEs include:  Anticholinergic effects Anti-adrenergic effects Sedation Weight gain Cardiovascular problems	Even though SSRIs are associated with fewer SEs, they can still cause adverse effects. Specific SEs include: Nausea Sexual dysfunction Headache Insomnia Agitation GI problems
Safety	TADs can be much more dangerous than SSRIs in overdose cases – especially within the CVS & CNS. TADs can induce seizures & fatal toxicity with OD since they directly affect fx of the heart.	SSRIs = safer than TADs, since it takes larger amounts of SSRIs to cause toxicities than for TADs. Overdose of SSRIs can still cause severe problems.

(*Note that both TADs & SSRIs can lead to a serious syndrome called Serotonin syndrome; due to the increase in 5-HT levels. 

What is the action of Mirtazapine? 

Mirtazapine = NaSSA (NA and specific serotonin antidepressant). This drug blocks alpha-2, 5-HT2A and 5-HT3 receptors. Mirtazapine additionally blocks Histamine1 receptors – which may lead to sedation and weight gain; and alpha-1 receptors – which may cause postural hypotension. 

• Mirtazapine causes blockade of the inhibitory alpha-2 R’s, that ↑ both NA (autoreceptors) and 5-HT release (heteroreceptors)

• Indirect stimulation of 5-HT1A – anxiolytic 

• Blockade of 5-HT3 – anxiolytic and anti-emetic 

• Blockade of 5-HT2 – anti-depressive effects 

What is the action of Venlafaxine? 

Venlafaxine = SNRI (Serotonin & Noradrenaline Reuptake Inhibitor). This drug causes moderately selective inhibition of both 5-HT and NA reuptake, more potent selectivity for 5-HT than for NA. Besides for depression, Venlafaxine can also be indicated for use in pain: neuralgia & fibromyalgia, GAD and vasomotor symptoms of menopause. 

What is the action of Agomelatine? 

Agomelatine = circadian rhythm regulator. This drug causes melatonergic (MT1 and MT2) agonism and 5-HT2C antagonism. 5-HT2C receptor antagonism leads to the disinhibition of DA and NA release in frontal cortex of the brain (increase DA & NA release). Agomelatine is indicated for use in Major Depressive Disorder.