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

• SSRI's ( Selective Serotonin Re-uptake Inhibitors): Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Sertraline, Paroxetine
• SNRI's (Selective Serotonin Norepinephrine Re-uptake Inhibitors): Venlafaxine, Duloxetine, Levomilnacipran
• TCA's (Tricyclic anti-depressants):    Tertiary amines- Amitriptyline, Imipramine, Trimipramine, Butriptyline, Chlorimipramine, Dothiepine   Secondary amines- Nortriptyiline, Desimipramine, Lofepramine
• 5-HT R Modulators : Nefazodone, Trazodone, Vortioxetine
• Tetracyclic/ unicyclic: Tetracyclic- Mianserin, Mianzepine, Maprotiline, Amoxapine      Unicyclic- Bupropione
• MAOI ( Monoamine Oxidase Inhibitor)- Tranylcypromine (non selective), Moclobemide ( A selective), Isocarboxazid( non selective irreversible)      Selegiline/Rasagiline/deprenil- (B selective), phenelzine ( non-selective irreversible)
• Circadian rhythm regulator: Agomelatine
• Selective NA re-uptake inhibitor- Reboxetine

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

Most antidepressants cause potentiation of neurotransmitter action of norepinephrine or serotonin or both at central synapses.

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

2-4 weeks or even longer for a clinical effect to start but about 6-8 weeks for optimal effects it is suspected that it takes about 2 weeks for neurotrophic factors to be synthesised to increase neurogenesis and synaptic connectivity so that monoamines are better regulated to induce desired responses. Even with an acute surge in the monoamines with the first dose of an antidepressant in order to reach homeostasis and provide a long term response in balancing the neurotransmitters in the brain it takes for the receptors and processes to acclimate to the antidepressant medication and fix the dysregulation. Possibly also because most ADs are highly protein bound and lipophilic so they distribute to various tissues

How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:?

• Efficacy: efficacy is the same, individuals just respond differently to the individual drugs
• Side effects: TADs have more anticholinergic and cardio related toxicities that include severe sedation, tachycardia, confusion, agitation, sweating, orthostatic hypotension, ECG abnormalities, weight gain and tremors. SSRIs have fewer side effects because it has a much higher affinity for blocking only serotonin reuptake transporters and may cause nausea, headaches, sexual dysfunction, anxiety, agitation, insomnia and jitteriness and CNS stimulation
• Safety: SSRI’s are safer than TCAs because they cause less interactions than the TCAs and also less cardiotoxic. TCAs lethal in overdose whereas as SSRIs are safer in overdose. SSRIs the most common side effects of SSRIs (nausea, vomiting, nervousness, insomnia, headache and sexual dysfunction) are usually mild and typically disappear as treatment continues.. Thus the severity and frequency of adverse effects experienced on an acute and chronic basis makes SSRIs a safer drug than TCAs .

     What is the action of mirtazapine?

   Increases amine release from nerve endings by antagonism of presynaptic alpha 2 adrenoceptors involved in feedback inhibition increasing both serotonin and norepinephrine release. Indirect stimulation   of HT-1A :  a   anxiolytic effect, antagonism of 5-HT 3: anxiolytic and decrease nausea as well as blockade of 5-HT2 with anti-depressive effects

   What is the action of venlafaxine?

   Blocks both the 5-HT and NA re-uptake, however more potently the 5-HT opposed to NA. Thereby increasing both serotonin and noradrenaline levels.

   What is the action of agomelatine?

I  A circadian rhythm regulator that normalised reduced amplitudes and phase modifications in sleep-wake cycle by antagonising 5-HT2C receptors thus having antidepressant and improved sleep action and  also having a    an agonism action on melatonergic MT 1 AND MT 2 receptors that benefits sleep by increasing melatonin production especially in the suprachiasmatic nucleus (anterior hypothalamus) region.