Antidepressants

Neurobiology
Depression is associated with a deficiency of 3 monoamine neuro-transmitters in the brain,they are, Serotonin, Noradrenaline and Dopamine. The principle action of  of effective antidepressants is to increase the synaptic action of one or more monoamine neurotransmitter.

Antidepressant medication
Antidepressants increase the synaptic action of one or more monoamine neurotransmitter but they also increase synaptic monoamine levels rapidly, and their clinical action (effect on patients) are felt weeks later.

1. Tricyclic antidepressants
This is a older type of antidepressants. Antidepressant properties of tricyclic antidepressants discovered in the 1950s-1960s. Their chemical structure contains three rings. The mode of action of tricyclic antidepressants is to block reuptake pumps for noradrenaline and/or serotonin. Examples of tricyclic antidepressants are:

• Amitriptyline
• Clomipramine (blocks reuptake of serotonin more)
• Imipramine
• Nortriptyline

Pharmacokinetics
Tricyclic antidepressants are administered orally. They absorbed well in the gut.The drug metabolized in liver and  T ½ can vary from 15-100 hrs, depending on medication. Tricyclic antidepressants have a good theraputic efficacy. Tricyclic antidepressants especially used to treat severe depression.

Side effects of Tricyclic Antidepressants 
Tricyclic antidepressants block muscarinic cholinergic receptors so they cause antimuscarinic effects such as dry mouth, blurred vision, urine retention (risk increased in elderly males), constipation, tremors and confusion, especially in elderly. They also block of alpha 1 receptors causing postural hypotension and dizziness. Sedation and weight gain can cause due to blockage of Histamine 1 receptors. Also they can precipitate mania, epilepsy and cardiac hazard such as blocks voltage gated sodium channels in heart (Eg: Sudden death in elderly, increased risk of cardiac arrhythmias).



Caution:
Tricyclic antidepressants must use with caution in elderly and those with cardiac disease.
Tricyclic antidepressants toxicity and overdose can cause cardiac arrhythmias, hypotension and fits.

Dosage: 
Once daily, usually at night (due to sedative effect)
   Gradually increase dose (e.g. starting with imipramine 50mg nocte, and working up to a maximum daily dose of 200mg nocte over 1-2 weeks).



2. Selective Serotonin Reuptake Inhibitors (SSRI)
This drug was introduced in the 1980s, now widely prescribed. It's mode of action is to selective inhibition of serotonin reuptake (at synapse), i.e inhibits the serotonin transporter (SERT). It is used in treatment of depression, anxiety disorders, eating disorders.

SSRIs in comparison to tricyclic antidepressants:
Selective serotonin reuptake inhibitors cause less severe side effects; patients may find it more tolerable. They are safer in overdose (less cardiotoxic) and SSRIs are not sedative; often have an activating effect.  Therefore selective serotonin reuptake inhibitors are given as a once daily dose in the morning. Examples of SSRI are:

• Fluoxetine (starting dose: Fluoxetine 20mg morn. This is an effective theraputic dose, but if needed can increase this gradually to maximum of fluoxetine 60mg morn).
• Sertraline
• Paroxetine
• Citalopram
• Escitalopram

Side effects of SSRI
Their side effects are usually due to activation of serotonin receptors in other areas of thebody: e.g. brain, spinal cord and gut.  They include nausea and vomiting (when starting treatment- tolerence develops quickly). Occasionally diarrhea and abdominal cramps can occur. Also they can cause headache (common- again when starting drug), increased agitation increased anxiety (when starting treatment), restlessness (akathisia), dystonic reactions and sexual dysfunction(e.g. delayed ejaculation in males).

3. Serotonin Noradrenaline Reuptake Inhibitors (SNRI s)
The drug blocks the re-uptake of noradrenaline and serotonin. Examples for SNRIs are:

• Venlafaxine (Used to treat both anxiety and depressive disorders.Dose: range from 75mg daily to a maximum of 300mg daily.Given as a bd dose;  or in the case of slow release preparations (XR)- once daily in morning.Caution in doses over 150mg daily:  may increase blood pressure; monitor BP and ECG).
• Duloxetine(Maybe more effective in treatment of depression presenting with physical pain symptoms).

4. Monoamine Oxidase Inhibitors (MAOIs)
This is also a older group of antidepressants. Antidepressant action of this class of drugs first described in the 1950s. This is an effective medication, but clinical use much less common now due high risk drug/food interactions. Examples are:

• Phenelzine
• Isocarboxazide
• Tranylcypromine
• Selegiline  (selective inhibitor MAO-B)

Mode of action:
They irreversibly inhibition of MAO enzyme. It has so-called ‘hit and run’ effect). Since the MAO is irreversibly inhibited, MAOI effects can last even 2-3 weeks after the drug is stopped (until the enzyme is re-synthesised).

MAO enzyme:  two types:

• MAO-A:  Found in brain, liver, intestine, lungs

                    Breaks down serotonin, NA, dopamine &
                    tyramine

• MAO-B:  Chiefly in brain.  Breaks down dopamine.

When MAO inhibitors are non selectively and irreversibly inhibited- increased serotonin & noradrenaline in central nervous system. It can also lead to dangerous dangerous interactions with other sympathomimetics such as cough syrups with ephedrine/ amphetamine and certain types of food that contain tyramine (cheese - “cheese reaction”), alcohol overripe fruit, smoked fish, etc


Drug/food interaction (“Tyramine reaction”)
This cause hypertensive crisis (due to vasoconstriction) causing severe throbbing head, palpitations, tachycardia. This could be life threatening. Therefore patients need to be warned ahead. Risk of interaction can last for 2-3 weeks after stopping treatment completely.