Selective Serotonin Reuptake Inhibitors (SSRI)

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)

MOA:

• Inhibits 5-HT only (not NA).
• Lack anticholinergic and α-blocking properties.

Drugs: Paroxetine, Sertraline, Citalopram,  Fluoxetine, Fluvoxamine & Escitalopram

Uses:

• DOC for depression, phobias, OCD, PTSD, bulimia, premenstrual tension syndrome, sustained treatment of generalized anxiety disorders & panic attacks.

Advantages over TCAs:

• No anticholinergic adverse effects.
• No sedation or weight gain.
• No propensity to cause seizures or arrhythmias.

1. Depression:

• Mild to moderate – Fluoxetine.

2. Panic disorder:

• Sustained treatment – Sertraline.

3. Neurotic disorders:

• Obsessive compulsive disorder – Fluoxetine.
• Post-traumatic stress disorder – Sertraline/paroxetine.
• Bulimia – Fluoxetine.
• Phobia – Sertraline.
• Impulse-control disorders – Fluoxetine.

4. GAD (generalized anxiety disorders):

• Paroxetine & venlafaxine – Indicated for chronic GAD treatment.

5. Severe premenstrual tension syndrome (PMS):

• Fluoxetine & sertraline.
• Effective as continuous treatment for 2 weeks out of a month in luteal phase.
• Associated with rapid increases in pregnenolone levels.

General adverse effects:

• Most common adverse effects:
  • Nausea –> Anxiety –> Diarrhea –
  • Due to 5-HT 3 receptor stimulation in CNS & periphery.
• Abnormal bleeding – 
  • Due to disturbance in platelet serotonin levels.
• Insomnia, anxiety, irritability, akathisia & decreased libido –
  • Due to excessive stimulation of brain 5-HT₂ receptors.
• Sexual side effects including erectile dysfunction, anorgasmia, ejaculation inhibition & ejaculatory delay (Mainly paroxetine) –
  • Due to excessive activity at spinal 5-HT₂ receptors.
• Serotonin syndrome (Coadministration of SSRIs & MAO-inhibitors).

Individual drugs:

1. Fluoxetine:

• Prototype SSRI.
• Prodrug
• Longest-acting & metabolized to nor-fluoxetine retaining anti-depressant activity.
• Hence, anti-depressant drug of SSRI.

2. Fluvoxamine:

• Shortest-acting SSRI.

3. Escitalopram:

• Most specific SSRI.

4. Paroxetine:

• Most teratogenic among SSRIs.
• Increased risk of congenital cardiac malformations.
• More prominent sexual side effects (erectile dysfunction, anorgasmia, ejaculation inhibition & ejaculatory delay).

6. Sertraline & citalopram:

• Safest SSRIs for combination with warfarin.

Discontinuation syndrome of SSRI’s:

• Withdrawal symptoms include dizziness, headache, nervousness, nausea & insomnia.
• Paroxetine (More intense) – Due to relatively short-acting nature.
• Fluoxetine – Safer in this regard due to very long-acting metabolite.