Pharmacology of Antidepressants and its mechanism

Antidepressants

1. DEPRESSION
Sreenu Thalla
Associate Professor
Department of Pharmacology

2. TYPES OF DEPRESSION
Major depression
Chronic depression (Dysthymia)
Atypical depression
Bipolar disorder/Manic depression
Seasonal depression (SAD)

3. SYMPTOMS
Persistently sad, anxious, or empty moods
Loss of pleasure, feelings of helplessness, guilt, or worthlessness
Crying , hopelessness, decreased energy
Loss of memory, concentration, or decision-making capability
Restlessness, irritability, sleep disturbances
Change in appetite or weight
Physical symptoms that defy diagnosis and do not respond to treatment (especially
pain and gastrointestinal complaints)
Thoughts of suicide or death, or suicide attempts.

4. DIAGNOSIS
Extensive patient and family history
Blood test for hypothyroidism
Current medication
Genetics
Death/Abuse
Medications
CAUSES

5. NEUROTRANSMITTERS HYPOTHESIS
Neurotransmitters pass along signal
Smaller amount of neurotransmitters causes depression

6. MAOIS MECHANISM OF ACTION
MAO contains a
cysteinyl-linked flavin
MAOIs covalently bind
to N-5 of the flavin
residue of the enzyme

8. MAOIS SIDE EFFECTS
Drowsiness/Fatigue
Constipation
Nausea
Diarrhea
Dizziness
Low blood pressure
Lightheadedness,
Decreased urine output
Decreased sexual function
Sleep disturbances
Muscle twitching
Weight gain
Blurred vision
Headache
Increased appetite
Restlessness
Shakiness
Weakness
Increased sweating

9. THE RECEPTOR SENSITIVITY HYPOTHESIS
Supersensitivity and up-regulation of post-synaptic receptors leads
to depression
Suicidal and depressed patients have increased 5HT-α
2 receptors

10. TRICYCLIC ANTIDEPRESSANTS (TCAS)
Imipramine

11. TCAS MECHANISM OF ACTION
TCAs inhibit serotonin, norepinephrine,
and dopamine transporters, slowing
reuptake
TCAs also allow for the downregulation of
post-synaptic receptors
All TCAs and SSRIs contain an essential
amino group that appears to interact with
Asp-98 in hSERT

12. TCAS SIDE EFFECTS
Muscarinic M1 receptor antagonism -anticholinergic effects
including dry mouth, blurred vision, constipation, urinary retention
and impotence
Histamine H1 receptor antagonism -sedation and weight gain
Adrenergic α receptor antagonism -postural hypotension
Direct membrane effects -reduced seizure threshold, arrhythmia
Serotonin 5-HT2 receptor antagonism -weight gain (and reduced
anxiety)

13. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Serotonin

14. SSRIS MECHANISM OF ACTION
Exact mechanism remains uncertain
Ser-438 residue in the human serotonin transporter (hSERT) appears
to be a determining factor in SSRI potency
Antidepressants interact directly with hSERT

15. SSRIS SIDE EFFECTS
Anhedonia
Apathy
Nausea/vomiting
Drowsiness or somnolence
Headache
Bruxism(involuntarily grinding
of the teeth)
Extremely vivid and strange
dreams
Dizziness
Fatigue
Changes in sexual behavior
Suicidal thoughts

16. SSRIS SIDE EFFECTS
Many disappear within 4 weeks (adaption phase)
Side effects more manageable compared to MAOIs and TCAs
Sexual side effects are common
SSRI cessation syndrome
Brain zaps
Sexual dysfunction

17. SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIS)
Slightly greater efficacy than SSRIs
Slightly fewer adverse effects than SSRIs
Current drugs
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Mechanism of Action
Very similar to SSRIs
Works on both neurotransmitters
Side effects
Similar to SSRIs
Suicide
Venlafaxine 1:1
Duloxetine

19. NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
Current drugs
Bupropion (Wellbutrin)
Mechanims of Action
Similar to SSRIs and SNRIs
More potent in inhibiting dopamine
Also anα3-β4 nicotinic antagonist
Adverse effects
Lowers seizure threshold
Suicide
Does not cause weight gain or sexual dysfunction
Bupropion 1:1