1. School of Pharmacy, University of Nizwa
Antidepressant Drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-25 and 26
April 15, 2012

2. Depression
Depression is a common psychiatric condition and a serious disorder that afflicts million of adults worldwide
Symptoms of depression:
intense feelings of sadness, and hopelessness
inability to experience pleasure in usual activities
changes in sleep patterns and appetite
loss of energy
suicidal thoughts
disturbed

3. Depression: Cause
Depression is due to a deficiency of monoamines, such as 5-HT and NE, in the key regions of brain
Key regions involved in depression:
Hippocampus
Frontal Cortex

4. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

5. Antidepressant Drugs: Mechanism of Action
Binding to:
5-HT transporter
NE transporter
Alteration in:
5-HT level
NE level
Structural changes:
Synapse formation
Neurogenesis
Clinical Efficacy

6. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

7. SSRI Drugs Name of few SSRIs: Fluoxetine Fluvoxamine Paroxetine
Citalopram

8. SSRIs: Mechanism of Actions
SSRIs block the reuptake of serotonin
Increased level of 5-HT
in the synaptic cleft
Greater postsynaptic
neuronal activity
SSRI X
Normal 5-HT Neurotransmission

9. SSRIs: Pharmacokinetics
Well absorbed after oral administration
Peak levels are seen in 2 to 8 hrs
Plasma half-lives between 16 and 36 hrs
Metabolized by CYP450-dependent enzymes
SSRIs: Adverse Effects
Adverse effects include headache, anxiety and agitation, weakness and fatigue, and sleep disturbances
Large intakes of SSRIs may cause seizures

10. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

11. SNRI Drugs
Name of few SNRI drugs:
Venlafaxine
Duloxetine

12. SNRIs: Mechanism of Actions
Selectively inhibit the reuptake of both 5-HT and NE
Increased level of 5HT and NE in the synaptic cleft
Greater postsynaptic
neuronal activity

13. SNRI, continued…… Metabolized in the liver Excreted in the urine
The half-life is approximately 12 hours
Side effects: nausea, dizziness, insomnia, dry mouth, and constipation
At high doses, venlafaxine may increase blood pressure and heart rate

14. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

15. Atypical Antidepressants
Mixed group of agents that have actions at several different sites
Few atypical antidepressant drugs:
Bupropion (DA and NE reuptake inhibitor)
Mirtazapine (enhances 5-HT and NE neurotransmission)
Nefazodone, Trazodone (5-HT reuptake inhibitor)

16. Atypical Antidepressants, continued….
Metabolized by CYP450 enzyme
Short half-life, may require more than once-a-day dosing
Side effects include dry mouth, sweating, nervousness
Bupropion produce seizures at high doses
Mirtazapine is markedly sedating, which may be used in depressed patients having difficulty sleeping

17. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

18. Tricyclic Antidepressants (TCAs)
Name of few TCAs:
Imipramine
Clomipramine
Desipramine
Nortriptyline
Protriptyline
Imipramine
TCAs: Mechanism of Action
TCAs are potent inhibitors of the neuronal reuptake of 5-HT and NE into presynaptic nerve terminals
By blocking major routes of neurotransmitter removal, the TCAs increase monoamines in the synaptic cleft

19. TCAs: Pharmacokinetics
Well absorbed upon oral administration
Lipophilic nature, widely distributed and readily penetrate into the CNS
Initial treatment period is typically 4 to 8 weeks
Metabolized by the hepatic microsomal system
Excreted as inactive metabolites via the kidney
TCAs: Adverse Effects
Blockade of muscarinic receptors leads to blurred vision, dry mouth, and constipation
Also cause orthostatic hypotension, and dizziness
Weight gain is a common adverse effect

20. Antidepressant Drugs Antidepressant agents:
Selective Serotonin Reuptake Inhibitors (SSRI)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
Atypical Antidepressants
Tricyclic Antidepressants (TCA)
Monoamine Oxidase Inhibitor (MAOI)

21. MAO Inhibitors: Mechanism of Actions
Name of few MAO inhibitors:
Phenelzine
Selegiline
MAO Inhibitors: Mechanism of Actions
MAO inhibitors form stable complexes with enzyme, causing irreversible inactivation. This results in increased stores of 5-HT, NE, and DA within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space

22. MAO Inhibitors: Pharmacokinetics
Well absorbed after oral dosing, but antidepressant effects require at least 2 to 4 weeks of treatment
Metabolized and excreted rapidly in the urine
MAO Inhibitors: Adverse Effects
Severe side effects due to drug-food and drug-drug interactions limit the widespread use of MAO inhibitors
Drowsiness, orthostatic hypotension, blurred vision, dry mouth, and constipation also reported