Antidepressants do not cure depression but are used to alleviate symptoms , often over long durations to prevent relapse or recurrence . They are primarily used in major depressive disorder (MDD) , dysthymia , and other psychiatric conditions such as anxiety disorders and bipolar disorder .
Understanding Depression
Depression is more than just sadness—it involves persistent low mood, anhedonia, fatigue, sleep disturbances , and somatic complaints . It may be:
- Reactive (situational) : Linked to external life events.
- Endogenous (biological) : Without identifiable cause, possibly due to neurotransmitter imbalance.
- Part of bipolar disorder : Alternates with mania.
Biological Basis: The Monoamine Hypothesis
The prevailing theory suggests that deficiency of monoamines (especially serotonin [5-HT] , norepinephrine [NE] , and dopamine [DA] ) in synaptic clefts contributes to depression. Antidepressants work by increasing monoamine availability in the central nervous system.
Goals of Antidepressant Therapy
- Acute phase : Achieve symptom remission.
- Continuation phase : Prevent relapse.
- Maintenance phase : Prevent recurrence, especially in chronic or recurrent cases.
Classes of Antidepressants
1. Tricyclic Antidepressants (TCAs)
Examples : Imipramine, Amitriptyline, Nortriptyline, Desipramine, Clomipramine, Doxepin, Trimipramine
Mechanism : Inhibit reuptake of 5-HT and NE , increasing their synaptic levels.
Therapeutic Use :
- Moderate to severe depression
- Neuropathic pain, fibromyalgia
- Nocturnal enuresis (Imipramine)
Adverse Effects :
- Anticholinergic : Dry mouth, constipation, urinary retention
- Cardiotoxicity : Prolonged QT, arrhythmias (especially in overdose)
- Sedation , weight gain
- Orthostatic hypotension
- Lowered seizure threshold
Clinical Note : Dangerous in overdose —monitor ECG and consider use of activated charcoal or sodium bicarbonate for TCA toxicity.
2. Monoamine Oxidase Inhibitors (MAOIs)
Examples :
- Non-selective irreversible : Phenelzine, Tranylcypromine
- Reversible MAO-A inhibitor : Moclobemide
Mechanism : Inhibit MAO-A and/or MAO-B , preventing monoamine breakdown.
Indications :
- Atypical depression
- Treatment-resistant depression
- Social phobia
Adverse Effects :
- Hypertensive crisis with tyramine-rich foods ("cheese reaction")
- CNS stimulation: Insomnia, agitation
- Orthostatic hypotension
- Dangerous drug interactions with SSRIs, TCAs, sympathomimetics → serotonin syndrome or hypertensive crisis
Clinical Note : 5-week washout required when switching from fluoxetine to MAOIs due to fluoxetine’s long half-life.
3. Selective Serotonin Reuptake Inhibitors (SSRIs)
Examples : Fluoxetine, Sertraline, Citalopram, Escitalopram, Paroxetine, Fluvoxamine
Mechanism : Selectively inhibit 5-HT reuptake , increasing its availability.
Indications :
- Major depression
- Generalized anxiety disorder (GAD)
- Panic disorder, OCD, PTSD
- PMDD, bulimia nervosa
Adverse Effects :
- GI upset (nausea, diarrhea)
- Sexual dysfunction (↓ libido, anorgasmia)
- Insomnia or somnolence
- Serotonin syndrome (especially with polypharmacy)
Clinical Note : Fluoxetine has the longest half-life; paroxetine is more sedating. SSRIs are first-line agents due to better safety and tolerability.
4. Atypical Antidepressants
a. Bupropion
- Mechanism : Inhibits NE and DA reuptake
- Indications : Depression, smoking cessation
- Advantage : No sexual side effects
- Contraindicated in epilepsy and eating disorders
b. Mirtazapine
- Mechanism : α2-antagonist → ↑ NE and 5-HT; also antagonizes 5-HT2 and 5-HT3 receptors
- Effects : Sedation and weight gain (good for anorexia or insomnia)
c. Trazodone
- Mechanism : 5-HT2 antagonist, weak SSRI
- Use : Insomnia (lower doses)
- Adverse effect : Priapism
d. Venlafaxine, Duloxetine (SNRIs)
- Mechanism : Inhibit 5-HT and NE reuptake
- Use : Depression, anxiety, neuropathic pain
5. Tricyclic Anxiolytics
Examples : Doxepin, Dosulepin
- Similar to TCAs but with milder antidepressant activity .
- Useful in mild depression with anxiety .
- Faster onset but similar side effects as TCAs.
Key Clinical Considerations
- Onset of Action : 2–4 weeks to notice significant effects.
- Trial Duration : Minimum of 6 weeks before considering a switch.
- Continuation : 6–12 months post-remission; longer for recurrent depression.
- Discontinuation : Taper slowly to avoid withdrawal symptoms.
High-Yield Notes
- SSRIs are first-line due to their favorable side effect profile .
- MAOIs are last-resort due to food and drug interactions.
- TCAs are effective but limited by cardiotoxicity and anticholinergic effects .
- Bupropion is ideal for patients with sexual dysfunction or needing help with smoking cessation.
- Monitor for serotonin syndrome when combining serotonergic drugs (triad: mental status changes, autonomic instability, neuromuscular abnormalities ).
- Always assess for suicidal ideation , especially at treatment initiation.
