What are the different classifications of antidepressants, including Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), and Monoamine Oxidase Inhibitors (MAOIs)?

Antidepressant Classifications

Antidepressants are categorized into four major classes based on their mechanism of action: Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), and Monoamine Oxidase Inhibitors (MAOIs), with each class offering distinct efficacy profiles and tolerability considerations that directly impact patient outcomes.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism and Examples

• SSRIs work by selectively inhibiting serotonin reuptake at the presynaptic terminal, with minimal effects on other neurotransmitter systems 1, 2.
• Common SSRIs include fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine 3, 4.

Efficacy Profile

• SSRIs demonstrate comparable efficacy to TCAs overall, with numbers needed to treat ranging from 7 to 8 for achieving remission, though they show inferior efficacy in severely depressed or hospitalized patients compared to dual-acting TCAs 3.
• Within the SSRI class, paroxetine and fluoxetine demonstrate stronger evidence of efficacy than sertraline for panic disorder 4.
• SSRIs may have a slower onset of action and lower remission rates compared to dual-action antidepressants 1.

Tolerability and Safety

• SSRIs are significantly better tolerated than TCAs, with dropout rates due to side effects of 15.4% compared to 18.8% for TCAs 3.
• Common adverse effects include nausea, diarrhea, fatigue, somnolence, sexual dysfunction, sweating, tremor, headache, dizziness, dry mouth, and weight gain 3, 5.
• Preferred SSRIs for older adults include citalopram, escitalopram, and sertraline due to lower rates of adverse effects 3.
• Paroxetine and fluoxetine should be avoided in elderly patients due to higher rates of anticholinergic side effects 3, 5.

Critical Drug Interactions

• SSRIs are absolutely contraindicated with MAOIs due to life-threatening risk of serotonin syndrome—at least 14 days must elapse between discontinuing an MAOI and starting an SSRI, and at least 5 weeks must elapse when switching from fluoxetine to an MAOI due to its long half-life 6, 7.
• All SSRIs inhibit cytochrome P450 2D6 to varying degrees, requiring dose adjustments when combined with TCAs 8.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Mechanism and Examples

• SNRIs inhibit reuptake of both serotonin and norepinephrine, providing dual neurotransmitter modulation 1, 2, 9.
• Available SNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran 3, 5, 10.

Efficacy Profile

• SNRIs demonstrate slightly superior efficacy compared to SSRIs, with remission rates of 49% versus 42%, though this advantage comes at the cost of higher adverse effect rates 3, 5.
• Venlafaxine shows significantly greater remission rates compared to SSRIs (fluoxetine, paroxetine, fluvoxamine) 3.
• SNRIs may provide more rapid onset of action and greater overall efficacy at higher doses compared to SSRIs 1, 10.

Tolerability and Safety

• SNRIs are associated with higher rates of nausea and vomiting compared to SSRIs, which are the most common reasons for discontinuation 3, 5.
• Duloxetine and venlafaxine have 67% and 40% higher risk of discontinuation due to adverse effects compared to SSRIs as a class 5.
• Dose-dependent blood pressure elevation can occur, particularly with venlafaxine at doses above 225 mg/day, though this is infrequently observed below this threshold 10.
• Common adverse effects include nausea, dry mouth, dizziness, constipation, insomnia, asthenia, hypertension, diaphoresis, tachycardia, tremors, and anxiety 10.

Special Considerations

• SNRIs are particularly beneficial for patients with comorbid pain disorders, including diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain 5, 10.
• Venlafaxine and desvenlafaxine have favorable drug-drug interaction profiles due to low protein binding and minimal CYP enzyme inhibition 10.
• Preferred SNRI for older adults is venlafaxine 3.

Critical Drug Interactions

• SNRIs are absolutely contraindicated with MAOIs due to risk of serotonin syndrome—at least 14 days must elapse between discontinuing an MAOI and starting an SNRI, or vice versa 6, 7.

Tricyclic Antidepressants (TCAs)

Mechanism and Examples

• TCAs inhibit reuptake of serotonin and norepinephrine, but also block cholinergic, histaminergic, and alpha-1-adrenergic receptors, causing multiple side effects 3, 2.
• Dual-acting tertiary amine TCAs include clomipramine and amitriptyline, while more selective TCAs include imipramine, desipramine, and maprotiline 3.

Efficacy Profile

• TCAs demonstrate superior efficacy compared to SSRIs in severely depressed, hospitalized patients, with dual-acting tertiary amine TCAs (clomipramine and amitriptyline) showing the strongest effect due to inhibition of both norepinephrine and serotonin reuptake 3.
• TCAs as a class rank as the most effective antidepressant class overall, followed by benzodiazepines and MAOIs 4.
• Numbers needed to treat range from 7 to 16 for TCAs 3.
• Amitriptyline is associated with a slightly greater proportion of responders compared to other antidepressants 3.

Tolerability and Safety

• TCAs are significantly less well tolerated than SSRIs, with dropout rates due to side effects of 18.8% compared to 15.4% for SSRIs 3.
• Anticholinergic side effects include tachycardia, urinary retention, constipation, dry mouth, blurred vision, and exacerbation of narrow-angle glaucoma 8.
• Central nervous system anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation, and delirium 8.
• Elderly patients are particularly sensitive to anticholinergic side effects and are at increased risk for falls 8.

Critical Drug Interactions and Contraindications

• TCAs are absolutely contraindicated with MAOIs due to risk of hypertensive crises, convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse—at least 14 days must elapse between discontinuing an MAOI and starting a TCA, and at least 5 weeks when switching from fluoxetine to a TCA 8, 7.
• Concomitant use with drugs that inhibit cytochrome P450 2D6 (including all SSRIs, quinidine, cimetidine) may require lower TCA doses 8.
• TCAs should not be combined with anticholinergic agents or sympathomimetic drugs due to risk of hyperpyrexia and hypertensive crisis 8.
• Paralytic ileus may occur when TCAs are combined with anticholinergic-type drugs 8.

Special Populations

• TCAs should be avoided in elderly patients due to high anticholinergic burden, though if used, a "start low, go slow" approach is essential 3, 8.

Monoamine Oxidase Inhibitors (MAOIs)

Mechanism and Examples

• MAOIs are multiple-action medications that inhibit monoamine oxidase enzymes, preventing breakdown of monoamines including serotonin, norepinephrine, and dopamine 1, 2.
• Available MAOIs include phenelzine, tranylcypromine, isocarboxazid, selegiline, and pargyline 6, 7.

Efficacy Profile

• MAOIs rank third in efficacy among antidepressant classes, after TCAs and benzodiazepines 4.
• Phenelzine demonstrates superior efficacy to imipramine in all trials, except those lacking patients with atypical symptoms 3.
• MAOIs are particularly effective for treatment-resistant depression, anxiety disorders with high anxiety levels, panic disorder, agoraphobia, and mixed anxiety-depressive states 6.

Tolerability and Safety

• MAOIs rank last among antidepressant classes for tolerability, with the highest dropout rates 4.
• MAOIs are reserved as third- to fifth-line treatments due to significant safety concerns 6.

Critical Drug Interactions and Contraindications

The following combinations with MAOIs are absolutely contraindicated and can be fatal:

• All other MAOIs, SSRIs, SNRIs, TCAs, bupropion, and serotoninergic drugs due to risk of serotonin syndrome, hypertensive crises, convulsive seizures, hyperthermia, and death 6, 7.
• All sympathomimetic drugs including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, norepinephrine, pseudoephedrine, phenylephrine, and related compounds (methyldopa, L-dopa, L-tryptophan, L-tyrosine, phenylalanine) due to risk of hypertensive crisis 6, 7.
• Meperidine is specifically contraindicated due to risk of excitation, seizures, delirium, hyperpyrexia, circulatory collapse, coma, and death 6, 7.
• Other opioids including tramadol, methadone, and fentanyl due to risk of serotonin syndrome and hypertensive crisis 6.
• Dextromethorphan (found in cough suppressants) due to risk of serotonin syndrome 6, 7.
• Buspirone due to risk of elevated blood pressure 7.

Dietary Restrictions

• Patients on MAOIs must avoid tyramine-rich foods including aged cheeses, pickled herring, beer, wine, liver, yeast extract, dry sausage (Genoa salami, hard salami, pepperoni, Lebanon bologna), fava beans, and yogurt, as well as excessive caffeine and chocolate, due to risk of hypertensive crisis 7.

Required Washout Periods

• At least 14 days must elapse between discontinuing an MAOI and starting any other antidepressant, stimulant, or serotoninergic agent 6, 7.
• At least 14 days must elapse between discontinuing another antidepressant and starting an MAOI, except for fluoxetine which requires at least 5 weeks due to its long half-life 6, 7.
• MAOIs must be discontinued at least 10 days prior to elective surgery requiring general anesthesia 7.

Additional Contraindications

• MAOIs are contraindicated in patients with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, history of liver disease, or abnormal liver function tests 7.
• MAOIs should not be used with cocaine or local anesthesia containing sympathomimetic vasoconstrictors 7.
• MAOIs are contraindicated in patients receiving guanethidine 7.

Class Comparison for Clinical Decision-Making

First-Line Treatment Selection

• For treatment-naïve patients with moderate depression, all second-generation antidepressants (SSRIs, SNRIs) are equally effective, so medication choice should prioritize patient preference, adverse effect profile tolerance, cost, and dosing frequency 3, 5.
• For severely depressed or hospitalized patients, dual-acting tertiary amine TCAs (clomipramine or amitriptyline) demonstrate superior efficacy compared to SSRIs and should be strongly considered despite higher side effect burden 3.

Tolerability Hierarchy

• Benzodiazepines rank first for tolerability, followed by TCAs, SNRIs, SSRIs, and lastly MAOIs 4.
• When tolerability is the primary concern, SSRIs should be chosen over SNRIs due to lower discontinuation rates, despite slightly lower efficacy 3, 5.

Treatment Duration

• Treatment for a first episode of major depression must last at least 4 months regardless of antidepressant class chosen 3, 5.
• Patients with recurrent depression benefit from prolonged treatment, often requiring long-term therapy 3, 5, 6.

Special Population Considerations

• For older adults, preferred agents include citalopram, escitalopram, sertraline (SSRIs), mirtazapine, venlafaxine (SNRI), with paroxetine and fluoxetine avoided due to higher adverse effect rates 3, 5.
• For patients with comorbid pain disorders, SNRIs provide additional therapeutic benefit 5.

Common Clinical Pitfalls to Avoid

• Failing to recognize that antidepressants are most effective in patients with severe depression, not mild depression 3.
• Discontinuing treatment before 4 months for a first episode, which increases relapse risk 3, 5.
• Overlooking the superior efficacy of dual-acting TCAs in severely depressed or hospitalized patients due to concerns about side effects 3.
• Not maintaining adequate washout periods when switching between antidepressant classes, particularly with MAOIs, leading to potentially fatal serotonin syndrome or hypertensive crisis 6, 8, 7.
• Selecting SNRIs for patients who are sensitive to gastrointestinal side effects without considering the 67-40% higher discontinuation rates 5.
• Prescribing paroxetine or fluoxetine to elderly patients when safer SSRI alternatives exist 3, 5.
• Failing to educate patients on MAOIs about dietary restrictions, over-the-counter medication avoidance, and recognition of hypertensive crisis symptoms 6, 7.
• Not recognizing that publication bias significantly exaggerates antidepressant benefits, with only 51% of FDA-reviewed trials showing positive results despite 94% of published trials appearing positive 3.