What are the recommended medications and treatment options for managing symptoms of depression?

Pharmacologic Management of Depression: Target Symptoms and Medication Selection

First-Line Antidepressant Recommendations

For treatment-naive patients with moderate to severe depression, second-generation antidepressants (SSRIs and SNRIs) are the recommended first-line pharmacologic treatment, with specific medication selection based on the target symptom profile. 1

For Cognitive Symptoms ("Brain Fog")

• Bupropion is the most effective first-choice antidepressant for cognitive symptoms including difficulty concentrating, indecisiveness, and mental fog due to its dopaminergic and noradrenergic effects and lower rate of cognitive side effects. 2
• Bupropion is particularly beneficial when fatigue and psychomotor retardation predominate. 2
• SNRIs (venlafaxine or duloxetine) are the second-choice option for cognitive symptoms, as their noradrenergic component may improve attention and concentration better than SSRIs. 2, 3
• Avoid paroxetine and fluoxetine for cognitive symptoms due to higher anticholinergic effects that can worsen cognitive function. 2
• Avoid all tricyclic antidepressants (TCAs) for cognitive symptoms due to anticholinergic effects. 2

For General Depressive Symptoms

• All second-generation antidepressants are equally effective for treatment-naive patients with general depressive symptoms. 1
• SSRIs have a number needed to treat of 7-8 for achieving remission. 1
• SNRIs (venlafaxine and duloxetine) are slightly more effective than SSRIs for symptom improvement overall, though they carry higher rates of nausea and vomiting. 1, 3
• Venlafaxine showed superior efficacy compared to fluoxetine in comparative studies. 2

For Older Adults (≥65 years)

Preferred agents for older patients include: 1

• Citalopram
• Escitalopram
• Sertraline
• Mirtazapine
• Venlafaxine
• Bupropion

Avoid in older adults: 1

• Paroxetine (higher anticholinergic effects)
• Fluoxetine (longer half-life, less favorable profile)

Medication Initiation and Titration

• Start at the lowest effective dose and titrate upward as needed. 2
• Assess initial response within 1-2 weeks of initiation. 2
• Evaluate full response at 4-6 weeks; if insufficient improvement, consider switching to another agent. 2
• If no adequate response within 6-8 weeks, switch to a different antidepressant. 2

Treatment Duration

• For a first episode of major depression, continue treatment for at least 4-9 months after symptom resolution. 1, 2
• Patients with recurrent depression may benefit from prolonged treatment beyond 9 months. 1

Common Adverse Effects and Management

Approximately 63% of patients on second-generation antidepressants experience at least one adverse effect: 1

Most common adverse effects: 1

• Nausea and vomiting (most common reason for discontinuation)
• Diarrhea
• Dizziness
• Dry mouth
• Fatigue
• Headache
• Sexual dysfunction
• Sweating
• Tremor
• Weight gain

Number needed to harm for discontinuation: 1

• SSRIs: 20-90
• TCAs: 4-30
• Duloxetine and venlafaxine have slightly higher discontinuation rates than SSRIs as a class

Sexual Dysfunction Considerations

• Bupropion has lower rates of sexual adverse events than fluoxetine and sertraline. 1
• Paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, and sertraline. 1

Severity-Based Treatment Approach

Antidepressants are most effective in patients with severe depression. 1

• The drug-placebo difference increases with initial severity: virtually no difference in mild depression, small difference in moderate depression, and medium difference in severe depression. 1
• Do not use antidepressants for initial treatment of adults with depressive symptoms in the absence of current or prior moderate-to-severe depressive episode. 1

Combination with Psychotherapy

Cognitive behavioral therapy (CBT) combined with antidepressant medication is preferred for more severe or chronic depression, showing greater symptom improvement than either treatment alone (standardized mean difference 0.30-0.33). 4

Critical Drug Interactions and Contraindications

Absolute contraindications: 5, 6

• Do not combine SSRIs with MAOIs (risk of serotonin syndrome)
• Do not combine SSRIs with pimozide (QTc prolongation)

Use caution with: 5, 6

• Triptans (risk of serotonin syndrome)
• Tramadol (risk of serotonin syndrome)
• Warfarin (altered anticoagulation; monitor closely)
• NSAIDs/aspirin (increased bleeding risk)
• TCAs (SSRIs inhibit TCA metabolism; monitor levels)

Monitoring Requirements

• Regularly assess both mood and cognitive symptoms using standardized measures. 2
• Monitor for emergence of side effects that could worsen function, particularly sedation and anticholinergic effects. 2
• In adolescents on fluoxetine, monitor closely for suicidal ideation and behavior. 1
• Monitor lithium levels when co-administered with fluoxetine due to reports of both increased and decreased lithium levels. 5

Common Pitfalls to Avoid

• Do not prescribe antidepressants for mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 1
• Do not routinely combine anticholinergics with antipsychotics when treating depression with psychotic features. 1
• Do not use TCAs as first-line agents due to higher adverse effect burden and overdose risk. 1
• Do not assume all SSRIs have identical profiles; paroxetine has notably higher anticholinergic effects and sexual dysfunction rates. 1, 2