What is the most suitable antidepressant for patients with various comorbidities, such as anxiety disorders, bipolar disorder, dementia, and attention deficit hyperactivity disorder (ADHD), considering factors like medical history, age, and potential side effects?

Antidepressant Selection by Patient Profile and Comorbidity

Select second-generation antidepressants based on adverse effect profiles, cost, and patient preferences rather than efficacy differences, as all second-generation antidepressants demonstrate equivalent effectiveness for major depression. 1

General Principles for All Patients

• No second-generation antidepressant demonstrates superior efficacy over another for treating major depressive disorder, with response rates of approximately 46% and remission rates of 46% across all agents 1
• Selection should prioritize side effect profiles, comorbid conditions, drug interactions, and patient-specific factors rather than presumed efficacy differences 1
• Monitor all patients within 1-2 weeks of initiation for treatment-emergent suicidality, particularly in adults 18-24 years of age 1
• Pharmacogenetic testing for CYP2D6 and CYP2C19 metabolizer status can guide dosing for antidepressants metabolized through these pathways, particularly fluoxetine and paroxetine 1

Antidepressant Selection by Comorbidity

Depression with Anxiety Disorders

• SSRIs are first-line therapy for comorbid depression and anxiety disorders including panic disorder, generalized anxiety disorder, social anxiety disorder, and PTSD 1
• Fluoxetine is FDA-approved for panic disorder, OCD, and PTSD; use 10 mg initially, maximum 20 mg daily 1
• Paroxetine is FDA-approved for panic disorder, social anxiety disorder, generalized anxiety disorder, and PTSD; use 10 mg daily initially, maximum 40 mg daily 1
• Sertraline is well-tolerated with less effect on metabolism of other medications; use 25-50 mg daily initially, maximum 200 mg daily 1
• Escitalopram is well-tolerated; use 10 mg daily initially, maximum 20 mg daily 1, 2

Depression with Bipolar Disorder

• Establish mood stabilizer therapy first before adding any antidepressant to prevent manic switch and mood destabilization 3
• Fluoxetine combined with olanzapine is the only FDA-approved antidepressant combination for bipolar depression 1
• Avoid antidepressant monotherapy as it carries risk of manic switch 3
• Anticonvulsant mood stabilizers and second-generation antipsychotics are preferred first-line agents per CANMAT guidelines 3

Depression with Chronic Pain (Including Fibromyalgia, Diabetic Neuropathy, Chronic Low Back Pain, Osteoarthritis)

• SNRIs provide superior benefit for patients with comorbid pain disorders, with remission rates of 49% versus 42% for SSRIs 1
• Duloxetine is FDA-approved for diabetic peripheral neuropathic pain, fibromyalgia, chronic musculoskeletal pain, and chronic low back pain 4
  • Dosing: Start 30 mg daily for one week, then increase to 60 mg daily (maximum for most indications) 4
  • Monitor for hepatotoxicity; contraindicated in hepatic impairment 4
• Venlafaxine is an alternative SNRI but has higher discontinuation rates due to nausea and vomiting (67% increased risk versus SSRIs) 1

Depression with Insomnia

• Mirtazapine promotes sleep, appetite, and weight gain; use 7.5 mg at bedtime initially, maximum 30 mg at bedtime 1
• Trazodone (sedating antidepressant) has little anticholinergic activity; dosing varies but typically started at low doses for sleep 1
• Nortriptyline (tricyclic) is sedating and useful for agitated depression with insomnia; use 10 mg at bedtime initially, maximum 40 mg daily divided 1
• Avoid activating agents like fluoxetine, bupropion, or desipramine in patients with prominent insomnia 1

Depression with Sexual Dysfunction Concerns

• Bupropion has significantly lower rates of sexual adverse events compared to fluoxetine or sertraline 1
  • Start 37.5 mg every morning, increase by 37.5 mg every 3 days, maximum 150 mg twice daily 1
  • Give second dose before 3 PM to minimize insomnia 1
  • Contraindicated in seizure disorders 1
• Paroxetine has the highest rates of sexual dysfunction among SSRIs and should be avoided if sexual function is a concern 1

Depression with Dementia/Alzheimer's Disease

• Desipramine (tricyclic) tends to be activating and reduces apathy; use 10-25 mg in morning initially, maximum 150 mg daily 1
  • Lower risk for cardiotoxic, hypotensive, and anticholinergic effects compared to other tricyclics 1
  • May cause tachycardia; blood levels may be helpful 1
• Nortriptyline is more sedating; use 10 mg at bedtime initially, maximum 40 mg daily divided; therapeutic blood level window 50-150 ng/mL 1
• Citalopram is well-tolerated; use 10 mg daily initially, maximum 20 mg daily in patients over 60 years due to QT prolongation risk 1, 2
• Sertraline is well-tolerated with fewer drug interactions; use 25-50 mg daily initially 1

Depression in Elderly Patients (≥65 Years)

• Preferred agents: citalopram, escitalopram, sertraline, mirtazapine, venlafaxine, and bupropion 1
• Avoid paroxetine and fluoxetine due to higher rates of adverse effects in older adults 1
• Escitalopram: Maximum 10 mg daily in elderly patients (half-life increased by 50% in elderly) 2
• Citalopram: Maximum 20 mg daily in adults over 60 years due to dose-dependent QT prolongation 1
• Monitor closely for hyponatremia, which occurs in 0.5-12% of older adults on SSRIs/SNRIs (OR 3.3 for SSRIs) 1
• Assess fall risk regularly, as SSRIs/SNRIs increase fall risk proportional to baseline risk, which increases with age 4

Depression in Pregnancy and Breastfeeding

• Sertraline and paroxetine are most commonly prescribed during breastfeeding and produce low or undetectable infant plasma levels 1
• Fluoxetine and venlafaxine produce the highest infant plasma concentrations and should be avoided during breastfeeding 1
• All antidepressants are associated with slightly increased risk of preterm birth, but untreated depression also carries this risk 5
• Monitor breastfed infants for excessive sedation, restlessness, agitation, poor feeding, and poor weight gain 2

Depression in Adolescents (12-17 Years)

• Fluoxetine is the only FDA-approved antidepressant for major depression in children/adolescents aged 8 years or older 1
• Escitalopram has established safety and effectiveness in adolescents 12-17 years for major depression 2
• Black box warning: Monitor closely for treatment-emergent suicidality, particularly in first few months and after dose changes 1, 4
• Monitor weight and growth regularly as decreased appetite and weight loss are common with SSRIs 4, 2

Depression with Substance Use Disorders

• Avoid benzodiazepines entirely in patients with comorbid substance use disorders 3
• Select antidepressants with lower abuse potential and fewer drug interactions 3
• Sertraline has less effect on metabolism of other medications, reducing interaction risk 1

Depression with Cardiovascular Disease

• SSRIs are preferred over tricyclic antidepressants due to lower cardiotoxicity risk 1
• Avoid citalopram doses >40 mg daily (>20 mg daily if >60 years) due to QT prolongation risk 1
• Escitalopram and amitriptyline also carry QT prolongation risk 1
• Sertraline is well-tolerated with favorable cardiovascular profile 1

Depression with Hepatic Impairment

• Contraindicated: duloxetine in patients with clinically evident hepatic impairment 4
• Nefazodone carries hepatotoxicity risk and requires monitoring; reduce dose with coadministered alprazolam or triazolam by 50% 1
• Reduce escitalopram dose in hepatic impairment 2

Depression with Diabetes or Obesity

• Avoid mirtazapine and paroxetine as both are associated with significant weight gain 1
• Bupropion is weight-neutral or may promote weight loss 1
• Duloxetine may be beneficial for diabetic peripheral neuropathy if present 4
• Consider inflammatory connection between diabetes/obesity and depression when selecting treatment 6

Depression with OCD

• Higher doses are required for OCD compared to depression 1
• Fluoxetine: 60-80 mg daily for OCD (versus 20 mg for depression) 1
• Paroxetine: 60 mg daily for OCD (versus 20-40 mg for depression) 1

Specific Dosing Considerations

Activating vs. Sedating Properties

Activating agents (useful for apathy, low energy):

• Fluoxetine: 10 mg every other morning initially, maximum 20 mg daily 1
• Bupropion: 37.5 mg every morning, increase by 37.5 mg every 3 days 1
• Desipramine: 10-25 mg in morning, maximum 150 mg daily 1

Sedating agents (useful for agitation, insomnia):

• Mirtazapine: 7.5 mg at bedtime, maximum 30 mg at bedtime 1
• Nortriptyline: 10 mg at bedtime, maximum 40 mg daily 1
• Paroxetine: Less activating than other SSRIs but more anticholinergic 1
• Trazodone: Dose varies, typically low doses for sleep 1

Common Pitfalls to Avoid

• Do not assume efficacy differences between second-generation antidepressants—they are equivalent for depression 1
• Do not use antidepressant monotherapy in bipolar disorder—establish mood stabilizer first 3
• Do not exceed citalopram 40 mg daily (20 mg if >60 years) due to QT prolongation 1
• Do not prescribe paroxetine when sexual function is a priority concern—it has the highest sexual dysfunction rates 1
• Do not use duloxetine in hepatic impairment—it is contraindicated 4
• Do not overlook pharmacogenetic testing for patients on fluoxetine or paroxetine, as CYP2D6 poor metabolizers have significantly altered drug levels 1
• Do not continue indefinitely without reassessment—few studies examine safety beyond 2 years 5

Treatment Duration and Discontinuation

• First episode of major depression requires at least 4 months of treatment after symptom resolution 1
• Recurrent depression may require prolonged or indefinite treatment 1, 5
• Gradually taper dosage over 10-14 days when discontinuing to limit withdrawal symptoms 1
• Provide concurrent cognitive behavioral therapy during tapering to decrease relapse risk 5
• Risk of relapse or recurrence is increased with discontinuation compared to continued use 5