Selecting an Antidepressant for Depression with Decreased Motivation
For patients with major depressive disorder presenting with decreased motivation, energy, pleasure, and interest, bupropion is the preferred antidepressant choice. 1, 2
Rationale for Bupropion in Motivational Symptoms
Bupropion specifically targets the neurochemical deficits underlying motivational symptoms through its unique mechanism as a norepinephrine and dopamine reuptake inhibitor, distinguishing it from serotonin-focused agents. 1, 3
Evidence Supporting Bupropion for Decreased Motivation
Targeted efficacy: A randomized, double-blind, placebo-controlled trial specifically evaluated bupropion XL (300-450 mg/day) in MDD patients with prominent symptoms of decreased energy, pleasure, and interest, demonstrating superior improvement compared to placebo (p = 0.007 for the energy/pleasure/interest domain). 2
Symptom profile: Bupropion shows particular efficacy for cognitive disturbance, psychomotor retardation, and symptoms reflecting decreased energy—the core features of motivational deficits in depression. 4
Remission rates: In patients with decreased energy and interest, clinician-rated remission rates were significantly higher with bupropion XL (32%) versus placebo (18%), with response rates of 50% versus 35%. 2
Practical Prescribing Algorithm
Starting dose: Initiate bupropion XL at 150 mg once daily for 3-4 days, then increase to 300 mg once daily. 5
Dose titration: If inadequate response after 4 weeks at 300 mg, may increase to maximum dose of 450 mg once daily (given as 300 mg in morning and 150 mg at least 8 hours later for non-XL formulations, or 450 mg once daily for XL). 5
Critical safety consideration: Never exceed 450 mg/day total dose due to dose-related seizure risk; the maximum single dose is 300 mg for XL formulation. 5
Alternative Second-Generation Antidepressants
While the American College of Physicians guidelines state that all second-generation antidepressants have similar efficacy for general MDD 6, this equivalence does not extend to specific symptom profiles like decreased motivation.
When to Consider Alternatives
Venlafaxine: Consider if patient has comorbid anxiety with motivational symptoms, as limited evidence suggests potential superiority over fluoxetine for anxiety in depression. 6
Sertraline: May be considered for patients with psychomotor agitation accompanying decreased motivation, though evidence is limited. 6
Mirtazapine: Has faster onset of action (significant by week 2-3) but lacks specific evidence for motivational symptoms. 6
Important Clinical Caveats
Seizure Risk with Bupropion
Bupropion is contraindicated in patients with: 5
- Current or prior seizure disorder
- Bulimia or anorexia nervosa (increased seizure risk)
- Abrupt discontinuation of alcohol, benzodiazepines, or barbiturates
- Conditions lowering seizure threshold
Tolerability Advantages
Bupropion offers distinct advantages over SSRIs: 6
- Minimal sexual dysfunction (significantly lower rates than fluoxetine and sertraline)
- No weight gain (may cause modest weight loss)
- No sedation (rates comparable to or lower than placebo)
- Minimal anticholinergic effects
Monitoring Requirements
- Assess response within 6-8 weeks of initiation; modify treatment if inadequate response. 6
- Monitor for neuropsychiatric symptoms (agitation, mood changes, suicidal ideation) especially in first few weeks. 5
- Continue treatment for 4-9 months after satisfactory response for first episode; longer for recurrent depression. 6
Treatment-Resistant Cases
If patient fails initial bupropion trial, the STAR*D study demonstrated that switching to another second-generation antidepressant (sertraline or venlafaxine) results in 25% achieving remission, with no significant difference between agents. 6
Augmentation strategy: Combining bupropion with an SSRI/SNRI has demonstrated improved outcomes in patients failing monotherapy, though this represents off-label use for initial treatment. 3