Treatment Approach for Comorbid Depression and ADHD
For a client with comorbid depression and ADHD, initiate a stimulant trial first if the depression is not severe (no psychosis, suicidality, or severe neurovegetative signs), as reduction in ADHD-related morbidity often substantially improves depressive symptoms, and you can rapidly assess response within days to weeks. 1
Initial Assessment and Treatment Sequencing
Determine Depression Severity First
If major depressive disorder is the primary disorder OR presents with very severe symptoms (psychosis, suicidality, or severe neurovegetative signs), treat the depression first before addressing ADHD. 1
If depression is less severe or not primary, proceed with a stimulant trial as the initial intervention. 1 This approach allows rapid assessment of whether ADHD symptom remission alone reduces the depressive burden, potentially avoiding unnecessary polypharmacy.
Rationale for Stimulant-First Strategy
Stimulants have rapid onset of action, enabling quick determination of ADHD symptom response within days. 1 The reduction in functional impairment from untreated ADHD often has substantial impact on mood symptoms.
After the stimulant trial, reassess depressive symptoms. 1 If both ADHD and depression have remitted, no additional pharmacological intervention may be necessary.
Contrary to older concerns, recent evidence demonstrates that ADHD patients with comorbid anxiety (and by extension, mood symptoms) do NOT have less robust responses to stimulants. 1 Early studies suggesting reduced stimulant efficacy in anxious ADHD patients were not replicated in larger, more rigorous trials.
Pharmacological Options
First-Line: Stimulant Monotherapy
Methylphenidate or amphetamine preparations are first-line pharmacotherapies for ADHD, including in the presence of comorbid depression. 1
For adults, methylphenidate 5-20 mg three times daily or dextroamphetamine 5 mg three times daily to 20 mg twice daily are appropriate starting regimens. 1
Long-acting formulations are associated with better medication adherence and lower risk of rebound effects. 1
If Depression Persists After Stimulant Trial
If ADHD symptoms respond to stimulants but depressive symptoms remain severe, add an SSRI to the stimulant regimen. 1
The combination of methylphenidate and SSRIs is safe and well-tolerated in adults with ADHD and comorbid depression, with no significant increase in adverse events compared to methylphenidate alone. 2 In fact, the combination was associated with a lower risk of headache.
In pediatric and adult case series, fluoxetine or sertraline combined with psychostimulants effectively addressed both ADHD and depressive symptoms without significant adverse effects, suicidality, or behavioral activation. 3
SSRIs are metabolized hepatically while 80% of methylphenidate metabolism is extrahepatic, explaining the lack of significant drug-drug interactions. 1
Alternative: Atomoxetine-Based Approach
Atomoxetine monotherapy is an alternative first-line option, particularly when stimulants are contraindicated or poorly tolerated. 1, 4
For adults, initiate atomoxetine at 40 mg daily, increasing after a minimum of 3 days to a target dose of 80 mg daily (single morning dose or divided doses). 4 After 2-4 additional weeks, may increase to maximum 100 mg daily if response is suboptimal.
Full therapeutic effect requires 4-6 weeks at therapeutic dose; assess effectiveness after 6-8 weeks. 5
Atomoxetine monotherapy appears effective for treating ADHD in pediatric patients with comorbid depressive or anxiety symptoms, with marked reductions in all symptom clusters. 6 However, the absence of placebo-only arms limits conclusions about specific antidepressant effects.
Combined atomoxetine/fluoxetine therapy is well-tolerated, though it produces greater increases in blood pressure and pulse than atomoxetine monotherapy. 6
Critical Considerations and Pitfalls
Screening Requirements
Prior to initiating any ADHD medication, screen patients for personal or family history of bipolar disorder, mania, or hypomania. 4 Patients with comorbid depressive symptoms require detailed psychiatric history including family history of suicide, bipolar disorder, and depression to assess risk of treatment-emergent mania.
Treatment-emergent psychotic or manic symptoms can occur with atomoxetine at usual doses in approximately 0.2% of patients without prior psychotic illness. 4 If such symptoms emerge, consider discontinuing atomoxetine.
Monitoring Parameters
Monitor blood pressure, heart rate, weight, and appetite regularly during treatment. 1, 4
Watch for emergence or worsening of aggressive behavior, hostility, or suicidal ideation, particularly in the first weeks of treatment. 4
Atomoxetine can cause orthostatic hypotension and syncope; use caution in conditions predisposing to hypotension. 4
What NOT to Do
Do not use bupropion or tricyclic antidepressants as first-line agents for treating both conditions simultaneously. 1 While these have proven antidepressant activity in adults and can treat ADHD, their utility in pediatric depression is not established, and they are second-line agents at best for ADHD.
Do not assume stimulants will worsen depression. 1 This outdated concern has not been supported by controlled trials; in fact, stimulants may improve mood through reduction of ADHD-related functional impairment.
Do not declare atomoxetine treatment failure before allowing full 6-8 weeks at therapeutic dose. 5 Premature discontinuation is a common error given the delayed onset of action.
Do not overlook the need for psychosocial interventions. 1 Pharmacological treatment should always be part of a multimodal approach including psychoeducation and, when depressive symptoms persist despite medication, cognitive behavioral therapy or interpersonal therapy. 1, 5
Special Population Considerations
In patients taking strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or known CYP2D6 poor metabolizers, initiate atomoxetine at lower doses and titrate more cautiously. 4 These patients experience higher heart rate and blood pressure increases that could be clinically significant.
For hepatically impaired patients, reduce atomoxetine dosing: 50% of normal dose for moderate impairment, 25% for severe impairment. 4