Can mirtazapine be used to treat low mood in an adult with attention‑deficit hyperactivity disorder who is already taking lisdexamfetamine and dexamfetamine?

Can Mirtazapine Be Used for Low Mood in Adults with ADHD on Lisdexamfetamine and Dexamfetamine?

Yes, mirtazapine can be safely added to lisdexamfetamine and dexamfetamine to treat persistent low mood in adults with ADHD, as there are no significant pharmacokinetic interactions between mirtazapine and stimulants, and this combination has been specifically studied and validated in clinical practice. 1, 2

Evidence Supporting the Combination

The American Academy of Child and Adolescent Psychiatry explicitly states that if ADHD symptoms improve on stimulants but depressive symptoms persist, adding an antidepressant to the stimulant regimen is the recommended approach. 1 While SSRIs are typically first-line for depression in this context 1, mirtazapine represents a valid alternative with specific advantages.

Chart review data directly support using mirtazapine as adjunct treatment to stimulant medications in adults with ADHD, particularly when stimulant-associated insomnia is present, as mirtazapine successfully reduced sleep disturbances in this population. 2

Mirtazapine's Unique Advantages in This Context

Mirtazapine offers several benefits that may be particularly relevant for ADHD patients on stimulants:

• Rapid onset of action: Mirtazapine demonstrates a statistically significantly faster onset of antidepressant effect than SSRIs (citalopram, fluoxetine, paroxetine, sertraline), though response rates equalize after 4 weeks. 3

• Sleep improvement: Mirtazapine has demonstrated important sleep-improving effects 4, which directly counteracts the insomnia commonly caused by stimulant medications. 1, 5 This dual benefit—treating depression while mitigating stimulant side effects—makes it particularly useful in this population. 2

• Anxiolytic properties: Mirtazapine demonstrates important anxiolytic effects 4, which may address comorbid anxiety that frequently accompanies ADHD and depression. 1

• No sexual dysfunction: Unlike SSRIs, mirtazapine does not appear to be associated with sexual dysfunction 4, an important quality-of-life consideration.

Safety Profile of the Combination

There are no clinically significant drug-drug interactions between mirtazapine and amphetamine-based stimulants (lisdexamfetamine, dexamfetamine). 1 The FDA label for mirtazapine lists amphetamines among medications to discuss with your healthcare provider 6, but this reflects a precautionary listing rather than a contraindication.

The only absolute contraindication is concurrent use with MAO inhibitors—mirtazapine must not be combined with MAOIs, and at least 14 days must elapse after stopping an MAOI before starting mirtazapine. 6

Practical Implementation

Start mirtazapine at 15 mg once daily at bedtime while continuing the current stimulant regimen (lisdexamfetamine and dexamfetamine). 7 The bedtime dosing leverages mirtazapine's sedative properties to counteract stimulant-induced insomnia. 2

Titrate mirtazapine based on response and tolerability, with a typical therapeutic range of 15-45 mg/day. 8 The most commonly reported adverse effects are somnolence (which may be beneficial in this context), increased appetite, weight gain, and dizziness. 7, 4

Monitoring Requirements

• Suicidality screening: Mirtazapine carries an FDA black box warning for increased risk of suicidal thoughts in individuals under 24 years of age, particularly in the first few months of treatment or with dose changes. 6 Monitor closely for new or worsening depression, suicidal thoughts, or unusual behavioral changes.

• Cardiovascular parameters: Continue routine blood pressure and pulse monitoring already indicated for stimulant therapy. 1

• Weight and appetite: Track weight given mirtazapine's tendency to increase appetite 7, 4, which may actually be beneficial if stimulants have caused excessive appetite suppression.

Alternative Consideration: SSRIs

While mirtazapine is appropriate, SSRIs (fluoxetine, sertraline, escitalopram) remain the treatment of choice for depression in ADHD patients on stimulants, with extensive evidence supporting their safety and efficacy in combination with stimulants and no significant pharmacokinetic interactions. 1 Consider an SSRI first if insomnia is not a prominent concern or if weight gain is undesirable.

Common Pitfall to Avoid

Do not assume mirtazapine alone will treat both ADHD and depression—no single antidepressant is proven for this dual purpose. 1 The patient must remain on effective ADHD treatment (the current stimulant regimen) while adding mirtazapine specifically for mood symptoms.