Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination

Abstract

This report reviews the medical literature on combining stimulants with monoamine oxidase inhibitors. A case is also presented documenting successful treatment of major depressive disorder and comorbid attention-deficit/hyperactivity disorder using the previously undocumented combination of transdermal selegiline and lisdexamfetamine. This combination should be used cautiously and with ongoing monitoring of heart rate and blood pressure.

Clinical Points

• ■ Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) commonly co-occur.

• ■ In cases of treatment-resistant MDD, stimulants have been successfully coadministered with monoamine oxidase inhibitors.

• ■ This report documents a case of successful treatment of MDD and comorbid ADHD using transdermal selegiline and lisdexamfetamine. This combination should be used cautiously and with ongoing monitoring of heart rate and blood pressure.

Attention-deficit/hyperactivity disorder (ADHD), once thought to be confined to childhood, is now understood to be a disorder that spans the lifetime¹ and may be diagnosed in approximately 4%–5% of the US adult population.² Psychiatric comorbidity with ADHD is common.³ Epidemiologic data show that the lifetime rate of comorbid major depressive disorder (MDD) in patients diagnosed with ADHD is estimated to be 35%–50%,⁴ which is considerably higher than the 15% lifetime rate of MDD found in the general population.⁵

For the treatment of ADHD, the stimulant medications methylphenidate (including Ritalin and Concerta) and amphetamine (including Adderall and Vyvanse) are the most effective pharmacologic agents.⁶ Approximately 70% of adults who are prescribed one of these medications will have immediate reductions in inattention and distractibility, at least in the short term.⁷

For the treatment of MDD, however, it is more challenging to provide patients with similarly effective pharmacotherapy. When remission is defined as nearly full resolution of symptoms and minimal functional impairment,⁸ 15%–30% of patients with MDD will not achieve remission with antidepressants, even after multiple-step pharmacologic interventions.⁹ These patients are considered to have “treatment-resistant” MDD.¹⁰

Strategies to address treatment-resistant MDD vary, and there is no clearly established treatment algorithm for clinicians to follow.¹¹ One class of antidepressants, the monoamine oxidase inhibitors (MAOIs), can be beneficial for some patients with treatment-resistant MDD^12,13 and may be of particular benefit in the treatment of patients with atypical MDD.¹⁴ Despite proven efficacy,¹⁵ MAOIs are used with decreasing frequency,¹⁶ most likely due to a combination of concerns regarding tyramine-induced hypertensive crises,¹⁷ the need for dietary restrictions,¹⁸ and the increasing number of easier-to-prescribe treatment options.¹⁹

The stimulant medications have long been considered to be contraindicated in combination with MAOIs due to concerns of toxicity that include hypertensive crisis, intracranial hemorrhage, hyperthermia, seizures,^20,21 and serotonin syndrome,²² but there have been no controlled trials examining the concurrent use of these medications. Nonetheless, there have been several case reports and series^23–31 over the years documenting combination therapy with the 2 medication classes.

METHOD

A literature search was performed in PubMed (1965–January 2015). The search terms used were psychostimulant, stimulant, amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate, monoamine oxidase inhibitor, and selegiline. References cited in the identified articles were manually searched. Nine published articles^23–32 met the criteria for documentation of clinical treatment combining stimulants and monoamine oxidase inhibitors.

A case report documenting successful treatment with the combination of the selegiline transdermal patch and lisdexamfetamine is also presented.

RESULTS

Literature Review

Two early case reports^23,24 documented severe reactions to the combination of stimulants and MAOIs. A report from 1965²³ described a case of hypertensive crisis and cerebral hemorrhage from the combination of dextroamphetamine and phenelzine. A case from 1969²⁴ reported nonfatal hyperpyrexia after combined treatment with dextroamphetamine and tranylcypromine.

Later cases have documented more successful treatment with this medication combination. Feighner and colleagues²⁵ treated a series of 13 patients with treatment-resistant MDD using either dextroamphetamine or methylphenidate along with an MAOI and found the combination safe and effective, with hypotension the most common adverse effect. Fawcett and colleagues²⁶ treated a series of 32 patients with treatment-resistant MDD with either pemoline up to 112.5 mg/d or dextroamphetamine up to 40 mg/d in combination with tranylcypromine, phenelzine, isocarboxazid, or pargyline (pemoline and pargyline are no longer manufactured). They, too, found the combination to be effective and medically safe, with no episodes of hypertensive crisis.²⁶ Three other case reports have documented safe and effective use of combining MAOIs and stimulants: 1 using dextroamphetamine 10 mg/d combined with tranylcypromine 40 mg/d for treatment-resistant MDD,²⁷ 1 combining methylphenidate 40 mg/d and moclobemide 600 mg/d for comorbid MDD and ADHD,²⁸ and another using phenelzine 45 mg/d and methylphenidate 17.5 mg/d for comorbid MDD and ADHD.²⁹ Feinberg³⁰ reported a successful case of treatment of MDD and ADHD using the combination of tranylcypromine 50 mg/d and methylphenidate 45 mg/d, again with no adverse medical outcomes. A less favorable medical outcome was documented by Bodner et al,³¹ who reported the case of a patient who developed serotonin syndrome while being treated with the combination of isocarboxazid 30 mg/d, trazodone 150 mg/d, and methylphenidate 10–20 mg/d, although it was not possible to determine to what degree, if any, the stimulant was a factor in this adverse event.

Thomas et al³² provide a thorough review of the literature on combining MAOIs with potentially contraindicated medications for treatment-resistant MDD, including SSRIs and stimulants. Their review includes the only published case to date on use of the transdermal selegiline patch with an MAOI, reporting 1 case of safe and beneficial treatment using the selegiline transdermal patch 12 mg/d along with amphetamine. This review³² also includes a case using phenelzine 60 mg/d with methylphenidate (as well as desipramine 75 mg/d and trazodone 300 mg/d) that resulted in hypotension and tachycardia.

The selegiline transdermal patch is an MAOI that was released in the United States in 2008 under the brand name EMSAM for the treatment of MDD. Oral selegiline at lower dosages is primarily an MAO-B inhibitor and at higher dosages becomes an MAO-A inhibitor as well. MAO-A inhibition has been considered important for antidepressant effects since this enzyme metabolizes serotonin and norepinephrine.³³ MAO-A inhibition takes place primarily in the gastrointestinal system, and MAO-B inhibition takes place primarily in the central nervous system. Transdermal administration of selegiline allows for MAO-B inhibition in the central nervous system, which bypasses first-pass metabolism and avoids MAO-A inhibition in the gastrointestinal system, thus lowering the risk of hypertensive crises³⁴ and conferring what appears to be a greater margin of safety. There have been reports of serotonin syndrome when combining transdermal selegiline with antidepressants,³⁵ and patients remain at risk for drug-drug interactions, but no dietary restrictions are considered necessary at lower dosages.³⁶

The effects of selegiline transdermal patch (6 mg/24 hours) in combination with the sympathomimetic agents pseudoephedrine and phenylpropanolamine, combinations that have been considered contraindicated, were examined in 12 healthy volunteers by Azzaro et al.³⁷ No adverse changes in heart rate or blood pressure were found in the patients treated with pseudoephedrine. Three of the 12 patients treated with phenylpropanolamine experienced an increase in blood pressure but no adverse medical outcomes. Selegiline transdermal patch (6 mg/24 hours) was added to an extended infusion of intravenous cocaine by Harris et al³⁸ and did not contribute to changes in heart rate or blood pressure. It is notable when considering combining selegiline with a stimulant that active metabolites of selegiline do include l-amphetamine and l-methamphetamine.³⁹

Case Report

Mr A is a 24-year-old man with a history of treatment-resistant MDD. The MDD diagnosis was confirmed at the time of the initial evaluation using DSM-5 criteria. Prior unsuccessful medication trials at the time of his initial evaluation included sertraline, bupropion, mirtazapine, and escitalopram, as well as escitalopram in combination with aripiprazole. At the time of his initial visit, Mr A was additionally diagnosed with ADHD, predominantly inattentive presentation, according to DSM-5 criteria. Treatment was initiated with osmotic-release oral system methylphenidate titrated to 36 mg/d; this dose was not beneficial for his symptoms of ADHD. A trial of lisdexamfetamine titrated to 70 mg/d was quite helpful for the symptoms of ADHD, but Mr A’s mood remained depressed. Subsequent unsuccessful antidepressant medication trials added to lisdexamfetamine were duloxetine (60 mg/d for 12 weeks), fluoxetine (20 mg/d for 4 weeks, then 40 mg/d for 4 weeks), and vilazodone (40 mg/d, used for only 6 weeks due to intolerance of side effects).

Lisdexamfetamine was then discontinued. After education regarding an MAOI diet, which consists of avoiding foods containing high levels of tyramine such as fermented meats, aged cheeses, and tap beers,⁴¹ he was started on the selegiline transdermal patch titrated to 12 mg/24 hours. By week 4, Mr A reported euthymic mood for the first time in many years, but his ADHD symptoms had fully returned, causing a resumption of professional and employment difficulties. After extended discussion of the potential risks, lisdexamfetamine was restarted, beginning at 20 mg/d and increased to 40 mg/d after 2 weeks. Tachycardia, with heart rate up to 117 bpm, was first noted after this dosage increase. Mr A purchased a blood pressure–heart rate cuff and began to monitor his vital signs regularly.

ADHD symptoms were not sufficiently improved with a dose of lisdexamfetamine 40 mg/d for 4 weeks, thus the dose was increased to 50 mg/d. At this dose, Mr A’s ADHD symptoms improved, and he resumed full functionality in his professional life. His blood pressure remained stable throughout treatment over a 12-month monitoring period; his systolic blood pressure ranged from a low of 98 mm Hg to a high of 132 mm Hg, but most days remained in the range of 100–120 mm Hg. His diastolic blood pressure ranged from 63 to 88 mm Hg and was generally in the range of 60–70 mm Hg. Mr A continued to experience episodes of tachycardia, with a resting heart rate ranging from 88 to 134 bpm. An electrocardiogram showed normal sinus tachycardia. He continued to report consistently euthymic mood and lack of inattention for the first time in many years, and he did not wish to have his psychiatric medication regimen altered. Instead, he worked with his primary care physician to control his heart rate using atenolol 25 mg/d. After this medication was initiated, there were no further episodes of resting heart rate higher than 100 bpm.

This report documents a successful case of treatment combining the selegiline transdermal patch and lisdexamfetamine. Lisdexamfetamine (manufactured in the United States by Shire under the trade name Vyvanse) is considered a prodrug; it is biologically inactive until after oral administration when it enters the bloodstream and is enzymatically converted within the red blood cells to lysine and dextroamphetamine, the latter being the active drug for treatment of ADHD.⁴⁰

The present case adds to the literature describing effective combinations of MAOIs and stimulants and suggests that the combination of transdermal selegiline and a stimulant may not need to be considered absolutely contraindicated. This combination therapy may be an option for some patients with comorbid ADHD and treatment-resistant MDD when used with caution and monitoring of heart rate and blood pressure.

CONCLUSION

The existing medical literature and the case report described in this article support the contention that combining stimulants with transdermal selegiline may be an appropriate treatment for some patients with comorbid ADHD and treatment-resistant major depressive disorder.

Potential conflicts of interest:

None reported.

Funding support:

None reported.