MAOIs: Issues in Treatment Adherence and Rates of Treatment Failure

Lawrence J. Cohen, PharmD, BCPP, FASHP, FCCP, FCP, and David A. Sclar, BPharm, PhD

From the Department of Pharmacotherapy, the Department of Health Policy and Administration, and the Pharmacoeconomics and Pharmacoepidemiology Research Unit, Washington State University College of Pharmacy, Spokane (Drs Cohen and Sclar); the Washington Institute for Mental Health Research and Training, Spokane (Drs Cohen and Sclar); and the Department of Pharmacotherapy, University of North Texas Health Science Center, Fort Worth (Dr Cohen).

MAOIs have proven efficacy for treating depression, particularly treatment-resistant and atypical depression.1 But, due to the risk of potentially serious side effects from both food and drug interactions, treatment guidelines2 typically reserve MAOIs for third- or fourth-line treatments for depression and clinicians may be hesitant to prescribe these agents.3 As remission rates for patients with depression remain low and recurrent episodes and chronic subsyndromal symptoms are common,4–6 a transdermal MAOI formulation with an improved safety profile may be a suitable option for patients with depression, especially those with treatment-resistant depression or adherence problems due to adverse side effects.

Adherence and Outcomes

The lack of therapeutic response, or treatment failure, with an antidepressant may be due to treatment resistance—despite taking the medication as prescribed at an adequate dosage for an adequate duration, the patient experiences little or no symptomatic improvement. However, nonresponse may also be due to treatment nonadherence—the patient has not followed the medication regimen irrespective of initial treatment response and, therefore, his or her depression may appear to be resistant to treatment. Treatment adherence and illness outcomes are strongly related: response and remission rates are significantly higher and time-to-recurrence rates are significantly longer for patients who adhere to their medication regimens than for those who do not.7

Treatment adherence refers to compliance with day-to-day treatment instructions (eg, timing, dosage, frequency), and treatment persistence means continuing to take the medication for the duration prescribed.8 Nonadherence can negatively affect treatment outcomes. For example, patients may take extra doses, resulting in increased adverse events, or they may unintentionally miss doses or intentionally take a drug holiday, resulting in discontinuation symptoms or nonresponse. Ongoing adherence is associated with the likelihood of treatment persistence: patients with lower adherence rates discontinue antidepressant treatment more frequently than those with higher adherence rates.9

Unfortunately, adherence to treatment is poor among patients with depression. During acute care, one-third of patients take too much medication at least once and another one-third take at least one 3-day drug holiday.9 Additionally, almost one-third of patients treated for depression discontinue their antidepressant in the first month of treatment, and more than half stop taking it by 6 months.10 Further, more than 60% of those who discontinue antidepressant treatment do so without consulting their physician.

Because depression is projected to be the second-leading cause of disability by 2020,11 the World Health Organization has designated it as 1 of 9 chronic conditions where efforts to improve medication adherence should be focused as a means of improving treatment outcomes.12 Improved treatment response would lower the burden of depression to society by reducing both direct health care costs and indirect costs, such as decreased work productivity, while increasing quality of life for patients.13

Enhancing Antidepressant Adherence

Systematic reviews14,15 conducted to identify interventions that improve adherence among patients taking antidepressants have generally been inconclusive, signifying a need for carefully designed clinical trials on the effects of single and combined interventions. The most commonly recommended interventions to improve adherence are15:


  • patient education
  • a strong patient-physician therapeutic alliance
  • family education
  • clinical management strategies
  • active management of side effects
  • simplified treatment regimen


AV 1. Multifaceted Interventions to Improve Patients’ Treatment Adherence (00:41)

Based on Chong et al16
Abbreviations are defined before the References

Although little evidence supports the idea that educational interventions alone enhance adherence—possibly due to poor study methodology—education as part of a multifaceted intervention employing behavioral, affective, and provider-targeted strategies does improve adherence (AV 1).16,17 The interventions that most successfully improve both adherence and treatment outcomes include more frequent follow-up visits, longer duration of treatment, collaborative care between mental health specialists and primary care physicians, and the inclusion of professionals such as nurses and pharmacists to provide education, feedback, surveillance, and medication support services.16

Other evidence-based recommendations include specifically discussing medication adherence with patients, asking patients about their motivation to take medications, and working with patients to identify and remove barriers to adherence.18 Evidence is also growing in support of cognitive-behavioral strategies and motivational interviewing as effective approaches for improving adherence.18


Transdermal Delivery and Adherence to Treatment

First-generation antidepressants, including older oral MAOIs, are associated with lower adherence rates and higher rates of treatment change than newer antidepressants.19 For MAOIs, this may be due to the dietary and drug restrictions patients must follow to avoid the potential for severe adverse events. However, with the development of the newer transdermal formulation of the MAOI selegiline, the dietary modifications required to avoid tyramine-induced hypertensive crisis are not needed with the lowest dosage (6 mg/24 h), improving the likelihood of adherence. Clinicians should be aware that dietary restrictions are still recommended with higher doses due to a lack of safety data, and precautions against potential drug interactions must still be observed with transdermal selegiline, as with all other MAOIs. Moclobemide, a newer oral MAOI, also has a mechanism of action that avoids interactions with tyramine-rich foods, but it is not available in the United States.

By avoiding the first-pass metabolism in the gut that occurs with the oral medication, transdermal selegiline is able to achieve an antidepressant effect with a lower dosage.20 As a result, the side effect profile of transdermal selegiline is superior to that of oral MAOIs and many other agents. In fact, except for application site reactions, transdermal selegiline has a tolerability profile similar to that of placebo.21 Therefore, patients who have been nonadherent to their earlier antidepressants due to intolerable side effects, such as weight gain or sexual dysfunction, might benefit from this newer agent.

AV 2. Blood Plasma Concentrations of Oral Versus Transdermal Formulations (00:31)

Reprinted with permission from Oertel et al24

In addition, delivering medication via a skin patch has several advantages over oral delivery that may increase treatment adherence. Patients rate transdermal delivery of medication highly, in part because patches are applied once daily, which can simplify the treatment regimen compared with oral medications that may have to be taken several times a day.22 The patch provides a visual reminder to the patient to take the medication each day, and caregivers can also see that the medication is being used. Additionally, oral drugs produce a rapid peak in plasma levels that then rapidly decline, while patches provide a continuous delivery of the medication that helps to keep plasma levels within the therapeutic range, thereby maintaining response and minimizing adverse effects (AV 2).23,24 Finally, some patients with adherence problems with oral medication due to bad taste or swallowing difficulty may prefer transdermal application.22 Application site reactions should be minimized, however, to promote adherence.


Treatment guidelines recommend newer antidepressants as first-line therapy for patients with depression, but response and remission rates remain low and multiple treatment trials are often needed. Adherence to medication can affect treatment response, and nonadherence to antidepressants is common among patients treated for depression. While MAOIs are not first-line treatment, they have proven efficacy for depression, particularly for patients with treatment-resistant or atypical depression. Newer MAOI formulations have improved safety and tolerability profiles and avoid or lessen the need for dietary restrictions, making them another option for treating patients who may be nonadherent or nonresponsive to their current antidepressant.

For Clinical Use


  • Determine whether a patient’s nonresponse to an antidepressant is due to nonadherence
  • Use a multifaceted approach to enhance treatment adherence
  • Consider newer formulations of MAOIs for your patients with treatment-resistant or atypical depression, especially if a transdermal formulation would help to address adherence barriers


Drug Names

selegiline transdermal system (EMSAM)


MAOI = monoamine oxidase inhibitor
PCP = primary care physician

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