Jolene R. Bostwick, PharmD, BCPS, BCPP

s Clinical Pharmacy Specialist, Mental Health, VA Ann Arbor Healthcare System

is a PharmD Candidate, University of Michigan College of Pharmacy;

is Associate Chair and Clinical Associate Professor, Department of Clinical Pharmacy, University of Michigan College of Pharmacy and Clinical Pharmacist in Psychiatry, Michigan Medicine, Ann Arbor, MI.

In the past decade, the effects of antidepressants on the QT interval and the subsequent risk of cardiac arrhythmias have become a notable concern. When the FDA released a 

 about the risk of abnormal changes in the electrical activity of the heart with citalopram, providers learned to consider this risk as not only an adverse effect of a specific medication, but also the consequence of drug-drug interactions.

While the caution exhibited by prescribers following the FDA warning about citalopram is understandable, the recommended changes in the prescribing of citalopram based solely on QT interval prolongation have had unintended consequences. Recent studies that evaluated the impact of these prescribing changes have shown increased rates of hospitalizations, along with increases in the number of prescriptions for benzodiazepines and sedative-hypnotics, since the lower maximum dose was instituted. Moreover, the association between citalopram and ventricular arrhythmias and mortality has not been verified in studies of citalopram doses greater than 40 mg. Therefore, clinical judgment and risks versus benefits need to be considered when prescribing antidepressants that may affect the QT interval.

When a patient is assessed for antidepressant therapy, providers should keep the risk factors for QT prolongation in mind (

). A thorough medical history, laboratory monitoring, and a baseline electrocardiogram (ECG) may be necessary to identify patients at risk for QT prolongation before starting an antidepressant that may prolong QT interval. Significant QT prolongation may occur through drug-drug interactions when another medication known to affect the QT interval is used concomitantly or when a medication alters the metabolism of another drug with known effects on the QT interval. This potential should always be considered when a new medication is added, even when therapy is brief, such as with antibiotics or antiemetics.

QT prolongation risk varies with each antidepressant, and specific medications should be chosen with consideration of these differences. Case reports of QT prolongation have been published with all of the SSRIs, with the exception of paroxetine, but many of these events were in the context of an overdose, inherent risk factors, and concomitant use of other medications known to increase the QT interval, which makes it difficult to draw conclusions.

 emphasize that SSRIs, including fluoxetine and paroxetine, are not statistically significantly associated with QT prolongation, as indicated by comprehensive, prospective studies regarding the corrected QT (QTc) interval. More caution should be used with escitalopram than with other SSRIs (excluding citalopram) because it causes a slight increase in the QTc interval. However, the 

 is less than the increase associated with therapeutic doses of 

, and it is within the FDA-approved dosing range (

 (Although the FDA has not issued any warning about QT prolongation with escitalopram, other countries’ regulatory bodies have issued warnings similar to those for citalopram.)

TCAs and SNRIs have also been shown to prolong the QT interval to varying degrees. Certain TCAs (eg, amitriptyline, maprotiline) may lead to QT prolongation, although others do not (eg, clomipramine).

 The risk of QT prolongation is similarly low for the SNRIs, including duloxetine and desvenlafaxine.

 Venlafaxine may require more caution, particularly in cases of overdose, and in elderly patients or those with hepatic impairment. Therapeutic use of bupropion and mirtazapine is likely safe; however, bupropion overdoses have been associated with 

 provides a comparison of QT prolongation risk among antidepressants. Selecting an alternative antidepressant to citalopram or agents that may be considered “higher risk” can be useful for patients with many risk factors for QT prolongation. This is not always necessary in healthy patients or in patients who are responding well to the medication with normal laboratory parameters and ECG. Treatment decisions must be individualized, based on patients’ risk factors, target symptoms, cost, etc.

Increases in the QT interval are significant because they increase the risk of torsades de pointes and other serious cardiac events. However, increases, such as the reported average 18.5-ms increase associated with 60 mg of citalopram, may not be clinically significant, because QT prolongation indicates only the potential for an event to occur.

 Use of citalopram and other antidepressants associated with an increased risk of QT interval prolongation is possible through proper monitoring and judicious use.

Monitoring throughout the course of treatment is necessary because 

 can occur anywhere from the first 5 days of treatment to after 30 days of treatment.

 To monitor a patient’s QT interval, an initial baseline ECG and electrolyte panels are recommended with periodic monitoring to follow.

 recommend that patients with one or more risk factors, such as female sex or age older than 65 years, should be monitored more closely with ECGs and electrolyte panels every month for the first 6 months and monitored once every 6 to 12 months thereafter. QTc is most commonly obtained through Bazett’s formula, although it is unable to correct for fast and slow heart rates. In general, any QTc above 500 ms requires discontinuation of the medication, while a modification of therapy may be necessary with intervals of 470 to 500 ms in males and 480 to 500 ms in females.

 that highlights the risk of QT prolongation associated with citalopram illustrates concerns about drug-induced QT prolongation; however, the risk with citalopram is not much higher than that associated with other medications and is typically clinically insignificant. Unnecessary changes in therapy in patients whose condition is stable on citalopram can prove harmful. Antidepressants, like all other medications, come with risks, but with knowledge and proper monitoring, the risk associated with QT interval prolongation can be safely managed.

The authors report no conflicts of interest concerning the subject matter of this article.

Unintended consequences of adjusting citalopram prescriptions following the 2011 FDA warning

 Beach SR, Celano CM, Noseworthy PA, et al. 

QTc prolongation, torsades de pointes, and psychotropic medications

A comparison of the risk of QT prolongation among SSRIs

Risk of QT/QTc prolongation among newer non-SSRI antidepressants

 Trinkley KE, Page RL II, Lien H, et al. 

QT interval prolongation and the risk of torsades de pointes: essentials for clinicians

 US Food and Drug Administration. FDA Drug Safety Communication: Revised Recommendations for Celexa (citalopram hydrobromide) Related to a Potential Risk of Abnormal Heart Rhythms With High Doses. 

Articles

In the past decade, the effects of antidepressants on the QT interval and the subsequent risk of cardiac arrhythmias have become a notable concern. When the FDA released a drug safety communication about the risk of abnormal changes in the electrical activity of the heart with citalopram, providers learned to consider this risk as not only an adverse effect of a specific medication, but also the consequence of drug-drug interactions.

QT Prolongation and Antidepressants

One of the most common questions regarding antidepressants involves strategies for switching medications. This is not surprising, considering that results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial drew attention to the high rates of initial treatment failure with first-line agents.

 More specifically, up to 65% of patients fail to achieve remission, and approximately half of all patients fail to achieve an adequate response from their first antidepressant medication trial. High treatment failure rates make it critical for prescribers to know how to safely and effectively switch antidepressants to ensure patient-treatment targets are met.

There is limited guidance on the efficacy and tolerability of various switch strategies, which makes it essential that providers have a strong foundation in the pharmacological properties of antidepressants to understand how pharmacokinetic and pharmacodynamic drug interactions affect patients during the switch period. For example, if a patient is completing a cross-taper to transition from an antidepressant that is a potent inhibitor of the cytochrome 450 metabolizing enzyme 2D6 (CYP2D6) (eg, bupropion, fluoxetine, paroxetine) to a new antidepressant metabolized primarily by CYP2D6, the serum concentration of the new medication will be elevated by the CYP2D6 inhibitor until the first medication is eliminated. This leads to slower titration of the second antidepressant.

An example of a pharmacodynamic drug interaction is the required 2-week antidepressant-free period after stopping an MAOI because of the risk of serotonin syndrome and hypertensive crisis from accumulated synaptic monoamines. Furthermore, providers must consider the severity of their patient’s mood symptoms and weigh it against the concern of adverse drug events. This may lead to a more rapid switch in the hope of realizing benefit from the new medication as quickly as possible.

Discontinuation syndrome can occur upon abruptly stopping or rapidly lowering the dose of an antidepressant. Symptoms of discontinuation syndrome associated with various neurotransmitter and receptor systems are summarized in 

. Withdrawal phenomena need to be considered based on the pharmacology of how specific antidepressant medications affect serotonergic, adrenergic, histaminergic, and cholinergic activity. For example, TCAs have significant anticholinergic properties. Therefore, rapid withdrawal of these agents may precipitate cholinergic rebound, which can be associated with vomiting, nausea, headache, sweating, and muscle spasms. Cholinergic rebound can also apply to other antidepressants with anticholinergic properties that may be discontinued abruptly, such as paroxetine.

Prescribers should focus on the pharmacology involved rather than on specific medication classes, as differences in pharmacology of drugs in the same class can be significant enough to induce disparate withdrawal syndromes. Another example of this might be abrupt discontinuation of SNRIs, which can result in serotonergic withdrawal in addition to increased gastrointestinal motility and urinary urgency due to loss of noradrenergic effects.

In the case of rapid discontinuation of mirtazapine, reports include hypertension, tachycardia, insomnia, and mild anticholinergic withdrawal.3 In the case of rapid discontinuation of MAOIs, potential symptoms may include flu-like symptoms, tachycardia, hypertension, restlessness, dysphoria, excitation, or psychosis.

The need to mitigate the risk of discontinuation syndrome is particularly important when directly switching antidepressants or rapidly decreasing the dose of the first antidepressant. Symptoms appear to be most common when antidepressants are taken for more than 6 weeks, especially those with short half-lives (eg, paroxetine, venlafaxine), or are discontinued abruptly.

 Fluoxetine has notably less propensity to cause discontinuation syndrome because of its long half-life of 4 to 16 days (when taking into consideration its active metabolite, norfluoxetine).

 Patients are more likely to experience discontinuation syndrome when they have had difficulty tolerating an antidepressant during the initial phase of treatment.

 describe various management approaches to minimize discontinuation syndrome symptoms when stopping or lowering the dose of antidepressants. In the case of severe withdrawal symptoms, they recommend restarting the antidepressant at the previous dose and initiating a slower taper. Although there was no consensus on best practice, many studies recommend at least 4 weeks of tapering the dose before discontinuing the medication. However, this is not always feasible in clinical practice. Ultimately, it is important for providers to monitor tolerability of the medication changes and to adjust the titration process according to individual reactions.

Switching strategies that we discuss are listed in 

. The direct switch approach can be employed if the first agent was used for a short period (< 1 week) or when switching between some SSRIs, SNRIs, and TCAs (for more details, see 

). It is best to switch to an equivalent dose when possible. If the agent was used for a long period, or the patient was taking a high dose of medication, the cross-taper method is recommended. Cross-tapering is beneficial for individuals who are at high risk for relapsing from any improvement gained with the first medication, or are prone to discontinuation symptoms. As a general strategy, it is best to taper over at least 4 weeks if the agent was previously taken for 6 weeks or longer, and reduce the dose of the first medication by 25% per week.

 The first medication can be reduced at a slower rate if discontinuation symptoms were experienced previously, or if the patient is not tolerating the initial switching strategy.

When completing a cross-taper, it is also important to be aware of available dose formulations to avoid instructing the patient to take doses that are not feasible during the taper. Both the direct switch and cross-tapering methods have increased risk of drug-drug interactions when compared with a conservative switch strategy that utilizes a washout period of no medication. In practice, this approach is rarely attempted, with the exception of discontinuing an MAOI. Fluoxetine also has specific recommendations because of its long half-life, as detailed in 

 may be used as a general guide for switching between antidepressant medications.

There are many patient-specific factors that affect how rapidly an antidepressant is switched or withdrawn when medication changes are made; practitioners must treat patients on an individualized basis. Factors such as withdrawal from the old antidepressant, discontinuation syndrome, or washout periods can prolong the achievement of remission, and successful switching may take several weeks to months. This may seem overwhelming to an already at-risk population, since it leads to further-protracted treatment response.

Clinicians should strongly encourage patients to closely monitor for adverse effects when switching agents. Milder adverse events will dissipate with time, but severe, life-threatening events require immediate medical attention. Each switch strategy must be tailored to the patient and realistic expectations given to help optimize treatment success.

Ms. Soreide is a third-year pharmacy student at the University of Michigan College of Pharmacy. Dr. Ward is Clinical Assistant Professor, the University of Michigan College of Pharmacy, and Clinical Pharmacist in Psychiatry, Michigan Medicine, Ann Arbor. Dr. Bostwick is Associate Chair and Clinical Associate Professor, Department of Clinical Pharmacy, University of Michigan College of Pharmacy and Clinical Pharmacist in Psychiatry, Michigan Medicine, Ann Arbor.

 Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. 

 Bhanji NH, Chouinard G, Kolivakis T, Margolese HC. Persistent tardive rebound panic disorder, rebound anxiety and insomnia following paroxetine withdrawal: a review of rebound-withdrawal phenomena. 

 Howland RH. Potential adverse effects of discontinuing psychotropic drugs: part 2: antidepressant drugs. 

 Warner CH, Bobo W, Warner C, et al. Antidepressant discontinuation syndrome. 

 Keks N, Hope J, Keogh S. Switching and stopping antidepressants. 

 Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. 

 Ogle NK, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. 

 Howland RH. Potential adverse effects of discontinuing psychotropic drugs. Part 1: Adrenergic, cholinergic, and histamine drugs. 

 Hirsch M, Birnbaum RJ. Switching antidepressant medications in adults. UpToDate. 

https://www.uptodate.com/contents/switching-antidepressant-medications-in-adults

High treatment failure rates make it critical for prescribers to know how to safely and effectively switch antidepressants to ensure patient-treatment targets are met.

Strategies and Solutions for Switching Antidepressant Medications

A Case Study in Treatment-Refractory Depression

Monoamine oxidase inhibitors (MAOIs) have a long and storied history as some of the earliest antidepressants created. The efficacy of these medications led to the development of the monoamine hypothesis of depression and the development of subsequent antidepressant medications. Despite their known efficacy, MAOIs have fallen out of favor in clinical practice, giving way to newer agents with more favorable adverse-effect profiles and improved tolerability. However, the contemporary psychiatrist would be remiss to disregard these medications as archaic or dangerous.

Depression is both common and challenging to treat. Most patients with MDD require more than one medication trial to obtain remission. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study highlighted the difficulty in treating depression to remission.

 Findings from this study indicate that only 67% of patients achieved remission after aggressive treatment through up to 4 levels of switching or adding medications and psychotherapy. Savvy clinicians would be well served to incorporate MAOIs into their arsenals for managing treatment-refractory depression.

To highlight the difficulty in treating refractory depression, consider the following Case Vignette.

A 66-year-old married, retired architect was treated at a large academic hospital and outpatient clinic for recurrent, severe, major depressive episodes. The depression was characterized by anxious distress, hypersomnolence, mood reactivity and, when severe, delusions of poverty. He was treated with several SSRIs and SNRIs without improvement, even when in combination with atypical antipsychotics.

He had some improvement with a course of ECT following a severe suicide attempt. Tranylcypromine was started after the course of ECT, which produced significant improvement in symptoms after titration to 70 mg daily in divided doses. Recurrence of depression was successfully treated with the addition of 100 mg of nortriptyline, and he remained in remission for many years. He resisted maintenance treatment with ECT because of lasting cognitive deficits.

The concept of atypical depression, characterized by mood reactivity, hyperphagia, hypersomnolence, leaden paralysis, and rejection sensitivity, is an important consideration in this case. MAOIs were shown superior to tricyclic antidepressants (TCAs) in treating these patients.

 One double-blind crossover study of nonmelancholic, treatment-resistant depression revealed 67% of patients who failed treatment with imipramine had symptom remission with phenelzine.

 Moreover, phenelzine and tranylcypromine were found to be superior to TCAs in the treatment of outpatients with atypical depression.

The consistency of these findings is remarkable because it is uncommon for studies of antidepressant efficacy to demonstrate comparative superiority of one medication over another. The utility of MAOIs extends beyond treatment of MDD. Primary anxiety disorders, particularly social anxiety disorder, have consistently responded to MAOIs-a finding that is supported by a meta-analysis.

The possibility of serious dietary and drug interactions, and the development of newer agents with better tolerability and safety, have caused MAOIs to fall out of favor. The American Psychiatric Association guidelines recommend that their use be limited to patients who have not responded to other agents.

 However, these guidelines also highlight the utility of MAOIs in treating atypical depression and consideration of patient preference.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines identified moclobemide and transdermal selegiline as preferable to other MAOIs because of lower risk of dietary interactions.

 Other medications are listed as third-line treatments to be considered in cases of refractory depression.

While it is true that serotonin syndrome and hypertensive crises are potential serious adverse effects, the incidence of these events is rare when high-risk medication combinations are avoided. The dietary restrictions also have been progressively liberalized over time. In fact, a review of the literature does not show any deaths reported due to hypertensive crisis from MAOIs used as monotherapy. Some of the most common adverse effects, including orthostatic hypotension, dizziness, insomnia, nausea, and weight gain, are often successfully mitigated by slow initial titration, divided dosing, and increased fluid intake.

Limited data exist regarding the use of MAOIs in combination with other psychotropic agents. The combination is generally considered contraindicated because of the risk of serotonin syndrome. Off-label combination use may be helpful in the management of treatment-refractory depression; however, caution is recommended. The combination of an MAOI and a TCA is generally safe and well tolerated; orthostatic hypotension is the most common adverse effect.

Despite a lack of significant tolerability concerns reported in clinical trials or case reports, most studies did not demonstrate improved efficacy with the combination compared with monotherapy. In fact, one study of 135 outpatients with mild or moderate depression demonstrated trimipramine (a TCA) was superior when compared with an MAOI (phenelzine or isocarboxazid) and the combination of trimipramine plus an MAOI.

 Another randomized controlled trial of bilateral ECT and the combination of low doses of phenelzine and amitriptyline showed higher remission rates with ECT.

 Although these studies did not reveal significant improvements in efficacy with combination therapy, they serve to further highlight the tolerability of MAOIs when used in combination with TCAs.

The efficacy and safety of MAOIs have been shown with bupropion, trazodone, and stimulants; however, these therapies are not approved for combination use by the FDA. Despite the theoretical risk of hypertensive crisis, 2 reports documented patients who tolerated tranylcypromine in combination with bupropion (dosed to 300 mg/d and 450 mg/d) to produce sustained remission.

 Except for one patient who did not adhere to dietary restriction, there were no instances of hypertensive crises in 32 patients treated with a combination of MAOIs and stimulants for refractory depression.

In the event of a hypertensive crisis, signaled by the onset of a severe, occipital headache after a meal or medication ingestion, early and successful management has been reported with administration of a 10-mg nifedipine tablet (calcium channel blocker).

 A small case study reported that all 29 patients who utilized this “bite and swallow” treatment had rapid relief of symptoms.

 Treatment with oral medication would not be recommended in severe cases because of the delay in onset compared with parenteral medications.

With regard to management of other potential adverse effects associated with MAOIs, in cases of orthostatic hypotension, concomitant use of stimulant medications can offset this otherwise prohibitive adverse effect for some patients. Finally, low doses of trazodone for insomnia can be used safely with MAOIs, although the combination should be used judiciously to avoid worsening of orthostatic hypotension, lightheadedness, and sedation.

One retrospective case series of 29 adult patients at a large academic medical center examined the tolerability and efficacy of MAOIs in combination with other antidepressants and stimulants.18 Among the agents used were trazodone, TCAs, bupropion, SSRIs, and mirtazapine. In total, 21% of patients experienced clinical improvement without adverse effects, 24% had no clinical improvement, and 45% had some adverse effects that necessitated discontinuation of one or both agents. No serious adverse effects were reported; hypotension, constipation, fatigue, dry mouth, and dizziness were most common.

The use of SSRIs and SNRIs should be avoided with an MAOI because of the risk of serious adverse effects and even death. The combination has a high risk of serotonin syndrome, and deaths have been reported when taken at therapeutic doses.

 These safety concerns have resulted in the general recommendation of discontinuing an SSRI or SNRI for 2 weeks before starting an MAOI.

A similar 2-week period should also be observed in transitioning from an MAOI to an SSRI or SNRI because of the irreversible inhibition of monoamine oxidase. An exception is fluoxetine, which should be discontinued for 5 weeks before starting an MAOI because of the long half-life of its active metabolite. Like SSRIs and SNRIs, clomipramine (a TCA) should be avoided in combination with an MAOI because of its prominent serotonergic reuptake inhibition and higher risk of serotonin syndrome.

Returning to the Case Vignette, the decision to prescribe tranylcypromine was based on the previous failed trials of multiple antidepressants, severity of symptoms, presence of atypical features, and patient willingness to adhere to drug and dietary restrictions. Although studies do not suggest consistent improvement with combination treatment, this patient achieved and maintained symptom remission with the addition of nortriptyline.

Because of concerns about tolerability as he aged, doses were tapered and the TCA was discontinued, which ultimately precipitated a recurrent depressive episode. In the months thereafter, nortriptyline and tranylcypromine were gradually returned to previous doses, and depressive symptoms remitted. It should be noted that if this combination is to be used, it is advised that the TCA is started first or at the same time as the MAOI, with slow titration to allow for careful monitoring.

While not recommended as first-line agents, MAOIs deserve special consideration in the treatment of refractory depression. Data suggest that a subset of depressed patients with atypical features and social anxiety may be particularly responsive to treatment with an MAOI. Unfortunately, there is limited information regarding the use of these medications in refractory depression or with other augmenting antidepressants, and further research is unlikely.

Studies have consistently shown that judicious use of MAOIs with other psychotropic agents-namely TCAs, trazodone, bupropion, mirtazapine, and stimulants-is well tolerated and safe, despite general consensus to the contrary. The use of MAOIs warrants careful patient selection and discussions about safety but should be a consideration in patients who continue to suffer from severe depression.

Dr. Morcos is Fourth-Year Resident, Department of Psychiatry, University of Michigan; Dr. Bostwick is Associate Chair and Clinical Associate Professor, Department of Clinical Pharmacy, University of Michigan College of Pharmacy, and Clinical Pharmacist in Psychiatry, Michigan Medicine, Ann Arbor.

 Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. 

 Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression: a subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. 

 Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine, and phenelzine. 

 McGrath PJ, Stewart JW, Nunes EV, et al. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. 

 Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. 

 Mayo-Wilson E, Dias S, Mavranezouli I, et al. Psychological and pharmacological interventions for social anxiety disorder in adults: a systematic review and network meta-analysis. 

 Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 3rd ed. 2010. 

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

 Kennedy SH, Lam RW, McIntyre RS, et al. CANMAT 2016 clinical guidelines for the management of adults with major depressive disorder: section 3: pharmacological treatments. 

 White K, Simpson G. The combined use of MAOIs and tricyclics. 

 Young JP, Lader MH, Hughes WC. Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients. 

 Davidson J, McLeod M, Law-Yone B, Linnoila M. A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. 

 Pierre JM, Gitlin MJ. Bupropion-tranylcypromine combination for treatment-refractory depression. 

 Quante A, Zeugmann S. Tranylcypromine and bupropion combination therapy in treatment-resistant major depression: a report of 2 cases. 

 Feinberg SS. Combining stimulants and monoamine oxidase inhibitors: a review of uses and one possible additional indication. 

 Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression. 

 Clary C, Schweizer E. Treatment of MAOI hypertensive crisis with sublingual nifedipine. 

 Golwyn DH, Sevlie CP. Monoamine oxidase inhibitor hypertensive crisis headache and orthostatic hypotension. 

 Thomas SJ, Shin M, McInnis MG, Bostwick JR. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression. 

 Feighner JP, Boyer WF, Tyler KL, Neborsky RJ. Adverse consequences of fluoxetine-MAOI combination therapy. 

MAOIs deserve special consideration in the treatment of refractory depression. Here's a case in point. 

Jolene R. Bostwick, PharmD, BCPS, BCPP

Articles

QT Prolongation and Antidepressants

Strategies and Solutions for Switching Antidepressant Medications

MAO Inhibitors: Is Concomitant Use Safe or Too Risky?