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R EVIEWS O F T HERAPEUTICS

Combination Therapy with Monoamine Inhibitors and Other or : Strategies for the Management of Treatment-Resistant

Samantha J. Thomas,1 Mirae Shin,2 Melvin G. McInnis,3 and Jolene R. Bostwick2,4,* 1Meijer Pharmacy, Dewitt, Michigan; 2Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan; 3Department of Psychiatry, University of Michigan Health System, Ann Arbor, Michigan; 4College of Pharmacy, University of Michigan, Ann Arbor, Michigan Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various trials. The utilization of inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription . Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepres- sants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the crite- ria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antide- pressant or medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experi- ence into two groups: 15 cases with the selective MAO type B inhibitor combined with medi- cations presumed to increase the risk of syndrome and 14 cases with nonselective MAOIs ( and ) combined with other contraindicated . Although risks of combination treatment certainly exist with selective serotonin inhibitors, serotonin and nor- reuptake inhibitors, or , the current literature supports cautious use of com- bining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consider- ation for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants. KEY WORDS , monoamine oxidase inhibitor, MAOI, combination antidepressants. (Pharmacotherapy 2015;35(4):433–449) doi: 10.1002/phar.1576 434 PHARMACOTHERAPY Volume 35, Number 4, 2015

Treatment-resistant depression (TRD) is a not be prescribed along with other antidepres- major health concern. More than 40% of sants or certain prescription drugs (e.g., tram- patients treated for major depressive disorder adol, meperidine, , or (MDD) with an appropriate antidepressant dose ) and nonprescription drugs. Psycho- for an adequate duration fail to respond.1 Fur- tropic agents that are contraindicated or recom- ther, approximately half of adults with MDD fail mended to be used with caution in combination to achieve sustained remission despite various with MAOIs are listed in Table 1.6, 8, 9 In addi- medication trials.2 Despite TRD now being a tion, a recent case study highlights the concern major public health concern, there is a paucity for severe due to the combination of data for the management of TRD to guide of high intake in combination with tran- informed decision-making about pharmacother- ylcypromine.10 Given the severity of the risks apy. The lack of consensus on the definition of involved with using MAOIs, in addition to the treatment resistance contributes to the deficiency lack of marketing, among prescribers, and of data.3 Definitions range from a poor response lack of experience using MAOIs, the overall use after proper dosing and duration of a single anti- of these agents in clinical practice today is to response failure after adequate low.11 dosing and duration of two or more antidepres- Largely, given the severity of the adverse effects – sants from different classes,3 5 which has and reactions, as well as relatively low utilization, become the working definition of TRD.2 a paucity of data is available on the efficacy of Monoamine oxidase inhibitors (MAOIs) were MAOIs in combination with other antidepressants one of the first classes of medications used for for the management of TRD. Considering the lim- the treatment of depression.6 These agents inhi- ited pharmacologic options in individuals with bit the monoamine oxidase, which is TRD, additional evidence is needed to support the present in the and other tissues such as clinical use of combination antidepressant ther- the intestine and .6 MAOIs currently avail- apy with MAOIs and other psychotropic agents, able in the , including selegiline, when appropriate. Thus, in this case series and lit- tranylcypromine, phenelzine, and , erature review, we aimed to illustrate the poten- irreversibly bind and inactivate monoamine oxi- tial utility, as well as risks, of combination dase, thus preventing the degradation of neuro- treatment in patients for the management of TRD transmitters such as serotonin, epinephrine, by comparing published experience with our local , and , leading to their experience (case series) to allow for more- accumulation.6 The use of MAOIs is limited due informed decisions regarding pharmacotherapy in to their widely known adverse effects and risk patients with TRD. for dietary and drug interactions. These include It should be highlighted that the cases we the risk of hypertensive crisis when - included in the case series are separated into rich foods are consumed, as well as the risk of two groups: cases including the selective MAO serotonin syndrome, which can occur when MA- type B inhibitor selegiline and cases including OIs are combined with other medications, which nonselective MAOIs (phenelzine and tranylcy- may be life threatening.6, 7 For this reason, it promine). Selegiline confers more selective has historically been recommended that MAOIs MAO-B inhibition at low doses, which improves and minimizes risk for dietary inter- actions with tyramine.12 However, as the dose increases, selegiline becomes less selective for Presented as a poster at the American College of Clinical 13 Pharmacy Virtual Poster Symposium, May 21–22, 2013; the MAO-B. A wider safety margin exists with the American Society of Health-System Pharmacists Midyear formulation of selegiline compared Clinical Meeting, Orlando, Florida, December 8–12, 2013; with nonselective MAOIs and oral selegiline, and the College of Psychiatric and Neurologic Pharmacists even in dosages up to 12 mg/day.14 Enhanced Annual Meeting, Phoenix, Arizona, April 27–30, 2014. *Address for correspondence: Jolene R. Bostwick, Clini- safety with the transdermal formulation is due cal Associate Professor of Pharmacy, Department of Clini- to avoidance of first-pass and the cal, Social, and Administrative Sciences, College of ability to minimize the inhibition of MAO-A in Pharmacy, University of Michigan, and Clinical Pharmacist, the .12, 14 Although selegi- Adult Psychiatry, University of Michigan Health System, line, in any form, still confers risk in combina- 1500 E. Medical Center Drive, 9D9814 University Hospital, Ann Arbor, MI 48109-0018; e-mail: [email protected]. tion with other antidepressants, its selectivity edu. should be distinguished from that of other non- Ó 2015 Pharmacotherapy Publications, Inc. selective MAOIs. MAOIS COMBINED WITH OTHER ANTIDEPRESSANTS OR STIMULANTS Thomas et al 435

Table 1. Psychotropic Agents Contraindicated or Recommended to Be Used with Caution in Combination with Mono- Oxidase Inhibitors6, 8, 9 Psychotropic Class Medications Potential Reaction Selective serotonin , , Serotonin syndrome reuptake inhibitors , , , , antidepressants , , Serotonin syndrome, clomipramine, , hypertensive crisis , , , , Serotonin and , , Serotonin syndrome norepinephrine , reuptake inhibitors Sympathomimetic , Hypertensive crisis , , , , , , Other antidepressants , , St. Increased risk of serious John’s wort, , adverse effects , Other monoamine Isocarboxazid, phenelzine, Hypertensive crisis, oxidase inhibitors tranylcypromine, selegiline, serotonin syndrome

serotonin syndrome are described. Inclusion cri- Methods teria consisted of any adult patient (≥ 18 yrs of age) with a diagnosis of depression who was Literature Review treated with an MAOI (tranylcypromine, phenel- A literature search of the PubMed database zine, selegiline, or isocarboxazid) plus another was performed. Any relevant article available in psychotropic agent, including an antidepressant English from inception through January 25, or stimulant medication, between 2003 and 2015, was included. Key search terms included 2012 was included. Of the 29 patients, six cases monoamine oxidase inhibitor, MAOI, selective sero- were further reviewed and are described in Data tonin , TCA, stimulants, trazo- S1. These six cases were representative of the done, antidepressants, treatment-resistant three most common combinations encountered: depression, depression, major depressive disorder, and an MAOI, tranylcypromine and combination, selegiline, phenelzine, and tranylcy- other antidepressants, and selegiline and other promine. Controlled and noncontrolled studies, antidepressants. A positive and negative clinical open-label studies, case reports, and case series outcome was chosen to exemplify each combina- were included. tion. Information was gathered to determine safety of treatment and efficacy of combination therapy. Case Series Medical records were reviewed and data were In addition, a retrospective case series was collected on medications used, along with dos- performed by reviewing the medical records of ages and durations of therapy. Duration of ther- 29 adult patients treated for depression at a apy was critical to fully determine the large Midwestern teaching hospital; this case ser- tolerability of therapy, given the half-lives of cer- ies was approved by the University of Michigan tain antidepressants. Any symptoms and/or institutional review board. More specifically, 14 adverse effects that were experienced were docu- cases of a nonselective (nonselegiline) MAOI mented to determine tolerability to combination combined with other contraindicated medica- therapy. Patient demographics, medical and fam- tions and 15 cases of selegiline combined with ily history, summary of illness, indication for medications presumed to increase the risk of combination treatment, any necessary laboratory 436 PHARMACOTHERAPY Volume 35, Number 4, 2015 values, diet, past medication trials, social his- trazodone or a TCA combined with an MAOI, tory, and were also collected. Diet was sometimes with an additional psychotropic evaluated based on information provided in the agent. The average duration of therapy for com- medical record, given that foods rich in tyramine bination MAOI with trazodone was 21 months. may be the cause of any symptoms or adverse At the time of this writing, the majority of effects. Finally, use of other agents patients receiving combination treatment with was noted, when applicable. an MAOI, a TCA, and possibly another antide- pressant were still taking the combination, with the exception of two cases. Results Eighteen articles were identified and reviewed, – Discussion and are described in Table 2.15 32 Additionally, the medical records of 29 patients that men- The following highlights the findings from tioned the use of MAOIs in combination with both the literature review and our case series. other antidepressants were reviewed. These data There were six combinations encountered, con- are presented in two separate tables: Table 3 sisting of MAOIs in combination with other an- summarizes 15 cases in which the selective tidepressants and/or stimulants. MAOI selegiline was used, whereas Table 4 sum- marizes 14 nonselegiline cases. Indications for MAOI plus SSRI/SNRI combination therapy included depression (eight cases), TRD (six cases), recurrent MDD (nine There is a paucity of controlled, prospective cases), (five cases), and border- data on combination therapy with an MAOI and line (one case). Combina- a selective serotonin reuptake inhibitor (SSRI) tions encountered include an MAOI in or serotonin and norepinephrine reuptake inhib- combination with either trazodone (16 cases), a itor (SNRI) due to the general recommendations (TCA) (four cases), to avoid combination use. Combination therapy bupropion (two cases), an SSRI (one case), or of MAOIs and SSRIs or SNRIs is dangerous due mirtazapine (one case). Additionally, MAOIs to the increased risk for serotonin syn- were combined with two or more antidepressants drome.6, 33, 34 Further, deaths associated with in five cases. Of note, these patients represented combination use involving SSRIs have been a heterogeneous group, with various indications reported in patients receiving therapeutic and and treatment regimens. overdose amounts.35, 36 To avoid this, it is rec- Among the 29 patients reviewed at our insti- ommended that SSRIs or SNRIs be discontinued tution, six patients (21%) who received combi- for at least 2 weeks before beginning MAOI nation therapy experienced improvement in therapy, with the exception of fluoxetine, which mood, with no or minimal tolerable adverse requires a 5-week washout period.37 Our single effects. Only one of these patients was receiving case of fluoxetine combined with an MAOI was transdermal selegiline (Table 3, case 4), whereas uninformative (see details in Table 3, case 1), as four were treated with tranylcypromine the MAOI was discontinued at an outside hospi- (Table 4, cases 5, 8, 11, and 13) and one with tal for unknown reasons. Further, in case 1 in phenelzine (Table 4, case 12). Similarly, seven Table 4 and case 2 in Table 3, when the SNRIs patients (24%) demonstrated no or minimal venlafaxine and duloxetine were used in combi- improvements in mood. Documented adverse nation with an MAOI and trazodone, no positive effects requiring discontinuation of one or more outcomes were noted. Data support avoiding of the medications occurred in 13 patients combinations of SSRIs or SNRIs with MAOIs (45%), including three suspected cases of seroto- (regardless of MAO selectivity), as the risk most nin syndrome, which were neither confirmed often exceeds any potential benefit, particularly nor required acute intervention. Two patients with concomitant use of trazodone.6, 15, 16, 33 using the selegiline patch discontinued treatment due to rash and other reasons. There were no MAOI plus Trazodone reports of major serious consequences due to combination therapy with MAOIs. The most Trazodone is effective for , and an open- common adverse effects included , label study and case series have shown that , , dry mouth, and . low-dose trazodone may be a safe and effective The most frequent combinations included either treatment option for associated with – Table 2. Summary of Published Literature Describing Patients Who Received MAOIs in Combination with Other Antidepressants or Stimulant Medications15 32 Combination Assessed Study Details Treatment Summary

MAOI plus SSRI Case series of 8 select reviews Fluoxetine plus MAOI Seven cases were fatal when the MAOI (6 STIMULANTS OR ANTIDEPRESSANTS OTHER WITH COMBINED MAOIS of adverse event reports to cases used tranylcypromine) was added to or the manufacturer15 started after the initiation of fluoxetine. Case series of 12 patients Fluoxetine plus MAOI Therefore, use of fluoxetine plus an MAOI or taking fluoxetine plus MAOI in “close proximity” to an MAOI is and 6 patients who started an contraindicated.15 In general, the authors MAOI at least 10 days after recommended against combining stopping fluoxetine16 serotonergic antidepressants, such as SSRIs, with MAOIs until more controlled data become available; however, the authors also highlighted that combination therapy may be used in treatment-resistant patients along with close monitoring and cautious dosing strategies.16 MAOI plus Trazodone Case series of 13 patients with Trazodone 25–200 mg/day Overall, response to trazodone was favorable. MAOI-induced insomnia17 plus phenelzine, Problematic adverse effects included tranylcypromine, or , lightheadedness, isocarboxazid daytime , nocturnal , Open trial of 21 patients with Trazodone 50–75 mg at , recall, and a manic episode major depression and MAOI- bedtime plus phenelzine, in a patient who also had bipolar induced insomnia18 tranylcypromine, or disorder. One patient experienced a fall isocarboxazid during the course of treatment.19 Additional of combination therapy for TRD19 Trazodone 300–600 mg/day well-controlled, longer term studies are plus phenelzine 90–120 mg/ warranted; however, low-dose trazodone may day plus lithium be a safe and effective treatment option for MAOI-induced insomnia.

(continued) hmse al et Thomas 437 Table 2. (continued) 2015 4, Number 35, Volume PHARMACOTHERAPY 438

Combination Assessed Study Details Treatment Summary MAOI plus TCA 6-wk randomized study of 135 Treatment groups consisted of The majority of studies emphasized the patients with mild or phenelzine alone, importance of drug and dietary restrictions, moderate depression20 isocarboxazid alone, and no serious adverse effects were reported. trimipramine alone, However, these studies do report dizziness phenelzine plus and orthostatic hypotension, prolonged P-R trimipramine, or interval, , and manic switch from isocarboxazid plus combination treatment. One study reported trimipramine. Dosage ranges greater efficacy in trimipramine only users.20 were as follows: phenelzine This study also found that MAOIs and TCAs 15–60 mg/day, isocarboxazid are more likely to be effective in individuals 10–30 mg/day, and with high depression scores, TRD, or atypical trimipramine 50–150 mg/day depression.20 Further, this combination Chart review of 150 inpatients MAOI plus TCA (primarily should only be used in patients with TRD at and 51 outpatients21 amitriptyline and low risk for , given the risk of imipramine) in overdose.21 Overall, these studies do not Double-blind study of 80 Amitriptyline monotherapy, support greater efficacy of combined patients with major tranylcypromine treatment compared to monotherapy. There depressive disorder22 monotherapy, or combination is a need for additional data regarding this treatment with amitriptyline combination, and alternative options for plus tranylcypromine TRD, such as lithium or Case report of a 30-yr-old man Trimipramine 100 mg/day augmentation, should be considered first.24 with refractory depression23 added to phenelzine 60 mg/ day Case report of a 65-yr-old man Tranylcypromine plus with a history of major trimipramine (dosing details depression24 not provided) Open-label study of 25 patients Isocarboxazid at dosages up to with TRD; responders (n=12) 50 mg/day plus amitriptyline were followed for 3 yrs25 at dosages up to 200 mg/day

(continued) Table 2. (continued)

Combination

Assessed Study Details Treatment Summary STIMULANTS OR ANTIDEPRESSANTS OTHER WITH COMBINED MAOIS MAOI plus bupropion Case report of a 27-yr-old Tranylcypromine plus After numerous medication trials, and even woman with chronic major bupropion at dosages up to use of ECT in two patients,27 this depression26 60 and 300 mg/day, combination resulted in sustained remission respectively of depression. No serious adverse effects Case reports of a 63-yr-old Tranylcypromine plus were noted. The authors highlighted the lack man and a 54-yr-old man, bupropion at dosages up to of controlled studies and recommended both with TRD27 20 and 300 mg/day, combination therapy be better studied. They respectively, in the first highlighted the risk of hypertensive crisis patient, and up to 50 and and other complications, including 450 mg/day, respectively, in and cardiac rhythm disorders, the second patient with combination therapy and note that careful use of this combination may be warranted in treatment-refractory cases. MAOI plus Stimulants Review and case report of a Tranylcypromine 50 mg plus Positive outcomes were reported overall. The 38-yr-old man with major methylphenidate at dosages authors supported the prudent addition of a depression and undiagnosed up to 45 mg/day low-dose stimulant to MAOI therapy in attention deficit hyperactivity patients with refractory depression to prevent disorder28 MAOI-related adverse events, including Case report of a 31-yr-old Phenelzine 15 mg 3 times/day orthostatic hypotension and sedation.28 No woman with TRD29 plus methylphenidate 10 mg major adverse effects were observed; however every morning and 7.5 mg at there was one case of hypertension due to noon nonadherence of dietary restrictions, but no Report of 32 patients with Low-dose or cases of hypertensive crisis were recorded. severe TRD30 added to Cases of manic switches were reported in tranylcypromine, one study.30 A subset of patients in this isocarboxazid, or , study was also treated with other titrated based on tolerability antidepressants, including trazodone and and partial response tricyclic antidepressants.30 Additional controlled research to further evaluate the safety and efficacy of stimulant and MAOI combination treatment is needed.30 Given the potential risks of combination therapy with stimulants, such combinations should be used following a trial of more well- established combination regimens and careful

evaluation of patient-specific factors. al et Thomas

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Combination Assessed Study Details Treatment Summary MAOI plus Authors reviewed the medical Combination of an MAOI plus Most patients exhibited fair to good Antidepressants records of 16 patients with TCA, MAOI plus direct improvement. There were no instances of plus Stimulants TRD and provided additional stimulant, or MAOI, TCA, hypertensive crises in these studies. case details for two cases31 plus stimulant Orthostatic hypotension was the most Case study of a 70-yr-old man Trazodone plus fluoxetine plus frequent and other less without adequate response to methylphenidate plus common complaints include , his regimen32 plus neuroleptic restlessness, agitation, irritability, nausea, (unspecified) plus ECT plus dizziness, impairment of short-term memory, isocarboxazid 5 mg/day insomnia, and .31 The authors (other dosages not specified) concluded that this combination is safe and effective and may especially be beneficial in patients who experience postural hypotension with the use of MAOIs, as the stimulant can help to normalize pressure. It is recommended that patients receiving combination therapy with all three agents first begin the TCA at bedtime, followed by a daytime MAOI after 4–5 days. After another 4–5 days, the stimulant should be added at low doses and titrated until blood pressure is stable and clinical improvement is noted.31 The author of the second study highlights the importance of caution when coprescribing MAOIs in combination with other medications, emphasizing informed consent, strong collaboration between the prescriber and patient, using low doses of MAOIs, as well as ensuring that the prescriber is well versed in .32 ECT = electroconvulsive therapy; TRD = treatment-resistant depression. Table 3. Summary of the 15 Case Series Patients Who Received Combination Therapy with Selegiline and Other Antidepressant or Stimulant Medications STIMULANTS OR ANTIDEPRESSANTS OTHER WITH COMBINED MAOIS Combination Therapy Duration of Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 1 53-yr-old Bipolar Coronary artery Selegiline 6-mg patch Lithium, , 8 mo Improved mood and Caucasian woman depression disease, and fluoxetine rosuvastatin, energy, followed by hyperlipidemia 40 mg ezetimibe admission to outside hospital for severe depression where selegiline was discontinued for unknown reason 2 57-yr-old Recurrent , Selegiline 12-mg , intranasal 3 mo (duloxetine Denied benefit from Caucasian man MDD hyperlipidemia, patch, duloxetine budesonide, for 1 mo) selegiline; experienced dry abuse 90 mg, and , mouth, blurred vision, trazodone 100 mg , weight gain, sleeplessness, poor concentration, memory loss, , and constipation 3 67-yr-old Recurrent Anxiety, Parkinson’s Selegiline 60 mg and , 4 mo Discontinued combination Caucasian man severe MDD disease, essential trazodone 300 mg , therapy due to unspecified , , “intolerability” and a lack degenerative , of improvement in mood disease , 4 36-yr-old Severe Anxiety, Selegiline 12-mg , 10 mo (and Improved mood and sleep Caucasian woman depression osteopenia, sexual patch and trazodone alendronate, ongoing) dysfunction, 50 mg , hypothyroidism, doxycycline, ADD , lamotrigine 5 62-yr-old Recurrent Type 2 Selegiline 9-mg patch Irbesartan, 4 mo Improved energy, Caucasian man MDD mellitus, and trazodone , motivation, and optimism, hypertension, 200 mg atorvastatin but discontinued traumatic brain combination treatment injury, alcohol and due to morning fatigue dependence and decreased cognitive al et Thomas efficiency

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Table 3. (continued)

Combination Therapy Duration of Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 6 24-yr-old MDD None Selegiline 6-mg patch Quetiapine, lithium, 9 mo Considerable improvements Caucasian woman and trazodone clonazepam, in depressive symptoms, 50 mg , ethinyl but patient switched from estradiol/ trazodone to a norgestimate for sleep 7 40-yr-old Bipolar None Selegiline 9-mg patch Lithium, aripiprazole 2 mo Patient discontinued Caucasian woman depression and trazodone trazodone after feeling 50 mg better and insomnia resolved 8 42-yr-old Depression HIV, diabetes, Selegiline 6-mg patch , , Unknown Patient lost to follow-up; Caucasian man , anxiety, and trazodone glargine, seen by outside hyperlipidemia 150 mg insulin aspart, psychiatrist levothyroxine, lisinopril, aspirin, , , , emtricitabine/ tenofovir/ 9 71-yr-old Bipolar Hypertension, Selegiline 12-mg Losartan, , Nearly 2 yrs Patient tolerated Caucasian woman depression GERD, patch and trazodone , combination well, but osteoarthritis 50 mg , trazodone was aspirin, albuterol, discontinued in case , selegiline was switched to tranylcypromine due to concerns for an interaction 10 26-yr-old Borderline IBS, , Selegiline 12-mg Aripiprazole, 1 yr, 8 mo; Patient discontinued Caucasian woman personality abuse patch, bupropion clonazepam, bupropion for selegiline due to disorder with 300 mg, and lamotrigine, ferrous 6mo ineffectiveness; remained MDD trazodone 150 mg sulfate depressed, fatigued, anxious 11 30-yr-old TRD IBS, rheumatoid Selegiline 6-mg patch None 1 mo Discontinued bupropion in Caucasian man arthritis, GERD, and bupropion XL preparation for ECT after borderline 450 mg patient felt it would hypertension provide better symptomatic relief

(continued) AI OBNDWT TE NIERSAT RSTIMULANTS OR ANTIDEPRESSANTS OTHER WITH COMBINED MAOIS

Table 3. (continued)

Combination Therapy Duration of Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 12 45-yr-old TRD Chronic back pain, Selegiline 6-mg patch Sildenafil 1 mo Patient discontinued Caucasian man ED, , and bupropion SR selegiline for unknown lumbar 450 mg reasons; felt symptoms degenerative disc may have worsened disease 13 39-yr-old TRD , IBS, Selegiline 9-mg patch , 8 mo for Switched from selegiline to Caucasian woman history of alcohol and nortriptyline liothyronine, selegiline; tranylcypromine after abuse 100 mg followed by lorazepam, 1 mo for slight increase in blood tranylcypromine aripiprazole tranylcypromine pressure; tranylcypromine 20 mg and titration halted and nortriptyline 50 mg nortriptyline discontinued due to suspicion of serotonin effects 14 32-yr-old TRD None Selegiline 12-mg Quetiapine, 1 wk Experienced significant Asian woman patch and clonazepam pruritis associated with nortriptyline selegiline patch 100 mg 15 19-yr-old Recurrent None Selegiline 12-mg Ziprasidone, lithium 1 yr for selegiline; Selegiline discontinued per Caucasian man MDD patch and 2 yrs, 8 mo for discussions with ECT nortriptyline tranylcypromine team; improvements seen 150 mg followed by with tranylcypromine, but tranylcypromine nortriptyline discontinued 80 mg and due to fatigue nortriptyline 150 mg ECT = electroconvulsive therapy; ED = ; IBS = ; MDD = major depressive disorder; TRD = treatment-resistant depression. hmse al et Thomas 443 4 HRAOHRP oue3,Nme ,2015 4, Number 35, Volume PHARMACOTHERAPY 444 Table 4. Summary of the 14 Case Series Patients Who Received Combination Therapy with Nonselegiline MAOIs and Other Antidepressant or Stimulant Medications Combination Therapy Duration of Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 1 56-yr-old Depression Hyperlipidemia, Phenelzine 45 mg, Aripiprazole, 1 mo Patient fell and hit Asian man GERD, venlafaxine atorvastatin, head; began ECT hyperparathyroidism, 300 mg, and levothyroxine, thereafter impotence, insomnia, trazodone 25 mg tadalafil, D deficiency pantoprazole 2 67-yr-old Depression Anxiety, ADD, Phenelzine 75 mg , Nearly 1 yr Discontinued both Caucasian woman hypothyroidism, and trazodone levothyroxine, phenelzine and migraines, 200 mg clonazepam, trazodone due to hypertension, possible serotonin atypical chest chloride, , syndrome pain, remote probiotic, history of intranasal fluticasone 3 52-yr-old TRD Long history of Tranylcypromine Liothyronine 3.5 yrs Discontinued trazodone Caucasian woman alcohol and 50 mg and due to difficulties with opioid abuse (in trazodone 75 mg sweating, palpitations, remission), , and dizziness; Crohn’s disease, experienced modest osteopenia, improvements in mood atypical chest during this time pain, hypertension 4 45-yr-old Recurrent MDD Hypothyroidism Tranylcypromine Levothyroxine, Nearly 8 mo Exhibited moderate woman, race not 80 mg and iron supplement, improvement, but reported trazodone omeprazole, trazodone discontinued 100 mg due to cognitive gel clouding 5 63-yr-old Recurrent MDD Osteoarthritis Tranylcypromine Divalproex, 4 mo Demonstrated Caucasian man 70 mg and clonazepam, improvements in trazodone simvastatin mood, but 100 mg discontinued trazodone due to lack of efficacy 6 58-yr-old Depression Migraines, Phenelzine 75 mg Lorazepam, 10 mo Dramatic Caucasian man osteopenia, and trazodone , improvements primary 50 mg pantoprazole with increased hyperparathyroidism, phenelzine dose, GERD but patient discontinued trazodone due to daytime sedation

(continued) Table 4. (continued)

Combination

Therapy Duration of STIMULANTS OR ANTIDEPRESSANTS OTHER WITH COMBINED MAOIS Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 7 30-yr-old Depression Chronic low back Tranylcypromine Albuterol, 1 yr, 2 mo Lack of Caucasian man pain, migraines, 60 mg and , improvement; idiopathic trazodone lamotrigine, switched from thrombocytopenic 100 mg lithium, trazodone to , alcohol propranolol, for dependence quetiapine, sleep as it was ziprasidone, helpful in the , past , lithium 8 62-yr-old Recurrent MDD Prostate , Tranylcypromine , ≥ 4 yrs Mood improvements Caucasian man ED, cardiac 70 mg and lisinopril, (and ongoing) followed by a defibrillation, trazodone150 mg , when patient had to , aspirin, discontinue alcohol abuse clonazepam tranylcypromine due to financial problems; improved/good mood on reinitiation 9 53-yr-old Depression Renal failure, Tranylcypromine Lamotrigine, 1.5 yrs Patient discontinued Caucasian man hypotension 120 mg and lorazepam, trazodone as it was secondary to trazodone lithium, agitating and caused volume 300 mg liothyronine, more sleep depletion, quetiapine, disturbances; lack of hypovolemic amlodipine/ improvement in mood benazepril, symptoms 10 41-yr-old TRD , Phenelzine 60 mg, Topiramate, 2 yrs, 7 mo Patient discontinued Caucasian woman fatigue, desipramine methylphenidate, desipramine due to , 75 mg, and lorazepam, symptomatic back pain, trazodone hypotension and 300 mg tachycardia; remained on tranylcypromine and trazodone for

unknown duration; al et Thomas experienced mild improvements in mood

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Combination Therapy Duration of Relevant Medical (Maximum Total Concomitant Combination Case Age, Race Diagnosis History Daily Doses) Medications Therapy Outcomes 11 56-yr-old Recurrent MDD Atrial fibrillation/ Tranylcypromine , 5 yrs (and Phenelzine and Caucasian man flutter 70 mg, , ongoing) nortriptyline ongoing malnutrition, nortriptyline gabapentin, with improvements in diabetes mellitus, 100 mg, and fluvastatin, mood and stability of hypertension, trazodone 50 mg , depression; trazodone coronary artery stopped and restarted disease, with no follow-up on congestive most recent use failure 12 57-yr-old Recurrent MDD Hyperlipidemia, Phenelzine 60 mg, Lithium, 2 yrs, after which Successfully Caucasian woman hypothyroidism, nortriptyline quetiapine, patient was lost remained on fibromyalgia, 150 mg, and tizanadine, to follow-up combination hypertension trazodone clonazepam, therapy with no 400 mg ipratropium relapse or solution, significant simvastatin, adverse effects lisinopril, levothyroxine, medroxyprogesterone acetate 13 73-yr-old Bipolar II disorder Hypertension, Tranylcypromine Hydrochlorothiazide, Nearly Patient remained Caucasian woman with depression hypothyroidism, 40 mg and lisinopril, 4 yrs stable on this nonischemic nortriptyline levothyroxine, iron (and ongoing) combination dilated 125 mg supplement cardiomyopathy, remote history of acute renal failure 14 67-yr-old Bipolar depression History of sciatica, Phenelzine 90 mg Quetiapine, Nearly 3 mo Discontinued phenelzine Caucasian man history of and mirtazapine aripiprazole, following hospital alcohol 15 mg propranolol admission for dependence symptoms of and serotonin syndrome, potentially due to supratherapeutic doses both agents MAOIs = monoamine oxidase inhibitors; ADD = attention-deficit disorder; ECT = electroconvulsive therapy; ED = erectile dysfunction; MDD = major depressive disorder; TRD = treatment- resistant depression. MAOIS COMBINED WITH OTHER ANTIDEPRESSANTS OR STIMULANTS Thomas et al 447 – MAOI use.17 19 There are limited data on the existing data that this combination is relatively use of higher doses of trazodone in combination safe, with variable efficacies. If this combination with MAOIs for TRD.18, 19 Overall, our cases is used, the TCA should be initiated first or at also support safe and effective use of low-dose the same time as the MAOI.9 It should be noted trazodone and MAOIs. It should be noted that here that clomipramine, a TCA, exhibits potent the trazodone doses used are largely targeting inhibition of serotonin should not be used in insomnia and are not effective antidepressant combination with an MAOI.38 doses. The addition of low-dose trazodone to MAOI therapy appeared to improve tolerability MAOI plus Bupropion of the MAOI and overall clinical improvement of patients. Reasons for discontinuation of trazo- There are three existing cases published done and MAOI combination therapy in our reporting on the use of bupropion and tranylcy- review included ineffectiveness, feeling overly promine in combination.26, 27 Each of these tired, experiencing more sleep disturbance, or cases resulted in improvement in depressive cognitive clouding. One patient we described in symptoms without reports of hypertension or our case series stopped trazodone and MAOI other problematic adverse effects. Among the combination treatment due to symptoms consis- cases in our study, one patient continued combi- tent with serotonin syndrome, although this was nation treatment with bupropion and selegiline not definitively diagnosed (Table 4, case 2). beyond 1 month, but efficacy was not well docu- Overall, however, patients receiving this combi- mented (Table 3, case 10). Of note, this patient nation averaged approximately 21 months of uti- was receiving transdermal selegiline, which lization. Further studies are needed, and the poses a lower risk for hypertensive crisis due to risks of combination treatment should remain a its increased selectivity for MAO-B at this low concern, including the risk of orthostatic hypo- dose, as previously highlighted. As such, it is tension, which should be monitored closely. It not as sensitive to dietary tyramine intake as should be noted that higher doses of trazodone higher doses of transdermal or oral selegiline or are likely associated with greater risk of seroto- other nonselective MAOIs. Two additional nin syndrome, and the risk would likely out- patients receiving bupropion in our case series weigh potential benefit in most cases. did not demonstrate benefit with combination treatment (Table 3, cases 11–12). Given the lim- ited published evidence, bupropion in combina- MAOI plus TCA tion with an MAOI may be considered; however, The literature on TCA-and-MAOI combination the risk for hypertension or other adverse effects therapy is mixed. Small studies and case reports should be monitored closely, and additional have demonstrated its safety, but the combina- studies of this combination are needed. tion has generally been found to be less well tol- – erated than either agent alone.20 22 In addition, MAOI plus Stimulants there are studies that suggest that the combina- tion is no more efficacious than either agent Stimulants have been used safely in combi- alone and should be reserved for individuals nation with MAOIs. Although stimulants are with high depression scores, TRD, or atypical not indicated for the treatment of depression, – depression.20 22 Our patients who received TCA these agents are used in clinical practice as an and MAOI combination therapy show sustained augmentation strategy for TRD.39 The litera- tolerability and efficacy (Table 3, cases 13–15; ture, of which the majority consists of case Table 4, cases 10–13). Three of the seven reports and case series, supports the use of – patients remained on this regimen for at least stimulants in combination with an MAOI.28 30 2 years, two of whom also received trazodone in Stimulants may help to normalize blood pres- combination with the TCA and MAOI. The com- sure in those experiencing hypotension as a bination was discontinued in four patients due result of MAOI therapy. It should be noted to one case of hypotension (patient was also that our case series did not highlight this receiving trazodone), one case with suspicion of combination. As with the other MAOI combi- serotonin syndrome, one patient who experi- nations, this should be reserved for treatment- enced fatigue with the combination, and one resistant patients under the supervision of a patient who could not tolerate pruritis associated qualified and experienced clinician, carefully with the selegiline patch. These results support assessing risk versus benefit. 448 PHARMACOTHERAPY Volume 35, Number 4, 2015

MAOI plus Antidepressants plus Stimulants and under the care of an experienced clinician in psychiatry, combination therapy with MAOIs The use of direct stimulants in combination and other antidepressants (with the exception of with an MAOI plus another antidepressant has SSRIs, SNRIs, or clomipramine) or stimulants demonstrated safety and efficacy in case may be a consideration for the challenging man- reports.31, 32 Our patients showed mixed results. agement of TRD in patients not responding to One patient taking amphetamine in addition to monotherapy or other combinations of antide- an MAOI and another antidepressant remained pressants or augmentation strategies. stable on this combination for longer than Two recent studies evaluated the use of the 10 months (Table 3, case 4). Another patient MAO type B inhibitor in patients with taking methylphenidate in addition to an MAOI Parkinson’s disease in combination with various and two antidepressants discontinued one of the antidepressants and found no reports of serotonin antidepressants due to symptomatic hypotension toxicity.40, 41 Coverage of this topic is important; and tachycardia, but the rest of her regimen however, recent literature to provide guidance on remained the same (Table 4, case 10). The addi- how to safely ude MAOIs for TRD in combination tion of stimulants to MAOI therapy has generally with other antidepressants or stimulant medica- been avoided by physicians given the risk of tions is sparse. The emerging use of electronic hypertensive and hyperthermic crises. Blood patient records offers the opportunity to gather pressure should be monitored closely as well as therapeutic and outcomes data on larger numbers signs of other adverse effects. Similar to other of patients. It is unlikely that clinical trials with a combinations, this approach should be used translational focus will be sponsored to study with caution and under the supervision of a MAOIs and other currently used antidepressants qualified and experienced clinician, particularly in TRD. This is unfortunate, as longitudinal stud- as a last resort option, including failure of elec- ies of individuals with TRD are needed and ide- troconvulsive therapy. ally will include embedded randomized controlled trials with combination treatment that Limitations includes MAOIs and other pharmacologic strate- gies. Focused environmental and pharmacologic The limitations of a retrospective case series inquiry aimed at determining why treatment highlight recall bias and the nature of recorded resistance occurs and is sustained is needed. Our clinical information. In the information we study with one health system shows that the data reviewed, patients may not have recollected their are accessible and that with existing data mining full diet or use of over-the-counter medications methods, we were able to show that one in five that may have contributed to adverse events. This patients with TRD responded to a combination of potentially results in inaccurate records and thus an MAOI and other antidepressant. This is of adverse effects associated with diet, and medica- major importance given that depression is so tions prescribed by providers outside of our sys- common and the finding that depression is the tem may have been missed. As a retrospective largest cause of disability and disability-adjusted case series, our data are strictly limited to medi- life-years worldwide;42, 43 disability due to cal records. Loss of patient follow-up could be depression is most likely TRD. mistaken as discontinuation of therapy, and the retrospective nature also relies on clear documen- tation in the medical record. Other limitations References include variability among patients. Each patient 1. Souery D, Amsterdam J, de Montigny C, et al. Treatment presented with various depression severities, resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999;9:83–91. medications, formulations (patch vs oral, and 2. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant selective vs nonselective MAO inhibition), and depression: definitions, review of the evidence, and algorithmic dosing regimens. These variances prevent the approach. J Affect Disord 2014;156:1–7. 3. Souery D, Serretti A, Calati R, et al. Switching antidepressant ability to make strong general conclusions on class does not improve response or remission in treatment- specific combination treatments. resistant depression. J Clin Psychopharmacol 2011;31:512–6. 4. Fava M. Diagnosis and definition of treatment-resistant depres- sion. Biol Psychiatry 2003;53:649–59. 5. The European Agency for the Evaluation of Medicinal Prod- Conclusion ucts. Committee for Proprietary Medicinal Products (CPMP). Note for guidance on clinical investigation of medicinal prod- Our case series and review of the literature ucts in the treatment of depression. Available from http:// suggest that when used under close supervision www.ema.europa.eu/docs/en_GB/document_library/Scientific_ MAOIS COMBINED WITH OTHER ANTIDEPRESSANTS OR STIMULANTS Thomas et al 449

guideline/2009/09/WC500003526.pdf. Updated April 25, 2002. 27. Quante A, Zeugmann S. Tranylcypromine and bupropion Accessed February 18, 2014. combination therapy in treatment-resistant major depres- 6. Krishnan K. Revisiting monoamine oxidase inhibitors. J Clin sion: a report of 2 cases. J Clin Psychopharmacol Psychiatry 2007;68(suppl 8):35–41. 2012;32:572–4. 7. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. 28. Feinberg SS. Combining stimulants with monoamine oxidase The Hunter Serotonin Toxicity Criteria: simple and accurate inhibitors: a review of uses and one possible additional indica- diagnostic decision rules for serotonin toxicity. QJM tion. J Clin Psychiatry 2004;65:1520–4. 2003;96:635–42. 29. Shelton Clauson A, Elliot ES, Watson BD, Treacy J. Coad- 8. Somerset Pharmaceuticals, Inc. Emsam [package insert]. Mor- ministration of phenelzine and methylphenidate for treatment- gantown, WV; 2009. resistant depression. Ann Pharmacother 2004;38:508. 9. Grady MM, Stahl SM. Practical guide for prescribing MAOIs: 30. Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant debunking myths and removing barriers. CNS Spectr 2012;17:2–10. potentiation of monoamine oxidase inhibitors in treatment- 10. van der Hoeven N, Visser I, Schene A, van den Born BJ. refractory depression. J Clin Psychopharmacol 1991;11:127– Severe hypertension related to caffeinated coffee and tranylcy- 32. promine: a case report. Ann Intern Med 2014;160:657–8. 31. Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA, 11. Shulman KL, Herrmann N, Walker SE. Current place of and direct stimulant therapy of treatment-resistant depression. monoamine oxidase inhibitors in the treatment of depression. J Clin Psychiatry 1985;46:206–9. CNS Drugs 2013;27:789–97. 32. Peterson GN. Strategies for fluoxetine-MAOI combination 12. Standaert DG, Roberson ED. Chapter 22. Treatment of central therapy. J Clin Psychiatry 1991;52:87–8. degenerative disorders. In: Brunton LL, Chab- 33. Hodgman MJ, Martin TG, Krenzelok EP. Serotonin syndrome ner BA, Knollmann BC. eds. Goodman & Gilman’s the phar- due to venlafaxine and maintenance tranylcypromine therapy. macological basis of therapeutics, 12th ed. New York, NY: Hum Exp Toxicol 1997;16:14–7. McGraw-Hill; 2011. Available from: http://accesspharma- 34. Brubacher JR, Hoffman RS, Lurin MJ. Serotonin syndrome cy.mhmedical.com/content.aspx?bookid=374&Sectio- from venlafaxine-tranylcypromine interaction. Vet Hum Toxi- nid=41266228. Accessed January 28, 2015. col 1996;38:358–61. 13. Sunderland T, Mueller EA, Cohen RM, Jimerson DC, Pickar 35. Keltner N, Harris CP. Serotonin syndrome: a case of fatal D, Murphy DL. Tyramine pressor sensitivity changes during SSRI/MAOI interaction. Perspect Psychiatr Care 1994;30:26– deprenyl treatment. Psychopharmacology 1985;86:432–7. 31. 14. Azzaro AJ, Vandenberg CM, Kemper EM, Sharoky M, Oren 36. Neuvonen PJ, Pohjola-Sintonen S, Tacke U, Vuori E. Five DA, Campbell BJ. Tyramine pressor sensitivity during treat- fatal cases of serotonin syndrome after -citalop- ment with the selegiline transdermal system 6 mg/24 h in ram or moclobemide-clompiramine overdoses. Lancet healthy subjects. J Clin Pharmacol 2006;46:933–44. 1993;342:1419. 15. Beasley CM, Masica DN, Heiligenstein JH, Wheadon DE, 37. Rapaport MH. Dietary restrictions and drug interactions with Zerbe RL. Possible monoamine oxidase inhibitor-serotonin monoamine oxidase inhibitors: the state of the art. J Clin Psy- uptake inhibitor interaction: fluoxetine clinical data and pre- chiatry 2007;68(suppl 8):42–6. clinical findings. J Clin Psychopharmacol 1993;13:312–20. 38. Pittenger C, Bloch MH. Pharmacologic treatment of obsessive- 16. Feighner JP, Boyer WF, Tyler DL, Neborsky RJ. Adverse con- compulsive disorder. Psychiatr Clin N Am 2014;37:375–91. sequences of fluoxetine-MAOI combination therapy. J Clin 39. American Psychiatric Association. Treatment of patients with Psychiatry 1990;51:222–5. major depressive disorder, 3rd ed. Arlington, VA: American 17. Nierenberg AA, Keck PE. Management of monoamine oxidase Psychiatric Association; 2010. doi: 10.1176/appi.books. inhibitor-associated insomnia with trazodone. J Clin Psycho- 9780890423387.654001. Accessed September 23, 2014. pharmacol 1989;9:42–5. 40. Panisset M, Chen JJ, Rhyee SH, Conner J, Methena J, the 18. Jacobsen FM. Low-dose trazodone as a in patients STACCATO study investigators. Serotonin toxicity association treated with MAOIs and other psychotropics: a pilot study. J with concomitant antidepressants and rasagiline treatment: ret- Clin Psychiatry 1990;51:298–302. rospective study (STACCATO). Pharmacotherapy 2014;34: 19. Zetin M. Combined use of trazodone and phenelzine in 1250–8 doi: 10.1002/phar.1500 depression: case report. J Clin Psychiatry 1984;45:182–3. 41. Smith KM, Eyal E, Weintraub D, the ADAGIO Investigators. 20. Young JP, Lader MH, Hughes WC. Controlled trial of trimipr- Combined rasagiline and antidepressant use in Parkinson dis- amine, monoamine oxidase inhibitors, and combined treat- ease in the ADAGIO study: effects on nonmotor symptoms ment in depressed outpatients. Br Med J 1979;2:1315–7. and tolerability. JAMA Neurol 2015;72:88–95. doi: 10.1001/ja- 21. Spiker DG, Pugh DD. Combining tricyclic and monoamine maneurol.2014.2472. oxidase inhibitor antidepressants. Arch Gen Psychiatry 42. World Health Organization. Depression, a hidden burden, 1976;33:828–30. 2012. Available from http://www.who.int/mental_health/man- 22. O’Brien S, McKeon P, O’Regan M. The efficacy and tolerability agement/depression/flyer_depression_2012.pdf. Accessed Sep- of combined antidepressant treatment in different depressive tember 23, 2014. subgroups. Br J Psychiatry 1993;162:363–8. 43. Lepine JP, Briley M. The increasing burden of depression. 23. Lippmann S, Baldwin H, Manshadi M. Combined trimipr- Neuropsychiatr Dis Treat 2011;7(suppl 1):3–7. amine/phenelzine treatment of depression: case report. J Clin Psychiatry 1982;43:430–1. 24. White K, Simpson G. Combined tricyclic-MAOI antidepres- sant treatment: a reevaluation. J Clin Psychopharmacol Supporting Information 1981;1:264–82. 25. Berlanga C, Ortega-Soto HA. A 3-year follow-up of a group of The following supporting information is available in the online treatment-resistant depressed patients with a MAOI/tricyclic version of this paper: combination. J Affect Disord 1995;34:187–92. Data S1. Additional details for select patient cases organized by 26. Pierre JM, Gitlin MJ. Bupropion-tranylcypromine combination combination. for treatment-refractor depression. J Clin Psychiatry 2000;61:450–1.