Systematic Overview of Drug Interactions With Antidepressant Medications
Depression is the second most common reason for visiting an office-based physician in Canada (1). Antidepressant drugs are commonly prescribed. Data from IMS Health for 2002 noted that antidepressants were the third ranked therapeutic class in global pharmaceutical sales, totaling $17.1 billion and growing at a rate of 5% annually (1). In Canada in 2004, more than 79 million prescriptions for antidepressant drugs were filled at a cost of more than $2.8 billion (1). In addition to treating depressive disorders, antidepressant drugs are increasingly used to treat other illnesses, including anxiety disorders, chronic pain, and eating disorders (2). In many cases, antidepressant drugs are used concurrently with other medications, thus exposing patients to potential harm owing to adverse drug interactions (3).
Drug interactions may be synergistic, antagonistic, or idiosyncratic. Interactions may be further classified as pharmacokinetic or pharmacodynamic. Many of the available antidepressant drugs are inhibitors and (or) substrates of the CYP 450 enzyme system and therefore have potential for pharmacokinetic interactions (3). The potential for pharmacodynamic interactions is also concerning given the range of physiologic systems affected by antidepressant drugs (for example, the genitourinary, cardiovascular, and endocrine systems) (2).
Of the many published reviews of drug interactions involving antidepressants (4–13), none offer a systematic review of the literature, formal evaluation of the quality of evidence, and summary of findings. Many reviews mix data from small trials with individual case reports, data from animal studies with human studies, and clinical with nonclinical outcomes. We previously published a systematic drug interaction evaluation methodology in which we evaluated the quality and clinical relevance of reports of drug interactions involving antidepressants commonly used in North America (14–16).
We consulted the relevant compendia to compile a list of antidepressant drugs to evaluate for potential drug interactions. On the evaluation, we included 24 antidepressant drugs and one herbal remedy, St John’s wort (Table 1). Although nefazodone was removed from the Canadian market prior to the completion of this review, we included the results as nefazodone remains available in the US and other countries. We searched MEDLINE from 1966 to November 2003, using the MeSH heading drug interactions in combination with the MeSH heading or textword for each individual drug name. The searches were restricted to articles in English and to those involving human studies. We also searched EMBASE from 1980 to November 2003, using the headings drug interactions combined with each individual drug name. We screened bibliographies of 60 review articles for other relevant studies. We checked the indexes of 2 drug-interaction textbooks for all interactions cited for each of the antidepressant drugs, and we retrieved any additional references (17,18). We did not evaluate articles involving animal or in vitro studies, nor did we review articles or interactions involving drugs unavailable for, or commonly used in, current clinical practice.
Drug Interaction Evaluation
All articles were evaluated independently by 2 reviewers. We resolved discrepancies by consensus. In cases where discrepancies were unresolvable, a third reviewer was consulted. Studies that reported positive interactions, such as enhancement of therapeutic response without precipitation of adverse events, were excluded, as were drug overdoses and unintentional drug ingestions. We excluded studies involving interactions with intravenously administered tyramine. Those involving orally administered tyramine were included as those studies may have potential relevance for adverse interactions between food containing tyramine and drugs such as MAOIs.
We evaluated interactions in 3 domains: clinical effect (outcome of interaction), clinical significance (clinical impact), and quality of evidence (rating from study design and sample size).
Outcome of Interaction. We classified interaction outcomes as augmentation, inhibition, no effect, or conflicting evidence. To define an interaction as augmentation, the drug effect had to be greater than the sum of the individual drug’s effects. To define an interaction as inhibition, the drug effect had to be less in the presence of another drug or substance than the expected effect of that drug alone. Outcomes in which drugs neither augmented nor inhibited each other’s effects were classified as no effect. Conflicting evidence was used when a particular study or mix of studies did not report a uniform clinical effect but found that certain patients exhibited drug augmentation while others exhibited drug inhibition or no effect.
Clinical Compared With Nonclinical Effect. If there was a clinically evident effect, such as symptomatology or laboratory evidence of a clinical effect (that is, INR), we classified an augmentation or an inhibition outcome as clinical. If there were statistically significant alterations in the pharmacokinetic parameters without evidence of clinical effect, an augmentation or inhibition outcome was classified as nonclinical.
From the severity of the outcome, we rated the clinical significance of an interaction as major, moderate, or minor. We classified a clinical outcome causing death or considered life-threatening as major (for example, conditions urgently requiring IV medications to lower blood pressure, intubation, IV fluids or electrolytes, or the application of cooling blankets). We classified a clinical outcome that required medical attention, caused the patient great discomfort, or interfered with a patient’s ability to function in daily activities as moderate. A clinical outcome that was not likely to affect a patient’s usual activities and could be tolerated without seeking medical attention (that is, symptoms causing mild discomfort, such as headache or slight nausea) was classified as minor. Interaction outcomes that were rated nonclinical were classified as having minor clinical significance.
Quality of Evidence
From the methodologic quality of the study and the sample size supporting the interaction (total number of patients in the report), we rated the quality of evidence for each interaction report as excellent, good, fair, or poor. We rated an RCT with more than 100 patients as excellent quality. We rated an RCT with 21 to 100 patients good quality. We considered an RCT with 10 to 20 patients fair quality and an RCT with fewer than 10 patients poor quality. Nonrandomized trials, such as cohort studies, case–control studies, case series, case reports, and pharmacokinetic studies, were all classified as poor quality.
Drug Interaction Summaries
We used a hierarchy of rating for situations in which the conclusions of individual reports differed: 1) when there were both patient-based and healthy volunteer-based studies, the conclusions of the studies involving patients took priority regardless of quality of evidence; 2) when the studies involved the same subject population, we used the interaction conclusion from the article with the highest quality of evidence; 3) for articles with the same quality of evidence and studying the same subject population, we used the conclusion of the one reporting a higher clinical significance; and 4) we gave a conflicting evidence rating to articles of the same quality of evidence and the same subject population that reported different interactions of the same clinical significance.
The summary criteria were inapplicable to 8 drug interactions. In these cases, an overall rating was devised by consensus in consultation with a third reviewer.
SS and NMS
All reports of SS were evaluated separately according to Sternbach’s criteria (19). Interactions were rated as SS only if all criteria were met. If criteria were possibly but not conclusively met, we rated the interaction unclear. If one or more criteria were not met, the interaction was rated no effect. Interactions were also evaluated for NMS according to DSM-IV criteria (20). We rated NMS in the same way as we rated SS.
Twenty-five antidepressant drugs were eligible for the analysis (Table 1). A total of 2541 citations were retrieved and 1478 articles were evaluated (the remainder were excluded for reasons noted in the methods section), resulting in a total of 904 reported interactions involving 9509 patients or volunteers. These were collated into 598 summary interaction reports. An interaction was suggested in 439 cases (73%), no effect in 148 cases (25%), and conflicting evidence in 11cases (2%). Of the 439 interactions, 389 (89%) augmented a drug’s clinical effect, whereas 50 interactions (11%) inhibited a drug’s effect. We classified 92 interactions (21%) as nonclinical. SSRIs and tricyclic antidepressants were involved in 32% and 33% of the interactions, respectively.
We classified 145 interactions (33%) as having major clinical significance, 128 (29%) as having moderate clinical significance, and 166 (38%) as having minor clinical significance. Table 1 summarizes the clinical significance and quality of evidence for each antidepressant drug’s interactions. Tables 2 and 3 summarize the interactions of major clinical significance, excluding SS and NMS. All the major interactions were derived from individual case reports or case series, with only 16 (18%) of the 88 interactions derived from more than one report. Fifteen (10%) of the major interactions involved antidepressant drug combinations. An additional 29 summary interactions (20%) involved nonantidepressant drugs with CNS activity. These included olanzapine, clozapine, chlorpromazine, haloperidol, thioridazine, trifluoperazine, fluphenazine, pimozide, benztropine, lithium, methylphenidate, clonazepam, nitrazepam, ethanol, cyproheptadine, and dextroamphetamine. Other medications involved in major adverse drug interaction combinations included fluconazole, estrogen, prednisone, dextromethorphan, ritonavir, propofol, clarithromycin, erythromycin, pentazocine, interferon, indapamide, altretamine, levodopa, presumed tyramine in foods, disulfiram, atracurium, droperidol, enflurane, isoproterenol, clonidine, propranolol, nifedipine, tinzaparin, warfarin, amiodarone, phenylephrine, simvastatin, irinotecan, chlorpropamide, cyclosporine, propoxyphene, meperidine, selegiline, and theophylline. Phenelzine and tranylcypromine were the most commonly implicated antidepressant drugs in major clinical adverse interactions.
Outcomes of the major interaction reports included death, organ failure, hypertensive emergencies, syncope, SS, delirium, psychosis, suicide attempts, transplant rejection, seizures, rhabdomyolysis, subarachnoid hemorrhage, and related adverse bleeding (Tables 2 and 3).
No interactions met the criteria for excellent quality of evidence. A total of 10 interactions (2%) had good quality of evidence (that is, an RCT of at least 21 patients) (21–27). Nine of these 10 interactions, 7 involving patients, found no effect. These included amitriptyline–flupenthixol, chlorpromazine–citalopram, imipramine–benztropine, imipramine–fluphenazine, morphine–desipramine, thioridazine–citalopram, zuclopenthixol–citalopram, alprazolam–citalopram, and fluoxetine-orlistat. We rated the tenth interaction exhibiting no effect as having minor clinical significance. It involved anefazodone–loratidine combination that resulted in a prolonged QT interval of unclear clinical significance and increased drug concentrations of loratidine.
Of the 67 interactions (11%) classified as having fair quality evidence, 39 (58%) were rated as having no effect and 26 (39%) were of minor clinical significance. Two fair quality interactions were classified as having moderate clinical significance. These interactions were between pentazocine and amitriptyline, which caused enhanced respiratory depression, and trazodone and ritonavir, which caused syncopal episode. The remaining 510 interactions (85%) had poor quality of evidence.
Various other drugs (n = 136) were involved in the interactions with antidepressant drugs. Virtually all major drug classifications were represented (Table 4). The most commonly implicated drugs were lithium (21 reports), carbamazepine (20 reports), ethanol (16 reports), and cimetidine (15 reports).
SS and NMS
SS was reported in 106 interactions (18%). Of the 106 reports, 34 interactions (n = 27 patients) met the criteria for SS. Of an additional 16 interactions, only one of several reports met criteria (Table 5). These interactions were also dominated by antidepressant drug combinations and antidepressant drugs given with other CNS drugs (that is, lithium, meperidine, and dextromethorphan). Outcomes, by definition, were characterized by mental status changes (that is, ranging from confusion and agitation to stupor and coma), tremor, rigidity, fever, and hyperreflexia. We rated 63 interactions (59%) as having major, 37 (35%) as having moderate, and 2 (2%) as having minor clinical significance. We evaluated 14 interactions for NMS. The interaction between venlafaxine and trifluoperazine met the criteria for NMS (that is, rigidity, increased creatine kinase, increased temperature, fluctuating blood pressure, anxiety, and malaise). In the remaining interactions, NMS was ruled out, although in many cases the signs and symptoms were more consistent with NMS than with SS. These cases, however, did not involve antipsychotics.
Given the frequency of antidepressant drug use and the important potential clinical consequences of adverse interactions, it is surprising that no previous systematic review of interactions with antidepressant drugs has been carried out. Other available resources are limited. The CPS lists general contraindications for several families of antidepressants, mainly involving MAOI drugs, but these are inconsistently applied to individual drugs within the families (28). The product monographs forming the basis of the CPS monograph are often outdated and nonspecific. Owing to this, they cannot be relied on for guidance on drug interactions. Standard drug interaction texts and Web sites are also available but are frequently inaccurate and outdated (29–33). Various drug interaction software programs (such as ePocrates, Lexi-Interact, and MICROMEDEX) are available on handheld computers and are thus advantageously available at the point of prescribing; they are updated regularly but have not been rigorously evaluated for accuracy (34). The CADRMP, also called MEDeffect, has recently made its database available for online searches (www.hc-sc.gc.ca/dhp.mps/ medeff/ index_e.html). However, the database is a collection of generally poor-quality, voluntary, unadjudicated case reports of suspected adverse reactions, some of which may involve a drug interaction. It is meant to generate signals of possible adverse events associated with drugs, not to prove cause and effect. The primary problem with the drug interaction literature and resources is not a lack of data, but a lack of valid, reliable, primary information. Randomized trials are required to solve this problem.
In this systematic review we found that, despite the publication of numerous reports and reviews of drug interactions with antidepressant drugs, most of the reported interactions were of poor quality of evidence (single case reports) and thus untrustworthy. Case reports have many limitations, perhaps the most important being that they provide no numerator of outcomes or denominator of drug use by which to judge frequency of the adverse event. Biases, such as channeling bias, diagnostic suspicion bias, and attribution bias, may void the validity of the report. Interactions with poor-quality evidence, however, are difficult to dismiss entirely because they may signal a problem and, given the underreporting of postmarketing events, could represent the start of a larger trend. Whether the quantity of reports of a specific interaction correlates with the eventual truth is unknown, given the lack of gold standard evidence. Randomized trials of drug interactions in patients are very rare, and analyses of large administrative databases are only beginning to emerge (35). As in other reviews, interactions supported by good-quality evidence tended to show no clinical effect, which most likely reflects the small sample size, the inclusion of healthy volunteers or relatively healthy patients, and the lack of adequately predictive surrogate outcome measures. The lack of large, high-quality trials that address drug interaction issues is not unique to psychiatry but is a problem in every therapeutic area. We suggest that this shortcoming represents a major, unmet need. Researchers must address this need, and drug regulators, such as Health Canada, should routinely request high-quality RCTs.
This review indicates that the reported interactions with antidepressant drugs are relatively equally distributed with respect to clinical significance (about 25% each, major, moderate, and minor). The number of interactions reported for each individual antidepressant drug varies. This may be related more to how long the antidepressant has been available, to patient selection, or to diagnostic suspicion bias than to the likelihood that certain agents will be involved in drug interactions. The 4 most commonly prescribed antidepressant drugs in Canada (venlafaxine, citalopram, paroxetine and amitriptyline) (36), were involved in 141 (23.5%) of the interactions. It is important to recognize that the absence of a reported interaction is not proof that there has been no interaction but may simply reflect that many antidepressants have not been properly evaluated for potential interactions with other drugs. For example, the SSRIs and tricyclic antidepressants, particularly fluoxetine, amitriptyline, and imipramine, are prominent in the drug interaction literature. This may represent a true propensity for drug interactions or a longer lifespan of clinical use. The MAOI drugs phenelzine and tranylcypromine also figure prominently in drug interactions, particularly for reactions causing major clinical harm.
A significant proportion of the interactions (17%) involved 2 antidepressant drugs, which reflects the widespread use of combination therapy for depression. Almost one-half of these interactions were of major clinical significance, which supports the need for caution and close monitoring when using combination antidepressant therapy. Combinations including MAOIs in particular should be avoided. Various other nonantidepressant drugs were also involved in the interactions with antidepressants, which attests to the high prevalence of depression and concomitant medical and psychiatric illnesses (3).
Many of the reported interactions provided possible mechanisms for the interactions, most of which involved a pharmacokinetic alteration (that is, primarily metabolic inhibition or induction of CYP 450 enzymes). From pharmacokinetic studies, Health Canada and the Food and Drug Administration issued a warning about drug interactions involving trazodone and CYP 3A4-altering medications (37). Metabolic pathways for the antidepressant drugs have been studied (38). The SSRIs demonstrated potent inhibition of CYP 2D6 (that is, fluoxetine and paroxetine), 1A2 (that is, fluvoxamine), 2C19 (that is, fluoxetine and fluvoxamine), and 3A4 (that is, fluvoxamine). Nefazodone is a potent inhibitor of CYP 3A4. Some tricyclic antidepressants demonstrated potent inhibition of CYP 2D6. St John’s Wort is an inducer of p-glycoprotein and CYP 3A4. Many of the antidepressant drugs are also substrates of CYP 450 enzymes: SSRIs (that is, all CYP 2D6, citalopram, fluoxetine, sertraline 3A4, and fluvoxamine 1A2), bupropion (that is, 2B6, 2D6, and 3A4), mirtazapine (that is, 1A2, 2D6, and 3A4), nefazodone and trazodone (that is, 3A4 and 2D6), venlafaxine (that is, 2D6), and tricyclic antidepressants (that is, 2D6 plus other sites depending on the specific drug). These effects on the CYP 450 system may explain some of the reported interactions. They do not account for pharmacokinetic interactions with the absorption, distribution, and excretion phases or for pharmacodynamic interactions, the latter of which tended to result in more clinically significant outcomes. Publications with validated links between pharmacologic mechanisms and clinical outcomes of drug interactions are also virtually nonexistant.
Less than one-half of the interactions reporting SS actually met Sternbach’s criteria (19). It is difficult to make definite conclusions about the frequency of SS related to drug interactions because many reports are incomplete and of poor quality. The syndrome may also be misdiagnosed and underreported (39). Additionally, there was evidence of diagnostic confusion between SS and NMS. With the advent of newer antipsychotic agents with a broader mechanism of action, including action on serotonin receptors, clinical criteria for these reactions may need to be adapted.
Our criteria for rating interaction reports is subject to criticism because, aside from their use and publication in previous reviews (14,15,40), they have not been independently validated. In this review, we did not carry out a detailed assessment of the causality of each case report. Although it is helpful to further rate the cause and effect relation between drug coadministration and outcome, we have found that this additional grading tends only to lower the estimated quality of report summaries that were of low quality to begin with. It is possible that our method of summary obscured the interindividual variability of potential for interaction; however, this would be impossible to analyze without much larger sample sizes and well-defined predictors of interaction. That we did not access the non-English literature or every available psychiatric resource for drug interaction reports further limits this review. These factors, plus possible publication bias, are unlikely to have produced high-quality literature.
Despite numerous reports of antidepressant drug interactions, none of these interactions are from high-quality evidence. Given the frequent need for other medications in patients with depression, this is indeed disappointing to clinicians and patients. Further, the small number of patients (often only one) involved in any individual interaction summary does not inspire confidence in the validity of the conclusions.
Although the evidence is poor and largely generated more than 20 years ago, we recommend caution when administering MAOIs with other substances. The several reports of serious drug interactions with tryptophan, combined with limited evidence of efficacy and concern regarding its association with EMS, should proscribe its use (2,41–45). Our findings of some major interactions (such as seizure and death) between SSRIs and tricyclic antidepressants support recommendations from professional organizations, such as the Canadian Psychiatric Association, that encourage close monitoring when these 2 classes of drugs are combined or when patients take them alternately (3). Of the nonantidepressant drugs, benzodiazepines, narcotics, benztropine, antipsychotics, stimulants, and levodopa were the more common interacting drugs. This could be owing to common coadministration of these drugs with antidepressants. While it is desirable to produce a list of drugs that could be safely administered simultaneously with antidepressant drugs, we feel that the poor quality of the drug interaction literature does not currently allow for such assurances.
Funding and Support
This study received partial funding from Organon Canada (to support the work of C Nieuwstraten and S Harb). The authors had full control of the research plan, all primary data, and analyses. Dr Holbrook is a recipient of a Career Investigator award from the Canadian Institutes of Health Research. Dr Labiris holds a Father Sean O’Sullivan Research Centre career award.
The authors thank Sandra Harb and Colette Raymond who participated in data extraction.
Funding and Support
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Manuscript received May 2005, revised, and accepted January 2006.
1. Professional Practice Leader, Pharmacy Pharmacotherapy Specialist, Mental Health Program, St. Joseph’s Healthcare, Hamilton, Ontario.
2. Assistant Professor, Department of Medicine, McMaster University, Hamilton, Ontario.
3. Director, Division of Clinical Pharmacology, McMaster University, Hamilton, Ontario
Address for correspondence: Dr A Holbrook, c/o Centre for Evaluation of Medicines, 105 Main Street East, P1 Level, Hamilton, ON L8N 1G6
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