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Review Paper

Systematic Overview of Drug Interactions With Antidepressant Medications Carmine Nieuwstraten, RPh, BScPhm1, N Renee Labiris, PhD2, Anne Holbrook, MD, PharmD, MSc, FRCPC3 Objective: Antidepressants are commonly used drugs with potential for numerous drug interactions. This study aims to systematically review the literature on drug interactions with antidepressants. Methods: We searched MEDLINE (1966 to November 2003) and EMBASE (1980 to 2003), using the heading drug interactions combined with individual antidepressant names. We restricted searches to English-language articles and human studies. We screened drug interaction texts and review articles for relevant studies. We included articles reporting original human data on drug interactions with antidepressants commonly used in North America. Articles were independently evaluated by 2 reviewers on clinical effect, clinical significance, and quality of evidence. Discrepancies were resolved by consensus. Results: There were 904 eligible interactions, involving 9509 patients, for a total of 598 summary interactions. Of these, 439 (73%) demonstrated an interaction, 148 (25%) had no effect, and 11 (2%) had conflicting evidence. For 510 interactions (85%), the quality of evidence was poor. It was fair for 67 (11%) interactions and good for 10 (2%) interactions. There were no interactions with excellent quality of evidence. There were 145 (24%) interactions of major clinical significance. These were predominantly hypertensive emergencies and serotonin syndrome. Most interacting drugs had central nervous system (CNS) activity. As expected, monoamine oxidase inhibitors (MAOIs) appear to be the most problematic family in terms of potential for serious drug interactions. Conclusions: Drug interactions with antidepressants are an important cause for concern, but this concern is based primarily on poor evidence. We recommend caution when combining antidepressants with other CNS drugs, particularly when coadministering MAOIs with other substances. (Can J Psychiatry 2006;51:300–316) Information on funding and support and author affiliations appears at the end of the article. Clinical Implications · Physicians should be aware of proposed drug interactions with antidepressant medications, but they should also recognize that the supporting literature is generally of poor quality. · Other CNS-active drugs are most commonly reported to interact with antidepressants. · MAOIs seem to be associated with major drug interactions more often than other groups of antidepressants. Limitations · The literature is of such poor quality that it is difficult to make any high-quality recommendations about definite interactions or lack thereof. · Since drug interactions are not currently targeted outcomes in clinical trials and are frequently unrecognized by clinicians, drug interactions are likely underreported. Adverse events attributed to medications are often inadequately assessed for other potential causes. · The search was limited to English language reports and did not include all psychiatric resources potentially containing drug interaction reports.

Key Words: antidepressant medications, drug interactions, systematic review, case reports, causation, bias, quality of evidence. 300

W Can J Psychiatry, Vol 51, No 5, April 2006

Systematic Overview of Drug Interactions With Antidepressant Medications

epression 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).

D

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

Abbreviations used in this article CADRMP Canadian Adverse Drug Reaction Monitoring Program CNS

central nervous system

CPS

Compendium of Pharmaceuticals and Specialties

CYP 450 cytochrome P450 EMS

eosinophilia-myalgia syndrome

INR

international normalized ratio

IV

intravenous

MAOI

monoamine oxidase inhibitor

NMS

neuroleptic malignant syndrome

RCT

randomized controlled trial

SS

serotonin syndrome

SSRI

selective serotonin reuptake inhibitor

Can J Psychiatry, Vol 51, No 5, April 2006 W

relevance of reports of drug interactions involving antidepressants commonly used in North America (14–16).

Methods Literature Review 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). Clinical Effect 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 301

The Canadian Journal of Psychiatry—Review Paper

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.

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.

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.

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.

Clinical Significance 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 lifethreatening 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 302

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.

Results 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, f l u p h e n a z i n e , p i mo z i d e , b e n z t r o p i n e , l i t h i u m, methylphenidate, clonazepam, nitrazepam, ethanol, W Can J Psychiatry, Vol 51, No 5, April 2006


Table 1 Drug interactions for each antidepressant medication: clinical significance, clinical effect, and quality of evidence Clinical significance

Antidepressant

Clinical effect

Quality of evidence

Augmentation

Inhibition

No effect

Good

Fair

Poor

n

n

n

n

n

n

2

0

15

4

2

18

8

1

6

77

5

0

4

30

13

0

3

35

9

0

8

34

3

0

3

5

2

0

1

24

5

0

6

10

2

0

1

15

15

1

12

21

SSRI Citalopram

Major

1

0

1 (4)

1 (0)

Major

27

0

Moderate

28

3

12 (3)

1 (1)

1

0

Moderate Minor (nonclinical) Fluoxetine

Minor (nonclinical) Fluvoxamine

Major

8

0

5 (14)

0 (1)

Major

9

2

Moderate

12

0

0 (1)

0 (0)

9

0

Moderate Minor (nonclinical) Paroxetine

Minor (nonclinical) Sertraline

Major Moderate Minor (nonclinical)

12

1

2 (7)

0 (2)

0

0

NDRI Bupropion


2

0

(0)

2 (1)

8

0

SNRI Venlafaxine


13

0

0 (2)

0 (0)

1

1

NaSSA Mirtazapine


5

0

1 (1)

0 (2)

5

1

SARI Trazodone

Major

5

1

1 (1)

0 (0)

Major

6

0

Moderate

3

0

7 (2)

0 (1)

Moderate Minor (nonclinical) Nefazodone

Minor (nonclinical)

Continued


303


Table 1 continued Clinical significance

Clinical effect

Quality of evidence

Augmentation

Inhibition

No effect

Good

Fair

Poor

n

n

n

n

n

n

Major

31

0

7

0

2

50

Moderate

7

0 5

0

2

30

9

0

6

26

16

3

3

48

8

1

0

35

9

2

5

41

0

0

0

1

3

0

1

22

12

0

1

41

2

0

2

10

3

0

0

12

1

0

0

5

0

0

0

0

Antidepressant MAOI Phenelzine

Minor (nonclinical) Tranylcypromine

5 (0)

0 (0)

Major

21

0

Moderate

2

0

3 (0)

0 (0)

4

0

Minor (nonclinical) RIMA Moclobemide


4

0

10 (5)

0 (0)

14

0

TCA Amitriptyline

Major

6

1

4 (6)

0 (4)

Major

7

0

Moderate

8

0

Moderate Minor (nonclinical) Desipramine

1 (7)

3 (2)

Major

9

1

Moderate

7

0

7 (12)

0 (2)

0

0

Minor (nonclinical) Imipramine

Minor (nonclinical) Trimipramine


Clomipramine

Major

0

Major

5

0

Moderate

11

0

2 (7)

2 (2)

4

0

Major

2

1

1 (0)

0 (2)

Major

4

0

Moderate

2

0

Moderate Minor (nonclinical)

0 (3)

0 (0)

Major

1

0

Moderate

0

0

Minor (nonclinical) Protriptyline

Minor (nonclinical) Amoxapine

304

0

0 (1)

Minor (nonclinical)

Maprotiline

7 4

Minor (nonclinical)

Doxepin

0 0 (0)

3 (4)

Moderate Nortriptyline

0 0 (1)

2 (0)

0 (1)

Major

0

0

Moderate

0

0

Minor (nonclinical)

0

0



Table 1 continued Clinical significance

Clinical effect

Quality of evidence

Augmentation

Inhibition

No effect

Good

Fair

Poor

n

n

n

n

n

n

Major

7

0

1

0

0

9

Moderate

0

0

0 (0)

0 (0)

0

1

3

0

0

18

Antidepressant Other Tryptophan

Minor (nonclinical) St John’s wort


6

1

0 (0)

1 (6)

n = number of reports of interactions; NDRI = norepinephrine dopamine reuptake inhibitor; NaSSA = noradrenergic specific serotonergic antagonist; RIMA = reversible inhibitor of monoamine oxidase A; SARI = serotonin agonist–reuptake ihibitor; SNRI = serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant References available at www.thecem.net

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 in c lu d e d amitr ip tylin e – f lu p e n th ix o l, 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. Can J Psychiatry, Vol 51, No 5, April 2006 W

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 N M S . T h e in t e r a c t i o n b e t w e e n v e n l a f a x i n e an d trifluoperazine met the criteria for NMS (that is, rigidity, increased creatine kinase, increased temperature, fluctuating blood pressure, anxiety, and malaise). In the remaining 305


Table 2 Interactions with major significance in which an antidepressant was affected Affected antidepressant drug

Interacting druga

Reports (n)

Subjects (n)

Comments

Antiinfective agent (fluconazole) (46,47)

2

4P

Death and torsades de pointes (also taking sertraline)

Estrogen (48)

1

1P

Agitation

SSRI (fluoxetine) (49)

1

1P

Chronic amiptriptyline intoxication (death). Other reports show moderate, nonclinical, or no effect

Second-generation antipsychotic (olanzapine) (50)

1

1P

Seizures


1

1P

Seizure, tachycardia (also report of increased levels)

First-generation antipsychotics (chlorpromazine, haloperidol, thioridazine, trifluoperazine) (52–54)

4

NSAID (ibuprofen) (55)

1

1P

Seizure and ventricular tachycardia with large dosages of ibuprofen

Estrogen (48)

1

1P

Severe akathisia

Prednisone (56)

1

1P

Psychosis

TCA Amitriptyline

Clomipramine

Desipramine

Doxepin

Imipramine

Maprotiline

Seizures, ventricular tachycardia, and psychosis


1

1P

Seizure

Stimulant (methylphenidate) (58)

1

2P

Suicidal ideation, aggression, and violent attacks (other report showed hematological effects)

SSRI (fluoxetine) (57,59)

2

2P

Seizure and loss of consciousness (other reports of moderate, minor, nonclinical effects)

SSRI (paroxetine) (60)

1

1P

Death (other reports of increased levels)

MAOI (phenelzine) (61)

1

1P

Death (other reports of moderate effects)

Ritonavir (62)

1

1P

ICU admission, also taking fluconazole

Ethanol (63)

1

1P

Seizure

Anesthetic (propofol) (64)

1

1P

Seizure and intubation

Protriptyline


1

1P

Hallucinations

Fluoxetine

Anticholingeric agent (benztropine) (66)

1

3P

Delirium

Antiinfective agent (clarithromycin) (67)

1

1P

Delirium and psychosis

First-generation antipsychotic (haloperidol) (68)

1

1P

EPS requiring IV treatment

Narcotic (pentazocine) (69)

1

1P

Increased blood pressure

SSRI

Paroxetine

Sertraline

306

MAOI (phenelzine) (70)

1

1P

Death (other reports of moderate effects)

Tryptophan (71)

1

1P

Death (NMS when patient received one dose of thioridazine and then started tranylcypromine 10 hours after stopping fluoxetine). Other reports of moderate effects

Anticholinergic agent (benztropine) (66)

1

2P

Delirium

Benzodiazepine (clonazepam) (72)

1

1P

Increased heart rate and agitation

Serotonin antagonist (cyproheptadine) (73)

1

1P

Suicidal ideation and delusions

Interferon-alpha (74)

1

1P

Recurrence of severe depression

Antihypertensive agent (indapamide) (75)

1

1P

Erythema multiform

RIMA (moclobemide) (76)

1

1P

Death (other study showed no effect)



Table 2 continued Affected antidepressant drug

Interacting druga

Reports (n) Subjects (n)

Comments

MAOI Phenelzine

Chemotherapeutic agent (altretamine) (77)

1

1P

Syncope

Serotonin antagonist (cyproheptadine) (78)

1

1P

Psychosis

Stimulant (dextroamphetamine) (79)

1

1P

Death (cerebral hemorrhage)

Antiinfective agent (erythromycin) (80)

1

1P

Syncope (hypotension)

Parkinson’s disease agent (levodopa) (81)

1

1P

Hypertensive crisis

Lithium (82,83)

2

12P

Death (NMS) when patient also taking tryptophan

Benzodiazepine (nitrazepam) (84)

1

1P

Loss of consciousness

Tyramine (relevant foods) (85–87)

3

3P

Hypertensive crisis


1

1P

Death (other report of moderate effects)

TCA (imipramine) (61)

1

1P

Mental status change and tachycardia)

Tryptophan (88,89)

4

4P

Death (NMS when patient also taking lithium). Other reports of delirium, moderate effects

Parkinson’s disease agent (levodopa) (90)

1

4P

Hypertensive crisis

Tyramine (relevant foods) (91,92)

2

1P, 3V

Hypertensive crisis

Disulfiram (93)

1

1P

Delirium

Moclobemide

SSRI (sertraline) (76)

1

1P

Death

Trazodone

Interferon-alpha (74)

1

1P

Recurrence of severe depression


1

1P

Death (NMS when patient received one dose of thioridazine and then started tranylcypromine 10 hours after stopping fluoxetine). Other reports of moderate effects

MAOI (phenelzine) (88,89)

1

4P

Death (NMS when patient also taking lithium). Other reports of moderate effects

Tranylcypromine

RIMA

SARI

Tryptophan Tryptophan

EPS = extrapyramidal symptoms; ICU = intensive care unit; NSAID = nonsteroidal antiinflammatory drug; P = patient; V = healthy volunteer a

drug(s) in parentheses were those involved in the interaction

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.

Discussion 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 Can J Psychiatry, Vol 51, No 5, April 2006 W

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 307


Table 3 Interactions with major significance in which an antidepressant drug was the interacting drug Affected drug (other)

Interacting antidepressant druga

Reports (n)

Subjects (n)

Comments

Anesthetic agents Atracurium (94)

Tranylcypromine

1

1P

Hypertensive crisis

Droperidol (95)

Phenelzine

1

1P

Increased blood pressure

Enflurane (96)

Amitriptyline

1

2P

Seizures (myoclonus)

Propofol (64)

Maprotiline

1

1P

Seizures, intubation

SSRI (fluoxetine, paroxetine, sertraline)

4

7P

Delirium, urinary retention requiring catheterization

SSRI (paroxetine)

1

1P

Increased heart rate and agitation

Isoproterenol (99)

Amitriptyline

1

1P

Death (high dosages in asthmatic patients)

Clonidine (100)

Amitriptyline

1

1P

Hypertension on withdrawal

Clonidine (101)

Imipramine

1

1P

Hypertension

Clonidine (102)

NaSSA (mirtazapine)

1

1P

Hypertension

Indapamide (75)

Sertraline

1

1P

Erythema multiform

Anticholinergic agents Benztropine (66,97,98) Benzodiazepines Clonazepam (72) Cardiovascular agents

Propranolol (103)

Fluoxetine

1

1P

Heart block

Nifedipine (104)

Fluoxetine

1

1P

Palpitations and orthostasis

Tinzaparin (105)

Fluoxetine

1

1P

Peritoneal, parietal hematoma and poor renal function

Warfarin (106,107)

Fluoxetine

2

4P

Death, hematoma (other reports show moderate to no effects)

Amiodarone (108)

SARI (trazodone)

1

1P

Prolonged QT

Phenylephrine (109)

MAOI (tranylcypromine)

1

4V

Hypertension

Simvastatin (110,111)

SARI (nefazodone)

2

2P

Rhabdomyolysis

Simvastatin (112)

SSRI (citalopram)

1

1P

Rhabdomyolysis

Altretamine (77)

MAOI (phenelzine)

1

1P

Syncope

Irinotecan (112)

SSRI (citalopram)

1

1P

Rhabdomyolysis,when also taking simvastatin

TCA (amitriptyline)

1

3P

Euphoria

Fluphenazine (114)

SSRI (fluoxetine)

1

1P

Laryngeal dystonia

Haloperidol (68)

SSRI (fluoxetine)

1

1P

Severe EPS – required IV treatment

Pimozide (115)

SSRI (fluoxetine)

1

1P

Severe bradycardia

Clozapine (116)

SSRI (fluoxetine)

1

1P

Death (other reports show moderate or no effects)

Olanzapine (50)

TCA (clomipramine)

1

1P

Seizures

TCA (nortriptyline)

1

1P

Hypoglycemia

Chemotherapeutic agents

Ethanol Ethanol (113) First-generation antipsychotics

Second-generation antipsychotics

Hypoglycemic agents Chlorpropamide (117)

308



Table 3 continued Affected drug (other)

Interacting antidepressant druga

Reports (n)

Subjects (n)

Comments

Immunosuppressant agents Cyclosporine (118–120)

St John’s wort

3

48P

Transplant rejection

Cyclosporine (121)

SARI (nefazodone)

1

2P

Abdominal pain and dysuria (another report showed increased levels)

Prednisone (56)

TCA (doxepin)

1

1P

Psychosis

MAOI (phenelzine)

2

13P

Death (NMS) when patients also taking tryptophan

Propoxyphene (122)

MAOI (phenelzine)

1

1P

Hypotension requiring IV treatment (another report showed minor effects)

Meperidine (123–127)

MAOI (phenelzine, tranylcypromine)

5

6P

Death, seizures, coma, fever, and hypertension

Levodopa (128)

TCA (amitriptyline)

1

1P

Hypertension and rigidity

Levodopa (128)

TCA (imipramine)

1

1P

Hypertensive crisis (nonclinical effects in volunteer case series)

Levodopa (129)

NaSSA (mirtazapine)

1

1P

Psychosis, and suicide attempt

Levodopa (81)

MAOI (phenelzine)

1

1P

Hypertensive crisis

Selegiline (130)

SSRI (fluoxetine)

1

1P

Hypertensive crisis, and seizure. Other reports show moderate to no effect

SSRI (fluvoxamine)

2

2P

Seizure and coma (other reports of moderate effects)

MAOI (phenelzine)

1

1P

Organic hallucinosis

Dextroamphetamine (79,133)


2

2P

Death (cerebral hemorrhage) and coma (patient recovered)

Methylphenidate (58)

TCA (imipramine)

1

2P

Aggression, violence, and suicidal ideation (another report showed hematologic changes)


8

28P, 3V

Lithium Lithium (82,83) Narcotics (and derivatives)

Parkinson’s disease agent

Respiratory agent Theophylline (131,132) Serotonin antagonist Cyproheptadine (78) Stimulants

Tyramine (relevant foods) Tyramine (relevant foods) (73,85,86,91,134–137)

Hypertensive crisis (report of death)

a

Drug(s) in parentheses were those involved in the interaction

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 Can J Psychiatry, Vol 51, No 5, April 2006 W

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 309


Table 4 Other drugs involved in interactions with antidepressants Drug

n

Drug

Benzodiazepines

54

Chemotherapy

Alprazolam

9

Altretamine

Bromazepam

2

Chlordiazepoxide

3

Clonazepam

5

Drug

10

Antiinfective agents

19

8

Clarithromycin

1

Irinotecan

1

Erythromycin

2

Tamoxifen

1

Immunosuppressants

n

Fluconazole

2

Itraconazole

1

Clorazepate

1

10

Ketoconazole

2

Diazepam

12

Cyclosporine

7

Minocycline

1

Lorazepam

5

Tacrolimus

3

Nitrazepam

6

Oxazepam

6

Triazolam

5

Efavirenz Indinavir

1

Tetracycline

1

9

Ritonavir

4

Linezolid

1

Anesthesia agents

HIV therapy

Quinidine

3

Quinine

1

7

Rifampin

2

2

Terbinafin

2

Atracurium

1

Baclofen

1

Droperidol

1

Carbamazepine

20

Cholestyramine

2

Enflurane

1

Lamotrigine

1

Cimetidine

15

Anticonvulsants

38

Gastrointestinal agents

24

Propofol

3

Phenytoin

9

Metoclopramide

2

Ropivacaine

1

Valproate

8

Omeprazole

1

Thiopental

1

Ranitidine

3

Food or herbal

19

Tolterodine

1

71

Charcoal

1

Amiodarone

1

Food

1

Atenolol

2

Ginseng

2

Estrogen

6

Captopril

1

Grapefruit juice

4

Thyroid hormone

2

Cilazapril

1

MSG

2

Clonidine

5

Protein supplement

2

Cardiovascular

Hormones

Neuroleptics

8

65

Digoxin

8

Smoking

1

Chlorpromazine

Diltiazem

2

Tyramine

6

Clozapine

7

Epinephrine

4

Flupenthixol

2

Indapamide

2

29

Fluphenazine

2

Isoproterenol

4

Aspirin

1

Haloperidol

12

Labetolol

1

Ibuprofen

2

Methotrimeprazine

5

Methyldopa

1

Meperidine

10

Olanzapine

7

Metoprolol

3

Methadone

4

Perphenazine

6

Nadolol

1

Morphine

7

Pimozide

2

Nifedipine

2

Pentazocine

3

Risperidone

4

Propoxyphene

2

Thioridazine

5

Thiothixene

1

Norepinephrine Phenylephrine

310

n

Analgesics

4

Pindolol

2

Pravastatin

1

Stimulants Dextroamphetamine

Proprafenone

1

Ephedrine

5

Propranolol

4

Methylphenidate

3

Simvastatin

4

Phentermine

2

Verapamil

2

Pseuodephedrine

2

Warfarin

8

8

16

Trifluoperazine

3

4

Zuclopenthixol

1



Table 4 continued Drug

n

Drug

n

Drug

n

Sedative–hypnotics

24

Other CNS agents

56

Other

33

Amobarbital

3

Amantadine

4

Caffeine

3

Chloral hydrate

1

Benztropine

6

Dextromethorphan

7

Ethanol

16

Buspirone

4

Disulfiram

5

Pentobarbital

1

Cyproheptadine

4

Interferon-alpha

2

Phenobarbital

2

Donepezil

1

Loratidine

1

Zopiclone

1

Levodopa

6

Orlistat

1

Lithium

21

Prednisone

2

5

Selegiline

10

Sumatriptan

5

Theophylline

3

Sulfonylureas Chlorpropamide

1

Glyburide

2

Tinzaparin

1

Tolbutamide

2

Yohimbine

2

Zolmatriptan

1

n = number of reports of interactions

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, Can J Psychiatry, Vol 51, No 5, April 2006 W

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 311


Table 5 Interactions meeting criteria for SS Interacting drugs Amitriptyline and SSRI (sertraline)

Clinical significance

Comments

Major

Amitriptyline and SNRI (venlafaxine)

Major

Also taking fluconazole

Clomipramine and MAOI (tranylcypromine)

Major

Patient died

Clomipramine and RIMA (moclobemide)

Major

Desipramine and MAOI (tranylcypromine)

Major

Dextromethorphan and SSRI (paroxetine)

Major

Dextromethorphan and MAOI (phenelzine)

Major

Fluoxetine and lithium

Major

Fluoxetine and MAOI (tranylcypromine)

Major

Fluvoxamine and lithium Imipramine and MAOI (tranylcypromine)

Moderate Major

Coma

Lithium and MAOI (tranylcypromine)

Major

Also taking tryptophan

Lithium and tryptophan

Major

Meperidine and TCA (amitriptyline)

Major


Meperidine and SNRI (venlafaxine)

Major


Nefazodone and SARI (trazodone)

Major

Nortriptyline and SARI (trazodone)

Major

Nortriptyline and Parkinson’s disease agents (selegiline)

Major

Paroxetine and SARI (nefazodone)

Major

Phenelzine and SNRI (venlafaxine)

Major

Ritonavir and SSRI (fluoxetine)

Moderate

Sertraline and MAOI (tranylcypromine)

Moderate

Sertraline and MAOI (phenelzine) Tranylcypromine and SNRI (venlafaxine) Tranylcypromine and Tryptophan

Major Major

Treated in ICU

Conflicting Evidence

References available at www.thecem.net

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 312

(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 W Can J Psychiatry, Vol 51, No 5, April 2006


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.

Conclusion 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 Can J Psychiatry, Vol 51, No 5, April 2006 W

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. Acknowledgement The authors thank Sandra Harb and Colette Raymond who participated in data extraction.

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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, [email protected]

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Résumé : Aperçu systématique des interactions des médicaments avec les antidépresseurs Objectif : Les antidépresseurs sont des médicaments fréquemment employés qui ont un potentiel d’interaction avec de nombreux médicaments. Cette étude vise à examiner systématiquement la documentation sur les interactions des médicaments avec les antidépresseurs. Méthodes : Nous avons cherché dans MEDLINE (de 1966 à novembre 2003) et EMBASE (de 1980 à 2003) au moyen de l’en-tête interactions des médicaments combinés avec le nom individuel des antidépresseurs. Nous avons limité les recherches aux articles en anglais et aux études sur les humains. Nous avons extrait les études pertinentes des textes sur l’interaction des médicaments et des articles de synthèse. Nous avons inclus des articles rapportant des données humaines originales sur l’interaction des médicaments avec les antidépresseurs communément utilisés en Amérique du Nord. Les articles étaient évalués indépendamment, par 2 analystes, en ce qui concerne l’effet clinique, la signification clinique, et la qualité des données probantes. Les écarts ont été résolus par concertation. Résultats : Il y avait 904 interactions admissibles, pour quelque 9 509 patients, pour un total de 598 interactions sommaires. Sur celles-ci, 439 (73 %) démontraient une interaction, 148 (25 %) n’avaient aucun effet, et 11 (2 %) avaient des données probantes conflictuelles. Pour 510 interactions (85 %), la qualité des données probantes était faible. Elle était passable pour 67 (11 %) interactions et bonne pour 10 (2 %) interactions. Ces dernières étaient principalement des urgences hypertensives et des syndromes de sérotonine. La plupart des médicaments interactifs avaient une activité sur le système nerveux central (SNC). Comme prévu, les inhibiteurs de la monoamine oxydase (IMAO) semblent être la famille la plus problématique en ce qui concerne le potentiel d’interaction médicamenteuse sérieuse. Conclusions : Les interactions des médicaments avec les antidépresseurs sont une importante source de préoccupation, mais cette préoccupation se fonde principalement sur de faibles données probantes. Nous recommandons la prudence lorsqu’on combine les antidépresseurs avec d’autres médicaments agissant sur le SNC, en particulier, lorsqu’on co-administre des IMAO avec d’autres substances.

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