ABSTRACT

Drug-drug interactions (DDIs) are a concern for the prescriber because they have the potential for causing untoward outcomes for everyone involved: morbidity and even mortality for the patient, liability for the prescriber, and increased costs for the healthcare system. The risk of unintended and untoward DDIs is increasing in concert with both the increasing number of pharmaceuticals available and the number of patients on multiple medications. Based on the 2004 Health and Human Services report, 7% of Americans >18 years of age and >20% of Americans >65 years of age had taken ≥5 prescription medications in the week preceding the survey. Additional studies have found that patients on psychiatric medications, such as antidepressants, are on more medications than patients not on psychiatric medications. It is important for prescribers to appreciate that medications interact not on the basis of their therapeutic use but on the basis of their pharmacodynamics and pharmacokinetics. For these reasons, the prescriber of psychiatric medications must consider all of the medications the patient is taking. Similar to the 2004 version, this educational review emphasizes the role of pharmacologic principles to guide the safe and effective use of multiple medications when such use is necessary. The review focuses on neuropsychiatric medications but also covers all other drugs to the extent that they interact with psychiatric medications. This review also presents tables outlining major pharmacodynamic and pharmacokinetic mechanisms mediating DDIs relevant to the patient on psychiatric medications.

Introduction

Doctors pour drugs of which they know little, to cure diseases of which they know less, into patients of whom they know nothing.¹

— Voltaire

The true polypharmacy is the skillful combination of remedies.²

— Sir William Osler

A physician without physiology and chemistry flounders along in an aimless fashion, never able to gain any accurate conception of disease, practicing a sort of popgun pharmacy, hitting now the malady and again the patient, he himself not knowing which.²

— Sir William Osler

The above quotes by Voltaire¹ and Osler² illustrate two sides of the same coin. That is, the advantages and the disadvantages of polypharmacy and the need for knowledge and skill to guide the clinician when using more than one drug in combination. The authors hope that this educational review will aid the reader in acquiring some of the needed knowledge and skill to safely and effectively prescribe multiple medications to a patient when that is truly needed. Still, the basic approach advocated by the authors is to use the simplest drug regimen whenever possible and to always review a patient’s regimen to see if any current medication can be stopped when a new drug is being added. A common mistake is simply adding drugs without stopping others. For this reason, it is critical to always have a goal for every drug that is added. If the drug does not meet that goal, then either its dose should be adjusted or the drug should be stopped. One way to reduce unnecessary polypharmacy is declaring therapeutic failure and stopping medications which have not produced the desired therapeutic response within the expected timeframe.

What is meant by a drug-drug interaction?

A drug-drug interaction (DDI) occurs when the presence of a co-prescribed drug (the perpetrator) alters the nature, magnitude, or duration of the effect of a given dose of another drug (the victim).
 
“Altered nature” means that the effect produced when the two drugs are used together is qualitatively different than would be expected when either drug is used alone. An example is serotonin syndrome, which consists of marked autonomic instability and can be fatal. This syndrome can occur when a serotonin uptake pump inhibitor is used in combination with a monoamine oxidase inhibitor (MAOI).³

“Altered magnitude,” on the other hand, means that the nature of the effect is the same as can be reasonably expected from the victim drug alone but is either more than or less than what would normally be expected for the specific dose ingested.

“Altered duration” means that the nature of the effect is reasonably the same as can be expected from the victim drug alone, but the effect is either shorter or longer lived than would normally be expected for the dose given.

How do Drug-Drug Interactions present and how important are they?

Given this definition, it is easy to understand why DDIs can mimic virtually any clinical presentation imaginable from catastrophic to the every day problems seen in practice. That is why DDIs occur but may not be seen by the prescriber. What the prescriber may not “see” is the connection between the combined effects that drugs are causing and the clinical outcome he/she is observing. DDIs can present in all of the following ways:

1. A multitude of different types of  serious adverse events (SAEs), such as sudden death,^4-6 seizures,⁷ cardiac rhythm disturbances,^8,9 serotonin syndrome,¹⁰ malignant hypertension,¹¹ neuroleptic malignant syndrome,¹² and delirium^13,14

2. Poor tolerability (ie, patient is “sensitive” to adverse drug effect)^8,9,15-19

3. Lack of efficacy (ie, patient is “resistant” to beneficial drug effect)²⁰

4. Symptoms that mimic or lead to a misdiagnosis of a new disease^21-23

5. The apparent worsening of the disease being treated^15-17

6. Withdrawal symptoms or drug-seeking behavior on the part of the patient²⁴

Preskorn has written a series of real-life case reports illustrating the myriad ways that DDIs can present and can be misdiagnosed leading to untoward outcomes for the patient and the prescriber, to aid prescribers in recognizing DDIs when they occur and to understand their clinical significance by giving them case-based examples. The interested reader can access those case discussions for free at www.preskorn.com under the section, “Columns, Case Studies.”²⁵

Some have wondered about the clinical relevance of DDIs from a population as opposed to a specific patient perspective (ie, what percent of a population experiences a clinically significant DDI). An extensive discussion of this issue is beyond the scope of this article but a few comments are warranted:

The first comment involves an estimate of the percentage of the population at risk for a potential DDI. Pharmacoepidemiology surveys done in Denmark,^26-28 England,^29,30 Sweden,³¹ and the United States have all found multiple medication use to be extensive. Most patients were found to be on a unique combination of medications, meaning that no other person in the population studied was on exactly the same combination of medications. The populations studied in these surveys numbered in the thousands. Thus, a sizable percentage of the population, at least in industrial countries, is at risk for a DDI by virtue of being on multiple medications and, more importantly, unique combinations of medications.

The second is the issue of what constitutes clinical relevance, which has been discussed at length.^32,33 In essence, some might consider only catastrophic outcomes to be clinically significant. The authors take the position that any clinically significant change in the patient’s status due to a DDI makes that DDI clinically significant and any of the outcomes listed above from SAEs to withdrawal symptoms can be clinically significant. In terms of SAEs, in their pharmacoepidemiology study, Ray and colleagues³⁴ found that the mortality rate in patients on erythromycin was five times higher than matched controls on comparable antibiotics which were not substantial cytochrome P450 (CYP) 3A inhibitors. Another population study, by de Leon and colleagues,¹⁹ took poor tolerability leading to the discontinuation of the victim drug as the clinically significant outcome. The study found that the co-prescription of risperidone and a substantial CYP 2D6 inhibitor, such as fluoxetine, produced a >3-fold increase in the odds ratio for discontinuation of risperidone due to the development of acute extrapyramidal side effects (EPS) compared to individuals on a comparable dose of risperidone but not on a substantial CYP 2D6 inhibitor.

Of course, a DDI which causes noncompliance with prescribed antipsychotic treatment in a patient with schizophrenia can lead to a psychotic relapse with all of its associated potential untoward outcomes and yet the DDI may be missed and the noncompliance simply blamed on the patient. That is why not seeing is not the equivalent of not occurring. The reader who is interested in more about this topic is referred to the following references which address the topic of the clinical relevance of DDIs from a population perspective in greater detail.^32,33

Goal of this Educational Review

The goal of this educational review is to provide a quick reference for prescribers about some of the major psychiatric DDIs. In doing so, it presents general concepts that can aid prescribers in avoiding untoward DDIs when possible, and quickly recognizing them when they occur. The latter is important because the rapid recognition that an untoward clinical outcome is due to an adverse DDI can permit the rapid implementation of corrective steps to minimize the consequences. This educational review is not intended to be comprehensive or authoritative. Given the speed with which new drugs are entering the market and new discoveries about the mechanisms underlying DDIs are being made, the authors recognize that this article, like all printed material on this topic, will quickly become dated. The authors have addressed some of these limitations by providing the reader with a list of Web sites that are more comprehensive and continuously updated (Appendix). This article provides an introduction to the topic and serves as a gateway to ready sources of additional information via the Internet.

Both authors maintain Web sites relevant to DDIs. Dr. Flockhart’s Web site³⁵ summarizes data on CYP enzymes and the drugs they metabolize and outlines which drugs inhibit or induce CYP enzymes. This information can be used to predict and avoid DDIs mediated by this mechanism. Dr. Preskorn’s Web site²⁵ provides content on topics relevant to the safe and effective use of psychiatric medications. For example, under “Columns, Case Studies”, real-life examples of how DDIs present clinically and the mechanisms responsible for the DDI are presented.²⁵ The authors will refer to these and other Web sites as readily available resources for the reader who wants a more extended discussion of a topic or for those who want to check for updates even long after this article has been published.

Beyond the inevitability of all print material to become dated, this article has several other limitations, starting with the one imposed by its title:  Drugs do not interact on the basis of their therapeutic class (eg, “psychiatric” vs “cardiac” medications) but instead on the basis of their pharmacodynamics (ie, their action on the body) and their pharmacokinetics (ie, the actions of the body on them, including their absorption from the site of administration, their distribution in the body, their metabolism, and their elimination).³⁶ For this reason, the authors acknowledge the limitations inherent in focusing on therapeutic class—even one as broad as psychiatric or neuropsychiatric medications. In fact, the authors will reclassify the drugs principally covered in this article into other functional classes based on their pharmacodynamics and pharmacokinetics, such as CYP enzyme substrates, inducers, and inhibitors. The reason for taking this approach is that those are the mechanisms that underlie clinically significant DDIs. For this same reason, the authors will also address the effects of psychiatric on nonpsychiatric medications and vice versa, where appropriate.

With these caveats, this review will focus on neuropsychiatric medications. The article will review the scope of the problem and discuss strategies and approaches to avoiding untoward and unintended DDIs. Summary figures embedded in the text and tables at the end of the article will highlight major DDIs involving psychiatric medications.

Changes Since 2004

Our original article was published in early 2004,³⁷ which means it was written in 2003. Since 2003, 51 new drugs have entered the US market (Table 1). That translates into 17 new drugs a year or a new drug every 3 weeks. While 51 new drugs entered the US market since 2003, only four were formally classified as psychiatric medications: acamprosate (Campral) for alcohol dependence, duloxetine (Cymbalta) for major depression, eszopiclone (Lunesta) for insomnia, and rameltron (Rozerem) for sleep-onset insomnia. This educational review will be updated for all 51 drugs in keeping with the principles outlined above, but those classified as psychiatric medications will receive special attention in accordance with the title of this article.

Of these drugs, duloxetine is arguably the most important because it will likely have the greatest use by the most diverse groups of practitioners given its antidepressant indication. For that reason, Table 2 has been added to present the differential effects of available antidepressants on CYP enzymes.³⁸ As can be readily seen in Table 2, the newer antidepressants with the most effects on CYP enzymes are fluoxetine and fluvoxamine. These two antidepressants would likely not be approved today for this reason and should be used cautiously, if at all, in patients on >1 medication or patients who may go on >1 medication. In other words, their use should be severely curtailed because they pose a significant risk of being a perpetrator of a clinically significant DDI. Bupropion, nefazodone, and paroxetine do not affect as many CYP enzymes as fluoxetine and fluvoxamine but nevertheless at usual clinical doses produce substantial inhibition of one CYP enzyme:  CYP 2D6 in the case of bupropion and paroxetine and CYP 3A3/4 in the case of nefazodone. Hence, the careful use of these antidepressants in combination with other drugs is also warranted and prudent. The reason for this admonition is that there are multiple antidepressants as seen in Table 2 that do not substantially inhibit any CYP enzyme at their usual antidepressant dose: citalopram, escitalopram, mirtazapine, sertraline, and venlafaxine. This caveat is particularly true for fluoxetine, fluvoxamine, and paroxetine because their pharmacology beyond CYP enzyme inhibition is so similar to that of citalopram, escitalopram and sertraline. The practitioner can thus use this table to help decide which antidepressant he/she wants as their preferred antidepressant in their personal formulary as discussed below.

 
While duloxetine is the most important for the reasons outlined above, all of the following deserve special mention in terms of CYP enzyme-mediated DDIs:

 

Returning to Table 1, a close examination reveals the forces that are at work in modern drug development and which have implications for the future of clinical psychopharmacology: Most of the drugs in that table are for relatively uncommon diseases but nevertheless diseases for which there is basic knowledge about their pathogenesis or pathophysiology. In contrast to this situation, virtually all psychiatric illnesses are still understood almost exclusively at the syndromic level of diagnostic sophistication.⁵⁰ As information about the pathogenetic and pathophysiologic mechanism underlying different psychiatric illnesses becomes available, the reader can expect that the number of psychiatric medications entering the market place will explode. They will be better targeted to specific disease processes and will likely occur concomitant with the division of current syndromic diagnoses into multiple different diagnoses based on pathophysiology or pathogenesis. Nevertheless, this anticipated explosion of psychiatric medications will undoubtedly increase the frequency and complexity of polypharmacy and thus further heighten the potential for DDIs and the need for prescribers to be knowledgeable about this issue for years to come.

Polypharmacy: The Real Landscape of Clinical Prescribing

The prescriber does not have to wait for the explosion of psychiatric medicines to feel somewhat overwhelmed. One such explosion already occurred following the introduction of fluoxetine in 1988.⁵¹ While that explosion was a blessing in many ways, it nevertheless has posed serious challenges for practitioners trying to keep abreast of new developments. The prescriber has more therapeutic options, each with different pharmacodynamics and pharmacokinetics, to understand and weigh.

In addition, treatment over the last several decades has moved from a focus on time-limited therapy (ie, a few weeks) of an acute illness (eg, antibiotics for an acute infection) to preventive or maintenance therapy for chronic illnesses as diverse as major depressive disorder (MDD), schizophrenia, Alzheimer’s disease, hypertension, human immunodeficiency virus infection, and atherosclerosis. For this reason, patients are much more likely to be on more than one medication at the same time.^52-55 In fact, they are likely to accumulate preventive therapy as they age. These therapies can often continue for many months or years, to perhaps the entire remaining life span of the individual once started. For this reason, the potential for DDIs increases over the life span of the individual.

As would be expected given the above, age is repeatedly found to be a risk factor for polypharmacy in pharmacoepidemiology studies as illustrated in Table 3.^56-58 However, some readers may be surprised to learn that being on a psychiatric medication is a greater risk factor for polypharmacy than is advanced age (Table 3). As is also seen in Table 3, the percentage of the different populations on a unique combination increases in direct relationship to the average number of drugs used to treat that specific population. Finally, one study found that the percentage of the population on ≥8 medications doubled as a function of the number of different prescribers the patient saw.^56,57 The fact that patients on antidepressants, for example, are on more multiple medications than patients not on these medications holds true regardless of whether they are being seen by a psychiatrist or another type of healthcare provider (Table 4).^59,60

 

There are undoubtedly numerous reasons why psychiatric medications, such as antidepressants, mark a population at risk for polypharmacy. First, psychiatric illnesses such as MDD have an increased frequency in patients with other medical illnesses (Figure 1).^61-64 Second, patients with one psychiatric illness are at increased risk for other psychiatric disorders.⁶⁵ Third, patients with depressive and anxiety disorders are high utilizers of healthcare services and thus may be treated symptomatically with other medications.^63,66-71 Regardless of the reason, the prescriber should be aware of this fact and take it into account when developing the treatment plan for their patient.

 

 

 

 

 

 

 

 

 

The use of multiple psychiatric medications has increased over the last 2 decades, probably reflecting both the increased availability of effective medications and the fact that they have a more focused or limited pharmacology. The latter leads to better tolerability but may also limit efficacy and, thus, require the use of more medications to optimize patient outcomes.

These factors may explain at least in part why the use of multiple psychiatric medications to treat patients is on the rise. For example, there has been a 15-fold increase in percentage of patients on three or more psychiatric medications being seen at the Biological Psychiatry Branch of the National Institute of Mental Health from the early 1970s to the mid-1990s (Figure 2).⁷²

 

 

 

 

 

 

 

 

 

For all of the above reasons, patients on psychiatric medications are at risk for DDIs, and these DDIs are likely to involve more than just two drugs. Thus, the problem may not just be the effect of drug A on drug B but this effect in the presence of drugs C, D,  and E.

To underscore the complexity of such DDIs, consider the following questions, which help to illustrate the size of the problem:

1. In 2006, how many discrete chemical entities could a physician prescribe for his/her patient?

2. Given that number of drugs, how many different combinations of up to five drugs, could the physician prescribe for his/her patient?

3. The first new drug approved in 2006 could be prescribed in how many different combinations (up to 5 drugs), given the number of drugs already on the market when that new drug is introduced?

4. On average, how many new drugs have been introduced to the US market every year over the last 3 years?

The answers are:

1. >3,200 different drugs

2. 2.8 X 1,015

3. 4.4 trillion

4. 17 every 3 weeks (ie, 51 divided by 3 years or 156 weeks).

Drug Interactions and Medication Errors

Given the above numbers, DDIs are, not surprisingly, a serious cause of concern for the US healthcare system. They are so numerous that the dictum to “do no harm” is seriously challenged. As illustrated by the answers above, this situation is in part due to the large number of new prescription drugs available to prescribers. For medical students who graduated from medical school in 2001, 115 new prescription drugs had been approved by the Food and Drug Administration during the time they were in medical school.⁷³ In contrast, students graduating in 1973 had to contend with only 57 new drugs being approved during their 4 years of medical school.⁷³ The number of drugs available over the counter (OTC) has also increased.

The potential number of DDIs has increased to the point where prescribers universally find it impossible to remember all conceivable interactions and are forced to rely on electronic media. To put their implications in perspective, consider that from 7,000 to as many as 98,000 deaths every year are caused by adverse drug events, mainly due to DDIs. That represents more deaths caused by DDIs than those caused by smoke inhalation or airplane accidents combined. While the US has generated elaborate, nationwide safety control systems to prevent deaths due to airplane accidents, nothing approaching such an effort has been done to prevent deaths due to DDIs.⁷⁴
 
In much the same way as it is important to develop some understanding of why fires occur and the characteristics of fatal airplane accidents, the importance to the public health of a mechanistic understanding of adverse drug events, and of a system to prevent them, cannot be over-emphasized. DDIs not only cause serious and even fatal adverse events but they have also been a significant contributor to the withdrawal of a number of otherwise safe and effective medicines from the US market over the last decade, including: terfenadine, cisapride, astemizole, mibefradil, and, most recently, cerivastatin.⁷⁵ The financial impact of such withdrawals on the manufacturers of these drugs conservatively involves
billions of dollars.⁷⁶

In addition, the prescriber’s task is made even more difficult as a result of the growing number of significant interactions that result from co-medication with herbal nutritional supplements, a market on which the US public spends more than they do on prescription medicines.⁷⁷ Finally, the US population is aging and the adverse events experienced by the elderly are markedly increased in those on ≥4 medications.⁷⁸

The convergence of these multiple complicating influences makes clear that the simple medication history that all physicians are taught to take, consisting of the question “What medications do you take and do you have any allergies to drugs?” has not evolved to accommodate the complexity of these concerns. Therefore, the authors have proposed a more detailed series of questions using the acronym AVOID (Table 5). The authors will attempt herein to describe the principal mechanisms by which important DDIs with neuropsychiatric drugs occur, and to list those that are most likely to occur and result in clinically significant changes in drug activity.

Strategies to Minimize Adverse Outcomes From Unintended Drug-Drug Interactions

A Personal Formulary: Concept and Criteria

While all physicians are taught pharmacology in medical school, many, if not most, of the drugs that the average prescriber uses were not available during their training. For this reason, the value of a personal formulary in an era of polypharmacy and pervasive and potent marketing cannot be overemphasized. Rational prescribing in an era when so many drugs are available is close to impossible without it. Such a formulary should consist of the drugs that are used virtually every day in the clinician’s practice and that he/she is intimately familiar with. Inevitably, this list cannot be that large. The number of drugs in a personal formulary will vary, but a reasonable number is 10–15 drugs for a practicing psychiatrist, family practitioner, or internist.

The physician should truly be an expert on these medications that he or she commonly uses. That includes their generic and brand names, pharmacokinetics, pharmacodynamics, adverse effects, and potential DDIs. A high level of knowledge about a few drugs insulates the physician against trivial advertising and protects one’s patients from prescribing errors. The essential elements of knowledge that the physicians should know about each drug in their personal formulary is listed in Table 6.

 
It should not be easy for a drug to enter a personal formulary. Diligent study of the drugs in question, careful evaluation of the literature pertaining to them, and ongoing checks of new developments should be a routine habit for the prescriber. If nothing else, these criteria allow the prescriber a means of focusing his or her attention within the sea of the medical literature. Thus, physicians become real experts in the use of a small number of drugs important to their practice.

In the 21st century, it is not enough to be an excellent diagnostician familiar with the use of laboratory and procedural testing: being expert in treatment is also required, and that requires an intimate knowledge not of all drugs available, but of 10–15 that a particular prescriber commonly uses. This foundation of knowledge can then serve as a basis for the evaluation of new drugs as they appear.

Generic Names
At a minimum, a prescriber should be aware of the generic name of a medication on their personal formulary, without which it is impossible to search the medical literature on it or to recognize it on a board exam. As medicine becomes more international and the world becomes smaller, the physician must be aware that medications have different brand names in different countries, and frequently have multiple brand names (Table 7).⁷⁹

For example, there are 18 different brand names for fluoxetine in Italy. 
The use of the generic name in prescriptions allows cheaper generic drugs to be used when they are available. Despite claims to the contrary, there are only a small number of examples where an approved generic is not an effective substitute for the brand name drug.

Lastly, persistent confusion over the similarity of drug names, either written or spoken, accounts for approximately 25% of all reports to the US Pharmacopeia Medication Errors Reporting Program, and the case for the use of both a generic name and brand name in legible handwriting on prescriptions is strong. For example, confusion has been reported between the antidepressant nefazodone (Serzone) and the antipsychotic quetiapine (Seroquel), both of which are available as 100 mg and 200 mg tablets. Also, the brand name of the antidepressant paroxetine (Paxil) has been confused with the brand name of the anti-platelet agent clopidogrel (Plavix).

To illustrate the above, a list of generic names of the most commonly used antidepressants in the US and their brand names is included in Table 8.⁸⁰ Although many have made the case that a switch to e-prescribing may obviate this problem, incorrect selection of a drug name from a computerized list has already been shown to be a significant problem; thus, there is one more argument making the case for routinely using both the generic and the brand names as a means of ensuring quality in prescribing.

Pharmacokinetics
Prescribers should be aware of the routinely used doses and the serum half-life of the drugs they frequently use. In the case of psychiatric drugs, they should also be aware of its mechanism(s) of action and binding profile for relevant specific receptors (Tables 8–11).^{5,47,51-55,80} This basic information can guide prescribing in a number of valuable ways, particularly by making prescribers aware of the potential pharmacodynamically mediated DDIs and their likely clinical outcomes for the patient.

The Therapeutic Alliance

A therapeutic alliance is a group of people who communicate with each other about an individual patient’s therapeutic plan and medications. Even the highest quality of prescribing cannot work if the patient is noncompliant, but patients, particularly those with brain diseases, often need help in maintaining adherence with what can be a demanding medication schedule. To this end, a therapeutic alliance involving the patient and the people around them is nearly always valuable. Family members should often be part of the therapeutic alliance, as well as the pharmacist, nurse practitioner, home health visitors, and friends (when appropriate). A system of prescribing, in which members of the therapeutic alliance are identified early in a patient’s therapeutic plan and then involved in the follow-up, is as important as the valuable practice of routine checks by telephone or e-mail within a few days after a drug is prescribed.

Establishment of a Therapeutic Goal

Any prescription should have a clear therapeutic goal. It might be reducing a serum low-density lipoprotein or blood pressure or relieving depression; regardless of the goal, a clear time expectation should be attached to it. For example, in the “Plan” section of a medical chart, an appropriate entry would be: “Reduction of depressive symptoms by 50% within 3–4 weeks.” The setting of such goals is important because it allows the iterative optimization of therapy: If the goal is not achieved, then it is reasonable to have a conversation with the patient about compliance and side effects and to consider dose adjustment. The same applies to the treatment of psychiatric disorders other than depressive disorders, as well as nonpsychiatric medical illness. Therapeutic goals should be clearly delineated in charts and communicated to patients and the care providers that are involved with each patient.

Conceptual Framework for Prescribing in an Era of Polypharmacy

Principles of Pharmacology

As mentioned at the beginning of this article, a DDI occurs when the presence of a co-prescribed drug (the perpetrator) alters the nature, magnitude, or duration of the effect of a given dose of another drug (the victim). Given this definition, DDIs can obviously be therapeutic or adverse, intended or unintended, but they are always determined by the pharmacodynamics and pharmacokinetics of the co-prescribed drugs. Parenthetically, the prescriber wittingly or unwittingly is counting on a therapeutic DDI whenever they use one drug to treat an adverse effect or to boost the therapeutic benefit of another drug.⁸¹ The focus of this article, however, is to minimize the risk of unintended and untoward DDIs and therefore will not consider therapeutic DDIs. Given the above definition of a DDI, the following two equations are essential to understanding and avoiding DDIs:


Equation 1 presents the three variables that determine the effect a drug will produce in a patient. First, the drug must work on a site of action (the first variable in Equation 1) which is capable of producing the effect observed. For all drugs, except anti-infectives, the site of action is a human regulatory protein such as a receptor, an enzyme, or an uptake pump. By binding to its target(s), the drug is capable of altering the functional status of the target(s) and thus altering human physiology. The ability of the drug to bind to the regulatory protein gives it its potential action (ie, its pharmacodynamics).

 

 

 

 

 

 

For the drug to express its potential action, it must reach the target to a sufficient degree to engage it to a physiologically relevant extent. That is the domain of the second variable in Equation 1. Drug concentration in relation to the drug’s binding-affinity profile determines what site of action the drug will bind to and to what degree. At low concentrations, the drug will bind to its most potent target. As the concentration increases, the drug will bind more substantially to that target until it is saturated. It will also begin binding to lower affinity targets when its concentration reaches a sufficiently high degree relative to its binding affinity for secondary targets.^82,83

Equation 2 illustrates that drug concentration is a function of the dosing rate the patient is taking relative to their ability to clear the drug. This equation explains why clearance is as important as dose in determining the nature, the magnitude, and the duration of a drug’s effect on the patient.

Clinical trials are, in essence, population pharmacokinetic studies in which the goal is to determine the usual dose needed for the usual participant (ie, usual clearance) enrolled in the clinical trial to achieve a concentration sufficient to engage the desired target sufficiently to produce the best balance between efficacy and safety/tolerability. Thus, the second variable in Equation 1 is the drug’s pharmacokinetics (or drug movement), which has four phases summarized by the acronym ADME: Absorption of the drug from the site of administration into the body, Distribution of the drug to the various compartments of the body (eg, plasma, termed the “central compartment,” and tissues, or “deeper compartments” such as the brain), Metabolism or biotransformation into more polar substances, and finally, Elimination from the body.³⁶

The last variable in Equation 1 is the interindividual differences among patients, which can shift the dose-response curve making patients either more or less sensitive to the effect of the drug. These differences (ie, biological variance among patients) are summarized by the acronym GADE: Genetics, Age, Disease, and Environment. The environment variable refers to the internal environment of the body, which includes other drugs or dietary substances the patient may be taking. These four variables modify the first two variables and, thus, explain how the magnitude, duration, or even the nature of the effect of the drug in a specific patient may differ from the usual effect produced by a given dose of the same drug. Thus, DDIs occur when one drug (the perpetrator) changes the effect of a given dose of another drug (the victim) by either interacting with it pharmacodynamically or pharmacokinetically (ie, the first and second variables in Equation 1). This concept is the essential principle underlying DDIs and the basis for the rest of this article.⁵⁹

Can Polypharmacy in Psychiatry Be Rational?

For polypharmacy to be rational, the prescriber in any area of medicine must be able to answer the following questions:

1. Why am I using more than one drug?
2. Do the drugs interact?
3. If so, what are the data that support the safety, tolerability, and efficacy of the combination?

Table 13 lists five major reasons why a prescriber may use more than one drug to treat a patient.^59,81 The first reason is the most obvious: The patient has more than one disease process and the prescriber must employ one or more agents for each disease. In this example, the prescriber is not planning a DDI, though one may occur because drugs interact on the basis of the mechanisms underlying their pharmacodynamics and pharmacokinetics rather than on the basis of their therapeutic indication. For this reason, the prescriber of psychiatric medications must be aware of and consider all of the medications the patient is taking.

The second reason listed in Table 12 is particularly relevant to psychiatry.^59,81 Conditions such as bipolar and schizoaffective disorder are complex symptom clusters that wax and wane over the course of the illness. Patients with these illnesses may need different medications for different phases of their illness. While mood stabilizers (eg, lithium) are usually the foundation for the treatment of a patient with bipolar disorder, the patient may at different phases of the illness need to have antidepressants, antipsychotics, or anxiolytics added and may even need treatment with >1 mood stabilizer. This situation is similar to that of epileptic patients. Many of these patients need to be on >1 anticonvulsant to achieve optimal control of their seizures.^84,85

The remaining reasons listed in Table 12 are all based on planned therapeutic DDIs, whether or not the prescriber thinks in these terms.^59,81 When a second drug diminishes, amplifies, or speeds the onset of the effect of a first drug, that is, by definition, a DDI. When using a drug for these purposes, the ideal situation would be one in which the pathophysiology of the illness and the effects of each drug on that pathophysiology are all clearly understood. An example is Parkinson’s disease, as outlined in Table 13.^59,81

The problem in psychiatry is that the pathophysiology of psychiatric illnesses is not well understood and, thus, the effects of the drugs on that pathophysiology cannot be well understood. Nevertheless, Table 14 lists a series of features that can be used to rationally prescribe two or more psychiatric medications together to accomplish the last three goals listed in Table 12.^25,59,81

Beyond Psychiatric Drugs: the Total Therapeutic Regimen

The prescriber of psychiatric medications cannot simply focus on those medications but must examine all of the medications the patient is taking, including OTC medications, illicit substances, herbal products, and even dietary substances. For example, ibuprofen, an OTC analgesic, can cause serious and even life-threatening elevations in lithium levels by affecting its rate of tubular re-absorption.⁸⁶ The duration of the effect of illicit substances can be prolonged by co-prescribed drugs, which inhibit the enzymes responsible for clearing the illicit substance. St. John’s Wort is a substantial inducer of CYP 3A and can accelerate the clearance of a number of co-prescribed medications.⁸⁷ Smoking can induce the metabolism of drugs such as clozapine, which are normally cleared by smoking-inducible CYP 1A2.⁴⁵ Thus, the prescriber must take the whole patient into consideration when trying to understand and/or predict the effect of a treatment regimen involving more than one medication.

Special Considerations for How DDIs Present in Psychiatry

The term “drug-drug interaction” frequently conjures images of a sudden catastrophic and even fatal outcome. While such an event can occur and is obviously important to prevent, DDIs can present as virtually anything, including the worsening of the illness being treated or the emergence of a new illness. For this reason, such “masked” DDIs can ironically lead to the use of more medications to treat the apparent worsening of the primary condition or to treat the apparent emergence of a new condition.

All drugs, except anti-infectives, are given to change human physiology.⁸⁸ Those changes can present in every way clinically imaginable. For this reason, the prescriber should keep in mind that the patient may not be doing well because of the medications he is receiving rather than despite the medications he is receiving.⁵⁹

Understanding and identifying DDIs with psychiatric medications is perhaps more challenging than in any other area of medicine. The reason is the complexity of the organ they affect and the complexity of its output (Table 15).⁸⁹ The average human adult is composed of approximately 10–20 billion cells arranged in hierarchal and integrated systems. Seventy-five neurotransmitters have been identified in the human brain. That number may double in the next 10 years as a result of discoveries made possible by the human genome project. Every identified neurotransmitter has 2–17 receptor subtypes. Thus, the human brain may contain thousands of receptors, which are the primary targets of drug action. There are also different enzymes for the synthesis and degradation of these neurotransmitters, different uptake pumps, and storage mechanisms. All of these regulatory proteins can be the target for drug action. Thus, current drugs may interact pharmacodynamically in ways that are neither understood nor predictable at the present time.⁵⁹ Their detection is dependent on the careful assessment at the time of a medication check by the prescriber.

As psychiatric drugs are more rationally developed to affect only the brain, their adverse effects will not be on peripheral systems but on the brain. The result of psychiatric DDIs can present as changes in mentation, reality testing, emotional control, interpersonal relationships, and memory function. The prescriber of psychiatric medications must be a good behavioral pharmacologist, as well as a good diagnostician, and must also keep in mind that changes in these outputs of the human brain may be because of the medications that the patient is receiving rather than in spite of them. This discussion further emphasizes the limitations of this article and of all information systems in clinical psychopharmacology. There is much more that needs to be known. In the interim, the goal of this article is to summarize what is known, to explain the limits of current knowledge, and to define good clinical practices as they relate to avoiding untoward DDIs.

Proper Use of Therapeutic Drug Monitoring

Equation 1 illustrates that drug concentration determines what site(s) of action are engaged and to what degree, while Equation 2 illustrates that drug concentration is the dosing rate divided by the clearance. By rearranging Equation 2, it is clear that:

If the prescriber is confident in the dosing rate (ie, noncompliance is not an issue), then measuring the drug concentration allows the prescriber to assess the patient’s clearance to determine whether it is usual or unusually fast or slow. For example, if the clearance is faster or slower than usual, then the dosing rate must be changed proportionately to reach the usual drug concentration achieved on the usually effective dose; the usual site(s) of action is engaged to the usual degree associated with optimal response as determined by the registration trials that led to the marketing of the drug. Thus, the goal of therapeutic drug monitoring (TDM) is not to simply know whether the concentration is therapeutic but to know whether the patient’s ability to clear the drug is usual or not. If not, the results of TDM can provide a rational basis for determining what sort of an adjustment in the dosing rate must be made to compensate for the patient’s unusual clearance.

This issue is of critical importance when understanding and avoiding untoward effects mediated by the co-prescription of a drug capable of either inducing or inhibiting the enzymes responsible for the clearance of the victim drug. Induction can increase the clearance of the victim drug such that its levels fall below what is usually therapeutic, resulting in either loss of efficacy or withdrawal symptoms.⁹⁰ Inhibition can decrease the clearance of the victim drug such that its levels rise, causing consequences, which may range from an increase in the frequency and severity of dose-dependent adverse effects, such as EPS in the case of conventional antipsychotics to life-threatening toxicity in the case of tricyclic antidepressants (TCAs).

The logic underlying pharmacokinetic interactions mediated by the induction or inhibition of CYP enzymes is outlined in Figure 3.^59,79 This logic forms the basis for the section on CYP enzyme-mediated DDIs with psychiatric medications.

 

 

 

 

 

 

 

 

 

Time Course of Interactions

Drugs have the potential to interact as long as they and/or their effects persist in the body. Thus, the potential for an interaction may persist for days to weeks and even months after one of the drugs has been discontinued.

This fact is illustrated in Figure 4 from a study examining the effect of fluoxetine on the metabolism of the CYP 2D6 model substrate desipramine.⁹¹ In this study, genotypically normal metabolizers via CYP 2D6 (>95% of the population) were first treated with desipramine 50 mg/day for 7 days to achieve steady-state conditions. On day 8, fluoxetine 20 mg/day was added to their regimen. Without changing the dose of desipramine, its levels increased >4-fold over the next 3 weeks as fluoxetine and its active metabolite, norfluoxetine, accumulated, resulting in the inhibition of CYP 2D6. The inhibition of CYP 2D6 resulted in a reduction in the clearance of desipramine (Equation 2) and hence an increase in desipramine levels without a change in its dose.

 

 

 

 

 

 

 

 

 

 

 

 

On day 28, fluoxetine was discontinued but desipramine was continued at the same dose. Over the next 3 weeks, the desipramine levels fell as fluoxetine and norfluoxetine cleared from the body and CYP 2D6 inhibition was reversed, leading to an increase in desipramine clearance. Nevertheless, desipramine levels even 3 weeks after fluoxetine was discontinued were still double what they were before fluoxetine was added, because norfluoxetine was still present in the body and still inhibiting CYP 2D6-mediated clearance. This time course is consistent with the fact that the half-lives of fluoxetine and norfluoxetine in young healthy individuals (such as those in this study) are 2–4 days and 7–15 days, respectively. Of note, the average half-life of norfluoxetine in healthy individuals >65 years of age is 3 weeks; it takes an average of 4 months to reach steady-state once the drug is started in healthy older individuals and 4 months to completely clear once the drug is discontinued.⁹²

While the study that provided the results in Figure 4 was about the effect of fluoxetine on CYP 2D6,⁹¹ it graphically illustrates the point that the effect of a co-prescribed perpetrator drug (eg, fluoxetine) on the response to the victim drug (eg, desipramine) can continue to increase for weeks after the perpetrator has been started and can persist for weeks after the perpetrator has been stopped. Sometimes that is because the perpetrator has a long residual time in the body, as in the case of fluoxetine, and sometimes it is because the perpetrator’s effect persists long after it has been cleared. An example of the latter would be the classic MAOIs, which cause irreversible inhibition of that enzyme; synthesis of new enzyme is, therefore, required to restore usual levels of activity once the classic MAOI has been stopped.^92,93 Thus, prescribers should wait >2 weeks after stopping an irreversible MAOI before starting a norepinephrine and serotonin agonist to minimize the risk of a hypertensive crisis or a serotonin syndrome, respectively. In a similar way, enzyme inducers have their induction effect immediately, though the time course for the maximum effect on increased clearance is not achieved until a new steady-state level of enzyme has been produced as a result of increased protein synthesis. For the same reason, the increased clearance persists for several weeks after the enzyme inducer has been stopped. These delayed onsets and offsets are not simply limited to pharmacokinetic interactions as witnessed by MAO inhibition (which is a pharmacodynamic interaction) but can be applied to all interactions in which the effect of the perpetrator persists for a sustained period after the perpetrator has been discontinued (eg, receptor supersensitivity or subsensitivity).

How to Avoid Drug-Drug Interactions

Table 16 summarizes the major principles relevant for minimizing the risk of DDIs. Next, the major tables for summarizing knowledge relevant to avoiding pharmacodynamic and pharmacokinetic DDIs are provided.

Pharmacodynamic DDIs

Drugs are approved and generally considered from the perspective of their therapeutic use; however, they interact on the basis of their pharmacodynamics and pharmacokinetics. They also are frequently used for reasons other than their initial labeled indication. For example, most selective serotonin reuptake inhibitors were initially approved as antidepressants, but several have subsequently gained approved labeling for the treatment of a variety of anxiety disorders. In a similar way, a number of atypical antipsychotics have gained an approved indication for use in bipolar disorders. In recognition of these facts, the tables in this article outlining DDIs will consider these drugs in terms of their pharmacodynamics and pharmacokinetics rather than in terms of their labeled therapeutic indication.

Table 17 lists the neuropsychiatric medications to be covered in this article by their principal mechanism of action. Table 18 enumerates the pharmacodynamically mediated DDIs that can occur for each mechanism of action listed in Table 17. Using these tables together, the reader can determine the potential DDIs that can occur when any drug in Table 17 is used with another drug having a mechanism of action that can interact with its mechanism of action.^80,94

A number of neuropsychiatric medications including tertiary amine TCAs and atypical antipsychotics affect more than one mechanism of action under clinically relevant dosing conditions. For this reason, Tables 9–11 were developed to show the relative effect of the most commonly used neuropsychiatric medications with multiple mechanisms of action.^95-98 In these tables, the most potent binding site of the drug was assigned the value of 1 and its relative binding affinity for other targets was expressed as its binding affinity for that target divided by its binding affinity for its most potent target. The resulting ratio reflects the increase in concentration needed for the drug to affect its less potent targets in relationship to its most potent target. For example, quetiapine binds most avidly to the α₁-adrenergic reaaceptor and binds almost as avidly to the histamine H₁-receptor, but requires a 23-fold increase in dose to bind to the dopamine D₂ receptor (Table 10). That explains why low doses of quetiapine can be used for sedative effects but why higher doses are needed for antipsychotic efficacy. For the same reason, quetiapine can have the same pharmacodynamic DDIs as other potent H₁-receptor antagonists even though those other drugs might not have any efficacy as an antipsychotic medication.

The reader can use Tables 8–11 to determine how a multiple mechanism of action drug may have the potential for interacting pharmacodynamically by a mechanism other than its major presumed therapeutic mechanism (as listed in Table 17) and have an approximate understanding of the relative likelihood of such an interaction based on its relative binding affinity for secondary targets in relationship to the dose that is being used and the concentration that is likely being achieved in the patient. The reader can also use this information to determine whether he or she might wish to employ TDM to further establish the actual concentrations being achieved in their specific patient and relate that to both relative binding affinity for its multiple targets as well as relative to the concentration usually achieved on the dose being used. The clinician could use TDM to determine whether his or her specific patient has unusually fast or slow clearance relative to the usual clearance found in the registration trials and whether the patient is developing concentrations comparable to or much higher or lower than those found in registration trials.

Pharmacokinetic Tables

These tables outline potential CYP enzyme-mediated DDIs. Parenthetically, CYP-mediated DDIs are the most common, clinically meaningful type of pharmacokinetic DDIs. Table 19 lists which CYP enzymes metabolize which drugs and which drugs inhibit or induce specific CYP enzymes.³⁵ Using these tables and the logic outlined in Figure 3, the reader can predict the major potential CYP enzyme-mediated DDIs.^59,79

Pharmacokinetic Drug Interactions that are Not Metabolism-Based

This educational review restricted its discussion of pharmacokinetic DDIs to those mediated by CYP enzymes because of their clinical relevance. Nevertheless, there are other possible pharmacokinetic DDIs (Table 18)⁹⁹ worth briefly mentioning as follows: the chelation of drugs in the gastrointestinal tract by iron salts prescribed to treat anemia or by antacids with high aluminum content; interactions that occur prior to the administration of intravenous (IV) drugs due to the incompatibility of IV solutions; interaction with drug-secreting transporters that line the renal tubules and the blood-brain barrier (eg, lithium intoxication due to co-administration with ibuprofen and possibly other nonsteroidal anti-inflammatory drugs); and nutritional interactions that deplete the cofactors required for the phase II metabolism of some drugs (ie, reduced acetylation and glycosylation due to persistent hypoglycemia or clinically significant malnutrition).¹⁰⁰

Important to note is that these mechanisms do not include protein binding (or “bumping”) interactions in which a perpetrator displaces a victim drug from serum proteins such as albumin or α₁ acid glycoprotein. This mechanism virtually never mediates a DDI of clinical significance, although it is well ensconced in the literature and the minds of physicians. This mechanism is virtually never clinically significant, because the resulting increased free drug persists for a short and clinically insignificant period before the access of the same free drug to elimination mechanisms, such as enzymes transporters, reduces the free concentration to a new equilibrium close to the original.¹⁰¹

Appendix I lists Web sites that the reader can use to find additional information.^{35,59,102-106} Web sites have the advantage of being regularly updated so that the information will stay current long after this article has been published. Appendix II lists software packages and their current limitations are in Table 20.^107-111

One major limitation is that there are no standard guidelines for producing such drug alert systems in terms of what constitutes sufficient evidence to list an interaction as possible. Thus, software packages can list interactions based on theory rather than fact or based on a single case report of dubious validity. This situation, in turn, can cause a high rate of false positive alerts (an “overly sensitive” approach) that can, ironically, lead the prescriber to ignore the system (ie, “the boy who cried wolf”).

Other systems may only include DDIs which have been demonstrated to occur in a formal study and do not generalize the interaction to other drugs with the same mechanism mediating the DDI. This situation leads to false negatives. An example is a system that reports fluoxetine’s ability to increase the level of desipramine (Figure 4) but does not warn about bupropion, which, at a dose of 300 mg/day, inhibits CYP 2D6 to a degree comparable to that of fluoxetine 20 mg/day.¹¹²

Another limitation is that most drug alert systems only consider the effect of drug A on drug B, whereas many patients are on multiple drugs that may interact in complex ways. An example would be a patient who is taking a drug equally cleared by CYP 2D6 and CYP 3A. That patient may not be at substantial risk for toxicity when treated with either a CYP 2D6 or CYP 3A inhibitor alone but may be if treated with both inhibitors at the same time.¹¹² Most systems focus on pharmacodynamic or pharmacokinetic DDIs as if they were mutually exclusive when, in fact, both can occur simultaneously; hence, amplifying each other.^12,25

Current DDI alert systems may alert but provide little or no guidance about what the prescriber can do to minimize risk of the interactions, such as finding a substitute for either the perpetrator or the victim drug, adjusting the dosage of the victim drug (in the case of CYP enzyme-mediated DDI), or specially monitoring (eg, TDM or electrocardiograms).

However, the greatest limitation is knowledge. While there are 520 quadrillion possible combinations of up to five drugs using the number of drugs in the 2006 Physicians’ Desk Reference,¹¹³ there are only approximately 700 published formal DDI studies, and virtually all of those are constrained to the effect of one drug on another drug. In fact, virtually all clinically significant DDIs were first discovered by astute and conscientious clinicians who published their findings as case reports in medical literature. Those reports served as a stimulus for scientific study, which uncovered the pharmacologic basis for the interactions and led to generalizable knowledge. For this reason, the authors encourage the readers to write up their cases and publish them in the medical literature, as well as to use the adverse drug reaction reporting system developed by the FDA (Table 21).^114,115

Given the above limitations, software packages do not replace the educated, astute, and conscientious prescriber who remains the major safeguard against the occurrence of  serious untoward interactions. The authors hope that this educational review can serve as an aid to these prescribers in providing safe and effective treatment for their patients.

Conclusion

DDIs are common, important, and growing in frequency in concert with both the increasing number of pharmaceuticals available and the number of patients on multiple medications. Each year more medications are added to the available armamentarium. There is an increasing use of multiple medications to treat patients, particularly as the focus of treatment has shifted from short-term therapy of acute illnesses (eg, bacterial infections) to long-term treatment and/or prevention of chronic illnesses (eg, schizophrenia and Alzheimer’s disease, respectively).

To avoid unintended and untoward DDIs, the prescriber must understand fundamental principles of pharmacology and good clinical management. The prescriber must have knowledge of the pharmacodynamic and pharmacokinetics of the drugs that his or her patients are taking. This educational review has addressed these principles and presented tables summarizing the major pharmacodynamic and pharmacokinetic interactions affecting and/or caused by commonly used neuropsychiatric medications. Additionally, appendices were provided listing Web sites, books, and cards containing additional information on specific DDIs. In addition, these Web sites are updated on a regular basis so the reader can stay informed of the rapid developments concerning DDIs. PP

 

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