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Genetics and Genomics in Schizophrenia

Ming T. Tsuang, MD, PhD, DSc, Stephen J. Glatt, PhD,
and Stephen V. Faraone, PhD

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Primary Psychiatry. 2003;10(3):37-40,50

Dr. DeVane is professor of psychiatry and behavioral sciences at the Medical University of South Carolina in Charleston. Dr. Nemeroff is Reunette W. Harris Professor and chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, Ga.

Disclaimer: Although every effort has been made to ensure that drug doses and other information are presented accurately in this article, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound currently under clinical investigation.

Acknowledgments: The authors report no financial, academic, or other support of this work.


 

Introduction

The present “2002 Guide to Psychotropic Drug Interactions” is an update of the past 2000 edition. Since the appearance of the 2000 Guide, new psychotropic drugs have been introduced which have specific data related to their potential drug interactions. Documentation of drug interactions with commonly used psychotropics continues to appear in the literature at a steady pace.
 

As this guide is intended to serve an educational role for both the psychiatrist-in-training and the nonpsychiatric physician less familiar with the interactions of psychoactive drugs, the bulk of the background discussion on drug metabolism and mechanisms of drug interactions remains unchanged. For the repeat reader, we have summarized in Table 1 important new findings on drug interactions appearing since the last update. The interactions of three new psychoactive drugs introduced recently to the market (oxcarbazepine, modafinil, and ziprasidone) are covered in Tables 17, 22, and 32. Other additions in the tables reflect new case reports and further documentation of drug interactions.
 

New knowledge related to the benefits of psychiatric drug treatment results in earlier initiation of drug therapy for some psychiatric disorders, and maintenance therapy is more and more commonplace during asymptomatic periods. In fact, maintenance therapy for affective anxiety and psychotic disorders, often continuing for years or decades, is now the accepted standard of care, especially for patients with a history of recurrent episodes of illness. Long-term pharmacotherapy requires awareness and management of drug interactions.
 

As the population ages, more drugs are prescribed on a chronic basis for maintenance of health without treatment of overt symptoms. Increasing numbers of patients take one of the serum lipid-lowering compounds from the class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. These drugs can be taken for primary prevention, regardless of whether or not the patient has previously experienced a vascular event such as myocardial infarction or stroke. With the exception of pravastatin, the drugs in this class are highly metabolized by cytochrome P450 (CYP) 3A4, a hepatic enzyme whose action can be inhibited by several antidepressants. As will be explained later, some knowledge of how the major antidepressants interact with specific liver enzymes allows the choice of an antidepressant that avoids such potential drug-drug interactions.
 

New drugs to treat psychiatric illness have been introduced to clinical practice in recent years. Additional antidepressants and antipsychotics are expected over the next few years. The recent introduction of ziprasidone reflects the high level of activity in drug development for treatment of psychotic conditions. Additional new drugs in this category are currently being tested in clinical trials. Each of these compounds possesses a certain potential to interact with other drugs. This is especially true since psychoactive drugs are generally highly metabolized compounds. Laboratory methodologies developed in recent years can identify the specific enzymes mediating various metabolic pathways. This information can be used to predict how a new drug will interact pharmacokinetically with a variety of other drugs already marketed. Some background knowledge of major drug-metabolizing enzymes is helpful in understanding how these predictions are made. Of course, in vitro predictions must be confirmed with in vivo studies, but supporting clinical data may not be available for months or years.
 

This guide summarizes psychotropic drug interactions from several viewpoints. First, examples of pharmacokinetics will be discussed to aid the reader in understanding how drugs may interact during the course of their absorption and elimination from the body. Secondly, because many interactions with psychotropic drugs occur via specific interactions with the CYP system, this hepatic enzyme system will be described and the most important enzymes involved in the metabolism or interactions of psychoactive drugs will be discussed. Some principles of drug interactions operating through competitive inhibition of hepatic enzymes will be explained, so that the reader may make informed judgments about the possibility of an interaction.
 

The bulk of the guide will be concerned with drug interactions that have been described with specific psychoactive drug classes. The degree of documentation varies for many interactions, from theoretical conjecture, to clinical experience with patients, to well-established research outcomes. The sources of interaction data will be noted to help identify the appropriate level of confidence in the predicted consequences of combining drugs in therapy. When possible, specific management guidelines are provided to avoid or minimize some potentially negative interactions. The major psychoactive drugs, classified according to their primary therapeutic indication, are listed in Table 2. Subsequent tables will list important drug interactions for each of these classes.
 

 

Classification of Drug Interactions

Drug interactions are commonly classified as occurring by either pharmacodynamic or pharmacokinetic mechanisms. A third category, pharmaceutical interactions, occurs from physical incompatibility of drugs. Examples of this last class include the precipitation of drugs following their addition to intravenous fluids of inappropriate pH, or the physical absorption of drugs to intravenous tubing. The intravenous dose of diazepam delivered can be far less than expected if it is injected into intravenous tubing distal to the point of venipuncture, due to drug absorption to plasticizer in the tubing. However, these types of interactions are rarely of concern, because the vast majority of psychoactive drugs are prescribed for oral administration.
 

Pharmacodynamic Drug Interactions

A pharmacodynamic drug interaction occurs when the pharmacologic response of one drug is modified by another drug without the effects being the result of a change in drug concentration. These interactions occur at the sites of drug action. Such sites can include receptors, ion channels, cell membranes, and enzymes. We lack a thorough understanding of these drug interactions, as they are generally more difficult to detect and study than pharmacokinetic interactions. The latter are more easily documented and quantified through measurement of plasma drug concentrations. The pharmacologic effects of psychoactive drugs can be difficult to measure, especially changes in behavior or mental status. Some examples are illustrative of pharmacodynamic interactions.
 

Drugs that produce sedation by different mechanisms often produce additive sedation when administered together. The combination of traditional antihistamines with benzodiazepines or alcohol provides an example. Another well-known pharmacodynamic interaction is the combination of a nonselective monoamine oxidase inhibitor (MAOI) with an over-the-counter (OTC) sympathomimetic nasal decongestant or foods rich in tyramine. Because of differing mechanisms of action, overstimulation of the sympathetic nervous system can result in pressor effects that produce hypertension. This interaction is becoming less of a clinical concern due to the diminishing use of the MAOIs. A more relevant example for current clinical practice is provided by serotonin syndrome. This is a potentially fatal disorder, which can result from combining highly serotonergic drugs. It was first recognized in laboratory animals given MAOIs and L-tryptophan, but has been documented with the newer antidepressants and other agents that have prominent serotonergic actions. It occurs in the absence of pharmacokinetic changes in drug disposition.
 

Some drug interactions at sites of action are specifically exploited for their therapeutic benefits. The pharmacodynamic interactions of competitive antagonists at receptor sites are the basis for development of several therapeutically useful drugs. Naloxone, propranolol, and flumazenil reverse the effects of opiates, catecholamines, and benzodiazepines at their respective receptor sites when given in close temporal proximity to their agonists. When adjunctive agents are combined with antidepressants (eg, lithium), or thyroid hormone with tricyclic antidepressants (TCAs), or pindolol with selective serotonin reuptake inhibitors (SSRIs), it is hoped that a pharmacodynamic interaction will result in an improvement in patient response.
 

Pharmacokinetic Drug Interactions

A pharmacokinetic interaction occurs when one drug alters the disposition of another drug, thereby resulting in a change in plasma or tissue drug concentration. The change in concentration may or may not result in clinically significant consequences. Any of the major components of drug disposition illustrated in Figure 1 can theoretically be affected.

 

For the psychoactive drugs, the drug dose is usually administered orally. Absorption occurs most often in the small intestine, where a favorable pH promotes transit across the gastrointestinal (GI) membranes. Some portion of the absorbed dose undergoes glomerular filtration and passes out through the urine in an unchanged form. The proportion varies both among individuals and between drugs. Generally, the psychoactive drugs are excreted unchanged only to a minor degree. Exceptions are lithium and gabapentin, which are excreted unchanged. Most drugs are biotransformed to either active or inactive metabolites. Either the administered parent drug and/or active metabolites can produce pharmacologic effects at various sites of action. In turn, metabolites are to some degree excreted in the urine, or they can be further metabolized. Eventually, the biotransformation process results in a metabolite that is sufficiently water-soluble to be renally excreted. Drug interactions may involve any of these various steps in the drug disposition process.
 

Interactions Involving Absorption

Absorption of orally administered drugs is a multistep process. Once a solid form (tablets, capsules) of a drug dosage is dissolved into solution in the GI tract, it transverses the gut lumen and wall in transit to the liver. A portion of the drug dose may never be absorbed, due to inadequate dissolution or drug interactions that promote further passage beyond the small intestine and elimination in the feces. The possible sites of drug elimination during absorption are shown in Figure 2. Drugs such as cholestyramine can physically bind to drugs in the GI tract and produce this effect. The nonabsorbable fat substitutes may also reduce the absorption of other drugs. Cimetidine, by altering GI pH, may reduce the rate or extent of absorption of many psychoactive drugs. Similarly, anticholinergic drugs can decrease the motility of the gut and alter drug absorption.

Drugs are subject to elimination during their absorption through the gut wall by the action of carrier proteins and metabolizing enzymes. P-glycoprotein (PGP) and CYP 3A4 act in concert to limit the absorption of a number of drugs. PGP is a carrier protein that exports drug molecules back into the GI tract. This creates a continual recycling of a portion of the unabsorbed drug dose and has the effect of increasing the exposure to CYP 3A4 and first-pass elimination (Figure 2). PGP transport is a saturable process, which partially explains why increasing absorption may occur with an increased dose.
 

The gut wall is the site of interaction of PGP or CYP 3A4 inhibitors that can increase the bioavailability of some drugs. Some natural chemicals in grapefruit juice down-regulate, or decrease, protein expression of CYP 3A4 in the gut wall, which allows greater amounts of drugs that are prominent 3A4 substrates to be absorbed. For cyclosporine, this interaction with grapefruit juice can increase drug bioavailability and result in decreased dosage requirements for immunosuppression and economic cost savings for patients.
 

The role of PGP in drug interactions is being increasingly recognized. The cardiac glycoside digoxin is not metabolized, but renally excreted, and St. John’s wort (SJW) decreases its plasma concentration. The likely mechanism is induction of intestinal PGP to limit digoxin’s oral absorption. A similar mechanism or CYP 3A4 induction may explain the lowering by SJW of indinavir, alprazolam, and cyclosporine plasma concentration. PGP also serves a protective function to limit access of drugs to the brain, due to its presence in capillary endothelial cells which comprise the blood-brain barrier. Tolerance to the analgesic effects of morphine in rats was recently shown to result from induction of PGP synthesis. Induction or inhibition of PGP is a drug interaction mechanism likely to be documented in future reports altering the actions of many psychoactive drugs.
 

Interactions Involving Distribution and Protein Binding

Almost all drugs circulate in blood, bound by some degree to specific plasma proteins, most often albumin and lipoproteins. This process presents an opportunity for drug-drug interactions to occur by one highly bound drug displacing another from its protein-binding sites. The potential consequences of this interaction can be seen in Figure 3. Normally, drug bound to protein in plasma is in equilibrium with unbound drug. It is an accepted principle of pharmacology that only unbound drug is free to diffuse to sites of action, usually in tissues, and produce pharmacologic effects. When the amount of unbound drug in plasma is increased due to displacement from proteins by another drug, more unbound drug is available to distribute to tissues, where it can produce increased pharmacologic effects.
 

Although several drug interactions can be shown to occur through protein-binding displacement, this type of pharmacokinetic interaction may not be significant unless the binding displacement actually modifies a drug’s dose-effect relationship. A classic example of this type of interaction is the displacement of warfarin from serum albumin-binding sites by phenylbutazone or salicylate analgesics. An increase in the plasma concentration of warfarin occurs accompanied by an increase in its pharmacologic effects, a prolongation of prothrombin time. However, as a result of more free (unbound) drug being in the systemic circulation not bound to plasma protein, more drug becomes available for hepatic metabolism. Eventually, the total concentration of warfarin in plasma returns to the pre- interaction level. This is a time-limited interaction in which homeostatic changes play a role in buffering the consequences of the increased free warfarin concentration.
 

Protein-binding interactions have been hypothesized to occur with most of the members of the SSRI class of antidepressants due to their high degree of plasma protein binding (>95% for some drugs); however, such interactions have not been shown to be a prevalent clinical problem. For example, sertraline produced a small increase in the free fraction of warfarin and a modest increase in prothrombin time in a study involving healthy male volunteers, but neither effect was considered to be clinically significant. The plasma binding of antidepressants and antipsychotics is generally greater to lipoproteins than to albumin, and, hence, warfarin-binding displacement interactions from albumin have been of more theoretical than practical significance. Nevertheless, these drugs may have a hypoprothrombinemic effect related to perturbations in platelet serotonin apart from any protein-binding interactions with anticoagulants. Alternatively, fluvoxamine may modify the enzymatic metabolism of warfarin, directly leading to enhanced pharmacologic effects.
 

Among the interactions of psychoactive drugs, the anticonvulsant mood stabilizers are most often involved in altering plasma protein binding. Valproate is highly bound to plasma proteins (>90%) and can displace the binding of diazepam, phenytoin, tolbutamide, and warfarin from their plasma albumin-binding sites. Valproate is also a weak inhibitor of several hepatic enzymes and may increase the pharmacologic effects of coadministered drugs. Overall, interactions involving protein binding occur with psychoactive drugs, but the examples are limited despite many psychoactive drugs being highly plasma protein-bound.
 

Interactions Involving Metabolism and/or Elimination

The liver is the primary site of elimination of most psychoactive drugs. It contains numerous Phase I and Phase II enzymes that oxidize or conjugate drugs, respectively. The most important of these enzymes in terms of understanding pharmacokinetic drug interactions is the Phase I CYP system. The majority of drug interactions of concern during the course of psychopharmacological treatment involve alterations of drug metabolism. Drug metabolism can occur in several tissues in the body, but hepatic metabolism is generally recognized as the most important, because proportionally the liver contains the highest enzyme content compared with other organs and is therefore most responsible for drug biotransformation.
 

Potential drug interactions involving Phase II metabolism are increasingly being recognized. The most important Phase II enzymes involved in drug metabolism are the glucuronosyltransferases. These enzymes perform conjugations by combing drug molecules with glucuronic acid, mostly in the liver. Three benzodiazepines (lorazepam, oxazepam, and temazepam) undergo Phase II reactions exclusively before being excreted into the urine. Both inducers and inhibitors of glucuronosyltransferases are known and have the potential to affect the plasma concentration and actions of important psychotropic drugs.
 

Drug interactions involving metabolism arise from enzyme induction or inhibition. Cigarette smoking and some specific drugs are recognized as inducers of hepatic oxidizing enzymes. The administration of these drugs can stimulate the synthesis of additional enzymes. Eventually, the increased enzyme activity results in an enhanced clearance of drugs that are substrates for the induced enzyme. Plasma drug concentration may fall, leading to diminished pharmacologic effects. An example is the treatment of a patient with carbamazepine who is taking an oral contraceptive. Carbamazepine can induce the activity of CYP 3A4, leading to increased steroid metabolism and a loss of contraceptive effect.
 

An interaction involving enzyme inhibition results in impaired drug clearance and a rise in plasma drug concentration. While several types of enzyme inhibition can occur, the most common is known as competitive enzyme inhibition. This occurs when two drugs have such a strong affinity for the same enzyme that one is preferentially metabolized at the expense of the other. The concentration of the drug whose elimination has been inhibited will rise with continued dosing, due to decreased clearance. The magnitude of inhibition depends upon several factors, including the affinity of the drugs for the enzyme, the drug concentration in the plasma, the degree of partitioning into hepatocytes, and others.
 

Interactions involving hepatic enzyme induction or inhibition are characterized by dose and time dependence. The greater the dose of an inhibitor that is administered within the range of clinically useful doses, the greater the extent of the inhibition that should occur. For example, fluoxetine is a competitive inhibitor of CYP 2D6 and should produce a greater inhibitory effect at a dose of 40 mg or 60 mg than at 20 mg/day. Eventually, increasing doses of an inhibitor will result in a maximum inhibition with no further effect from increasing doses.
 

Interactions involving competitive enzyme inhibition occur with the first dose of inhibitor, as it is the presence of the two competing drugs at the enzymatic site in the liver or GI tract that results in an interaction. In contrast, interactions occurring as a result of enzyme induction require several days to become apparent, as the inducing agent must stimulate the synthesis of additional metabolizing enzymes.
 

Drug interactions involving changes in renal elimination of drugs are infrequent with psychoactive drugs. An exception is lithium, which is totally renally cleared. Drugs and physiologic conditions that alter renal function affect lithium clearance. Foremost among the drugs that inhibit lithium clearance and increase its plasma concentration are most non-steroidal anti-inflammatory drugs (NSAIDs) and the thiazide diuretics. Drug interactions involving changes in renal elimination are unlikely to occur with the antidepressants, antipsychotics, and anxiolytics because these are highly metabolized drugs with typically less than 5% of an administered dose excreted in the urine in an unchanged form.
 

Prediction of Metabolic Drug Interactions

Based on an abundance of theoretical and experimental data, drug interactions as a result of competitive inhibition for the same metabolizing enzyme can be predicted. Prediction rests upon knowledge of substrate specificity for particular enzymes, the degree of affinity of a competing drug for the same enzyme, and the concentrations of the substrate and inhibitor. Mathematical equations can predict the degree of change in clearance of one drug by another under these circumstances in in vitro laboratory experiments using liver slices, intact hepatocyte preparations, or microsomes. Rarely is such complete information available for patients under clinical circumstances. In practical terms, by knowing the metabolic pathways of a drug (ie, which enzymes are involved in its metabolism) and whether a drug to be combined in therapy has inhibitory effects on that enzyme, an interaction can be predicted. The degree of interaction and whether the consequences will be clinically meaningful will depend upon multiple factors. Some of these include the specific drugs involved, drug dosage and length of therapy, and the clinical state of the patient.
 

While many enzymes in the liver are capable of biotransformation reactions, emphasis has focused recently on the CYP enzymes because it is estimated that collectively they participate in the metabolism of greater than 80% of all available drugs used in humans. CYP enzymes play additional roles in the metabolism of some endogenous substrates, including prostaglandins and steroids. At least 30 related enzymes are divided into different families according to their amino acid homology. Some enzymes exist in a polymorphic form, meaning that a small percentage of the population possesses mutant genes that alter the activity of the enzyme, usually by diminishing or abolishing activity. A genetic polymorphism has been well characterized with the CYP 2C19 and CYP 2D6 genes. Recently discovered but poorly categorized are polymorphisms of CYP 3A4. Table 3 lists the most important CYP enzymes, along with some of their substrates. Remarkably, for many drugs in clinical use for years, the enzymes involved in their metabolism have not been identified. This is an active research area, and information is continually being updated.
 

In the current approach to new drug development, candidate compounds are screened for their affinity for various P450 enzymes. A high affinity for one or more enzymes suggests a likelihood of interactions with other drugs metabolized by the same enzyme. These predictions can then be confirmed with targeted drug interaction studies in human volunteers or patients. The degree to which an interaction will occur also depends upon the concentration of the substrate and inhibitor at the enzyme site, which in turn depends upon the size of administered doses. The significance of blocking or inducing a particular cytochrome enzyme for a drug interaction will depend upon the importance of the enzyme in the overall elimination of the drug. Most drugs are eliminated through more than one pathway, and some degree of renal clearance also contributes to the elimination of many drugs. The existence of parallel pathways of elimination moderates the effects of inhibiting a single enzymatic pathway.
 

A qualitative approach to the prediction of drug interactions can be used by clinicians to identify the combinations of drugs that should be used cautiously or avoided, especially when preexisting information about their potential interaction is unavailable. Psychoactive drugs that inhibit or induce the enzymes listed in Table 2 would be expected to interact with the substrates of those particular enzymes. This approach provides a rough screen to predict the potential for pharmacokinetic interactions. It should be remembered that concentration changes do not necessarily translate into clinically meaningful interactions. Most drugs have acceptable therapeutic indices so that minor alterations in clearance, steady-state plasma concentration, or half-life, although statistically significant, may be clinically unimportant. Also, pharmacodynamic interactions are not predicted by this approximation and may occur in addition to or apart from pharmacokinetic interactions.
 

CYP Enzymes

CYP enzymes exist in a variety of body tissues, including the brain. Clearly, their presence in the GI tract (especially CYP 3A4) and in the liver is important for the elimination of administered drugs. The molecular and pharmacologic characterization of CYP enzymes and the corresponding genes that determine their synthesis is an active research area. The most prominent enzymes are discussed below, due to their importance for drug metabolism and participation in drug interactions.
 

CYP 1A2

The CYP 1A subfamily includes CYP 1A1 and CYP 1A2, with both genes located on human chromosome 15. CYP 1A2 is an important enzyme in the metabolism of several widely used drugs (Table 3). It comprises about 13% of the total P450 content of the human liver and is highly inducible.

Nonpsychiatric drugs metabolized by CYP 1A2 include theophylline,  aminophylline, caffeine, and the antiarrhythmic propafenone. The ß-blocker propranolol is believed to have a minor component of its biotransformation mediated by CYP 1A2. The tertiary amine tricyclic antidepressants undergo demethylation to their secondary amine active metabolites by this enzyme. The traditional antipsychotic drug haloperidol and the newer atypical antipsychotics clozapine and olanzapine are partially metabolized by CYP 1A2. Tetrahydroacridinamine (tacrine) is hydroxylated by CYP 1A2.
 

CYP 1A2 is induced by cigarette smoke, charcoal-broiled foods, and some cruciferous vegetables (eg, Brussels sprouts). The effect of cigarette smoking can be prominent, and patients who stop or substantially reduce smoking can be expected over the subsequent few weeks to have a return to baseline of their CYP 1A2 activity. This situation has resulted in the appearance of seizures in a patient taking clozapine who quit smoking during therapy.
 

Fluvoxamine and ciprofloxacin are potent inhibitors of CYP 1A2, and interactions have been described with theophylline and clozapine. One of the most notable interactions of fluvoxamine is its ability to inhibit theophylline metabolism. Because the elevation of serum theophylline could double or more, it is recommended that when this antidepressant is prescribed for a patient receiving this bronchodilator, the patient’s theophylline dose be reduced by one third of the prior dosage. Fluvoxamine is unique among the newer antidepressants in the ability to inhibit CYP 1A2. While the choice of another antidepressant in these circumstances could avoid this potential interaction, these drugs may be used safely together when dosed appropriately and cautiously. Appropriate clinical care would include monitoring of theophylline plasma concentration and vigilance to the appearance of side effects. Although other psychoactive drugs, including haloperidol, some tertiary amine tricyclic antidepressants, and olanzapine, are partially metabolized by CYP 1A2, their participation in competitive enzyme interactions appears to be a result of a stronger affinity for enzymes other than CYP 1A2.
 

CYP 2A

The genes for the expression of the CYP 2A subfamily are localized on the long arm of chromosome 19. Three genes for CYP 2A6, CYP 2A7, and CYP 2A13 have been identified and sequenced. A variant allele for CYP 2A6 has been associated with individuals who are deficient in their ability to metabolize warfarin. In in vitro studies, orphenadrine decreased the activity of CYP 2A6, but the clinical significance of this effect, if any, is unknown. CYP 2A6 comprises about 4% of the P450 content of the human liver, and its contribution to the metabolism of therapeutically used drugs is probably small.
 

CYP 2B

The cytochrome 2B subfamily consists of the closely related P450s 2B1, 2B2, and 2B6. CYP 2B1 has been the focus of study as it oxidizes toluene, aniline, benzene, and other solvents to reactive metabolites thought to be important in promoting carcinogenesis. It can be induced by acetone, phenobarbital, and carbamazepine. It plays a minor role in the metabolism of a few drugs used in humans, including caffeine, theophylline, coumarin, and lidocaine. In animal studies, clonazepam has been found to be a potent inhibitor of catalytic activities mediated by CYP 2B in microsomes derived from phenobarbital-pretreated rats. The MAOIs selegiline and clorgyline have been found to inactivate the activity of CYP 2B in vitro. The clinical significance of these effects is unknown.
 

CYP 2B6 is thought to be a minor component of P450 content in the liver, normally constituting less than 0.5% of total P450, although substantial interindividual variability has been observed. CYP 2B6 plays a role in the metabolism of the anticancer drug cyclophosphamide and is the major enzyme responsible for converting bupropion to its primary active metabolite, hydroxybupropion. Orphenadrine is a CYP 2B6 inhibitor in vitro. In a human pharmacokinetic study, carbamazepine and valproate both increased hydroxybupropion concentration, but their function as CYP 2B6 inhibitors has yet to be established.
 

CYP 2C9/19

The CYP 2C subfamily consists of several closely related enzymes: 2C9, 2C10, 2C19, and others. CYP 2C comprises about 18% of the total P450 content of the human liver. A genetic polymorphism exists with CYP 2C19, with approximately 18% of Japanese and African Americans reported as poor metabolizers of CYP 2C19 substrates. Only about 3% to 5% of whites inherit this deficiency. Affected individuals are identifiable by phenotyping with mephenytoin administration. Poor metabolizers have higher than normal plasma concentrations of the CYP 2C19 substrates from usual doses (Table 3). Rare polymorphisms of CYP 2C9 have been discovered.
 

Nonpsychiatric drugs metabolized by the CYP 2C subfamily include S-mephenytoin (2C19), phenytoin (2C19), tolbutamide (2C9), S-warfarin (2C9), ibuprofen (2C9), diclofenac (2C9), and piroxicam (2C9). Other substrates of CYP 2C9 and CYP 2C19 include diazepam, clomipramine, amitriptyline, and imipramine (Table 2). Several of the NSAIDs are substrates of CYP 2C, but clinically significant metabolic interactions with negative consequences have not been described involving psychoactive drugs combined with NSAIDs.
 

Several antidepressants with affinity for CYP 2C (sertraline, fluoxetine, fluvoxamine) appear to have a moderate although measurable affinity for the CYP 2C isoenzymes. The nature of the dose response curves for the NSAIDs may minimize or preclude important interactions unless substantial rises in plasma drug concentration occur. In general, drug interactions are likely to be of significance when a small increase in the concentration of an inhibited drug results in substantially increased pharmacologic effects. This situation characterizes phenytoin, and significant interactions involving this anticonvulsant with fluoxetine have been reported.
 

CYP 2D6

This is the best characterized of the CYP enzymes. The CYP 2D6 gene locus is on chromosome 22. A genetic polymorphism exists, with 7% to 10% of whites inheriting an autosomal recessively transmitted defective allele. Four genotypes can be distinguished: homozygous and heterozygous efficient metabolizers, homozygous poor metabolizers, and ultrarapid metabolizers carrying a duplicated or multiduplicated CYP 2D6 gene. In African Americans, the percentage of poor metabolizers is less, generally between 1% and 4%. Poor metabolizers among Asians are rare. These ethnic differences may explain different dosage requirements of some drugs in different populations.
 

Poor metabolizers lack sufficient functional enzyme to metabolize the CYP 2D6 substrates listed in Table 3. They can therefore be expected to have higher plasma drug concentrations and prolonged elimination half-lives of these drugs when given in usual doses. The significance of this metabolic defect is that an exaggerated pharmacologic response is possible following standard doses of drugs that are CYP 2D6 substrates.
 

CYP 2D6 comprises a small percentage of the total P450 content of the liver, about 1.5%, but many useful drugs are specific substrates. Nonpsychiatric drugs metabolized by CYP 2D6 include propranolol (also 1A2 and possibly 2C19), metoprolol, timolol, mexiletine, propafenone (also 1A2 and 3A4), codeine, and dextromethorphan (also 3A4). Several of the newer antidepressants are partially metabolized by CYP 2D6. They include paroxetine, venlafaxine, and fluoxetine. The tertiary amine tricyclic antidepressants are hydroxylated by CYP 2D6.
 

No inducers of CYP 2D6 have been identified. While CYP 2D6 substrates have shown decreased plasma concentration under conditions of cigarette smoking and barbiturate administration, this is not a laboratory-reproducible phenomenon. Alternative explanations include effects on other enzymes that mediate parallel pathways of elimination, or increases in hepatic blood flow that increase drug clearance.
 

Several antidepressants, discussed below, are inhibitors of CYP 2D6, but they vary widely in their potency. For example, adding fluoxetine or paroxetine to a drug regimen including desipramine will increase the plasma TCA concentration by interference with the hydroxylation pathway. Fluvoxamine, citalopram, and sertraline in low doses are less likely to exert a similar effect.
 

CYP 2E

This subfamily of enzymes, with genes localized on chromosome 10, is important in the bioactivation of several carcinogens and the metabolism of organic solvents. Cytochrome 2E1 is the focus of current research for its role in alcohol metabolism. It comprises about 7% of the total P450 content of the human liver. Substrates of CYP 2E1 include chlorzoxazone, acetaminophen, halothane, enflurane, and methoxyflurane. In in vitro studies, significant inhibition of CYP 2E1 occurred with TCAs, phenothiazines, and flurazepam. Although these psychoactive drugs are not substrates for CYP 2E1, they have the potential to modulate the toxicity of nondrug xenobiotics metabolized by this isoenzyme. CYP 2E1 is induced by alcohol, which may be an important factor in its toxicity. CYP 2E1 is an active area of investigation, with limited current relevance, however, for the practice of clinical psychopharmacology.
 

CYP 3A4

This enzyme metabolizes the largest number of drugs used therapeutically. It constitutes approximately 30% of the P450 present in the liver and 70% of the cytochrome enzymes in the gut wall. There is little evidence for a genetic polymorphism. Everyone possesses CYP 3A4 hepatic enzyme, although there is broad variability in expressed activity among subjects. A study of the metabolism of carbamazepine suggested that CYP 3A4 activity may peak in children and show a gradual decline to adult levels of activity. This would partly account for why older children and adolescents require larger doses of some drugs than adults. The elderly, especially individuals aged 70 years and above, show a reduction in overall drug metabolism related to a decrease in CYP content, although comparative rates of decline in specific CYP enzymes are not well characterized.
 

Nonpsychiatric drugs metabolized by CYP 3A4 include diltiazem, verapamil (also 1A2), nifedipine, alfentanil, tamoxifen, testosterone, cortisol, progesterone, ethinyl estradiol, cisapride, cyclosporine, terfenadine, astemizole, quinidine, and the protease inhibitors (Table 3). Psychoactive drugs that are metabolized by CYP 3A4 include alprazolam, diazepam (also 2C19), triazolam, carbamazepine, nefazodone, and sertraline.
 

Marked enzyme induction of CYP 3A4 occurs after long-term administration of rifampin and rifabutin. Other inducers include carbamazepine, dexamethasone, and phenobarbital. Significant inhibition of CYP 3A4 substrates occurs after administration of nefazodone and fluvoxamine. The most potent inhibitors of CYP 3A4 are the azole antifungal drugs (eg, ketoconazole) and the macrolide antibiotics. A recent report of the sudden death of a child receiving pimozide who was treated with clarithromycin is a case of suspected CYP 3A4 inhibition by this antibiotic. Inhibition of terfenadine metabolism by ketoconazole, itraconazole, erythromycin, or clarithromycin poses a risk of cardiotoxicity. The noncardioactive metabolite of terfenadine, carboxyterfenadine, was recently marketed as a nonsedating antihistamine, and either this agent or loratadine is strongly preferred if a psychoactive drug must be prescribed together with an antihistamine. Among the SSRIs, paroxetine, fluoxetine, and sertraline have been specifically combined with terfenadine in in vivo pharmacokinetic studies and found not to produce a significant interaction. Fluvoxamine and nefazodone, among the newer antidepressants, are contraindicated in combination with terfenadine due to their potent CYP 3A4 isoenzyme inhibition.
 

Glucuronosyltransferases

The recent focus on psychotropic drug interactions has primarily emphasized the Phase I CYP system. The metabolism of drugs by Phase II reactions is accomplished by a variety of enzymes, but the emerging role of the glucuronosyltransferases as important in clinical psychopharmacology is being increasingly recognized. The uridine diphosphate-glucuronosyltransferases exist as multiple families of enzymes and have been defined with a nomenclature similar to that used to define the P450 system. The symbol UGT has been chosen to represent the superfamily of enzymes. Different UGT families are defined as having <45% amino acid sequence homology, while in subfamilies there is approximately 60% homology. As many as 33 families have been defined, with three families identified in humans. The most important of the enzymes for psychopharmacology are discussed below and listed with prominent substrates in Table 4.
 

UGT 1A1

The UGT 1A subfamily includes enzymes which can glucuronidate bilirubin, phenol derivatives, and estrogens. UGT 1A1 has been implicated in the metabolism of several opiate analgesics, including buprenorphine, nalorphine, and morphine. Phenobarbital and rifampin have been shown to induce UGT 1A1. Rifampin is also a PGP inducer.
 

UGT 1A3/1A4

Several tricyclic antidepressants undergo conjugation mediated by UGT 1A3 and UGT 1A4. In addition, chlorpromazine, lamotrigine, cyproheptadine, and zidovudine are substrates. Probenecid and valproate are inhibitors while several anticonvulsants/mood stabilizers are inducers. Olanzapine circulates in plasma, to a large extent, as a glucuronide conjugate, but the precise UGT enzymes have not been identified.
 

UGT 2B7

The benzodiazepines metabolized exclusively or primarily by conjugation (oxazepam, tenazepam, lorazepam) are glucuronidated by UGT 2B7, along with some opiate analgesics. A number of NSAIDS are competitive inhibitors. Phenobarbital, rifampin, and oral contraceptives appear to act as inducers of UGT 2B7.
 

Specific Drug Interactions

In this section, specific drug interactions are discussed for some of the major psychoactive agents in widespread clinical use. For each drug class, tables are presented that list the medications with which the drugs in the class may interact, how the drugs may interact, and the type of data that support the relevance of the interaction. Guidelines for management are also presented.
 

While these tables summarize the current state of our knowledge regarding interactions of psychoactive drugs, new agents are being introduced to the market at a rapid pace, and new or suspected interactions are increasingly being described in the biomedical literature each month. Suspected drug interactions generally appear first in the form of clinical case reports. This is frequently the first indication to the physician that two drugs may interact in a previously undescribed manner. The publication of several case reports of a similar nature frequently stimulates further investigation in the form of formal pharmacokinetic studies. Often, the period of time between the publication of a previously undescribed drug interaction and subsequent prospective investigation is considerable. Given the importance of case reports to the clinician, who must decide whether a particular case represents a sufficiently significant finding to merit a change in prescribing behavior, questions are posed in Table 5 as guidelines for interpretation of reports of suspected drug interactions. Consideration of these issues may be helpful in determining the potential risks or benefits of combining similar drugs.
 

TCAs

Remarkably, TCAs are still extensively prescribed in some communities. Their generic status, allowing for relatively low cost, is a major factor in their continued prescription. Some significant interactions have been documented, which are summarized in Table 6.
 

The TCAs are metabolized by several P450 enzymes. CYP 1A2, 2C, and 3A4 are thought to be involved in the demethylation of the TCAs that are administered as tertiary amines (clomipramine, amitriptyline, imipramine). CYP 2D6 is involved in the hydroxylation of the secondary amine TCAs (desipramine, nortriptyline). They are further glucuronidated before being excreted in the urine. While not all TCAs have been carefully scrutinized, it can be expected that, for example, the metabolism of doxepin and trimipramine proceeds in a similar fashion.
 

Coadministration of the TCAs with MAOIs is contraindicated. Hyperpyretic crises or severe seizures may occur in patients receiving such combinations. At least 2 weeks should elapse between the discontinuation of an MAOI and the initiation of a TCA.
 

Cimetidine is a broad CYP enzyme inhibitor and has been documented to increase the plasma concentration of several TCAs. Increased side effects, including anticholinergic-induced delirium, are a possible consequence of cimetidine and other inhibitor-induced concentration elevations. All of the SSRIs have been noted in case reports to increase TCA plasma concentrations. Their relative potency in this regard is discussed in the section below. Whenever an SSRI is prescribed to a patient already receiving a TCA, caution should be exercised and the dose of the TCA reduced, if necessary.
 

Enzyme inducers, including cigarette smoking, carbamazepine, phenobarbital, and phenytoin, can increase the clearance of TCAs and lower their plasma concentration. Thus, in smokers, average TCA doses may be higher than in nonsmokers. Because plasma concentration measurements of the TCAs are widely available, this resource can be used to monitor the effect of adding or eliminating other drugs in a TCA-treated patient.

 

SSRIs

Drug interactions with the SSRIs have been the subject of intensive study. Five drugs are available for prescribing that vary considerably in their specificity and potency to inhibit various P450 enzymes. It was noted at an early point in the development of the SSRIs that inhibition of CYP enzymes, particularly CYP 2D6 in vitro, was a property of the majority of these drugs. Since their initial clinical use, numerous studies and reports have clarified some differences among these drugs. A summary of the inhibitory potential of the SSRIs and other newer antidepressants is provided in Table 7. The estimated potencies are based on a consideration of in vitro evidence, case reports, and formal pharmacokinetic studies. The significance of a predicted interaction in an individual patient may vary widely. A summary of the interactions with the SSRIs is provided in Table 8.
 

The first SSRI marketed in the United States, fluoxetine, is a potent in vitro and in vivo inhibitor of CYP 2D6. It produces an active metabolite with similar potency. The extended elimination half-life of fluoxetine and norfluoxetine means that when CYP 2D6 substrates are combined in treatment (Table 3), their metabolic elimination mediated by this enzyme can be compromised. This effect can lead to higher drug concentrations, an extended elimination half-life, and potentially increased pharmacologic effects. Interactions have been most often documented with TCAs. Fluoxetine also has some inhibitory effects on CYP 2C19, though it is not as potent an inhibitor on this enzyme as it is on CYP 2D6. Its effect on the former enzyme is sufficient to interact with diazepam and phenytoin. These drugs, therefore, should be used cautiously with fluoxetine. Fluoxetine has no recognized inhibitory potential for CYP 1A2 substrates, but its effects on CYP 3A4 are complex. A drug interaction has been noted in a pharmacokinetic study with carbamazepine, a well-documented CYP 3A4 substrate, but fluoxetine appears not to alter the metabolism of terfenadine. Fluoxetine has a potential to interact with CYP 3A4 substrates, especially as its metabolite possesses CYP 3A4 inhibition, but few reports of interactions when combined with such substrates are available.
 

Paroxetine is also a potent in vivo and in vitro inhibitor of CYP 2D6, and lower doses of drugs that are substrates for the isoenzyme should be used if paroxetine is combined in treatment. Paroxetine has no clinically meaningful effects on other CYP enzymes.
 

Sertraline is a relatively weak inhibitor of CYP 2D6, CYP 2C19, and CYP 3A4, but when used in the upper range of clinically recommended doses, it may inhibit CYP 2D6 substrates to a significant extent. This effect is inconsistent across patients but should be recognized as a possible interaction when sertraline is prescribed. The drug’s effects on tolbutamide, a CYP 2C19 substrate, were documented in a pharmacokinetic study, but clinically significant case reports involving patients are lacking.
 

Fluvoxamine is the only SSRI that has potent inhibitory effects on the CYP 1A2 enzyme. Interactions are documented with several substrates, including clozapine, TCAs, and theophylline. This last combination requires substantial dosage decreases of the bronchodilator to avoid potential toxicity. Fluvoxamine also inhibits CYP 2C19 and CYP 3A4 to a significant extent, and dosage modifications are recommended for some substrates, such as alprazolam.
 

Citalopram has been shown in a pharmacokinetic study to raise plasma concentrations of desipramine, a CYP 2D6 substrate. However, its potency as an inhibitor is quite weak, and this SSRI has the least potential to interact with P450 substrates compared to the other drugs in its class. Recently, a case was reported of citalopram combined with clomipramine in which the suspected mechanism of increased tricyclic plasma concentration was glucuronosyltransferase inhibition.
 

Several drugs can potentially elevate concentrations of the SSRIs. This has not been shown to be a major concern in clinical practice because patients tolerate a broad range of SSRI plasma concentrations. However, when using cimetidine or another known inhibitor in combination with an SSRI, caution should be exercised.
 

 

Other Newer Antidepressants

SJW is one of the most commonly utilized herbal agents. Available data from clinical studies and case reports suggests that SJW is unlikely to inhibit CYP 3A4 or 2D6, but it is likely an inducer of CYP 3A4 and possibly PGP. The accumulating evidence of significant drug interactions with SJW (Table 13) should serve as an example for clinicians to be aware of the potential for herbal products to participate in important herb-drug interactions. Concomitant use of herbal agents and conventional medications should be discouraged until further information is available.
 

Bupropion is thought to produce its antidepressant effects primarily through enhancement of noradrenergic and perhaps dopaminergic neurotransmission without any appreciable serotonergic effects. These properties should theoretically confer a low propensity to interact pharmacodynamically with other drugs to produce a serotonin syndrome. Bupropion’s proconvulsant effects in a small number of patients suggest that it should be combined cautiously with other drugs that may increase the seizure threshold, though the sustained-release form of the drug has reduced this risk. Bupropion is metabolized by multiple pathways and enzymes. Theoretically, CYP 2B1, CYP 2D6, or CYP 3A4 inhibitors could increase its clinical effects, but specific documentation is lacking. Although bupropion and its major metabolite, hydroxybupropion, are not CYP 2D6 substrates, in a healthy volunteer study one or both are potent inhibitors of this enzyme as indicated by a 2- to 5-fold rise in desipramine plasma concentration. The pharmacokinetic consequences of coadministration of bupropion with other CYP 2D6 substrates have not been published, but caution is advised for this potential interaction. Selected drug-drug interactions related to bupropion are summarized in Table 9.
 

Nefazodone possesses serotonergic activity as a 5-HT2 antagonist and a serotonin reuptake inhibitor. The usual precautions involving combinations of drugs resulting in excessive serotonergic activity are warranted for nefazodone. The drug is a very potent CYP 3A4 inhibitor and will theoretically inhibit the metabolism of the relevant substrates listed in Table 3. Specific interactions have been documented with alprazolam and triazolam. Nefazodone increased the plasma concentration of alprazolam 2-fold and that of triazolam 4-fold. Thus, doses of these benzodiazepines should be reduced whenever nefazodone is coadministered or when initiating anxiolytic therapy in the presence of nefazodone. One favorable report used the combination of nefazodone and alprazolam to advantage to lengthen the interdosing interval of the antipanic medication. Nefazodone’s drug interactions are summarized in Table 10.
 

Mirtazapine has multiple effects on serotonergic neurotransmission, acting as a 5-HT2, 5-HT3, and presynaptic α2-receptor antagonist. While mirtazapine is highly metabolized, it apparently possesses insufficient affinity for any of the specific CYP enzymes to be a meaningful metabolic inhibitor. Thus, specific interactions of this type have not been reported. Mirtazapine possesses significant sedative effects, so that in combination with other drugs producing sedation or psychomotor impairment, additive or synergistic effects are possible. Mirtazapine’s drug interactions are summarized in Table 11.

Venlafaxine is a structurally novel antidepressant that inhibits norepinephrine and serotonin reuptake, with the latter action being the more potent of the two, and predominant at lower doses. It has a low propensity for drug-drug interactions. While its active metabolite has a measurable CYP 2D6 inhibitory effect, reports of clinically significant metabolic interactions with CYP 2D6 substrates are lacking. It does, however, have the potential to interact pharmacodynamically with potent serotonergic agents, and toxicity has been reported when combined with MAOIs. Venlafaxine’s drug interactions are summarized in Table 12.

MAOIs

Interactions of the MAOIs are summarized in Table 14. Some unusual interactions have been reported, including their combination with meperidine or fentanyl to produce an apparent serotonin syndrome. The interactions of MAOIs with the TCAs have already been discussed. The extensive list of medications that these drugs have been reported to interact with has limited their popularity, despite their efficacy for major depression, atypical depression, panic disorder, and other anxiety syndromes.

The most feared interaction of the MAOIs has been the possible hypertensive crisis from combination with tyramine-rich foods or various OTC or prescription sympathomimetic amines. This possibility requires the counseling of patients receiving these drugs regarding the potential for diet constituents and OTC medications to interact with MAOIs.
 

Lithium

Lithium has a very narrow therapeutic range of serum concentration associated with therapeutic effects, above which serious toxicity can occur. Lithium is renally cleared, and drugs and physiologic conditions that influence its renal elimination pose a potential risk to increase serum lithium concentration. Among the commonly used drugs that pose such a risk are thiazide diuretics, NSAIDs, and angiotensin-converting enzyme (ACE) inhibitors. They all increase plasma lithium levels.
 

Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk varies with the type of diuretic. Lithium is completely filtered and then reabsorbed along the proximal renal tubule in parallel with sodium. The thiazide diuretics act distally and produce a natriuresis that leads to an increase in the reabsorption of sodium and lithium. Diuretics that act on the proximal tubule, such as furosemide, have less effect on lithium reabsorption. The degree of these interactions is variable, but a decrease in lithium dosage is almost always necessary, especially in patients receiving a thiazide diuretic.
 

The osmotic diuretics enhance lithium excretion and have been used in the treatment of lithium toxicity. Potassium-sparing diuretics (triamterene, amiloride, spironolactone) have exerted variable effects on lithium clearance, sometimes increasing its clearance. Theophylline and caffeine decrease lithium concentrations to a significant degree, and dosage adjustments are likely when used together.
 

When the NSAIDs are used with lithium, plasma concentrations can rise to a toxic level. Because some of these drugs are now available OTC, there is controversy as to whether the lower recommended OTC doses produce as dramatic a change in lithium clearance as prescribed doses. When an NSAID must be used in combination with lithium, aspirin and sulindac are recommended because they exert the least increase, if any, on lithium concentration.
 

Lithium toxicity has been reported with the concomitant use of ACE inhibitors and valsartan. Case series and formal pharmacokinetic evaluations document the interaction, but the precise mechanism is uncertain. Frequent monitoring of lithium concentration is recommended when these therapies are used together. The calcium channel antagonists diltiazem and verapamil have been associated with lithium toxicity through an unknown mechanism but likely involve changes in lithium’s renal clearance. These combinations require close monitoring. The continued development of anticonvulsant mood stabilizers for treatment of bipolar disorder means that some patients will receive these drugs in combination with lithium. Topiramate transiently decreased lithium concentrations when added to a lithium regimen in healthy volunteers. A similar effect in patients has not yet been reported, but closer monitoring of lithium serum concentration appears warranted when these drugs are used together. Drug-drug interactions of lithium are summarized in Table 15 .

Other Mood Stabilizers

Carbamazepine is both a substrate of CYP 3A4 and an inducer. These characteristics account for the autoinduction and decrease in its plasma concentration observed several weeks following initiation of dosing. As a CYP 3A4 substrate, carbamazepine’s clearance and plasma concentration are subject to change in the presence of inhibitors, including valproate, nefazodone, cimetidine, and others. Erythromycin can significantly increase carbamazepine concentration and produce signs of toxicity. These commonly include confusion, sedation, and ataxia. Should these appear, dosage should be decreased and plasma drug concentration should be assessed for subsequent monitoring. Valproate is often combined with carbamazepine and it may slightly impair carbamazepine clearance; carbamazepine may decrease valproate concentration. This situation requires plasma concentration monitoring of both drugs to avoid excessive concentration changes, and therefore guides dosing. Carbamazepine added to a regimen of lamotrigine decreased the latter’s plasma concentration by 40%, but lamotrigine had no effect on carbamazepine concentration. The concentration of carbamazepine epoxide was increased in one study, so plasma concentration monitoring is recommended if these drugs are used concurrently. Carbamazepine and gabapentin do not affect each other’s disposition.
 

Carbamazepine has been reported to decrease the concentration of other CYP 3A4 substrates as a result of its enzyme-inducing effects. Some dosage adjustments may be necessary. A significant interaction is the well-described effect of diminishing the concentration of oral contraceptives. These interactions are summarized in Table 16.

Oxcarbazepine, structurally related to carbamazepine, appears to be as effective as carbamazepine in the treatment of epilepsy and slightly better tolerated. Thus, it may find utility as a mood stabilizer alternative to carbamazepine. It appears to possess dose-dependent enzyme induction, like carbamazepine, and may participate in a variety of similar drug interactions (Table 17).

Valproate’s interactions (see Table 18) result from mild enzyme inhibition and the additional capacity to displace other drugs from their plasma protein-binding sites. Caution is warranted when combining valproate with aspirin, because the free fraction of valproate may increase dramatically (see Figure 3). This may not be reflected by an increased measurement of total drug concentration in plasma. In turn, valproate may increase the anticoagulant effects of aspirin.
 

The precise interactions between valproate and specific CYP isoenzymes are unclear. It inhibits glucuronosyltransferase, as evidenced by an effect on zidovudine and lorazepam, as well as producing apparent inhibitory effects on substrates of CYP 2C9 and CYP 2C19 (phenytoin and diazepam). Its interactions with other mood stabilizers are complex. An interaction with phenytoin may result from both a metabolic inhibition and an increased concentration of unbound phenytoin, but without an apparent increase in total drug concentration. When lamotrigine was added to existing valproate therapy, valproate concentrations decreased by 25%. When valproate was added to lamotrigine therapy, lamotrigine concentrations increased 2-fold. These changes suggest that close monitoring of combined mood stabilizer therapy is necessary to optimize treatment and avoid adverse effects. Gabapentin pharmacokinetic parameters are unaffected by valproate.
 

Lamotrigine is metabolized predominantly by conjugation with glucuronic acid, a Phase II metabolic process by 1A4, with little or no involvement of CYP enzymes. The drug has not been reported to affect CYP enzymes. Its interactions have only been systematically studied with the common anticonvulsants. With the exception of valproate, the addition of lamotrigine to other mood stabilizers does not affect their steady-state plasma concentration. No significant effect was noted after the addition of lamotrigine to regimens of phenytoin or carbamazepine. As noted above, lamotrigine decreased valproate concentration. Phenytoin and carbamazepine decrease and valproate increases concentrations of lamotrigine. Lamotrigine is approximately 55% bound to human plasma proteins, so drug interactions secondary to binding displacement are not expected. No clinical value has yet been shown from monitoring plasma concentrations of lamotrigine. Its potential interactions with other drugs should be monitored by close clinical observation. The drug interactions of lamotrigine are summarized in Table 19.

Topiramate is an anticonvulsant with possible mood-stabilizing effects. When combined with other anticonvulsants, such as carbamazepine, phenobarbital, or primodone, topiramate has no effect on their concentrations. Nor does it have clinically relevant effects on plasma levels of classical neuroleptics, TCAs, theophylline, and warfarin. However, concomitant use of this compound with central nervous system (CNS) depressants can cause excessive sedation. When combined with acetazolamide or other carbonic anhydrase inhibitors, it can increase the risk of renal stones. Also, topiramate can interfere with the efficacy of contraceptive medication by decreasing levels of ethinyl estradiol by one third (Table 20).

Gabapentin has been reported to have mood stabilizing effects and to be effective for social phobia. Gabapentin is not metabolized by the liver and has no significant pharmacokinetic interactions. Its elimination is reduced in patients with impaired renal function. Gabapentin does not interact with hepatic enzymes, causing neither inhibition nor induction.
 

Psychostimulants

The psychostimulants methyl-phenidate, dextroamphetamine, and pemoline are among the most common medications used in child and adolescent psychiatry, and are often used in combination with other medications. A variety of case reports describe suspected metabolic drug interactions, but sparse data from systematic study are available. Methylphenidate appears to be involved primarily in pharmacokinetic interactions suggestive of CYP inhibition, while dextroamphetamine and pemoline are more often involved in apparent pharmacodynamic interactions. Selected interactions are summarized in Table 21.

Methylphenidate is highly metabolized but the specific enzymes involved have not been characterized. A pharmacokinetic interaction study observing methylphenidate concentration with and without quinidine found no evidence for the involvement of CYP 2D6 in its metabolism. Methylphenidate plasma concentration monitoring is seldom practiced clinically. The drug’s reported interactions all involve the effect of methylphenidate on the disposition of other drugs. No reports have been published that document alterations in methylphenidate concentration. Potential drug interactions should be monitored by careful patient observation of signs and symptoms suggestive of enhanced or diminished effects.
 

Modafinil is a recently introduced psychostimulant labeled for the treatment of narcolepsy. It may find use as a treatment for attention-deficit/hyperactivity disorder and other conditions. In vitro examination of its enzyme inductive/inhibitory effects has found little evidence for potential drug interactions (Table 22).

Anxiolytics/Hypnotics

The drugs used as anxiolytics are primarily the benzodiazepines and buspirone. The benzodiazepines zolpidem and zaleplon are used as hypnotics. Their interactions are summarized in Tables 23, 24, and 25. The benzodiazepines increase the sedative and CNS-depressive effects of other drugs. Some metabolic interactions have been documented (eg, alprazolam and diazepam concentrations increased when coadministered with CYP 3A4 inhibitor/antidepressants—nefazodone, fluoxetine, and fluvoxamine). Dosage adjustments are necessary to avoid excessive effects. These interactions usually present clinically as an exaggeration of the expected pharmacologic effects (Table 26).

Zaleplon is a hypnotic agent indicated for the short-term management of insomnia. It is metabolized by CYP 3A4 with a short half-life of 1 hour. It has been shown to lack any pharamokinetic interaction with digoxin, ibuprofen, or thioridazine; however, it had an additive pharacodynamic effect with thioridazine on psychomotor testing. The short half-life of zaleplon should preclude most clinically significant interactions with CYP 3A4 inhibitors. Considerations that apply to zolpidem influence by CYP 3A4 inducers and inhibitors shoud also apply to zaleplon. In combination with alcohol or other CNS depressants, enhanced residual effects should be kept in mind.

 

Antipsychotic Agents

Drug interactions involving the conventional and atypical antipsychotics are summarized in Tables 25–31. These are all highly metabolized drugs producing multiple metabolites. The specific oxidizing enzymes for the metabolism of haloperidol and the atypical drugs have been reported, but fewer data are available for the older conventional drugs from which to predict drug-drug interactions. Hence, the interactions of the phenothiazines are grouped together while haloperidol and the newer drugs are considered separately.

Numerous drug interactions have been reported with the conventional antipsychotics. Antacids and anticholinergics may reduce their absorption. Formal pharmacokinetic studies have revealed mutual metabolic interactions with the TCAs, but dosage adjustments as a result are rarely considered in clinical practice. As these drugs are likely metabolized by several P450 enzymes, broad enzyme inducers, such as barbiturates, and inhibitors, such as cimetidine, predictably lead to altered plasma concentrations in the expected direction.

The metabolism of haloperidol has been studied for more than 30 years. One metabolite, reduced haloperidol, possesses 10% to 20% of the pharmacologic activity of haloperidol. The interconversion of haloperidol with its metabolite was initially hypothesized to involve CYP 2D6, based on evidence that haloperidol is apparently a CYP 2D6 inhibitor. Subsequent studies with poor and extensive CYP 2D6 metabolizers have failed to confirm evidence for CYP 2D6 involvement. There is more substantial evidence of CYP 3A4 and CYP 1A2 involvement in the metabolism of haloperidol. Rifampin, a potent CYP 3A4 inducer, decreases the concentration of haloperidol, as does carbamazepine. Nefazodone increases its concentration, as do fluoxetine and fluvoxamine, agents with CYP 3A4 inhibitory effects. Reduced haloperidol has recently been shown to be a potent CYP 2D6 inhibitor, which suggests a basis for interactions of haloperidol and CYP 2D6 substrates. Although long known to cause dose-related QTc interval prolongation, the package insert of Mellaril (thioridazine) was recently changed to reflect warnings that the CYP 2D6-mediated metabolism of thioridazine results in elevated drug plasma concentrations in patients with CYP 2D6 deficiency or in patients receiving drugs that potently inhibit CYP 2D6. Thioridazine is now contraindicated by its manufacturer with certain other drugs, including fluvoxamine, propranolol, pindolol, and any drug that inhibits CYP 2D6 (paroxetine, fluoxetine, quiaidine).

Clozapine was the first atypical antipsychotic marketed in the US. It undergoes extensive hepatic metabolism to over 10 metabolites in humans. Multiple CYP enzymes are involved in its metabolism; however, two prominent enzymes are CYP 1A2 and CYP 3A4. There is less evidence for involvement of CYP 2D6. Clozapine disposition was found to co-vary with CYP 1A2 activity, and fluvoxamine has caused robust increases in clozapine and desmethylclozapine plasma concentrations. Sertraline, paroxetine, and fluoxetine have been reported to increase plasma concentrations of clozapine. Reports are available in which coadministration of erythromycin, a relatively specific inhibitor of CYP 3A4, resulted in significant increase in clozapine concentration. Additionally, coadministration of clozapine with carbamazepine and rifampin has been shown to diminish clozapine concentration. Because the plasma concentration of clozapine has been related to its antipsychotic effect in more than six controlled studies, concomitant use with inducers or inhibitors should be accompanied by plasma concentration and clinical monitoring.

Risperidone produces a pharmacologically active metabolite, 9-hydroxy-risperidone, mediated by the actions of CYP 2D6. Its formation is highly correlated with the patient’s phenotype. Combining risperidone and its metabolite in poor or extensive CYP 2D6 metabolizers did not affect the overall pharmacologic effects. These findings suggest that CYP 2D6 inhibitors will interact to alter the plasma concentration of risperidone, but its effects may be unchanged. No routine dosage adjustments are recommended for coadministration of risperidone with CYP 2D6 inhibitors. An interaction with carbamazepine has been reported by the manufacturer, but confirmatory reports of patient complications are lacking. Risperidone’s metabolism is mediated to a minor degree by CYP 3A4. Drugs that induce/inhibit CYP 3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions appears to be minimal. Multiple studies and case reports document a lack of significant problems when combining risperidone with SSRIs. Overall, risperidone appears to have a relatively benign drug interaction profile.

Olanzapine undergoes extensive hepatic metabolism, with at least 10 metabolites identified. Principal enzymatic pathways involve CYP 1A2 and glucuronidation. Although plasma concentration monitoring of olanzapine is not a routine clinical procedure, preliminary data suggest that plasma concentrations may predict clinical response. Theoretical drug interactions with olanzapine can be proposed, but few actual reports are available.

In vitro studies indicate that CYP 3A4 is the primary enzyme involved in the metabolism of quetiapine. A lesser role has been found for CYP 2D6. Coadministration of the CYP 3A4 inducer phenytoin resulted in a 5-fold increase in the clearance of quetiapine; however, coadministration of cimetidine did not significantly affect its steady-state concentration. Unexpectedly, thioridazine, which is regarded as a CYP 2D6 inhibitor, decreased the concentration of quetiapine. Other interactions are theoretical involving CYP 3A4 inducers or inhibitors. Because the plasma concentration of quetiapine has not been reported to be correlated with clinical responses, monitoring cannot be recommended at the present time.
 

Ziprasidone has been introduced for oral administration as an antipsychotic. Its major routes of elimination include metabolism by a non-P450 enzyme, aldehyde oxidase, and CYP 3A4 and CYP 1A2 oxidation. Ziprasidone had little in vitro inhibitory effects on the major P450 enzymes and would be expected to participate in few pharmacokinetic interactions (Table 32).

Cholinesterase Inhibitors

There are currently three cholinesterase inhibitors available for the treatment of Alzheimer’s disease (AD): donepezil, tacrine, and rivastrigmine. These drugs work by enhancing cholinergic function, and are based on theories that some AD symptoms are due to a deficiency in cholinergic neurotransmission. Due to this mechanism of action, these drugs will interfere with and be counteracted by the activity of any anticholinergic medications, and this combination should therefore be avoided. Similarly, a synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol. They are, therefore, likely to exaggerate succinylcholine-type muscle relaxation during anesthesia, and a clinically appropriate washout period is recommended. No in vivo clinical trials have investigated the effect of donepezil on the clearance of cisapride, terfenadine (CYP 3A3/4), or CYP 2D6 substrates. However, in vitro studies show a low rate of binding to these enzymes, which indicates little likelihood of interference. Ketoconazole and quinidine, inhibitors of CYP 450, 3A4, and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect is unknown. Inducers of CYP 2D6 and CYP 3A4 (eg, phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil.
 

Coadministration of tacrine with theophylline increases theophylline plasma concentrations via competition with CYP 1A2. Theophylline concentration levels should therefore be monitored upon coadministration, and the dose of theophylline should be reduced as necessary. Formal interaction studies suggest that donepezil does not have a significant interaction with digoxin, warfarin, theophylline, and cimetidine. Rivastigmine is minimally metabolized by CYP enzymes, has low protein binding, a short plasma half-life, and a relatively short duration of action. Combination with a variety of drugs has not revealed any significant pattern of pharmacodynamic drug interactions. Rivastigmine is not thought to have CYP drug interactions. No pharmacokinetic interactions were apparent with diazepam, digoxin, fluoxetine, or warfarin. Selected drug interactions related to the cholinesterase inhibitors used in the treatment of AD are summarized in Table 33.
 

 

Anorectic/Anti-Obesity Agents

The anorectic agents should not be administered with MAOIs. It is advised to wait 14 days following the administration of an MAOI before taking these drugs.
 

Phentermine may decrease the hypotensive effect of adrenergic neuron-blocking drugs such as guanethidine. Combination with phentermine may result in overstimulation, restlessness, dizziness, insomnia, or tremors at some doses. Phentermine may alter insulin requirements for patients with diabetes mellitus. Related drug interactions are highlighted in Table 34.

Sibutramine, a newer anorectic agent that works as a sympathomimetic amine, is expected to have side effects similar to other anorectic agents. It has potential for causing hypertension, should not be combined with MAOIs, and may cause serotonin syndrome when combined with SSRIs.
 

Orlistat, a new selective inhibitor of GI lipases, reduces dietary fat absorption and could potentially interfere with the absorption of coadministered drugs. It has been shown not to affect the absorption of oral contraceptives, nifedipine, atenolol, furosemide, captopril, phenytoin, warfarin, and vitamin A. It did significantly reduce the absorption of vitamin E, which is taken by some patients for treatment of movement disorders. The influence, if any, on absorption of other drugs taken for psychotropic effects has not been reported.
 

Methadone

Methadone is a synthetic opiate agonist that is used in psychiatry primarily in the detoxification and maintenance treatment of opiate addiction, as well as in chronic pain management programs. Despite the therapeutic use of methadone for nearly 50 years, details of its pharmacokinetics are incomplete. Consequently, regimens for methadone are often empirical, titrating dosage against clinical response. Methadone appears to be metabolized extensively by CYP 3A4 and secondarily by CYP 2D6. Methadone is a mild in vitro inhibitor of CYP 2D6, which explains its ability to increase desipramine plasma concentration. It has also blocked nifedipine oxidation, a CYP 3A4 pathway in vitro, but case reports of methadone inhibiting CYP 3A4 substrates are lacking. Fluvoxamine, more potently than fluoxetine, increased methadone plasma concentration when added to chronic therapy. Thus, any CYP 3A4 inhibitors should be used with caution in patients treated with methadone. Table 35 lists selected methadone interactions.

Conclusions

Clinicians need to be alert for possible interactions in patients using multiple drugs. Many drug interactions probably cause subtle effects that are not recognized clinically. Most drug interactions are not life-threatening. Nevertheless, some interactions cause side effects that interfere with compliance or cause a decrease in drug efficacy. Whatever their consequences, drug-drug interactions represent a major public health concern. Preventable drug therapy problems increase medical costs by nearly $100 billion annually, and about 20% of that additional cost is attributed to drug-drug interactions.
 

Much of the emphasis on drug interactions focuses on the CYP system. The importance of other factors as determinants of plasma drug concentrations is underscored by findings involving serum protein binding and extrahepatic drug disposition. For example, serum α-1-acid glycoprotein, a serum protein to which drugs bind, fluctuates in various disorders. It is elevated in depression, arthritis, and autoimmune disorders. These elevated levels alter the disposition and actions of highly bound drugs, such as the TCAs and the SSRIs. The lungs have also been found to function as a reservoir for drugs, with high affinity for the serotonin transporter. Another agent may displace an antidepressant that has accumulated in the lungs, with a resultant increase in plasma concentrations and possible toxicity.
 

No discussion of potential psychotropic drug interactions can be all-inclusive. Current understanding of the variables that contribute to drug pharmacokinetics and pharmacogenetics is incomplete, and no interactions can be predicted or ruled out with absolute certainty. Drugs known to be potent enzyme inhibitors may fail to produce a predicted interaction, while a supposedly “clean” drug can cause a fatal interaction. New information emerges daily. Readers are encouraged to supplement this article with other sources and to be familiar with drug interactions listed in the product information sheets included in the packaging of each drug they prescribe.   PP
 

References

1. Akula SK, Rege AB, Dreisbach AW, Dejace PM, Lertora JJ. Valproic acid increases cerebrospinal fluid zidovudine levels in a patient with AIDS. Am J Med Sci. 1997;313:244-246.
2. Apseloff G, Wilner KD, Gerber N, Tremaine LM. Effect of sertraline on protein binding of warfarin. Clin Pharmacokinet. 1997;32(suppl 1):37-42.
3. Barbhaya RH, Shukla UA, Kroboth PD, Greene DS. Co-administration of nefazodone and benzodiazepines: a pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol. 1995;15:320-326.
4. Bergstorm RF, Goldberg MJ, Cerimele BJ, Hatcher BL. Assessment of the potential for pharmacokinetic interaction between fluoxetine and terfenadine. Clin Pharmacol Ther. 1997;62:643-651.
5. Bergstrom RF, Peyton AL, Lemberger L, et al. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther. 1992;51:239-248.
6. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet. 1997;32:210-258.
7. Brosen K. Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet. 1990;18:220-239.
8. Curry SH, DeVane CL, Wolfe MM. Cimetidine interactions with amitriptyline. Eur J Clin Pharmacol. 1985;29:429-433.
9. DeVane CL. Principles of pharmacokinetics and pharmacodynamics. In: Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology. 2nd ed. New York, NY: APA Press. 1998:155-169.
10. DeVane CL. Clinical implications of dose-dependent cytochrome P450 drug-drug interactions with antidepressants. Hum Psychopharmacol. 1998;13:329-336.
11. Edge SC, Markowitz JS, DeVane CL. Clozapine drug-drug interactions: a review of the literature. Hum Psychopharmacol. 1997;12:5-20.
12. Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system: the role of cytochrome P450 2D6. Clin Pharmacokinet. 1995;29(suppl 1):10-19.
13. Finley PR, Warner MD, Peabody CA. Clinical relevance of drug interactions with lithium. Clin Pharmacokinet. 1995;29:172-191.
14. Flockhart DA, Richard E, Woosley RL, Pearle PL, Drici MD. A metabolic interaction between clarithromycin and pimozide may result in cardiac toxicity [abstract]. Clin Pharmacol Ther. 1996;59:189.
15. Greene DS, Salazar DE, Dockers RC, Kroboth P, Barbhaya RH. Co-administration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazam. J Clin Psychopharmacol. 1995;15:399-408.
16. Ketter TA, Callahan AM, Post R. Nefazodone relief of alprazolam interdose dysphoria: a potential therapeutic benefit of 3A3/4 inhibition [letter]. J Clin Psychiatry. 1996;57:307.
17. Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol. 1995;15:387-398.
18. Korinthenberg R, Haug C, Hannak D. The metabolism of carbamazepine to CBZ-10,11 epoxide in children from the newborn age to adolescence. Neuropediatrics. 1994;25:214-216.
19. Martin DE, Zussman BD, Everitt DE, Benincosa LJ, Etheredge RC, Jorkasky DK. Paroxetine does not affect the cardiac safety and pharmacokinetics of trefenadine in healthy adult men. J Clin Psychopharmacol. 1997;17:451-459.
20. Maynard GL, Soni P. Thioridazine interferences with imipramine metabolism and measurement. Ther Drug Monitor. 1996;18:729-731.
21. McCarthy R. Seizure following smoking cessation in a clozapine responder. Pharmacopsychiatry. 1994;27:210-211.
22. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry. 1996;153:311-320.
23. Owen JR, Nemeroff CB. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depress Anxiety. 1998;7(suppl 1):24-32.
24. Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of desipramine co-administered with sertraline or fluoxetine. J Clin Psychopharmacol. 1994;14:90-98.
25. Rau SE, Bend JR, Arnold MO, Tran LT, Spence JD, Bailey DG. Grapefruit juice—terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clin Pharmacol Ther. 1997;61:401-409.
26. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet. 1996;31:198-214.
27. Sporer KA.?The serotonin syndrome: implicated drugs, pathophysiology and management. Drug Safety. 1995;13:94-104.
28. Suhara T, Sudo Y, Yoshida K, et al. Lung as reservoir for antidepressants in pharmacokinetic drug interactions. Lancet. 1998;351:332-335.
29. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exp Ther. 1994;268:1278-1283.
30. Wilkinson GR. Plasma and tissue binding considerations in drug disposition. Drug Metab Rev. 1983;14:427.
31. Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR. Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol Ther. 1996;60:48-53.
32. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22:1-21.
33. Chang TKH, Weber GF, Crespi CL, Waxman DJ. Differential activation of cyclophoshamide and ifosphamide by cytochromes P450 2B and 3A in human liver microsomes. Can Res. 1993;53:5629-5637.
34. Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol. 2001;21:500-515.
35. Miners JO, Mackenzie PI. Drug glucuronidation in humans. Pharmacol Ther. 1991;51:347-369.
36. Green MD, Tephley TR. Glucuronidation of amine substrates by purified and expressed UDP-glucuronosyltransferase proteins. Drug Metab Disp. 1998;26:860-867.
37. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther. 1998;64:661-671.
38. Hartman D, Guzelhan C, Zuiderwijk PB, Odink J. Lack of interaction between orlistat and oral contraceptives. Eur J Clin Pharmacol. 1996;50:421-424.
39. Weber C, Tam YK, Schmidke-Schrezenmeier G, Jonkmann JH, van Brummelen P. Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers. J Clin Pharmacol. 1996;51:87-90.
40. Melia AT, Mulligan TE, Zhi J. Lack of effect of orlistat on the bioavailability of a single dose of nifedipine extended-release tablets in healthy volunteers. J Clin Pharmacol. 1996;36:352-355.
41. Zhi J, Melia AT, Guerciolini R, et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol. 1996;36:659-666.
42. Melia AT, Mulligan TE, Zhi J. The effect of orlistat on the pharmacokinetics of phenytoin in healthy volunteers. J Clin Pharmacol. 1996;36:654-658.
43. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamin A and E in healthy volunteers. J Clin Pharmacol. 1996;647-653.
44. Haffen E, Vandel P, Bgonin B, Vandel S. Citalopram pharmacokinetic interaction with clomipramine. UDP-glucuronosyltransferase inhibition??A case report. Therapie. 1999:54:767-770.
45. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (hypericum perforatum). Clin Pharmacol Ther. 1999;66:338-345.
46. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John’s wort. Lancet. 2000;355(9203):547-548.
47. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophyline. Ann Pharmacotherapy. 1999;33:502.
48. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart transplant rejection due to St. John’s wort. Lancet. 2000;355(9203):548-549.
49. Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC. Effect of St. John’s wort (hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci. 2000;66:PL133-139.

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Antidepressant Withdrawal Syndrome in Two Patients Taking Fluoxetine

John Norton, MD

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Primary Psychiatry. 2003;10(3):51-52

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Recognizing and Managing the Treatment-Disruptive Effects of Adult Attention-Deficit Disorder

Marc D. Schwartz, MD

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Primary Psychiatry. 2003;10(3):59-62

 

Dr. Schwartz is director of the Adult Attention-Deficit Center, psychiatric consultant to the Clinical Psychology Outpatient Clinic, and research associate at Yale University, all in New Haven, Connecticut.

Disclosure: The author reports no financial, academic or other support of this work.

Please direct all correspondence to: Marc D. Schwartz, MD, 26 Trumbull St, New Haven, CT 06511; Tel: 203-562-9873; Fax: 203-624-2422; E-mail: mschwartzmd@hotmail.com


 

Abstract

What treatment-disruptive behaviors suggest that an adult being treated for a disorder such as depression or anxiety may also have attention-deficit disorder (ADD)? How can clinicians manage their clinical contacts with comorbid ADD patients so that these behaviors do not undermine treatment? This article describes certain behaviors that may interfere with the psychological therapy of adults. Once clinicians recognize that these behaviors are symptoms of ADD, they can employ specific strategies to manage them more effectively. In addition, once comorbid ADD is diagnosed, other treatments, including the use of medications for ADD, can be considered. Under these circumstances, treatment is more likely to succeed.

 

Introduction

Imagine that you have been seeing a patient with anxiety or depression. The sessions went well at first, but now, a month or two later, you have become concerned about changes in his treatment behavior. The patient has started arriving late for sessions and rather than pursuing important treatment topics, the patient now begins sessions with social chit-chat. While these verbal communications had been fairly well organized at first, they are now often filled with anecdotes and digressions. Shortly before a scheduled session, the patient leaves a phone message canceling because of an unavoidable conflict. The patient asks to be called back but does not leave a telephone number. When he arrives late for the following session, you gently start exploring whether these behaviors might represent resistance to treatment, but this does not seem to be successful. Another month goes by, and the bill has not been paid.

Treatment-disruptive behaviors like these are very common among adults with comorbid ADD. Until around 10 years ago, it was generally thought that ADD was basically a childhood disorder that resolved during adolescence and did not persist into adulthood.1 This belief is reflected in the fact that the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition2 (DSM-IV) makes only one passing reference to adults in its description of the disorder.

Over the past 7 years, a number of studies have demonstrated that, while hyperactivity disappears in most children with ADHD during adolescence, 70% to 80% continue to suffer from attentional and other cognitive deficits into adulthood.3

Adult ADD is frequently comorbid with other disorders that bring people to treatment, including depression, anxiety, bipolar II disorder, substance abuse, and alcoholism.4 Many psychiatrists practicing today were trained during the era in which the disorder was thought not to exist. In part, because “we do not see what we do not look for,”2 the disorder has often been overlooked in patients treated for comorbid disorders. This article presents methods for recognition of comorbid ADD in adults who are in treatment and suggests strategies for making their treatment more successful.

 

Recognizing Comorbid ADD

There are a number of reasons why comorbid ADD is difficult to recognize in patients being seen in treatment for a comorbid disorder:

(1) Patients with ADD are usually unaware that they have the disorder. Most often, they view their own distracted behavior as frequent interruptions of others, or lack of attention to details merely as bad habits. Under these circumstances they are not likely to mention these ADD symptoms during initial clinical visits. Without this information, the clinician may not consider the diagnosis of ADD.

(2) The cognitive dysfunctions of ADD (such as poor organization, memory difficulties, distractibility, and impulsivity) are not usually evident during diagnostic and early treatment sessions, when patients are generally focused and attentive.

(3) When patients become more comfortable later in therapy, ADD symptoms that emerge are often mistaken for poor motivation, irresponsibility, or resistance to treatment.

When therapy becomes disrupted by certain patient behaviors, clinicians need to be alert to be aware of the possibility that these behaviors may be symptoms of ADD.

 

DSM-IV Symptoms and Treatment-Resistant Behaviors

Individuals with ADD often have difficulty organizing tasks and activities.2 Most people are able to keep the main idea they are discussing firmly in mind even while they occasionally digress. However, many patients with ADD cannot do this and their narratives during sessions become filled with irrelevant detail. Perhaps after talking for a while, patients may return to their point, but a great deal of time can be wasted. Poorly organized, circumstantial, and tangential speech is as striking in many patients with ADD as in those with schizophrenia.

Individuals with ADD often do not follow through.2 Patients may not follow up on significant topics addressed in prior sessions and may fail to pursue important issues in treatment.

Individuals with ADD often talk excessively.2 Patients may be garrulous or engage in extended social chitchat. Sometimes their speech will meander from one subject to another in a very fluid way, with no apparent boundary between topics. One patient compared his verbal style to channel surfing. Conversely, when their attention is captured by an idea, they may be unable to move on to another and will elaborate long after they have made their point.

They often interrupt and may not attend when spoken to directly.2 Patients with ADD frequently ignore questions, comments, and interpretations made by their treating clinician.

They often dislike tasks that require sustained mental effort.2 Patients with ADD may have difficulty maintaining energy, focus, and motivation in treatment. They may forget their treatment goals or change them with little or no discussion with the treating clinician. Fluctuations in their motivation may contribute to their periodically missing appointments, losing interest in therapy, and even forgetting why they entered treatment to begin with. This can be particularly troublesome to clinicians who invest a great deal of effort in helping these frequently disorganized patients manage their lives. When patients fail to follow through with plans that were carefully worked out with them, the therapist may feel disappointed, even demoralized.

They are often forgetful.2Patients with ADD often forget to bring up significant events in their lives, like major disputes with their spouse or significant setbacks at work. Distracted by their own amusing anecdotes, they may even lose track of issues they have discussed in the current session. They may forget to take their medication or neglect to call for a refill until they run out over the weekend. When leaving phone messages for the therapist, they frequently forget to leave their telephone numbers. They often fail to pay their bills on time and may not submit their bills for insurance reimbursement until it is too late.

There are also other treatment-resistant behaviors as well. For examples, ADD patients exhibit a number of time-related problems. Not infrequently they forget appointments or call to cancel shortly before the scheduled visit time, citing an unavoidable conflict or unanticipated event. If a patient being treated for depression or anxiety manifests this behavior more than once or twice in a period of a month of two, it should alert the clinician to the possibility that the patient has comorbid ADD.

In addition, ADD patients frequently come late for sessions. They may forget or misremember appointment times, and may arrive at the wrong hour or even the wrong day. Reflecting their overall difficulty with time, they often do not “pace” treatment sessions so take longer to get started talking about therapy issues. They frequently have little awareness of the passage of time and do not sense when an office visit is nearing its end. They may not bring up important issues until the clinician states that the session is over. Many, if not interrupted, will talk beyond the scheduled end time, never glancing at their watches or a clock. Even when they are reminded that the time is up, they may continue talking (Table 1).

 

Differential Diagnosis

The disruptive behaviors described are manifestations of disorders in cognitive executive functioning. Whenever such disordered cognitive functions are seen, it is important to determine whether they are caused by ADD or by another disorder. In outpatient treatment, the most common disorders that may present with dysfunctions similar to those seen with ADD include hypomania/mania, mild dementia, depression, and schizophreniform disorders. Resistance to treatment can also be difficult to distinguish from ADD. The main considerations in making the differential diagnosis are as follows:

 

Hypomania/mania

Patients with mania or hypomania differ from those with ADD by having the following symptoms: an episodic rather than chronic course; increased or fluctuating energy; grandiosity and psychotic features; a family history of bipolar disorder; and decreased need for sleep. It should be noted that ADD and bipolar disorder are sometimes comorbid.

 

Dementia, including Alzheimer’s

Patients with dementia are more likely than those with ADD to have normal premorbid executive functioning; progressively worsening symptoms; more difficulties finding words and remembering names; and more severe recent memory problems.

 

Depression

Patients with depression may have memory problems and difficulties staying focused, but they differ from those with ADD by being quieter, less chatty, and sad; more likely to exhibit physical symptoms such as loss of appetite, weight loss, and difficulties with sleep; and more likely to have a personal and family history of depression. When a patient is both depressed and has disordered executive functions, it is generally best to treat the depression first to see if executive functions return to normal when the depression clears. If they do not, ADD diagnosis and treatment should be considered.

 

Schizophrenia/Schizophreniform Disorders

Schizophrenic or schizophreniform patients differ from those with ADD by being more likely to have positive or negative symptoms of schizophrenia; less likely to interrupt or be forgetful; and less likely to be impulsive.

 

Resistance to Treatment

ADD symptoms can easily be mistaken for treatment resistance (Table 2). Patients exhibiting treatment resistance are more likely to achieve conscious or unconscious gain by disrupting the treatment and are more likely to modify their behavior once they understand its motivation.

 

General Principles for Managing Comorbid ADD

Once the diagnosis of ADD is made, patients should be informed that they have the disorder and educated about its causes, symptoms, treatment, and course.5 The use of appropriate medication for ADD should be discussed.6 For most patients, medication, when effective, is the most rapidly acting and least expensive treatment available for the disorder. A positive response to stimulants can reduce or eliminate many treatment-disruptive symptoms. If medication is prescribed, its use and effectiveness should be regularly and carefully monitored. Patients with ADD often do not fully appreciate the nature of their deficits and are not always able to monitor accurately the dysfunctions caused by their deficits. For this reason, feedback about treatment effects should be obtained not only from the patient but, if possible, from an objective observer chosen by the patient.

When treating individuals with comorbid ADD, the clinician should keep in mind that they, like patients with a stroke or other neurological problem, have only a limited ability to overcome the cognitive difficulties that contribute to their interrupting, forgetfulness, lateness, and other ADD symptoms.

 

Specific Strategies for Managing Comorbid ADD

The clinical literature describing how to recognize and deal with comorbid ADD is sparse. With few exceptions,7 the focus of most articles on the topic is either on the treatment of ADD comorbid with substance use,8 or on strategies designed to modify behavior or thought patterns that disrupt patients’ lives outside of treatment.9

Clinicians can utilize a number of strategies to manage treatment-disruptive ADD behaviors.

 

Keep Sessions Organized

If the patient is unable to keep his or her presentation organized, the therapist may find it helpful to solicit a list of topics that the patient would like to address at the beginning of sessions, and suggest any important items that the patient omitted toward the end of the session. It is best to write down the items and defer discussion of them until the list has been completed.

The patient and clinician can prioritize and order the topics, scheduling how much time to allocate for each before the session begins. After using this method for a while, many patients get better at keeping the sessions organized and, with some, the structured planning becomes less necessary.

 

Actively Pursue Important Topics

In view of the frequency with which ADD patients forget, the clinician should feel free to bring up important issues if the patient fails to do so.

Because ADD patients are more likely than others to fail to hear or understand important comments, the clinician should monitor how well their patients understand what he or she said. It may be useful to review the topics discussed at the end of the session and/or at the beginning of the subsequent session.

 

Limit Circumstantial Talk

When patients with ADD talk excessively or get off the topic, the clinician’s desire to let the patient get to his point at his own speed may result in a great deal of wasted time. In these circumstances it may be more helpful for the therapist to gently shift attention back to the main topic, remind the patient of scheduled agenda, or merely to state the point that the patient was trying to make.

It can be helpful to tactfully let the patient know that talking at length without getting to the point is a common symptom of ADD. If the patient accepts this, he or she may better understand and cooperate with the clinician’s efforts to get the discussion back on track.

 

Deal With Vacillating Motivation

It is sometimes helpful to write down a statement of the patient’s goals and reasons for being in therapy. This statement can later be used to orient the treatment when the patient shows signs of treatment-disruptive behavior. Sometimes, the best one can do is to wait patiently for motivation to return. If the patient and therapist are aware of the fact that this issue is common among patients with comorbid ADD and not a manifestation of resistance or a moral deficiency, it can help the clinician and patient through fallow periods to a time when more active treatment of the primary disorder can be resumed.

 

Help the Patient Listen

Interrupting and not listening are classical symptoms of ADD, yet they can come as a challenging surprise to the clinician when they are manifested in therapy, where patients are usually politely attentive. Once the clinician recognizes that a patient’s difficulty shifting from talking to listening is a manifestation of ADD and not resistance to therapy or impoliteness, it becomes easier to deal with the behavior calmly and persistently.

 

Deal With Lateness and Absences

To avoid excuses for lateness and fruitless discussions about treatment motivation, it is helpful to point out to the patient that these behaviors are common in ADD. At the same time, it is important to have a clear policy about ending sessions on time even when the patient has arrived late. If the patient is consistently late, it is sometimes useful to ask him or her to arrive 10 minutes early to ensure that the patient receives the benefit of a full session.

 

Reduce the Frequency of Absences

To minimize the number of missed appointments, the clinician can implement any or all of the following strategies: have the patient write down appointment times while still in the office; have an unambiguous agreement about charges for missed sessions; make all appointments for the same time and day of the week, if possible; and offer forgetful patients the option to be phoned with a reminder on the day before the appointment.

 

Pace Sessions

To allow time for important issues to be dealt with during the treatment sessions, it is wise to keep to the planned agenda and schedule. Sometimes it is helpful to notify the patient when there are 10 minutes left in the session. Unfortunately, this will not stop some patients from continuing to talk until the clinician firmly ends the session.

 

Conclusion

Unrecognized comorbid ADD often undermines the treatment of adults being seen for other psychological disorders. If clinicians are familiar with the treatment-disruptive symptoms of ADD, they can employ effective strategies to control them. These strategies require that therapists be more managerial than usual to ensure that patients stay organized, pursue relevant therapy issues, and begin and end sessions when scheduled. Once comorbid ADD is recognized, other treatments, including specific medication for ADD, can also be considered. Under these circumstances, treatment is more likely to succeed. PP

 

References

1. Mattes JA, Boswell L, Oliver H. Methylphenidate effects on symptoms of attention deficit disorder in adults. Arch Gen Psychiatry. 1984;41:1059-1063.

2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:78-85.

3. Biederman, J, Faraone SV, Milberger S, et al. Predictors and persistence and remission of ADHD into adolescence: results of a four year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351.

4. Weiss M, Hechtman LT, Weiss G. ADHD in Adulthood: A Guide to Current Theory, Diagnosis and Treatment. Baltimore, MD: Johns Hopkins Press; 1999.

5. Barkeley RA. Attention Deficit Hyperactivity Disorder. New York, NY: Guilford Press; 2000.

6. Weiss G, Hechtman L. Hyperactive Children Grow Up. 2nd ed. New York, NY: Guilford Press; 1993.

7. Ratey J, Greenberg MS, Bemporad JR, et al. Unrecognized attention-deficit disorder in adults presenting for outpatient psychotherapy. J Child Adolesc Psychopharmacol. 1992;2:267-275.

8. Aviram RB, Rhum M, Levin FR. Psychotherapy of adults with comorbid attention deficit hyperactivity disorder and psychoactive substance use disorder. J Psychother Pract Res. 2001;10:179-186.

9. Weinstein CS. Cognitive remediation strategies: an adjunct to the psychotherapy of adults with attention-deficit disorder. J Psychotherapy Pract Res. 1994;3:44-57.

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Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications

Alvaro Camacho, MD

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Primary Psychiatry. 2004;11(9):42-46
 

Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.

Disclosure: The author reports no financial, academic, or other support of this work. 

Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: acamacho@ucsd.edu.
 

Focus Points

• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
• Alcohol and stimulants are the most commonly abused substances in patients with bipolar disorder.
• Patients with bipolar disorder and substance abuse should be started sooner rather than later on a mood stabilizer, despite the risks and side effects associated with the particular medication.
• Clinicians should pay close attention to premorbid dysphoria and irritability associated with states of withdrawal from substances, which could be the prodromal phase of a bipolar depressive episode; if left untreated, further relapse and exacerbation of mood symptoms is possible.
• Bipolar and substance abuse conditions may share a common diathesis, which may in part explain the overlap in therapeutic modalities.

 

Abstract

The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.

 

Introduction

 

Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.

 

Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.

 

This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.

 

Neurobiology of Addiction

 

Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7

 

Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11

 

CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.

 

Epidemiology

 

Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17

 

A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.

 

Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).

 

Clinical Correlation

 

The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.

 

Emerging Treatment Approaches

 

Treatment with Mood Stabilizers

 

Divalproex Sodium

 

The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.

 

Carbamazepine

 

A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.

 

Lithium

 

Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.

 

Gabapentin

 

Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38

 

Oxcarbazepine

 

Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41

 

Topiramate

 

Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45

 

Lamotrigine

 

Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47

 

Zonisamide

 

This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.

 

Other Potential Treatments

 

Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55

 

However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.

 

New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.

 

Discussion

 

This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24

 

A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62

 

When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65

 

Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68

 

Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.

 

Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80

 

Conclusion

 

To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP

 

References

 

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47. Southam E, Kirkby D, Higgins GA, Hagan RM. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats. Eur J Pharmacol. 1998;358(1):19-24.
48. McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65(1):50-56.
49. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.
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55. Batki SL, Moon J, Delucchi K, et al. Methamphetamine quantitative urine concentrations during a controlled trial of fluoxetine treatment. Preliminary analysis. Ann N Y Acad Sci. 2000;909:260-263.
56.  Brown ES, Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord. 2002;4(6):406-411.
57.  Kampman KM, Pettinati H, Lynch KG, Sparkman T, O’Brian CP. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend. 2003;70(3):265-273.
58. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Addict Relat Clin Probl. 2003;5(2):7-98.
59. Khantzian EJ. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatry. 1997;4(5):231-244.
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61. Helfrich AA, Crowley TJ, Atkinson CA, Post RD. A clinical profile of 136 cocaine abusers. NIDA Res Monogr. 1983;43:343-350.
62. Craig RJ. Psychological functioning of cocaine free-basers derived from objective psychological tests. J Clin Psychol. 1988;44(4):599-606.
63. van Harten PN, van Trier JC, Horwitz EH, Matroos GE, Hoek HW. Cocaine as a risk factor for neuroleptic-induced acute dystonia. J Clin Psychiatry. 1998;59(3):128-130.
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67.  Schuckit MA, Tipp JE, Bucholz KK, et al. The life-time rates of three major mood disorders and four major anxiety disorders in alcoholics and controls. Addiction. 1997;92(10):1289-1304.
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70. Bschor T, Muller-Oerlinghausen B, Ulrich G. Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: a case study. Clin Electroencephalogr. 2001;32(1):36-39.
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Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications

Alvaro Camacho, MD

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Primary Psychiatry. 2004;11(9):42-46
 

Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.

Disclosure: The author reports no financial, academic, or other support of this work. 

Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: acamacho@ucsd.edu.
 

Focus Points

• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
• Alcohol and stimulants are the most commonly abused substances in patients with bipolar disorder.
• Patients with bipolar disorder and substance abuse should be started sooner rather than later on a mood stabilizer, despite the risks and side effects associated with the particular medication.
• Clinicians should pay close attention to premorbid dysphoria and irritability associated with states of withdrawal from substances, which could be the prodromal phase of a bipolar depressive episode; if left untreated, further relapse and exacerbation of mood symptoms is possible.
• Bipolar and substance abuse conditions may share a common diathesis, which may in part explain the overlap in therapeutic modalities.

 

Abstract

The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.

 

Introduction

 

Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.

 

Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.

 

This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.

 

Neurobiology of Addiction

 

Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7

 

Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11

 

CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.

 

Epidemiology

 

Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17

 

A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.

 

Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).

 

Clinical Correlation

 

The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.

 

Emerging Treatment Approaches

 

Treatment with Mood Stabilizers

 

Divalproex Sodium

 

The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.

 

Carbamazepine

 

A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.

 

Lithium

 

Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.

 

Gabapentin

 

Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38

 

Oxcarbazepine

 

Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41

 

Topiramate

 

Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45

 

Lamotrigine

 

Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47

 

Zonisamide

 

This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.

 

Other Potential Treatments

 

Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55

 

However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.

 

New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.

 

Discussion

 

This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24

 

A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62

 

When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65

 

Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68

 

Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.

 

Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80

 

Conclusion

 

To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP

 

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38. Raby WN, Coomaraswamy S. Gabapentin reduces cocaine use among addicts from a community clinic sample. J Clin Psychiatry. 2004;65(1):84-86.
39. Grunze H, Walden J. Relevance of new and newly rediscovered anticonvulsants for atypical forms of bipolar disorder. J Affect Disord. 2002;72(suppl 1):S15-S21.
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41. LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004;291(5):605-614.
42. Nemeroff CB. Safety of available agents used to treat bipolar disorder: focus on weight gain. J Clin Psychiatry. 2003;64(5):532-539.
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44. Komanduri R. Two cases of alcohol craving curbed by topiramate. J Clin Psychiatry. 2003;64(5):612.
45. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for the treatment of alcohol dependence: a randomized controlled trial. Lancet. 2003;361(9370):1677-1685.
46. Brown ES, Nejtek VA, Perantie DC, Orsulak PJ, Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. J Clin Psychiatry. 2003;64(2):197-201.
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49. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.
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Return

Focus Points

• The tolerability and adverse-effect profiles of the newer psychotropic drugs for bipolar disorder affect the therapeutic benefits of these agents.

• The ability of clinicians to provide optimal treatments after considering differential adverse effects and tolerability increases medication compliance in patients who might otherwise discontinue treatment due to adverse effects.

• Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic agents.

• Clinical decisions to switch primary medications due to adverse effects—rather than treat through adverse effects—must reflect careful balancing of drug efficacy (benefits) versus side-effect liability (costs).

Abstract

How do the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits? The growing range of pharmacotherapy options across all phases of bipolar illness should, ideally, enhance the ability of clinicians to provide optimal treatments while considering differential adverse effects and drug tolerability. Such approaches help to increase medication adherence in patients who might otherwise discontinue treatment due to adverse effects. Clinically diverse, often significant adverse effects are evident with both older and newer drug therapies for bipolar illness. Most notably, problems related to gastrointestinal upset, weight gain, glucose dysregulation, sexual dysfunction, cognitive impairment, dermatologic reactions, and central nervous system effects are a potential liability with numerous compounds. Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic agents. These include slow-dose escalations, preferential use of delayed-release formulations, and adjunctive treatments with additional agents. Clinical decisions to switch primary medications due to adverse effects—rather than treat through adverse effects—must reflect careful balancing of drug efficacy (benefits) versus side-effect liability (costs).

Introduction

Rates of medication nonadherence among patients with bipolar disorder are unacceptably high, ranging from 10% to 60% (median 40%) of patients discontinuing treatment.1 Evidence of this high rate was shown in a recent study of the bipolar medication lithium,2 which found that health maintenance organization enrollees with bipolar disorder discontinued lithium a median of only 72 days after starting it. With such high rates of treatment nonadherence in bipolar patients, it is therefore critical for clinicians to understand how the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits. As such, this article provides an overview of common adverse effects associated with current pharmacotherapies for bipolar disorder, and describes strategies for their management in order to optimize treatment outcomes.

Paradoxically, while psychotropic medications are prescribed in efforts to enhance patient functionality and quality of life, they may actually create new physical, cognitive, or other problems that can jeopardize treatment adherence and physical well-being (Table). In fact, patients may interpret the adverse effects of medications such as lithium as problems that mimic physical illness and may obscure diagnostic issues related to patients with bipolar disorder.3

Additionally, while current texts and guidelines caution against or limit the use of antidepressants in patients with bipolar disorder,4,5 data from the National Disease and Therapeutic Index indicate that antidepressants are prescribed more frequently than mood stabilizers.6 Therefore, common side effects associated with antidepressant use are also enumerated in this article.

Adverse Effects and Treatment Adherence

Among bipolar patients, attitudes and expectations about adverse effects appear to contribute more to medication nonadherence than do actual adverse effects themselves.7 That aside, the balance between therapeutic efficacy and adverse effects is illustrated in clinical trials that compare benefits versus dropout rates due to adverse effects. For example, a recent 18-month comparison of bipolar relapse prevention8 compared lithium or divalproex plus placebo or olanzapine. Although one might expect more dropout due to adverse effects among those taking more medications, trial completion was three times more likely for those on combination therapy (31.4%) than monotherapy (10.4%), while adverse effects were more common for those on monotherapy (9.8%) than combination therapy (16.7%). Similarly, Keck and colleagues9 found significantly greater medication adherence during combined maintenance treatment with lithium plus divalproex compared to either one alone, again suggesting that if combinations produce better efficacy than monotherapies, better efficacy in turn may help to promote treatment adherence.

Adverse Effects Associated with Medications Used in Bipolar Disorder

Gastrointestinal Disturbances

Nausea, vomiting, and diarrhea are commonly seen with lithium, valproate, and selective serotonin reuptake inhibitors (SSRIs). Bowden and colleagues10 demonstrated that nearly 50% of patients treated with lithium experienced nausea and diarrhea. The onset of nausea tends to be related to peak serum levels and may reflect the rapidity with which plasma levels are increased.4,11 Therefore, temporarily reducing the dose (as long as clinical efficacy is not compromised) or prescribing a slow-release formulation may alleviate nausea and other upper gastrointestinal (GI) effects. However, in some patients, diarrhea is reportedly increased by some slow-release formulations due to more distal absorption.12,13 Nausea may also be alleviated by taking lithium with meals.4 Use of lithium citrate syrup is also reported to decrease GI side effects.14

Similarly, GI disturbances are the most frequent adverse events associated with valproate. Zarate and colleagues15 demonstrated that approximately 63% of patients discontinued generic valproate treatment due to GI side effects; subsequent treatment with the enteric-coated formulation of divalproex was better tolerated. The extended-release formulation of divalproex may be associated with less nausea than the delayed-release preparation.16

All SSRIs have been shown to produce some degree of nausea and GI disturbance. Such effects appear to be transient and typically resolve within the first month of treatment.17 Gradual dose titration may be helpful in avoiding onset of these symptoms.

Weight Gain

Although weight gain is not the most common side effect associated with bipolar medication use, it may be the most distressing.18 In addition, overweight and obesity are significant public health concerns in the United States: they affect >61% of all American adults19 and are associated with hypertension, type II diabetes, and cardiovascular disease, as well as many other medical conditions.20 Independent of pharmacotherapy, rates of overweight and obesity are substantially elevated among individuals with bipolar disorder and may be directly related to recurrent depressive episodes as well as poorer functional outcome.21

The majority of agents currently used to treat bipolar disorder have been associated with some degree of weight gain, although variability may exist across compounds. Data from a 1-year monotherapy study10 of relapse prevention comparing lithium, divalproex, and placebo demonstrate that only patients treated with divalproex experienced significantly more weight gain than those taking placebo. However, weight gain has been associated with lithium use in other reports.22 In early reports, carbamazepine was associated with less weight gain than lithium,23 although data from a more recent controlled maintenance trial24 revealed appetite increases as occurring more often with carbamazepine (33%) than lithium (17%). Weight has been shown to remain stable or slightly decrease with the anticonvulsant lamotrigine.25

In both short- and long-term comparative studies of olanzapine or divalproex monotherapy in bipolar disorder, patterns of weight gain have differed with each treatment. For example, more weight gain was evident with olanzapine than divalproex during a 12-week acute mania study,26 and total weight was more extensive with olanzapine than divalproex monotherapy over a 1-year relapse prevention study.27 When weight gain occurs with olanzapine it tends to arise rapidly during the first few weeks and months, plateauing by 9 months.28 By contrast, weight gain with divalproex appears to occur more gradually (such that, for example, the magnitude of weight gain with divalproex matched that seen with olanzapine after 9 months in a trial by Tohen and colleagues27).

An inherent problem in attributing weight increases to psychotropic drug therapy involves judging the extent to which it may alternatively reflect illness-specific phenomena, such as hyperphagia, lethargy, and other vegetative signs. Further complicating the picture is the observation that some patients may be genetically predisposed to gain more weight when taking an atypical antipsychotic, such as clozapine.29 This indicates that not all patients may share the same adverse effect vulnerability.

Generalizations about weight changes associated with second-generation antipsychotics are limited by intermixed data involving patients with bipolar disorder, schizophrenia, and other diagnoses.20,28 Across diagnoses, clozapine and olanzapine appear to be associated with the most weight gain (ranging from approximately 2.7–5.3 kg).20 Ziprasidone produces nominal weight gain (approximately 0.5 kg), while risperidone and quetiapine have been associated with intermediate gain (approximately 1.6–2.4 kg).20,30 Aripiprazole appears to be associated with minimal weight gain in the existing short-term studies for bipolar disorder31; longer-term (ie, 1-year) trials in schizophrenia patients reveal a >7% increase in body weight for 30% of patients with low (<23) body mass index (BMI), 19% for those with normal BMI (23–27), and 8% for those with BMI >27.32

Adjunctive treatment with the anticonvulsant topiramate may be beneficial in reducing psychotropic drug-induced weight gain. Data show that patients treated with topiramate in combination with lithium, valproate, carbamazepine, or an antipsychotic lost an average of 9.4 pounds over 5 weeks.33 However, topiramate itself is associated with a range of side effects, including paresthesias, renal calculi, increased intraocular pressure, secondary narrow-angle glaucoma, and cognitive dysfunction.34 Preliminary findings with the anticonvulsant zonisamide, which is potentially useful in bipolar disorder,35 suggest that it too may be associated with weight loss.36

It is often difficult for clinicians to know when it is more advantageous to attempt remedial strategies aimed at overcoming an adverse effect, such as weight gain, and when it is preferable to substitute an alternative agent. The obvious limitation of this latter strategy is that therapeutic efficacy for a given patient cannot be assumed across diverse agents, even within a given class (as exemplified by the variable efficacy across antimicrobials, antiarrhythmics, antiepileptics, and other types of medication classes).

Nonpharmacologic interventions that have shown success for psychotropic-induced weight gain include dietary counselling prior to prescribing medications,37 diet programs,38 exercise programs,39 and behavior modification programs, although the success of behavioral programs may not always be sustained long-term.7,40

Dyslipidemias and Glucose Dysregulation

Awareness has grown regarding the potential for individuals with bipolar disorder to be at risk for cardiovascular disease,41 as well as adult-onset diabetes mellitus.42 Both conventional and atypical antipsychotics have been associated with an increased risk for new-onset type II diabetes,43,44 and some second-generation antipsychotics may impose a heightened risk for elevated low-density lipoprotein cholesterol and triglyceride levels.44,45 The mechanisms by which conventional or second-generation antipsychotics may be associated with glucose dysregulation are likely complex and not merely the byproduct of peripheral insulin resistance due to weight gain.31 Serious instances of diabetic ketoacidosis have been described within weeks of beginning some second-generation antipsychotics.31,45 A nested case study43 in the United Kingdom observed that antipsychotic exposure may increase risk for type II diabetes alongside a range of other baseline risk factors, including psychiatric diagnosis, hypertension, and alcoholism.

Recently, the Food and Drug Administration requested updated product labeling for all atypical antipsychotics; this labeling includes a warning regarding the risk of hyperglycemia and diabetes.46 However, the FDA did not address the differing amounts of risk relevant to each agent. Rather, the label only states that patients who develop suggestive symptoms during treatment with an atypical antipsychotic should be tested for diabetes. Patients at risk for diabetes (eg, those with obesity or family history of diabetes) should undergo fasting glucose testing at baseline, and periodically throughout treatment, and patients with a history of diabetes who begin taking atypical antipsychotics should be monitored for a worsening of glucose control.46

Sexual Dysfunction

Effects on sexual function ranging from diminished libido to orgasmic and erectile dysfunction are considered to be relatively prevalent with SSRIs (incidence rates reported have been as high as 34%)47; however, they may also occur with other psychotropics. Depression and other severe psychiatric disorders can themselves obviously contribute to loss of sexual interest, requiring careful clinical evaluation to differentiate iatrogenic from illness-related symptoms.

A number of pharmacologic and nonpharmacologic strategies have been described, each with varying degrees of success. In the case of SSRIs, undesired pharmacologic agonism at the postsynaptic 5-HT2A receptor has been implicated in the mechanism of sexual dysfunction,48 suggesting that agents which block this receptor, such as nefazodone, mirtazapine, or second-generation antipsychotics, may entail fewer sexual side effects.

SSRI dosage reductions have been advocated by some authors as one possible strategy, although no controlled trials exist to examine this approach rigorously.47 Drug holidays have been reported to have a modest degree of success with some SSRIs,49 although periodic planned drug cessation interferes with spontaneity and may discourage overall patient compliance. Moreover, in the case of SSRIs with a longer half-life, such as fluoxetine, this approach may be of little value. Using medications that either modify or compensate for the increased genitourinary serotonergic tone, such as cyproheptadine,50,51 represents another plausible strategy, particularly for patients who have shown good response and otherwise tolerate the SSRI well. Varying degrees of evidence, from controlled trials to clinical reports, exist to support the use of numerous adjunctive agents, including granisetron,52 sildenafil,53 yohimbine,54 ginkgo biloba,55 methylphenidate,56 amantadine,57 or buspirone,58 although most controlled trials with these agents have yielded only modest success. The antidepressant bupropion also has been suggested as a possible substitution strategy for an SSRI, based on its relatively lower incidence of sexual side effects,59 although clinicians should not automatically assume that the substitution of any one antidepressant for another will show equal efficacy. Open trials augmenting serotonergic drugs with bupropion also suggest its value as an adjunctive strategy to help diminish SSRI-associated sexual dysfunction.60 A recent placebo-controlled trial61 of bupropion augmentation of SSRIs found improved sexual desire and frequency but no global change in sexual functioning with bupropion compared to placebo.

Cognitive Impairment and Sedation

Cognitive dysfunction—particularly impaired attention and executive function—have increasingly become recognized as common features that are intrinsic to bipolar disorder across its illness phases.62 Thus, clinicians must discern the extent to which subjective complaints involving memory, attention, or concentration are reflections of a genuine neurocognitive deficit,63 or likely the result of the illness or of medication.

Mental sluggishness is often described as an adverse effect associated with lithium, even among healthy individuals.64 One uncontrolled study65 reported improvement in the cognitive complaints associated with lithium after switching to divalproex. Among anticonvulsant agents, cognitive impairment appears to be less likely to occur with either lamotrigine or gabapentin among both epilepsy and bipolar patients.66 Topiramate is associated with somnolence, impaired concentration or attention, word-finding difficulties, and subjective cognitive dulling.66 In the authors’ experience, adverse effects such as these occur most often when dosages are escalated too rapidly above 50–100 mg/day. In the aftermath of several negative randomized controlled trials to assess the antimanic efficacy of topiramate for bipolar mania, increasing attention has focused on its potential value for ancillary problems related to bipolar illness, such as weight gain.

Cognitive dysfunction is well established with the use of first-generation antipsychotics, particularly low-potency neuroleptics that possess significant anticholinergic effects. Cognitive impairment has generally been described as less extensive with second-generation antipsychotics in schizophrenics67 or in healthy volunteers,68 although little information is available specifically for patients with bipolar disorder. In one of the few existing preliminary studies of neurocognitive function and pharmacotherapy for bipolar disorder, Reinares and colleagues69 observed better attentional functioning in bipolar patients taking risperidone than conventional antipsychotics.

Dermatologic Effects

Many psychotropic drugs have been associated with cutaneous reactions. In the case of lamotrigine, skin rashes have been the most frequent adverse event leading to drug discontinuation in controlled trials in epilepsy.70,71 However, in nearly all instances, such rashes have been benign and likely the result of rapid dose escalation strategies which were previously recommended in the first few years lamotrigine was available. Currently, rashes of any kind occur in approximately 10% of patients treated with lamotrigine; severe cases resulting in hospitalization occur in 0.3% of adults and 1% of children. Importantly, the revised slower-dose escalation schedule established in 1994 has led to a marked reduction in the incidence of skin rash. The incidence of rash is higher when given with concomitant valproate due to their pharmacokinetic interaction, although lamotrigine can be safely co-prescribed with valproate when doses are escalated twice as slowly as with monotherapy.34 Rash and Stevens-Johnson syndrome have also been associated with use of divalproex72 and carbamazepine.34

In the case of lithium, case reports have described exacerbations or first occurrences of psoriasis,73 which may be improved with the use of appropriate dermatologic preparations or by lowering the lithium dose. Severe pustular acne that does not respond well to dermatologic treatment is also associated with lithium treatment and resolves only with lithium discontinuation.3

Tremor

Tremor, whether resting or exacerbated by activity, is a common problem for patients taking lithium. Incidence rates range from 4% to 65%. The wide variability is due to differences in definition and reporting and possibly also to differences in peak lithium levels.74 Lithium-induced tremor is frequently treated successfully with β-blockers, such as propranolol, although patients should be monitored for bradycardia due to this combination.74

Symptomatic tremor also occurs in approximately 10% of patients treated with valproate.75 Valproate-induced tremor may be treated with amantadine or propranolol, both of which are associated with side effects of their own.76

Mania Induction and Rapid Cycling

Antidepressants have been reported to induce mania in approximately one-third of patients overall with bipolar disorder,77-80 although the likelihood that any given antidepressant trial might lead to a manic or hypomanic episode in a known bipolar patient is probably <15% to 20%.79,81 Although practitioners frequently assume that SSRIs or other newer-generation antidepressants are substantially less likely than older antidepressants to induce mania, the database from which this impression has arisen is not extensive.80-85 Growing evidence has begun to suggest that some patients with bipolar disorder may inherently be at higher risk for developing antidepressant-induced mania; such vulnerability factors may include a history of prior antidepressant-induced mania, a family history of bipolar disorder or other genetic factors, exposure to multiple antidepressant trials, and comorbid substance abuse.79,80 Recent naturalistic studies86-88 have begun to challenge a prior literature linking antidepressant overuse with mood destabilization or cycle acceleration. However, while these reports attest to the persistence of depression in bipolar disorder, it is difficult to conclude from such noncontrolled, nonrandomized studies which bipolar patients are or are not suitable candidates for receiving standard antidepressants to manage their depression.

Standard mood stabilizers, such as lithium or valproate, are thought to confer some protection against the possibility of antidepressant-induced mania, although this assumption is not robustly reported within the literature.80,89,90 By contrast to standard antidepressants or standard mood stabilizers, the compound lamotrigine has demonstrated antidepressant efficacy both acutely91 and long term,92,93 without a greater risk than placebo for inducing mania.

Depressive episodes in bipolar disorder are traditionally difficult to treat. The depressive episodes in bipolar patients often do not respond favorably to many of the mood stabilizers currently approved for use in bipolar disorder, and this may encourage antidepressant use. On the other hand, both lithium and valproate have some antidepressant properties.3,96,97 The magnitude of lithium’s protective effect against recurrent depression appears substantially smaller than its efficacy to prevent manias,98 although lithium and lamotrigine are nonetheless both considered appropriate first-line pharmacotherapies for bipolar depression according to the revised American Psychiatric Association’s “Practice Guidelines for the Treatment of Patients with Bipolar Disorder.”4

Special Considerations in Women

While epidemiologic studies indicate that bipolar disorder equally afflicts men and women,99 a number of gender differences have been observed, including a higher incidence of rapid cycling and mixed states among women than men,100 as well as a higher likelihood of comorbid alcohol abuse or dependence among bipolar women than bipolar men compared to proportional rates in the general population.101 Therapeutic outcomes with certain core treatments, such as lithium, appear comparable in both men and women,102 although gender differences become important when considering adverse-effect profiles across existing psychotropic agents.

First-generation (and some second-generation) antipsychotics, and to some extent SSRIs, may elevate serum levels of prolactin, leading to galactorrhea, sexual dysfunction, impaired fertility, and menstrual disorders.4 In addition, menstrual disturbances associated with valproate use are common among female epileptic populations.103 It has been suggested that polycystic ovarian syndrome (PCOS) and/or hyperandrogenism occur at increased rates among females taking valproate for epilepsy.103,104 Links between PCOS and valproate use remain controversial among nonepileptic women, such as those with migraine or bipolar disorder.105-108

Carbamazepine, oxcarbazepine, and topiramate all increase the metabolism of oral contraceptives, reducing their effectiveness and necessitating the use of other forms of birth control.4 A case series of seven women with epilepsy who received oral contraceptives while being treated with lamotrigine demonstrated that the oral contraceptives reduced lamotrigine plasma levels by 41% to 64% (mean 49%), leading the authors to recommend serum level monitoring of lamotrigine when prescribed concomitantly with an oral contraceptive.109

Laboratory Monitoring

Periodic laboratory testing has the potential to negatively impact patient compliance. In addition, there is no clear agreement even among experts as to the frequency with which laboratory monitoring should be conducted when prescribing lithium, divalproex, or other anticonvulsant drugs used for bipolar disorder.110 The revised APA practice guideline for bipolar disorder4 notes that most psychiatrists obtain hematologic and hepatic function tests at least every 6 months for stable patients taking divalproex, or more often based on clinical status. Among patients taking lithium, the APA practice guideline recommends monitoring renal function every 2–3 months during the first 6 months of treatment, and thyroid function once or twice during this time; these parameters may be checked every 6–12 months thereafter in stable patients, or more often if clinically indicated. In the case of carbamazepine, the APA practice guideline advises obtaining a complete blood count, platelet measures, and liver function tests every 2 weeks during the first 2 months of treatment, and every 3 months thereafter in stable patients.4

At present, atypical antipsychotic agents, as well as newer-generation anticonvulsants, such as topiramate and lamotrigine, do not require monitoring for these side effects, nor is regular monitoring of serum levels required.4 However, in September 2003, the FDA called for the manufacturers of all atypical antipsychotics to include a product warning label regarding the potential increased risk for diabetes and hyperglycemia, particularly among patients with intrinsic background factors for diabetes, such as obesity or a family history of Type II diabetes.46

Clinicians should always give female patients a pregnancy test before initiation of any psychotropic medication, due to the risks of teratogenesis.

Conclusion

Aside from acquiring a sound knowledge of the efficacy of a drug, it is the responsibility of the clinician to closely consider the side-effect profile of a given medication, as well as the unique concerns of the individual patient.

While medications used in treating bipolar disorder have traditionally been associated with numerous adverse events, new information is emerging regarding ways to reduce the incidence and severity of side effects. In addition, new treatment options for treating bipolar disorder continue to emerge. Many of these offer safer side-effect profiles and do not require laboratory monitoring, although the risks and benefits of choosing any pharmacotherapy must be individually tailored to a patient based on their unique clinical circumstances. Safe and appropriate pharmacotherapy for bipolar illness today involves the thoughtful integration of evidence-based efficacy with the anticipation and management of potential adverse effects.

Controversies persist about the potential for antidepressants to worsen the course of bipolar disorder by inducing mania or potentially accelerating cycle frequency in a subgroup of patients. Current practice guidelines advise against the use of antidepressants without mood stabilizers for bipolar I disorder, and caution is warranted when clinicians augment mood stabilizers with standard antidepressants in order to minimize the risk for destabilizing mood both short-term and long-term. PP

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69. Reinares M, Martinez-Aran A, Colom F, Benabarre A, Salamero M, Vieta E. Long-term effects of the treatment with risperidone versus conventional neuroleptics on the neuropsychological performance of euthymic bipolar patients [in Spanish]. Actas Esp Psiquiatr. 2000;28(4):231-238.

70. Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40(7):985-991.

71. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother. 1999;33(10):1037-1042.

72. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry. 2002;63(11):1012-1019.

73. Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol. 2000;22(3):231-233.

74. Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry. 1995;56(7):283-287.

75. Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Treatment of valproate tremors. Neurology. 1983;33(10):1380-1382.

76. Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Valproate tremors. Neurology. 1982;32(4):428-432.

77. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411.

78. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152(8):1130-1138.

79. Goldberg JF, Whiteside JE. The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study. J Clin Psychiatry. 2002;63(9):791-795.

80. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5(6):407-420.

81. Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord. 2001;3(5):259-265.

82. Post RM, Leverich GS, Nolen WA, et al, for the Stanley Foundation Bipolar Network. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord. 2003;5(6):396-406.

83. Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148(7):910-916.

84. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55(9):391-393.

85. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. 1994;164(4):549-550.

86. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry. 2001;62(8):612-616.

87. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003;160(7):1252-1262.

88. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914-920.

89. Bottlender R, Rudolf D, Strauss A, Moller HJ. Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord. 2001;63(1-3):79-83.

90. Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry. 2001;62(4):249-255.

91. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD, for the Lamictal 602 Study Group. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60(2):79-88.

92. Bowden CL, Calabrese JR, Sachs G, et al, for the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400. Erratum in: Arch Gen Psychiatry. 2004;61(7):680.

93. Calabrese JR, Bowden CL, Sachs G, et al, for the Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013-1024.

94. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079-1088. Erratum in: Arch Gen Psychiatry. 2004;61(2):176.

95. Ketter T, Tohen M, Vieta E, et al. Open-label maintenance treatment for bipolar depression using olanzapine for olanzapine/fluoxetine combination. Poster presented at: 6th International Society for Bipolar Disorders Conference; February 9–13, 2004; Sydney, Australia.

96. Strakowski SM, McElroy SL, Keck PE. Clinical efficacy of valproate in bipolar illness: comparisons and contrasts with lithium. In: Halbreich U, Montgomery SA, eds. Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders. Washington, DC: American Psychiatric Press; 2000:143-157.

97. Winsberg ME, DeGolia SG, Strong CM, Ketter TA. Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord. 2001;67(1-3):207-212.

98. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.

99. Leibenluft E. Women with bipolar illness: clinical and research issues. Am J Psychiatry. 1996;153(2):163-173.

100. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.

101. Frye MA, Altshuler LL, McElroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160(5):883-889.

102. Viguera AC, Tondo L, Baldessarini RJ. Sex differences in response to lithium treatment. Am J Psychiatry. 2000;157(9):1509-1511.

103. Isojarvi JI, Tauboll E, Pakarinen AJ, et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med. 2001;111(4):290-296.

104. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med. 1993;329(19):1383-1388.

105. Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry. 2002;63(suppl 4):42-55.

106. Rasgon NL, Altshuler LL, Gudeman D, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry. 2000;61(3):173-178.

107. O’Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry. 2002;63(4):322-330.

108. McIntyre RS, Mancini DA, McCann S, Srinivasan J, Kennedy SH. Valproate, bipolar disorder and polycystic ovarian syndrome. Bipolar Disord. 2003;5(1):28-35.

109. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47(1-2):151-154.

110. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar disorder 2000. Postgrad Med. 2000;(spec)


Dr. Anderson is assistant professor of psychiatry in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago.

Dr. Goldberg is research scientist in the Department of Psychiatry Research at the Zucker Hillside Hospital of the North Shore–Long Island Jewish Health System in Glen Oaks, New York.

Dr. Harrow is professor in the Department of Psychiatry at the University of Illinois College of Medicine.

Disclosure: Dr. Anderson is on the speaker’s bureau of AstraZeneca. Dr. Goldberg is a consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Ortho-McNeil, Pfizer, and UCB Pharma; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Novartis; and has received grant and/or research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Pfizer, The Robert Wood Johnson Foundation, Shire, and UCB Pharma.

Funding/support: This work was supported in part by grant nos. MH-26341 and MH-01936 from the National Institute of Mental Health awarded to Drs. Goldberg and Harrow, by a National Allegiance for Research on Schizophrenia and Depression Young Investigator Award to Dr. Goldberg, and by an unrestricted grant from GlaxoSmithKline.

Please direct all correspondence to: Joseph F. Goldberg, MD, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004; Tel: 718-470-4134; Fax: 718-343-1659; E-mail: Jgoldber1@lij.edu.


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Focus Points

• Many of the recommendations in the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Bipolar Disorder” are supported by a limited evidence base.

• Guideline recommendations may change rapidly as new evidence is generated.

• Some treatments, including antipsychotics, benzodiazepines, and arguably newer antidepressants, could be considered mood stabilizers.

• The frequent recommendation in the guideline of adding medications to nonresponsive patients does not consider the possibility that switching medications is also reasonable.

• Olanzapine and lamotrigine have new evidence of efficacy beyond that which is described in the guideline.

• Directional response is important in choosing medications for bipolar patients.

Abstract

The American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Bipolar Disorder” represents a major synthesis of the available research and expert clinical opinion on bipolar disorder. The guideline extends beyond the clinical research evidence base and bridges the highly-controlled conditions of clinical trials and the broader range of clinical situations encountered in practice. However, any practice guideline is inevitably outdated by the time it is published, due to the time required in the process of its creation and publication. This article summarizes the recommendations in the APA bipolar practice guideline and reviews new relevant research available since its publication. The concept of a “mood stabilizer,” which is not incorporated in the guideline, is reviewed. In addition, the numerous clinical assumptions underlying the recommendations in the guideline are described, and the strength of the research evidence supporting them is reviewed. These include the assumptions that lithium and anticonvulsants are preferred treatments while antipsychotics and benzodiazepines are not, that nonresponding patients should always have additional medication added rather than switching to a new medication, that all antidepressants have a significant liability for causing switching into mania, and that all bipolar patients should receive long-term maintenance. New research with lamotrigine, olanzapine, and other atypical antipsychotics in bipolar disorder is reviewed, as well as the implications of this research on the recommendations in the guideline. The concept of directional efficacy of mood stabilizers, only briefly mentioned in the guideline, is discussed and expanded. Finally, the importance of understanding the research basis of the guideline before applying its recommendations to clinical practice is described.

Introduction

The current American Psychiatric Association (APA) “Practice Guideline for the Treatment of Patients with Bipolar Disorder”1 was published in 2002 and is a revision of an earlier version published in 1994. The latest revision represents a summary of a much larger evidence base than the previous version and is a distillation of both available research and expert opinion.

Unfortunately, the guideline has several problems: first, such an endeavor, by nature, is outdated by the time it is published. Second, while the guideline contains descriptors that indicate the level of author confidence in the evidence supporting its recommendations, many of the recommendations are based essentially on opinion and are not supported by well-designed trials. Recommendations primarily based on expert opinion or clinical consensus with either no evidence basis or an uncontrolled case series may be erroneous. Such untested or unproven treatments that are popular among clinicians may find their way into the practice guideline simply on the basis of their popularity, which can lead to the widespread perpetuation of clinical myth and folklore. For example, topiramate and gabapentin are common treatments for acute mania that have failed to demonstrate efficacy in placebo-controlled trials. Their popularity developed from numerous case series suggesting efficacy in mania. Despite the negative trial data, clinicians have already become familiar with using these medications; currently, ancillary uses include prescribing topiramate for drug-induced weight gain and gabapentin for insomnia or anxiety. Unfortunately, neither the practice guideline nor Food and Drug Administration product labels are designed to discuss such ancillary uses. Should such a treatment or practice be included in the guideline simply because it is popular?

A third problem with the practice guideline is that it is indirectly impacted by commercial influences. While any obvious influence can be reduced by mechanisms such as those utilized in the development of the APA guideline, such as independent review and full disclosure of potential conflicts, both subtle and conspicuous influences from the industry still make their way into the guideline. For example, clinical trial data from pharmaceutically-funded projects is often considered proprietary; theoretically, the industry sponsor could conduct multiple controlled trials and suppress any negative results. Recent proposals to create an inclusive registry of all clinical trials may reduce this problem. Even the recommendations arising from scientifically high-caliber, placebo-controlled, double-blind studies are based overwhelmingly on industry-sponsored trials, which are subject to bias introduced through both study design and selective reporting of results. Thus, the myriad of choices made in designing any clinical trial are often driven by potential drug sales rather than science. Furthermore, the use of leading academics as authors seldom reflects the independent control of the design, the statistical analysis, or the reported results of the study, as is perhaps implied.

Clearly, limiting recommendations exclusively to medications derived from high-quality, placebo-controlled clinical trials is impractical. Unfortunately, solely using clinical practice as a guide can also be risky, since the majority of clinical practice involves patients who do not meet the inclusion criteria of highly-controlled clinical trials, and the majority of clinical decisions are beyond the tightly-defined conditions of clinical trials. The practice guideline, though, despite its many problems, represents an important effort to bridge the gap between clinical trials and clinical practice.

This review summarizes the APA guideline’s strengths and weaknesses (Table 1), and introduces new research completed since its publication. In addition, it examines many of the guideline’s recommendations that are not evidence based. It discusses alternative rationales that warrant consideration and presents several key questions, which have not as yet been studied but are important for the development of future standards of treatment for bipolar disorder.

What is a Mood Stabilizer?

Despite its widespread use, the term “mood stabilizer” was intentionally omitted from the APA practice guideline due to a lack of consensus on a definition. Simplistically speaking, the term is most often used to describe a first-line treatment for bipolar disorder that would not destabilize the disorder. Beyond this, though, there is disagreement about whether both acute antimanic and antidepressant (for bipolar depression) efficacy are required or whether both acute and maintenance efficacy are required. While the term is technically based on use of treatments in bipolar disorder, medications identified as mood stabilizers are also often used for lability, impulsivity, and aggression in bipolar patients and in patients with other psychiatric disorders. Clinicians can benefit from a clarification of this term.

If the term mood stabilizer is a proxy for a “first-line treatment for any phase of bipolar disorder,” as is often the intent with clinicians who use it, then both uni-directional antimanic treatments, as well as uni-directional bipolar depression treatments, could be considered mood stabilizers regardless of whether bi-directional or maintenance efficacy has been convincingly demonstrated. This is, of course, assuming that the treatment does not worsen the course of the illness by causing a switch to the other pole or by exacerbating rapid cycling.

Lithium, divalproex, valproate, and carbamazepine have been shown to have efficacy in mania without exacerbating depression and are generally considered mood stabilizers (Figure 1).2 Likewise, lamotrigine has been shown to have efficacy in bipolar depression without exacerbating mania.3 Paroxetine has shown some evidence of efficacy in bipolar depression4 with little liability of inducing switching. Buproprion may also have efficacy in bipolar depression with a low liability for switching,5 although its efficacy has never been tested in a placebo-controlled trial.

Switching is the most relevant problem for many treatments of bipolar depression. One review that attempted to examine switching in more detail compiled data from placebo-controlled trials of sertraline, paroxetine, tricyclic antidepressants (TCAs), and placebo in bipolar depression. This review included a post-hoc analysis of 242 cases of bipolar depression treated under controlled conditions with selective serotonin reuptake inhibitors (SSRIs) and found an associated switch rate into mania of 3.7%, which was no different from the switch rate on placebo. The 125 bipolar depressed patients treated with TCAs had a switch rate of 11.2%, which was clearly greater than the switch rate on placebo.6 This report supports the well-documented and clearly demonstrated risk of switching with TCAs (primarily imipramine). Monoamine oxidase inhibitors were also found in controlled trials to have significant risks of switching. Thus, the logical conclusion is that the risk of switching caused by SSRIs is comparatively low.

It is important to separate evidence from controlled trials and anecdotal reports or case series, especially in the case of induction of mania, which occurs naturally in bipolar depressed patients anyway. In fact, to address this issue, it is critical to estimate the expected switch rate on placebo. While there is no single large set of data that allows for a direct comparison of switch rates on antidepressants versus placebo, switch rates on placebo from smaller sets of data are as high as 5%.3

Whether drugs traditionally considered tranquilizers (specifically typical antipsychotics, benzodiazepines, and atypical antipsychotics) should also be considered safe first-line treatments for bipolar disorder is a controversial issue. There is extensive evidence of the efficacy of typical antipsychotics in acute mania,7 and indeed these drugs are used for acute and maintenance treatment of bipolar disorder. While typical antipsychotics are often described as causing depression, the evidence for this is unconvincing and derived largely from two early reports on flupenthixol decanoate. Both reports had design problems and did not statistically test for this side effect.8,9 Furthermore, there are case reports of bipolar patients who became more depressed when a typical antipsychotic was discontinued. The benzodiazepines clonazepam and lorazepam have also been shown to have efficacy for acute mania10-15 with no suggestion of any aggravation of depressive symptoms. Thus, typical antipsychotics, clonazepam, and lorazepam could arguably be considered mood stabilizers.

Typically, though, these medications are not regarded as mood stabilizers because of tolerability issues. The risk of tardive dyskinesia from typical antipsychotic use and substance dependence with benzodiazepines may relegate these drugs to second-line choices. It is notable that reports of an increased risk of tardive dyskinesia in bipolar patients on typical antipsychotics compared to schizophrenic patients were based on methodologically limited studies,16 and the question of how likely dependence on benzodiazepines occurs in bipolar patients under medical supervision, even for long periods of time, has never been studied. Furthermore, it is clear that many bipolar patients do use benzodiazepines chronically with apparently good efficacy and without any dependence problems.

More interesting is the question of whether atypical antipsychotics are mood stabilizers. Olanzapine has demonstrated efficacy in acute mania (Figure 2),17 bipolar depression, and bipolar maintenance.17-20 Quetiapine, risperidone,21 ziprasidone, and aripiprazole (Figure 3)22 also have been shown to be effective in treating acute mania, either as monotherapy or in combination with lithium or divalproex (Figures 4 and 5).21,23-26 The liability of such atypical antipsychotics for inducing depression or tardive dyskinesia seems to be low. These drugs are commonly used for bipolar disorder but only olanzapine is listed in the guideline as a first-line treatment for mania. Generally, the atypical antipsychotics as a class are not recommended as first-line treatments because of limited available research regarding long-term use, although such data is emerging rapidly. They are recommended for patients with persistent psychosis or for those who relapse in spite of other treatments.

The industry-supported research on atypical antipsychotics for bipolar disorder has to some degree avoided this question by designing studies that combine atypical antipsychotics with an accepted mood stabilizer, specifically lithium or divalproex. The implication is that the other medication (ie, lithium or divalproex) is the primary treatment and the atypical antipsychotic is the added tranquilizer. Unfortunately, most of these trials have underdosed lithium or divalproex, which further leads to difficulty in interpreting the results. Trials of atypical antipsychotics in mania, bipolar depression, and maintenance treatment should consider monotherapy designs to avoid the need to interpret the effects of the other drug.

The question remains: should atypical antipsychotics be considered first-line treatments for bipolar disorder? Their potential to be useful in this role is clear, but more research is needed. On the other hand, anticonvulsants such as divalproex and lamotrigine have, in some ways, been considered mood stabilizers despite only slight or no evidence of bi-directional effects.

Other mood-stabilizing treatments that are considered by the practice guideline include electroconvulsive therapy (ECT) and psychotherapy. ECT may be effective for both mania and bipolar depression, and psychotherapies are generally accepted as helpful in bipolar depression, although controlled data for this is lacking. A comprehensive index of possible mood stabilizers (ie, treatments that do not exacerbate bipolar disorder) is listed in Table 2 and Table 3.1

Combination Therapy Versus Sequential Monotherapy

Important to consider when using mood stabilizers is the concept of adding rather than switching treatments, which is one of the key underpinnings of the guideline. This practice has been studied only minimally due to the many logistical problems associated with attempting to research this topic. At issue is whether multiple medications should be used early or if they should be utilized only after sequential monotherapy has failed.

The answer to this question relates to some degree to culture: the tradition of psychopharmacology in the United States has for decades emphasized monotherapy. Monotherapy was largely driven by the FDA approval process, which has principally required placebo-controlled monotherapy studies due to their clear interpretability. Clinicians in many other countries, however, routinely prescribe multiple medications and can be highly respected for their skills at safely combining medications. US practices have shifted toward polypharmacy, as reflected in the bipolar practice guideline. Combination therapy or polypharmacy can hold theoretical benefits of enhanced efficacy and reduced side effects with lower doses of multiple medications, but is fraught with the risks of additive side effects and, most importantly, subtherapeutic dosing of medications.

There appears to be a growing clinical impression reflected in the practice guideline that response rates to multiple medications are greater than response rates to a single medication. This is based on case reports, uncontrolled case series, and very few actual clinical trials. This impression has led to widespread recommendations for combination therapy and polypharmacy, with the implication that combinations work together synergistically. However, from a scientific viewpoint, such conclusions may be premature since two medications used at adequate doses in sequence could theoretically produce comparable response rates. Consider a scenario in which two treatments, Drug A and Drug B, have both been shown to be effective as monotherapy for some specific disorder. Each achieved a response rate of 70% based on some predetermined definition of response, such as a reduction in symptoms. This means that 30% of subjects given each drug did not achieve the predefined response. However, the 30% of exposed subjects who are nonresponsive to each of the two medications differs in each study. In fact, while Drug A and Drug B could each produce efficacy in 70% of subjects, these are not the same subjects. In other words, while there may have still been a 70% response rate had the subjects in the study of Drug A instead been in the study of Drug B, it would have been different subjects who responded.

Another study starts similar subjects on a combination of Drugs A and B and achieves a response rate of >70%. This is often interpreted as either additive or synergistic efficacy of combination treatment. However, even without any synergistic or additive efficacy, a higher rate of response would be expected from two efficacious treatments because some of the nonresponders to Drug A are responders to Drug B and vice versa. Had the study started with Drug A and then given Drug B to the Drug A nonresponders, a total response rate might have equaled that of combination treatment. Thus, higher response rates in combination treatment could be explained simply by individual differences in drug responsiveness, rather than by additive or synergistic efficacy.

A small number of reports on synergistic effects and differences in individual drug responsiveness have led to widespread recommendations for combination treatments. The effort to achieve higher efficacy rates is clearly desirable, and the side effects may not necessarily be worse with more medications, especially if they are all underdosed. On the other hand, if clinicians plan to combine medications either at the start of treatment or shortly thereafter, there is a strong likelihood that the dosing of each medication will be lower, which leads to an inadequate trial of the first treatment in terms of both dose and duration. Such an approach may also minimize clinical efficacy of each medication and is clearly a divergence from the largely FDA-driven American practice of using a single drug at a high enough dose to better determine either drug responsivity or drug refractoriness.

Combining or switching medications is difficult to address in clinical trials, but as a routine clinical practice is legitimate material for a consensus-based guideline. However, the add versus switch question is complex and may not only reflect scientific issues, but also philosophical and cultural ones beyond the scope of such a guide. Essentially, adding additional medications for nonresponders makes sense, but switching to another medication is also a reasonable option that has not been considered. While combination therapy is common in other specialties such as oncology and infectious disease, such treatments are recommended based on clinical trial evidence. Combination treatments for psychiatric disorders work, but their superiority over sequential use of monotherapies has not been clearly demonstrated by clinical trials. In the absence of better-designed studies on the efficacy of combination therapies that address the questions of proper dosing of each medication and adding versus switching, it is likely that use of combination therapy for bipolar disorder will become arbitrary and without a credible evidence base.

Treatment of Manic or Mixed Episode

The bipolar practice guideline recommends lithium, divalproex, and olanzapine as first-line treatments for mild to moderate mania or mixed episode of bipolar disorder. For severe mania or mixed episode, a combination of either lithium or divalproex with an antipsychotic is recommended. For mixed episode, divalproex is preferred over lithium (Figure 6).2 Alternatives to lithium and divalproex include carbamazepine and oxcarbazepine. In addition, short-term use of benzodiazepines is recommended. Tapering of antidepressants and psychosocial treatments is also recommended.

There are many assumptions regarding treatment of manic or mixed episode that underlie these recommendations (Table 4).1 While these assumptions may reflect standard clinical care, the rationale behind them is based on limited research. The first assumption is that lithium and divalproex are appropriate for both acute and maintenance treatment, while antipsychotics and benzodiazepines are not. Supporting this is the fact that substantially more clinical and research trials with lithium and divalproex in bipolar maintenance have been performed. Although the guideline avoids calling such medications mood stabilizers, the authors clearly consider lithium and divalproex mood stabilizers, but do not consider other antipsychotics or benzodiazepines as such (Table 5).

This conceptual dichotomy between anticonvulsants and antipsychotics arises out of the long history of lithium as the primary treatment for mania, and the assumption that anticonvulsants should be used like lithium while antipsychotics should not. The dichotomy developed in the era of typical antipsychotics and was largely driven by concerns about acute extrapyramidal side effects, tardive dyskinesia, and the unproven perception that typical antipsychotics could make patients depressed. This dichotomy seemed sensible since the development, FDA labeling, and early use of anticonvulsants and antipsychotics had previously been for completely different disorders, specifically epilepsy and schizophrenia. Today, the dichotomy makes less sense, as atypical antipsychotics clearly have a reduced risk of both acute extrapyramidal side effects and tardive dyskinesia. Also, as more clinical trials of atypical antipsychotics in bipolar disorder are made available, the potential use of atypicals for all phases of bipolar disorder will become more apparent. The point is that a dichotomy separating anticonvulsants and atypical antipsychotics is not fundamentally driven by any research that has been done in bipolar disorder. Recent clinical trials, with a few exceptions,18,19,26 have done little to reduce the perpetuation of this now-outdated conceptual dichotomy.

Furthermore, the question of whether lithium and divalproex are better tolerated than atypical antipsychotics in long-term treatment has never actually been addressed by a clinical trial. Since many medications are effective for mania, suitability for long-term treatment is a key issue in drug selection. Antipsychotics may have long-term side effects, but the long-term effects of lithium and divalproex are also considerable. Lithium is associated with tremor, weight gain, acne, cognitive impairment, hypothyroidism, diabetes insipidus, nephrotoxicity, gastrointestinal problems, alopecia, and edema. Divalproex is associated with tremor, weight gain, alopecia, hepatotoxicity, leukopenia, thrombocytopenia, pancreatitis, and possibly polycystic ovarian syndrome. Thus, the preference of lithium and divalproex over atypical antipsychotics for maintenance treatment is partly based on an assumption of better tolerability that has never been tested and is questionable at best.

A second assumption underlying treatment of a manic or mixed episode maintains that if a patient is nonresponsive to a single treatment, other treatments should be added rather than substituted. Adding versus switching has not been well addressed by clinical trials, and the few studies that have addressed it primarily studied a combination of lithium and carbamazepine or divalproex and had small numbers or methodological limitations.27-32 One small study found a lithium-divalproex combination superior to lithium alone for maintenance treatment,33 but there were only five subjects on the combination. Systematic attempts to address adding or substituting other drugs have failed to consistently show that combination treatment produces superior efficacy compared to a single efficacious treatment, especially if the treatment is an adequately dosed antipsychotic for mania.34-37 One large well-designed multicenter acute mania study38 found that the addition of valproate to a flexible-dose typical antipsychotic allowed lower antipsychotic dosing and superior efficacy, but the antipsychotic in the study was dosed openly. The finding of superior efficacy in the combined valproate plus antipsychotic group is one of the rare examples of a demonstrated advantage to combination over antipsychotic alone.

Adding another medication for an unresponsive or partially-responsive patient may be a clinically reasonable approach, and the practice guideline has clearly endorsed this approach as a routine recommendation. However, the research evidence supporting the idea that combination treatments produce greater efficacy than optimal dosing of both drugs separately and sequentially is quite limited. Whether automatically prescribing combination treatments makes sense for completely unresponsive patients is questionable, as most treatments cause some adverse events.

The recommendation to combine either lithium or divalproex with an antipsychotic for severe mania also does not consider the option of antipsychotic monotherapy. This is one of several examples in the practice guideline that favors combination therapy or polypharmacy over monotherapy with a different medication. The clinical trials of antipsychotics in mania have included at least moderately ill subjects, which suggests that antipsychotic monotherapy may be efficacious for these patients. Furthermore, the addition of lithium has never been demonstrated to produce additional efficacy for acute manic patients who receive an efficacious dose of an antipsychotic.34,35,37

The possibility that using lithium or divalproex together with an antipsychotic might reduce antipsychotic dosing has been studied at least twice under controlled conditions. One haloperidol study34 found that combining lithium with a low dose of haloperidol for acute mania produced efficacy comparable to a higher dose of haloperidol monotherapy. Muller-Oerlinghausen and colleagues38 also found in a multicenter placebo-controlled acute mania study that when adding valproate versus placebo to typical antipsychotics dosed openly, the antipsychotic-valproate group was treated with lower doses of antipsychotic and had a greater clinical response than the antipsychotic-placebo group. Thus, considering a reduced-dose antipsychotic as the primary treatment and lithium or divalproex as the added treatment may be an alternative approach to combination therapy. For manic patients not fully responsive to atypical antipsychotic monotherapy, it might be reasonable to increase the dose of the antipsychotic first, and then consider adding lithium or divalproex (similar to what is often done with antidepressants and lithium in unipolar depression).

The practice guideline has also avoided considering the possibility of adding carbamazepine to either lithium or divalproex instead of an antipsychotic, in the case of severe or nonresponding patients. This combination is not considered despite the fact that double-blind data, albeit from a small number of subjects, suggests that it has efficacy in refractory patients.30

The practice guideline for mania recommends considering oxcarbazepine as an alternative to carbamazepine, under the assumption that oxcarbazepine has comparable efficacy. Oxcarbazepine has never been tested in a placebo-controlled clinical trial for acute mania. The available double-blind literature for oxcarbazepine and mania is limited to two small studies from the same principal investigator who found oxcarbazepine comparable in efficacy to either haloperidol or lithium.39 These two studies have limited utility in determining the antimanic efficacy of oxcarbazepine, due to the absence of a placebo control. Why the practice guideline has elevated oxcarbazepine to a prominence which has been reserved only for other treatments that have been tested in placebo-controlled trials is unclear (Table 6). The assumption that oxcarbazepine is as efficacious as carbamazepine for treatment of mania should be considered unproven at best.

The role of benzodiazepines has also been largely ignored. Despite the evidence that clonazepam and lorazepam are efficacious in mania, albeit at high doses (clonazepam 16 mg/day and lorazepam 30 mg/day), their use has been largely discouraged due to concerns about dependence. There are many cases, however, in which benzodiazepines have been used for long-term treatment with apparent prolonged efficacy. The true incidence rate and risk of dependence with chronic use when prescribed under the supervision of a psychiatrist is unknown and may have been overestimated in the interest of being cautious.

Treatment of Refractory Mania

The same concerns described above for mania or mixed episode also apply to the refractory mania recommendations. The guideline recommends lithium, divalproex, or an antipsychotic for refractory patients, followed by carbamazepine and oxcarbazepine, as well as clozapine or ECT (Table 7).1 Again, the question of the definition of an adequate trial of monotherapy for mania is avoided. It is notable that neither lithium nor divalproex was shown to have efficacy in treatment of a manic episode in <7 days,2 suggesting that >1 week may be necessary to define nonresponse. The guideline for refractory mania does not clearly define the condition itself. Should clinicians wait for 7–10 days before considering a patient refractory? If this decision is made sooner, has lithium or divalproex been given a reasonable opportunity to work? What blood level of lithium or valproate should be achieved before a patient is considered refractory? Should the same duration criteria be used for atypical antipsychotics that appear to have more rapid onset of efficacy?25

The recommendation to add an antipsychotic to lithium or divalproex for refractory mania suffers from the same problems as discussed for manic episode. Specifically, why should an atypical antipsychotic be added to lithium or divalproex instead of substituted? If lithium or divalproex alone is not working, why would they be continued if an antipsychotic is going to be used anyway? Haloperidol and lithium data suggest that if an adequate dose of antipsychotic is used, adding lithium produces no additional benefit.34

Treatment of Bipolar Depressive Episode

The early research basis of treatments for bipolar depression has been thoroughly reviewed by Zornberg and Pope.40 Many problems have limited the interpretability of these earlier studies, though, including the use of both unipolar and bipolar depressed subjects in early lithium trials; slow antidepressant response to either antidepressants or lithium in bipolar depression; and low overall rates of response. The guideline makes several assumptions about bipolar depression treatment (Table 8). The practice guideline recommends lithium or lamotrigine as first-line treatments, although it places a higher level of confidence in lithium, followed by a combination of an antidepressant with lithium or electroconvulsive therapy. In addition, interpersonal and cognitive-behavioral psychotherapies are suggested, although the limited evidence of their efficacy is acknowledged (Table 9).1

Since the guideline was published, a new pivotal study (Figure 7)20 has led to the first FDA approval for a treatment for acute bipolar depression, a combination of olanzapine and fluoxetine. This study, with over 700 randomized subjects, showed that both olanzapine and an olanzapine/fluoxetine combination have acute antidepressant efficacy in bipolar depression.20 Olanzapine alone was statistically superior to placebo in acute efficacy but had a relatively small clinical effect. More interestingly, a combination of olanzapine and fluoxetine was superior to both placebo and olanzapine monotherapy. The average dose of olanzapine was 9.7 mg/day. The average doses of olanzapine and fluoxetine in combination were 7.4 mg/day and 39.3 mg/day, respectively. Neither active treatment caused more switching into mania than placebo.20

This is the first study to show acute antidepressant efficacy for an antipsychotic in bipolar depression. It seems likely that studies of other atypical antipsychotics for acute bipolar depression will be conducted rapidly, hopefully creating more treatment options. Prospective studies in this area should consider whether to use atypical antipsychotic monotherapy; a combination of an atypical antipsychotic with an antidepressant; or an atypical antipsychotic combined with lithium, divalproex, or lamotrigine.

The clear and robust efficacy of the olanzapine-fluoxetine combination for acute bipolar depression may suggest a wider role for antidepressants in bipolar depression. However, as the first study showing acute efficacy of either an antipsychotic or an antipsychotic-antidepressant combination, the study raises many new questions. Unfortunately, this study did not have a cell on fluoxetine alone. Is antidepressany monotherapy a reasonable option? If not, and if antidepressants should always be combined with an antimanic drug, is lithium the logical choice, or are other mania treatments, such as olanzapine, worth considering? Furthermore, how long should the antidepressant be continued following remission? Perhaps the biggest question raised by this study is that of whether the terminologies of antipsychotic and antidepressant are really relevant to bipolar disorder.

Other research in this area includes an acute bipolar I depression trial of lamotrigine (Figure 8), which demonstrated clinically significant antidepressant efficacy and an overall mania switch rate equal to placebo.3 This study led to the inclusion of lamotrigine as a first-line treatment in the guideline. The onset of efficacy was seen by 3 weeks, although at that point the lamotrigine dose was only 50 mg/day; response increased further with subsequently increased doses up to 200 mg/day. This trial provides evidence of antidepressant efficacy in bipolar depression and suggests that lamotrigine could be considered as a first-line treatment. Furthermore, although lamotrigine must be titrated slowly to reduce the risk of serious rash, the statistically significant separation from placebo by 3 weeks of treatment, even at a dose of only 50 mg/day, indicates that the antidepressant response to lamotrigine may be no slower than that of antidepressants. Unfortunately, there is no evidence of efficacy in acute mania.

On the other hand, there are several arguments supporting the preference of lithium over lamotrigine for acute bipolar depression. These include the demonstrated efficacy of lithium in both acute mania and acute bipolar depression, efficacy in prevention of mania in both responder-enriched and nonresponder-enriched samples, strong antisuicide efficacy based on retrospective comparisons to suicide attempts prior to taking lithium, and extensive clinical experience. There is no available trial directly comparing lithium and lamotrigine in acute bipolar depression.

The recommendation against using antidepressant monotherapy for treatment of bipolar depressive episodes is so widespread and well-accepted that it warrants inclusion in the practice guideline. Even the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,41 allows the savvy clinician to easily diagnose substance-induced mood disorder (mania) secondary to an antidepressant. The question of whether the manic episode was caused by the antidepressant is left to the clinician’s judgement—specifically, no minimum dose of antidepressant or duration of exposure is required. Without a controlled trial, the individual clinician faced with an antidepressant-treated patient who becomes manic assumes that the manic episode is antidepressant induced because there is no way to determine if the patient would have become manic even without an antidepressant. The rate of switching of bipolar depressed patients receiving acute treatment with placebo has ranged from 2% to 5%.3,4,6

Research evidence supporting this recommendation is not as convincing as might be assumed. While TCAs clearly have a high rate of switching into mania, the data for newer antidepressants is far from convincing. Recommendations for using bupropion and paroxetine arise from one small non-placebo–controlled study of bupropion suggesting a lower switch rate than desipramine,5 and one larger study of paroxetine.4 Notably, in the paroxetine trial, there was no switching at all reported in paroxetine-exposed depressed patients, although it is possible that some subjects had other adverse events that were consistent with mania but were not reported as such (Figure 9).4 Even if these are considered switches, the rate of switching on paroxetine is still low. It seems likely that different antidepressants have different liabilities for causing switching into mania and that newer antidepressants are safer. One report of a large series of 242 bipolar patients treated with SSRIs6 suggests a switch rate of only 3.7%, which was comparable to placebo.

The recommendation to use antidepressants with lithium (if antidepressants are used at all) to “cover” and reduce the possibility of switching into mania is more widely accepted. Unfortunately, the evidence basis for this recommendation in controlled trials is, at best, limited. In fact, in a paroxetine versus imipramine versus placebo in acute bipolar depression study,4 all patients were given combination treatment with lithium in addition to the study drug. In this trial, imipramine-treated patients had a switch rate of 8% despite being on lithium, while placebo-treated patients had a switch rate of only 2%. Imipramine-treated patients did have a lower switch rate when lithium was at a serum level of >0.8 mEq/L, but it was still higher than placebo. The fact that the switch rates reported in this trial represent a total of only four switches out of 117 subjects in the entire study should be considered.

A new study with >700 randomized subjects showed that both olanzapine and a combination of olanzapine-fluoxetine have antidepressant efficacy in bipolar depression.20 In this study, olanzapine alone was statistically superior to placebo but had a relatively small clinical effect. More interestingly, a combination of olanzapine and fluoxetine was superior to both placebo and to olanzapine monotherapy. This study suggests that both olanzapine monotherapy and an olanzapine-fluoxetine combination should be recommended as first-line acute bipolar depression treatments also.

The recommendation for psychosocial treatments in bipolar depression, including psychotherapy, has been essentially universally accepted by the academic community. Unfortunately, there is almost no controlled research on psychotherapy in bipolar disorder. The guideline recommendations on psychosocial or psychotherapeutic treatments are largely derived from the unipolar depression literature, where cognitive-behavioral therapy (in addition to medication) has been shown to be helpful. Psychodynamic psychotherapy, while widely used, also remains untested for bipolar depression.

Treatment of Rapid Cycling

The practice guideline recommendations for treatment of rapid cycling (Table 10)1 are based on a very small and incomplete research database (Table 11). The majority of the literature on treatments for rapid cycling is either in the form of case series or retrospective analyses and only clearly shows that rapid cycling is associated with poor response to lithium and also possibly carbamazepine. Hence, the assumptions that are made elsewhere in the practice guideline reappear in the rapid-cycling section (Table 12). For example, while efficacious mania treatments including lithium and valproate are recommended, atypical antipsychotics and benzodiazepines are omitted despite their documented efficacy in mania. The widely accepted notion that antidepressant use is associated with rapid cycling has been consistently documented in retrospective analyses of current rapid-cycling patients42,43 but has never been tested in a prospective trial (Table 13).42,44-56 The concept of adding rather than substituting, which was discussed earlier, is repeated in this section of the guideline.

The guideline for rapid cycling also discusses whether bipolar I and bipolar II rapid cycling are different. A recently published and well-designed study of rapid-cycling suggests that, in fact, they are quite distinct.57 In this trial, rapid-cycling subjects who were able to tolerate withdrawing from most of their medications took at least 100 mg/day of lamotrigine, and were randomly assigned to either continue on flexible-dose lamotrigine or placebo (withdrawal of lamotrigine) for 6 months. Lamotrigine was efficacious in reducing rapid cycling, and was found in a post hoc analysis be effective in the bipolar II subset but not the bipolar I subset (Figure 10). Due to the use of outcome measures which were not primarily related to relapse into either mania or depression, the potential efficacy of lamotrigine to selectively prevent depression but not mania could not be assessed from the study. However, the results suggest a differential drug response between bipolar I and II rapid-cycling patients.

Maintenance Treatment of Bipolar Disorder

The research literature about maintenance treatment is certainly more modest than that available for manic episode. The most important new development since the publishing of the practice guideline is the FDA approval of lamotrigine for maintenance treatment of bipolar I disorder. Since lithium and lamotrigine are now the only two FDA-approved medications for bipolar maintenance, clearly they should both be considered first-line treatments.

One important and often underappreciated feature of the literature for maintenance treatment is that nearly all of the controlled trials showing that any treatment has maintenance efficacy superior to placebo have done so based on responder-enriched samples. In other words, maintenance studies have tested medications primarily in subjects who were either known acute responders to that medication or had at least been shown to tolerate the study drug before being randomized. For example, the early studies documenting lithium efficacy in maintenance used subjects who had been acutely stabilized on lithium. Recent olanzapine and lamotrigine bipolar maintenance trials have selected only subjects who were either known drug responders or at least able to tolerate the drug being studied.19,57-59

In fact, the one major study that did not select a responder-enriched sample was the divalproex maintenance trial.60 Using an unselected study sample, divalproex could not be shown to have convincing and statistically significant maintenance efficacy when compared to lithium or placebo. However, when a post hoc subanalysis was performed on subjects treated with divalproex in their acute episode prior to the maintenance trial (and hence enriched with divalproex responders) divalproex was found to be efficacious.

Two lamotrigine maintenance trials58,59 selected lamotrigine-tolerating subjects for randomization and what could be considered lamotrigine-responder–enriched samples. The two studies differed in terms of the patients entered: one trial enrolled recently manic subjects, while the other enrolled recently depressed subjects. Both trials found lithium and lamotrigine superior to placebo in maintenance of bipolar disorder when relapse to either mania or depression was analyzed. More interestingly, when the direction of relapse was analyzed separately, lithium was superior to placebo in preventing mania (while lamotrigine was not), and conversely, lamotrigine was superior to placebo in preventing depression (while lithium was not). These studies also provide convincing confirmation of lithium’s efficacy in prophylaxis of mania since the study samples were definitely not enriched with lithium responders.

The results of these well-designed maintenance trials raise two important clinical points. The first is that results were similar regardless of whether the most recent episode was mania or depression. This could have important clinical implications. Common sense might suggest that the most important type of episode to prevent in each patient would be the same as the most recent episode (in other words, recently manic patients should have maintenance treatment focused primarily on prevention of mania while recently depressed patients should have maintenance treatment focused primarily on prevention of depression). These trial results suggest that this distinction may not be necessary and that long-term tendencies to relapse in either direction may be more important.

Secondly, the two active treatments, lithium and lamotrigine, have differences in the direction of their prophylactic efficacy. This may indicate that patients who historically had primarily manic or hypomanic episodes require one type of treatment (either lithium or valproate), while those with a history of depressive episodes require a different type of treatment (either lamotrigine or lithium). Thus, longitudinal course may be more important than recent history in terms of choosing a maintenance treatment. Furthermore, those having both types of episodes may require two treatments simultaneously.

There is nothing inherently unacceptable about using responder-enriched samples in a maintenance trial; in fact, this reflects the almost universal clinical practice of continuing efficacious acute treatments during maintenance. The principal conclusion from all of the bipolar maintenance trials confirms this practice by demonstrating that the first-choice maintenance treatment should be whatever worked for the acute episode. The exception to this observation is the finding that lithium was shown to be an efficacious maintenance treatment for prophylaxis of mania in the lamotrigine trials,59,60 which did not use a lithium-responder–enriched design. This demonstrates that lithium has mania prophylaxis efficacy even in nonresponder-enriched samples.

The inclusion of oxcarbazepine in this section of the guideline is highly questionable. There is no maintenance study of this medication at all in bipolar disorder, much less a placebo-controlled trial. Again, apparently the assumption is that oxcarbazepine works as well as carbamazepine for maintenance. This assumption has never been tested in bipolar disorder.

The issue of antipsychotics in maintenance treatment has largely been avoided by the practice guideline, which recommends antipsychotics only for psychosis or relapse prevention. These drugs, although commonly used for bipolar disorder, lack a clear role in maintenance treatment because there is little clinical research on their effectiveness. Recently, two large trials documented olanzapine’s maintenance efficacy in responder-enriched samples.19,61 The first trial randomly assigned olanzapine mania responders to continue on olanzapine or to withdraw from olanzapine, and to be treated with placebo. Olanzapine was superior to placebo in preventing both mania and depression.19 In the second trial,61 olanzapine combined with either lithium or valproate was compared to placebo combined with either lithium or valproate in maintenance treatment of recently manic responders. The olanzapine plus lithium or valproate was superior to the lithium or valproate alone (olanzapine withdrawal) in preventing relapse to mania.

These studies suggest that olanzapine is a legitimate first-line candidate for both acute and maintenance treatment and that olanzapine should clearly be considered a mood stabilizer. A major concern, though, particularly for olanzapine, is long-term tolerability with regard to metabolic side effects. Olanzapine has been associated with significant weight gain, diabetes, and hyperlipidemia in long-term studies of schizophrenia. Moreover, the magnitude of weight gain is greater than that estimated for lithium or divalproex. Other atypical antipsychotics with fewer long-term metabolic concerns may be important options for maintenance treatment, but there are no data yet available to demonstrate efficacy.

Lithium, carbamazepine, divalproex, lamotrigine, and olanzapine all have some placebo-controlled evidence of maintenance efficacy (Table 14). However, there is limited data available allowing direct comparisons of the efficacy of these medications in bipolar maintenance (Tables 15 and 16). Therefore, treatment choices are typically made based on tolerability and continuing the medication that worked in the acute episode.

Who Should Receive Maintenance Treatment?

The practice guideline recommends maintenance treatment for all bipolar patients. While this common sense recommendation is clearly popular, at least among mental health providers who prescribe medication, it should be considered in the context of the supporting research data. Obviously, all clinical maintenance trials have been conducted only with clearly identified bipolar patients and have included subjects with moderate and severe histories. Clinical trials nearly always intentionally attempt to exclude mildly ill patients because of the likelihood that such subjects may have a high placebo response rate, potentially undermining the ability of the study to show drug-placebo differences.

There are several rationales that suggest that maintenance medication may not be helpful for all patients. First, subjects in clinical trials may not actually represent the patients seen in standard clinical care. It is certainly likely that milder patients may benefit less from maintenance treatment. Second, while placebo has often performed worse than active medication in bipolar maintenance trials, this has not always been the case. For example, a lower-than-expected placebo relapse rate in the divalproex maintenance trial was one of several factors leading to the overall negative results of the study. Lithium was also unable to produce efficacy greater than placebo.61 Finally, the recommendation considers only efficacy in relapse prevention and ignores side effects. It is left to the individual clinician to decide whether the tolerability issues of any specific medication outweigh the potential benefits.

Conclusion

Bipolar disorder is a complex disorder often requiring a complex treatment plan. The APA practice guideline has summarized the research literature and expanded its conclusions on the basis of standard clinical practice. However, the guideline makes assumptions that have limited supporting evidence, including: atypical antipsychotics are more poorly tolerated than lithium or divalproex; combining a new treatment with one that is not working is preferable to switching to a new treatment; oxcarbazepine works as well as carbamazepine; all antidepressants cause mania; and adding lithium to an antidepressant will reduce chances of switching.

The practice guideline does represent a major synthesis of research and clinical opinion distilled into easily understood recommendations. However, most patients do not fit perfectly into any of its recommendations. In order to apply the practice guideline, it is important to understand the underlying assumptions, as well as the limitations of, the evidence on which the guideline is based. Only then can the clinician make a more educated decision about when to go beyond the recommendations in the guideline. PP

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53. Mattsson A, Seltzer RL. MAOI-induced rapid cycling bipolar affective disorder in an adolescent. Am J Psychiatry. 1981;138(5):677-679.

54. Extein I, Pottash AL, Gold MS. Does subclinical hypothyroidism predispose to tricyclic-induced rapid mood cycles? J Clin Psychiatry. 1982;43(7):290-291.

55. Oppenheim G. Drug-induced rapid cycling: possible outcomes and management. Am J Psychiatry. 1982;139(7):939-941.

56. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808.

57. Calabrese JR, Suppes T, Bowden CL, et al, for the Lamictal 614 Study Group. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61(11):841-850.

58. Bowden CL, Calabrese JR, Sachs G, et al, for the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400.

59. Goodwin FK, Bowden CL, Calabrese JR, et al. Maintenance treatments for bipolar I depression (lithium, lamotrigine, and placebo). Poster presented at: Annual Meeting of the American Psychiatric Association; May 17–22, 2003; San Francisco, CA.

60. Bowden CL, Calabrese JR, McElroy SL, et al, for the Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57(5):481-489.

61. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004;184:337-345.


Dr. Chou is research associate professor at New York University School of Medicine in New York City.

Disclosure: Dr. Chou is a consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hoechst, Janssen, Merck, Novartis, Ortho-McNeil, Otsuka, and Pfizer; receives grant and/or research support from Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hoechst, Janssen, Merck, Novartis, Ortho-McNeil, Otsuka, and Pfizer; and is a major stock holder in Bristol-Myers Squibb and Pfizer.

Please direct all correspondence to: James C-Y. Chou, MD, New York University School of Medicine, Department of Psychiatry, NBV 20 20W 13A, 462 1st Ave, New York, NY 10016; Tel: 212-263-6202; Fax: 914-359-7029; E-mail: chou@nki.rfmh.org.


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Pediatric Bipolar Disorder or Disruptive Behavior Disorder?

Joseph Biederman, MD, Eric Mick, ScD, Stephen V. Faraone, PhD, and Janet Wozniak, MD

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Primary Psychiatry. 2004;11(9):36-41
 

 

Faculty Affiliations and Disclosures

Dr. Biederman is professor of psychiatry at Harvard Medical School and chief of the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital in Boston.

Dr. Mick is assistant professor of psychiatry at Harvard Medical School and assistant director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Faraone is professor in the Department of Epidemiology at Harvard School of Public Health, clinical professor of psychiatry at Harvard Medical School, and director of research in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Dr. Wozniak is assistant professor of psychiatry at Harvard Medical School and director of the bipolar program in the Pediatric Psychopharmacology Research Unit at Massachusetts General Hospital.

Disclosure: Dr. Biederman serves on the speaker’s bureaus for Cephalon, Eli Lilly, Novartis, Ortho-McNeil, Pfizer, Shire, and Wyeth; receives research support from Cephalon, Eli Lilly, Janssen, National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse, National Institute of Mental Health (NIMH), Novartis, Pfizer, Shire, the Stanley Foundation, and Wyeth; and is on the advisory boards of CellTech, Cephalon, Eli Lilly, Janssen, Johnson & Johnson, Novartis, Noven, Ortho-McNeil, Pfizer, and Shire. Dr. Mick is a consultant for Janssen, receives grant and/or research support from NIMH, and receives honoraria and/or expenses from Ortho-McNeil. Dr. Faraone is a consultant for Eli Lilly, Noven, Ortho-McNeil, and Shire; serves on the speaker’s bureaus for Eli Lilly, Ortho-McNeil, and Shire; and receives research support from Eli Lilly, NICHD, NIMH, National Institute of Neurological Diseases and Stroke, Ortho-McNeil, and Shire. Dr. Wozniak is a consultant for Shire; serves on the speaker’s bureaus of Eli Lilly and Janssen; and receives grant and/or research support from Eli Lilly. 

Funding/support: This work was supported in part by grant #98-325B from the Theodore and Vada Stanley Foundation awarded to Dr. Biederman.

Acknowledgment: Aspects of this work were presented at the conference, “Bipolar Disorder: From Preclinical to Clinical, Facing the New Millennium,” held January 19–21, 2000 in Scottsdale, Arizona. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted education grant provided by Eli Lilly.

Please direct all correspondence to: Joseph Biederman, MD, Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114-3139; Tel: 617-726-1731; Fax: 617-724-1540; E-mail: jbiederman@partners.org.

 

Focus Points

• Bipolar disorder is a highly morbid and disabling disorder that can afflict children and adolescents.

• Studies of children with bipolar disorder document a high overlap with attention-deficit/hyperactivity disorder.

• A bi-directional and robust overlap between bipolar disorder and conduct disorder has also been documented in studies of bipolar youth and studies of conduct disorder youth.

 

Abstract

Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged by case reports and systematic research. This research suggests that pediatric mania is more common that previously assumed, although it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include a pattern of comorbidity that may be unique by adult standards, especially due to its overlap with attention-deficit/hyperactivity disorder and conduct disorder.

 

Introduction

The atypicality (by adult standards) of the clinical picture of childhood mania has long been recognized.1,2 Notably, the literature consistently shows that mania in children is seldom characterized by euphoric mood.3,4 Rather, the most common mood disturbance in manic children is severe irritability, with “affective storms,” or prolonged and aggressive temper outbursts.2 This irritability observed in manic children is very severe, persistent, and often violent.5 The outbursts include threatening or attacking behavior toward family members, other children, adults, and teachers. In between outbursts, these children are described as constantly irritable or angry in mood.3,4,6 Thus, it is not surprising that these children frequently receive the diagnosis of conduct disorder (CD). These aggressive symptoms may be the primary reason for the high rate of psychiatric hospitalization noted in manic children.5

In addition to the predominant abnormal mood in pediatric mania, its natural course is also atypical compared with the natural course of adult mania. The course of pediatric mania tends to be chronic and continuous rather than episodic and acute.3,4,7,8 For example, in a recent review of the past 10 years of research on pediatric mania, Geller and Luby6 concluded that childhood-onset mania is a nonepisodic, chronic, rapid-cycling, mixed manic state. Such findings have also been reported by Wozniak and colleagues,5 who found that the overwhelming majority of 43 children from an outpatient psychopharmacology clinic who met diagnostic criteria for mania on a structured diagnostic interview presented with chronic and mixed presentation. Furthermore, Carlson and colleagues9 reported that early-onset manic subjects were more likely to have comorbid behavior disorders in childhood and to have fewer episodes of remission in a 2-year period than those with adult-onset cases of mania. Thus, pediatric mania appears to present with an atypical picture characterized by predominantly irritable mood, mania mixed with symptoms of major depression, and a chronic—as opposed to euphoric, biphasic, and episodic—course.

The chronicity of pediatric mania has been documented by an emerging, although limited, literature. Using data from a 2-year follow-up study, Geller and colleagues10 recently reported high levels of persistence and recurrence of manic symptomatology in children with bipolar disorder. Similar findings were reported by Biederman and colleagues11 in a longitudinal sample of children with attention-deficit/hyperactivity disorder (ADHD) and comorbid bipolar disorder. These investigators documented that 90% of these children failed to attain euthymia over a 10-year course.11 The findings suggest that pediatric cases with mania may develop into adults with mixed mania.

 

Bipolar Comorbidity with Attention-Deficit/Hyperactivity Disorder

A leading source of diagnostic confusion in childhood mania is its symptomatic overlap with ADHD. Systematic studies of children and adolescents show that rates of ADHD range from 60% to 90% in pediatric patients with mania.5,12-14 Although the rates of ADHD in samples of youth with mania are universally high, the age of onset modifies the risk for comorbid ADHD. For example, while Wozniak and colleagues5 found that 90% of children with mania also had ADHD, West and colleagues14 reported that only 57% of adolescents with mania had comorbid ADHD. Examining further developmental aspects of pediatric mania, Faraone and colleagues15 found that adolescents with childhood-onset mania had the same rates of comorbid ADHD as manic children (90%) and that both of these groups had higher rates of ADHD than adolescents with adolescent-onset mania (60%). Most recently, Sachs and colleagues16 reported that, among adults with bipolar disorder, a history of comorbid ADHD was only evident in those subjects with onset of bipolar disorder before 19 years of age. The mean onset of bipolar disorder in those with a history of childhood ADHD was 12.1 years of age.16 Similarly, Chang and colleagues17 studied the offspring of patients with bipolar disorder and found that 80% of manic children had comorbid ADHD and that the onset of mania in adults with bipolar disorder and a history of ADHD was 11.3 years of age. These findings suggest that age of onset of mania, rather than chronological age at presentation, may be the critical developmental variable that identifies a highly virulent form of the disorder that is heavily comorbid with ADHD. 

Although ADHD has a much earlier onset than pediatric mania, the symptomatic and syndromatic overlap between pediatric mania and ADHD raises a fundamental question: do children presenting symptoms that are suggestive of mania and ADHD have ADHD, mania, or both? One method to address these uncertainties has been to examine the transmission of comorbid disorders in families.18,19 If ADHD and mania are associated due to shared familial etiologic factors, then family studies should find mania in families of ADHD patients and ADHD in families of manic patients.

Studies that have examined rates of ADHD (or attention-deficit disorder) among the offspring of adults with bipolar disorder all found higher rates of ADHD among these children compared with controls.20 Although the difference in rates attained statistical significance in only one study, the meta-analysis of Faraone and colleagues20 documented a statistical and bi-directional significant association between bipolar disorder in parents and ADHD in their offspring, as well as between ADHD in a child proband and mania in relatives.

Wozniak and colleagues21 used familial risk analysis to examine the association between ADHD and mania within families of manic children. They found that relatives of children with mania were at high risk for ADHD; this risk was indistinguishable from the risk in relatives of children with ADHD and no mania. However, rates of mania and comorbid ADHD selectively aggregated among relatives of manic youth were comparable to those of ADHD and comparison children.21 Almost identical findings were obtained in two independently defined family studies of ADHD probands with and without comorbid mania.20,22 Taken together, this pattern of transmission in families suggests that mania in children might be a familially distinct subtype of either bipolar disorder or ADHD. The existence of a familial, developmental subtype is consistent with the work of Strober and colleagues,23 Strober,24 and Todd and colleagues,25 who proposed that pediatric mania might be a distinct subtype of bipolar disorder with a high familial loading.

One problem facing studies of ADHD and mania is that these disorders share diagnostic criteria. Of seven Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R)26 criteria for a manic episode, three are shared with DSM-III-R criteria for ADHD: distractibility, motoric hyperactivity, and talkativeness. To avoid counting symptoms twice toward the diagnosis of both ADHD and mania, two different techniques of correcting for overlapping diagnostic criteria have been used to evaluate the association between ADHD and pediatric mania.27

In the first technique, the subtraction method, overlapping symptoms are simply not counted when making the diagnosis. In the proportion method, overlapping symptoms are not counted but the diagnostic threshold is lowered. However, the same proportion of symptoms is required in both the reduced set and the original diagnosis.28 Using these methods, Biederman and colleagues27 showed that 48% of children with mania continued to meet criteria by the subtraction method and 69% by the proportion method. Eighty-nine percent of children with mania maintained a full diagnosis of ADHD using the subtraction method and 93% maintained the ADHD diagnosis by the proportion method. These results suggest that the comorbidity between ADHD and pediatric mania is not a methodological artifact due to diagnostic criteria shared by the two disorders.

The potential for different rates of comorbidity with mania in the combined subtype, the inattentive subtype, and the hyperactive-impulsive subtype of ADHD is in need of further research. Faraone and colleagues20 studied 301 ADHD children and adolescents consecutively referred to a pediatric psychopharmacology clinic. Among these, 185 (61%) had the combined type of ADHD, 89 (30%) had the inattentive type, and 27 (9%) had the hyperactive-impulsive type. Bipolar disorder was highest among combined-type youth (26.5%) but was also elevated among hyperactive-impulsive (14.3%) and inattentive (8.7%) youth.

 

Bipolar Comorbidity with Conduct Disorder

An emerging literature documents an elevated risk for CD among children with bipolar disorder. Kovacs and Pollock29 reported a 69% rate of CD in a referred sample of bipolar youth. In that study, the presence of CD heralded a more complicated course of bipolar disorder. Similarly, Kutcher and colleagues30 found that 42% of hospitalized youth with bipolar disorder had comorbid CD; Wozniak and colleagues5 showed that preadolescent children satisfying structured interview criteria for bipolar disorder very frequently had comorbid CD. Notably, an epidemiologic study of children and adolescents31 found high rates of comorbidity between bipolar and disruptive behavior disorders. These findings in children, which report a nearly 7-fold increase in the risk for bipolar disorder among individuals with antisocial personality disorder (ASPD), are consistent with those in adults.32

While the reasons for these intriguing associations between CD and bipolar disorder remain unknown, a close inspection of the characteristics of juvenile bipolar disorder offers some clues. The literature indicates that juvenile bipolar disorder is frequently mixed, and that the most common mood disturbance in manic children is irritability, with “affective storms,” or prolonged, aggressive, and frequently violent temper outbursts.2-4 The irritable outbursts include threatening or attacking behavior toward others, including family members, children, adults, and teachers.

In conceptualizing the overlap between bipolar disorder and CD, Kovacs and Pollock29 suggested that the high prevalence of comorbid CD in bipolar youth might confuse the clinical presentation of childhood bipolar disorder and possibly account for some of the documented failure to detect bipolarity in children. Thus, the heterogeneity of bipolar disorder and that of CD may have important implications in helping to identify a subtype of bipolar disorder with early onset characterized by high levels of comorbid CD,29 as well as a subtype of CD with high levels of dysphoria and explosiveness.

Although these aberrant behaviors are consistent with the diagnosis of CD, they may be due to the behavioral disinhibition of bipolar disorder, or the irritability and low frustration tolerance that frequently accompanies pediatric bipolar disorder. Considering the extreme severity of juvenile bipolar disorder, its emergence in CD children (and, conversely, the emergence of CD in bipolar children) seriously complicates their already compromised condition.

Biederman and colleagues33 attempted to delineate this relationship between bipolar and CD in a series of studies. These studies relied on systematic evaluation of clinical correlates in affected youth and their relatives. Biederman and colleagues33 first tested the hypothesis that subtypes of CD with and without bipolar disorder could be distinguished from one another in a family study of 140 ADHD probands and 120 controls without ADHD ascertained from psychiatric and pediatric clinics. All probands were Caucasian, non-Hispanic males who were 6–17 years of age. Of 140 ADHD probands, 38 (27%) also met diagnostic criteria for CD and 30 (23%) for bipolar disorder at either baseline or follow-up assessments; of those, 21 (55% of CD cases and 71% of bipolar disorder cases) had both CD and bipolar disorder. The researchers reexamined the degree of overlap in a larger sample of clinically referred children that were not selected to participate in a study of ADHD.34 In this sample, the prevalence of bipolar disorder was 17% and the prevalence of CD was 18%. Of the pool of consecutively referred youth evaluated comprehensively with a structured diagnostic interview as described above, 186 subjects with mania and 192 subjects with CD were identified. Seventy-six patients satisfied criteria for both CD and bipolar disorder (ie, 40% of CD youth [76 of 192] and 41% of youth with bipolar disorder [76 of 186] also had the other disorder). This larger study of children with bipolar disorder and/or CD conducted outside the context of an ADHD sampling scheme34 provided greater precision and more clearly demonstrates the bi-directional overlap of these two disorders in clinical samples.

Further examination of the symptoms of bipolar disorder and CD indicated that the presence of one disorder did not alter the presentation of the other.34 The symptom profile of bipolar disorder was the same in bipolar disorder children and children with comorbid CD and bipolar disorder, just as the symptoms of CD were strikingly similar in children with bipolar disorder and CD irrespective of the comorbidity with the other disorder. Similarly, there were few differences in the frequency of CD symptoms between CD youth with and without comorbid bipolar disorder. These findings lend support to the notion that this may be true comorbidity and not simply the misdiagnosis of both conditions due to aggressive behavior endorsed in both modules of the interview. CD was also not found to modify the course of mania, with equal numbers of subjects reporting a chronic course (≥1 year duration) irrespective of the comorbidity with CD (65% versus 71% for bipolar disorder alone and comorbid bipolarity and CD, respectively).34 This pattern of symptoms, onset, and course suggests that the disorders behave similarly whether they are comorbid or exist separately from each other, and do not necessarily overlap concurrently. Longitudinal studies that examine the course of the disorders repeatedly over brief intervals are needed to disentangle this difficult clinical diagnostic confusion.

Rates of psychiatric hospitalization also differed dramatically in CD youth with and without comorbid bipolar disorder, with children with both CD and bipolar disorder accounting for most of the psychiatric hospitalizations in youth with CD. Psychiatric hospitalization was very low outside the context of bipolar disorder. Since many children in psychiatric hospitals with the diagnosis of CD commonly have a profile of severe aggressiveness, it is likely that these children required psychiatric hospitalizations because of the manic picture and not necessarily due to the CD. More work is needed to better test this hypothesis and to determine other factors that lead to hospitalization in children with either CD or bipolar disorder.

Because both CD and bipolar disorder are known to be familial disorders, one useful approach to disentangling these diagnoses and answering questions regarding the nature of their association is the use of family aggregation data.19,35-38 Such an approach can provide evidence external to the complicated diagnostic questions posed by the complex comorbid phenotype of individual patients. In other words, examining familial patterns of psychopathology can help answer whether children with a mix of mood and antisocial symptoms have bipolar disorder, CD, or both. Familial risk analysis showed that bipolar disorder probands had significantly higher rates of familial bipolar disorders and CD probands had higher rates of familial antisocial disorders compared with ADHD probands, irrespective of the presence of comorbidity with the other disorder.33

Wozniak and colleagues39 confirmed and expanded these findings in a second familial risk analysis that pooled resources from smaller studies in order to estimate the risk in relatives from a study with an increased sample size. This study pooled data from two samples of youth with DSM-III-R bipolar disorder (n=45) and their first-degree relatives (n=145), who were evaluated with identical methodologies. These were stratified into two proband groups defined by the presence or absence of CD and bipolar disorder. The first group contained 26 probands with both CD and bipolar disorder and 92 relatives, and the second group contained 19 probands with bipolar disorder without CD and 53 relatives. Compared with controls, the rate of bipolar disorder was significantly higher in relatives of both bipolar proband groups, irrespective of comorbidity with CD. The rate of CD/ASPD was significantly higher in relatives of both CD proband groups, irrespective of comorbidity with bipolar disorder. In addition, the rate of CD/ASPD in relatives of CD and bipolar disorder probands was nearly twice as large as the rate of CD/ASPD in relatives of CD probands (34% versus 19%, P<.05).39,40

The researchers also found significant co-segregation between antisocial disorders and bipolar disorder among the relatives of CD and bipolar disorder probands. That is, nearly all the bipolar disorder among relatives of co-occurring CD and bipolar disorder probands occurred in those relatives who also had CD or ASPD (χ2=10.9, P=.001). Two types of CD/ASPD were identified in relatives of co-occurring CD and bipolar disorder probands: those with and those without comorbid bipolar disorder. While relatives of CD and bipolar disorder probands had almost exclusively the comorbid type of bipolar disorder, the overrepresentation of CD/ASPD in relatives of CD probands consisted exclusively of CD/ASPD individuals without comorbid bipolar disorder.39 These findings were consistent with prior work suggesting a three-way familial association among bipolar disorder, CD/ASPD, and ADHD.20 The results from these family studies support the concept of heterogeneity of bipolar disorder and CD and provide compelling evidence that subtypes of CD and of bipolar disorder can be identified based on patterns of comorbidity with the other disorder.

 

Treatment Implications

Biederman and colleagues41 systematically reviewed the clinical records of all pediatrically referred patients who, at initial intake, satisfied diagnostic criteria for mania based on a structured diagnostic interview with the mother. Mood stabilizers were frequently used in these children and their use was associated with significant improvement of manic-like symptoms (as recorded by their psychiatrists in the medical record). However, although treatment with mood stabilizers was associated with a statistically significant decrease in manic-like symptoms, this improvement was slow to develop and was associated with frequent relapses. Antidepressants, typical antipsychotics, and stimulants were not associated with improvement of manic-like symptoms. 

Kowatch and colleagues,42 using an 8-week open study design, compared the effectiveness and tolerability of lithium carbonate, divalproex sodium, and carbamazepine in children with bipolar disorder. They found a 53% rate of improvement for divalproex sodium and much lower rates for lithium carbonate and carbamazepine. Likewise, Wagner and colleagues43 reported similarly modest effects in another trial of divalproex sodium in pediatric bipolar disorder.

Recently, somewhat more optimistic findings have resulted from investigations of atypical neuroleptics in the treatment of juveniles with bipolar disorder. In a retrospective chart review study of 28 youths with bipolar disorder, 82% of subjects showed improvement in both manic and aggressive symptoms with risperidone treatment.44 In contrast to the duration of treatment required for improvement with mood stabilizers, the average time to optimal response was 1.9±1.0 months of therapy. Moreover, no serious adverse effects were observed.

Similarly encouraging results were reported by Frazier and colleagues45 in an open trial of olanzapine monotherapy. They found that treatment with olanzapine was associated with significant improvements in 23 manic children after 8 weeks of monotherapy on doses ranging from 2.5–20 mg/day, according to both the Children’s Depression Inventory and the Young Mania Rating scale. Using the same prospective 8-week open study design, Biederman and colleagues46 reported that treatment with risperidone monotherapy improved both manic and depressive symptoms in youth with bipolar I, bipolar II, or bipolar spectrum disorder in youth. Also, DelBello and colleagues47 recently reported results from a randomized clinical trial that documented that the combination of divalproex sodium plus quetiapine was superior to divalproex sodium alone in the treatment of an inpatient sample of adolescents with bipolar disorder.47,48 

Because pediatric bipolar disorder is frequently mixed and comorbid with ADHD, its pharmacologic management can be complicated, as treatments for bipolar disorder do not treat ADHD, treatments for ADHD do not treat bipolar disorder, and antidepressants can precipitate mania. Biederman and colleagues41,49 used a novel chart review methodology to systematically evaluate the clinical records of psychiatrically referred youth with a diagnosis of bipolar disorder and comorbid ADHD. The results showed that the presence of mania interfered with the improvement of ADHD symptomatology during anti-ADHD pharmacotherapy and that ADHD symptoms were much more likely to improve after mood stabilization. These results suggest that the successful management of children with both mania and ADHD requires the deployment of disorder-specific treatments and that treatment of ADHD symptomatology is only possible after mood stabilization.48 However, because of the severe disruption in functioning associated with exacerbation of manic symptoms, caution is needed in prescribing anti-ADHD treatments to ADHD children with mania.

The diagnosis of bipolar disorder in some CD children offers important therapeutic possibilities, since sociopathy and bipolar disorder may require very different treatment strategies. A series of controlled clinical trials50-54 documented the efficacy of mood stabilizers (lithium carbonate and carbamazepine) in the treatment of aggressive CD children. However, these psychiatrically hospitalized CD youth were treated for severe, uncontrollable, and disorganized aggression and not necessarily for delinquency. Thus, it is possible that the therapeutic benefits observed in these children could have been due to the effects of these well known antimanic medications in treating aggressive manic children satisfying criteria for CD.51,55

Findling and colleagues56 recently reported that risperidone was effective in treating aggression in children with conduct disorder and Aman and colleagues57 reported results from a double-blind study that documented that risperidone was superior to placebo in the treatment of youth with CD and subaverage intelligence. A recent secondary analysis of the study results of Aman and colleagues57 documented the efficacy of risperidone in improving both manic and depressive symptoms in this population (Biederman and colleagues, unpublished data, 2004). Taken together, these initial results support the need for additional short- and long-term controlled trials of atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers.

 

Conclusion

The emerging literature indicates that mania can be identified in a substantial number of referred children using systematic assessment methodology. Thus, this disorder may not be as rare as previously considered. Children with mania tend to show an atypical picture by adult standards, with a chronic course, severely irritable mood, and a mixed picture with depressive and manic symptoms co-occurring. Most children with childhood-onset mania may also have ADHD and CD, which requires additional treatment. Initial clinical evidence suggests that atypical neuroleptics may play a therapeutic role in the management of such youth. The high levels of comorbidity with other disorders is common, further requiring the cautious use of a combined pharmacotherapy approach. PP

 

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30. Kutcher SP, Marton P, Korenblum M. Relationship between psychiatric illness and conduct disorder in adolescents. Can J Psychiatry. 1989;34(6):526-529. 

31. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry. 1995;34(4):454-463. 

32. Boyd JH, Burke JD Jr, Gruenberg E, et al. Exclusion criteria of DSM-III. A study of co-occurrence of hierarchy-free syndromes. Arch Gen Psychiatry. 1984;41(10):983-989. 

33. Biederman J, Faraone SV, Hatch M, Mennin D, Taylor A, George P. Conduct disorder with and without mania in a referred sample of ADHD children. J Affect Disord. 1997;44(2-3):177-188. 

34. Biederman J, Faraone SV, Chu MP, Wozniak J. Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. J Am Acad Child Adolesc Psychiatry. 1999;38(4):468-476. 

35. Pauls DL, Towbin KE, Leckman JF, Zahner GE, Cohen DJ. Gilles de la Tourette’s syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship. Arch Gen Psychiatry. 1986;43(12):1180-1182. 

36. Pauls DL, Hurst CR, Kruger SD, Leckman JF, Kidd KK, Cohen DJ. Gilles de la Tourette’s syndrome and attention deficit disorder with hyperactivity. Evidence against a genetic relationship. Arch Gen Psychiatry. 1986;43(12):1177-1179. 

37. Reich T, James JW, Morris CA. The use of multiple thresholds in determining the mode of transmission of semi-continuous traits. Ann Hum Genet. 1972;36(2):163-184. 

38. Reich T, Rice J, Cloninger CR, Wette R, James J. The use of multiple thresholds and segregation analysis in analyzing the phenotypic heterogeneity of multifactorial traits. Ann Hum Genet. 1979;42(3):371-390. 

39. Wozniak J, Biederman J, Faraone SV, Blier H, Monuteaux MC. Heterogeneity of childhood conduct disorder: further evidence of a subtype of conduct disorder linked to bipolar disorder. J Affect Disord. 2001;64(2-3):121-131. 

40. Biederman J, Russell R, Soriano J, Wozniak J, Faraone SV. Clinical features of children with both ADHD and mania: does ascertainment source make a difference? J Affect Disord. 1998;51(2):101-112. 

41. Biederman J, Mick E, Bostic JQ, et al. The naturalistic course of pharmacologic treatment of children with maniclike symptoms: a systematic chart review. J Clin Psychiatry. 1998;59(11):628-637. 

42. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(6):713-720. 

43. Wagner KD, Weller EB, Carlson GA, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1224-1230. 

44. Frazier JA, Meyer MC, Biederman J, et al. Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry. 1999;38(8):960-965. 

45. Frazier JA, Biederman J, Wilens TA, Spencer TJ. Advanced issues in psychopharmacology: psychotic disorders and bipolar disorders in children and adolescents. Paper presented at: 46th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 19–24, 1999; Chicago, IL. 

46. Biederman J, Mick E, Johnson MA, et al. A prospective open-label treatment trial of risperidone monotherapy in children and adolescents with bipolar disorder. Paper presented at: 50th Anniversary Meeting of the American Academy of Child and Adolescent Psychiatry; October 14–19, 2003; Miami Beach, FL.

47. DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1216-1223. 

48. Wagner KD, Weller EB, Carlson GA, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1224-1230. 

49. Biederman J, Mick E, Prince J, et al. Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder. J Child Adolesc Psychopharmacol. 1999;9(4):247-256. 

50. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1995;34(4):445-453. Erratum in: J Am Acad Child Adolesc Psychiatry. 1995;34(5):694. 

51. Campbell M, Small AM, Green WH, et al. Behavioral efficacy of haloperidol and lithium carbonate. A comparison in hospitalized aggressive children with conduct disorder. Arch Gen Psychiatry. 1984;41(7):650-656. 

52. Cueva JE, Overall JE, Small AM, Armenteros JL, Perry R, Campbell M. Carbamazepine in aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1996;35(4):480-490. 

53. Malone RP, Delaney MA, Luebbert JF, Cater J, Campbell M. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry. 2000;57(7):649-654. 

54. Rifkin A, Karajgi B, Dicker R, et al. Lithium treatment of conduct disorders in adolescents. Am J Psychiatry. 1997;154(4):554-555. 

55. Campbell M, Gonzalez NM, Silva RR. The pharmacologic treatment of conduct disorders and rage outbursts. Psychiatr Clin North Am. 1992;15(1):69-85. 

56. Findling RL, McNamara NK, Branicky LA, Schluchter MD, Lemon E, Blumer JL. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(4):509-516. 

57. Aman MG, De Smedt G, Derivan A, Lyons B, Findling RL, for the Risperidone Disruptive Behavior Study Group. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry. 2002;159(8):1337-1346.

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The Bipolar Spectrum in Psychiatric and General Medical Practice

Hagop S. Akiskal, MD

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Primary Psychiatry. 2004;11(9):30-35

Focus Points

• Bipolar disorder is more prevalent than previously believed.

• This higher prevalence is largely accounted for by a spectrum of bipolar disorders, which include bipolar type I, type II, and beyond.

• In different community studies, 5% of individuals on average are estimated to have bipolar spectrum disorders.

• Although counterintuitive, 30% to 70% of all depressions seen in various clinical settings, including both psychiatric and general medical practices, have been found to belong to the bipolar spectrum.

• The bipolar spectrum frequently presents clinically in association with panic, anxious-phobic, bulimic, addictive, and erratic personality disorders.

Abstract

This introductory article examines the emerging scientific and clinical literature on bipolar types beyond those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½, type III, and type IV. Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in private psychiatric, community mental health, and general medical practice. Thus, identifying bipolar disorder as a spectrum has clinically meaningful implications for comorbid conditions, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Introduction

Until recently, it was believed that bipolar disorder occurred in 1% of the general population. This figure pertains to what is known as bipolar I disorder (manic-depressive illness). However, the current bipolar schema in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),1 also includes bipolar II, cyclothymia, and bipolar not otherwise specified. Thus, it should not come as a surprise that, in a wave of new epidemiologic studies, the prevalence of the entire spectrum has been revised up to at least 5% of the general population.2 Although the DSM-IV does not use the construct of “bipolar spectrum,” its bipolar subtypes implicitly adhere to such a broad schema.

The work reviewed in this article examines the emerging scientific and clinical literature on bipolar types beyond DSM-IV bipolar I and II. These include new “softer” expressions of bipolarity, such as type II with briefer hypomanias, type II½ (depression superimposed on cyclothymia), type III (depression plus antidepressant-associated hypomania), and type IV (depression superimposed on a hyperthymic temperament).2,3

Patients within the soft spectrum beyond the DSM-IV prototypes are highly prevalent in psychiatric and primary care community and private practice settings. However, they often present clinically with a volatile mix of depression and biographical instability (ie, so-called erratic personality disorders), along with addictive, phobic-anxious, panic, and bulimic comorbidities. History of hypomania is more often than not overshadowed by the lifelong nature of these complex manifestations. It is important for psychiatrists, other mental health professionals, and general medical practitioners to be vigilant concerning the bipolar spectrum in patients presenting with the foregoing conditions. They should therefore conduct a diligent search for hypomania.

There is credible evidence that, depending on the study and the setting, somewhere between 30% and 70% of all depressions observed in clinical settings belong to this complex spectrum.2 The atheoretical position of the DSM-IV diagnostic system may serve as a blueprint for a research document, but regrettably it does not do justice to the clinical complexity of bipolarity as seen by the practitioner, nor does the DSM-IV provide any guidance on how to make sense of the conditions that accompany bipolar illness. Reformulating bipolar disorder as a spectrum has clinically meaningful implications for comorbidity, the nature of a putative shared underlying pathophysiology, clinical management, and public health.

Defining the Bipolar Spectrum

There is an emerging international consensus2 that bipolar disorder extends beyond the boundaries of an illness historically defined by an alternation of mania and depression. Indeed, between the extremes of full-blown manic-depressive illness (ie, bipolar I, where the patient has at least one acute manic episode) and strictly-defined unipolar depression (without personal or family history of mania or hypomania), there exists a prevalent spectrum of soft bipolar conditions with various admixtures of depression, hypomania, and temperamental instability.3

Those with spontaneous hypomania are now formally considered bipolar II in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).4 Moreover, in many clinically depressed patients, elements of hypomanic activation can occur during an episode of major depressive disorder (MDD), resulting in “depressive mixed states” (which are not officially recognized in the DSM-IV). These patients pose diagnostic and therapeutic challenges for clinicians.3,5,6 Depressions with antidepressant-associated hypomania also appear, on the basis of extensive recent work,2,7 to be related to bipolar II (although some refer to them as bipolar III, also not an official rubric in the DSM-IV). Premorbid and interepisodic cyclothymic (a variant of bipolar II8) or hyperthymic traits (ie, bipolar type IV, consisting of overcheerful, overenergetic, and overconfident people who succumb to depression in their 40s and 50s9) represent prominent characteristics of other soft expressions of this spectrum. Patients across the soft spectrum may present with depression, anxiety, or mood swings. These mood swings are recurrent, biphasic, and abrupt, and are frequently induced by antidepressants (or stimulant and alcohol abuse) and/or by seasonal changes.3 Falling in and out of love and other excitements that could lead to sleep deprivation represent common contributory factors to the instability of these patients.3,9 Table 1 presents this proposed bipolar spectrum schema.

Although the DSM-IV-TR only includes bipolar types I and II, the aforementioned schema provides characterization for the remainder of the spectrum types, which in the DSM-IV are dubbed under the nondescript rubric of “bipolar not otherwise specified.” The proper specification of the entire spectrum is important for clinical practice. It makes little sense for a diagnostic manual developed for clinicians to categorize patients as having an unspecified disorder. Most physicians diagnose and manage conditions on the border of prototypical disorders. This is where the DSM-IV fails them. For a more in-depth description of this schema, the reader is referred to work by Akiskal and Pinto.9

Bipolar Disorder in Clinical and Community Settings

There has been a major recent research thrust in the study of bipolar disorder in its psychotic and ambulatory variants. It is now well accepted that mania can manifest in extreme psychotic forms,10 including “schizobipolar” phenotypes.11 Careful research has also delineated mixed or dysphoric forms of mania that also frequently reach psychotic proportions.12-17 Patients with such intense activation typically require psychiatric hospitalization. Current data indicate that at least two depressive symptoms exclusive of insomnia and agitation are sufficient for defining dysphoric mania. More provocatively, such mixed manic forms have been shown to arise from the baseline of a dysthymic (depressive) temperament, whereas pure mania is more typically superimposed on a hyperthymic temperament.

Current official systems of classification (such as the DSM-IV) are couched within the unipolar-bipolar distinction, yet a newer conceptual framework, in development since 1977,3,9,18-21 has accumulated data in favor of the existence of a prevalent group of intermediary, predominantly ambulatory, conditions. Recent studies in psychiatric settings,3,22-24 in general medical practice,25 and in the community26-29 have revealed a large spectrum of patients with soft or subtle signs of bipolarity. Bipolar II, the best known of these conditions, was first delineated by Dunner and colleagues.30 Typically these patients present with MDD, but upon expert interviewing31 reveal a history of activated behavior, mood lability, explosive behavior, or marked irritability.32 The soft bipolar spectrum, which is more prevalent than full-blown manic-depressive illness, constitutes a “clinical bridge” between unipolar and psychotic bipolar disorders,3 indicating the need for a partial return to Kraepelin’s33 broad concept of manic-depressive illness.

Based on the finding that depressive forms exceed definite bipolar cases in manic-depressive pedigrees by 4–5-fold,11 Akiskal and Mallya3 estimated in 1987 that the rates for the bipolar spectrum should be 4% to 5%. Epidemiologic studies have actually shown that these softer expressions of bipolarity have a prevalence range of 3.7% to 8.3%,26-29 as opposed to the conventionally reported rate of 1% for manic-depressive illness.34 Most interestingly, in private psychiatric, community mental health,2,3 and general medical25 settings, somewhere between 30% and 70% of patients presenting with MDD belong to the bipolar spectrum.

Focus on the Soft Spectrum

There are several intermediary conditions between bipolar I and strictly-defined unipolar MDD. The common feature of these intermediate bipolar conditions is the occurrence of manic activation at a subthreshold level.3,9 Bipolar II, the most prototypical of the soft bipolar spectrum, appears to be the most prevalent clinical expression of bipolar disorders.35 Spontaneous hypomania is needed for the diagnosis of bipolar II. Because bipolar II patients present clinically with depression and almost never with hypomania, the diagnosis of bipolar II requires skillful interviewing about history of such episodes. Current clinical guidelines2 indicate that the duration of hypomanic episodes is less important when numerous such episodes have occurred in the past. Hypomania is a distinct episode of mild elevation of mood, positive thinking, and increased activity level occurring over at least a few days. It is distinguished from ordinary happiness by the tendency of episodes to recur (happiness usually does not, unfortunately) and by the fact that it can be mobilized by antidepressants.3 Despite DSM-IV conventions to the contrary, the preponderance of evidence based on family history for bipolar disorder and clinical course2,7 indicates that hypomania during antidepressant treatment of an episode of MDD merits a bipolar designation (ie, bipolar III).

Individual hypomanic episodes may also be associated with positive emotions and creative thinking.36 However, the judgment of patients may be impaired. Repeated episodes of hypomania in association with mood swings may cumulatively contribute to the unstable course of bipolar II disorder, as well.2 Moreover, the experience of hypomania itself is often that of a “nervous high,” with marked irritable and hostile admixtures. According to the DSM-IV, hypomania typically presents without the marked impairment characteristic of manic episodes. Judging from the above symptoms of hypomania, however, the DSM-IV characterization of bipolar II as a milder condition is misleading. Table 2 provides a summary of findings on hypomanic episodes taken from clinical experience.3,9,18

Another characteristic of some, but not all, bipolar II patients is their labile cyclothymic temperamentality8 prior to and between MDD episodes.24 These patients, who can be considered “cyclothymic depressives,” exhibit a great deal more instability than bipolar II patients who present without cyclothymia; in fact, they are often mistaken for patients with borderline personality disorder. Prospective follow-up leading to MDD and/or hypomania rather than mania,18 and familial bipolar history, are the strongest evidence for the inclusion of these patients within the bipolar spectrum.8 One might consider them bipolar II variants or bipolar II½.9 The validated self-rated criteria for cyclothymia37 are summarized in Table 3. Patients with MDD endorsing at least six of these criteria are likely to belong to this bipolar variant.

In yet another soft bipolar subgroup, hypomanic and cyclothymic episodes as such are absent; instead, the individual has a persistent upbeat disposition, is overoptimistic, and functions at a high level of energy and confidence premorbidly and between depressive episodes. Unlike hypomania, which is an episode distinct from the patient’s habitual self, the hyperthymic traits of bipolar IV patients represent their habitual baseline.38 These traits have been found to define a subtype of MDD with bipolar family history indistinguishable from other disorders in the spectrum.9,22 The criteria for the hyperthymic temperament3 are summarized in Table 4. It is usually best to elicit these traits by clinical interview or from significant others; a patient with MDD meeting at least four of these criteria can be clinically assigned to bipolar type IV.

Evidence for the importance of temperamental attributes in defining bipolar spectrum subtypes has come from the National Institute of Mental Health Collaborative Study of Depression (CDS) database. As demonstrated in a 12-year prospective examination of bipolar switching in the CDS,39 trait attributes consisting of “mood-lability” and “energetic-activity” permit a more precise characterization of the bipolar spectrum than the hypomanic periods emphasized in the DSM-IV and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).40 To properly diagnose soft bipolar conditions, the clinician must therefore carefully assess lifelong cyclothymic (mood-labile) or hyperthymic (active-energetic) traits. MDD episodes often complicate the life course in these individuals, and during these episodes, their conditions would therefore warrant the additional diagnosis of bipolar spectrum disorders.

In official diagnostic systems, bipolarity is characterized by the presence of alternating manic (or hypomanic) and depressive phases. However, a more fundamental characteristic of bipolarity is the reversal of the basic temperament into its opposite episode.41 Research22,24 has actually shown that the MDD expression in bipolar II disorder commonly arises from cyclothymic temperament. On the other hand, bipolar I disorder, characterized by a predominance of manic attacks, is more likely to arise from a dysthymic or hyperthymic temperament and, in bipolar I, a hyperthymic baseline is typically limited to patients with a predominantly manic course. Thus, the biphasic disturbance in bipolar illness often consists of the development of episodes that can be considered opposite in polarity to that of the antecedent temperament.41

As a result, the depressive episodes of many patients with soft bipolarity arising from cyclothymic and/or hyperthymic baseline are often mixed in nature (ie, isolated hypomanic symptoms, such as psychomotor acceleration, flight of ideas, and intense sexual arousal, intrude into MDD).3,5,42 Clinicians, when confronted with activated (labile, aroused, hostile, or agitated) MDD patients in psychiatric or general medical settings, must first rule out a bipolar spectrum condition. The same is true for a proportion of major depressions with intense anxious-phobic arousal.43

Comorbidity Within the Bipolar Spectrum

Mixed bipolar depressive states are ignored in both the DSM-IV and the ICD-10. This failure to recognize the bipolar nature of the volatile mix of temperament, depression, and anxious-phobic features often gives rise to such misleading characterologic diagnoses as borderline, histrionic, psychopathic,18,44 or atypical depressions.45

In the offspring of bipolar patients, affective storms can be misconstrued as attention-deficit/hyperactivity disorder (ADHD) and/or conduct disorder.46-48 ADHD and bipolar are distinct disorders, yet they often coexist. Thus, if family history is bipolar, considering these patients as a special ADHD-bipolar subtype is justified. Although such overlap is most common in manic or mixed manic children, it is at times observed in adults across the bipolar spectrum.

Substance and alcohol abuse are particularly prevalent among soft bipolar conditions.18,49,50 They often represent an attempt to enhance the hyper periods (with stimulants), rather than an attempt to self-medicate during depressed periods.32 Often comorbid appetitive behaviors, such as bulimia,51 can also be considered to have relevance to the bipolar spectrum. McElroy and colleagues51 contend that other impulse-control disorders, such as kleptomania and gambling, might have affinities to the bipolar spectrum as well. This is not to say that addictive, bulimic, and impulse-control disorders are secondary to bipolarity. Their common coexistence with bipolar disorder raises the possibility of shared underlying neurobiologic mechanisms. This is analogous to the common coexistence of obesity, diabetes, and hypertension, which are all diseases in their own right that are linked by the metabolic syndrome.

Bipolar spectrum patients with prominent temperamental dysregulation also appear vulnerable to the cycling effect of antidepressants.18,52,53 The excesses of bipolar II patients and the associated circadian disruptions appear relevant to the irregular cycling so often encountered in ambulatory bipolar patients today. A soft bipolar diagnosis is crucial, precisely because these patients need protection from antidepressant monotherapy (eg, with mood-stabilizing anticonvulsants or atypical antidepressants).

Interestingly, current data also suggest an intriguing association between soft bipolar conditions, especially cyclothymic conditions, and artistic creativity. Individuals with hyperthymic temperament are also over-represented among prominent individuals in leadership positions.54 In the same vein, professional achievement is over-represented among healthy relatives of bipolar patients.55,56 Thus, high achievement in various professional domains, or family history for such achievement, in the patient presenting with clinical depression can be used as a clinical pointer in favor of soft bipolarity.

On a more clinical note, pointers toward bipolarity include certain course, episode, phenomenological, and familial characteristics listed in Table 5.3,9,19

Discussion

Since bipolar spectrum was first proposed,18,19 the literature has been enriched by conceptual extensions, modifications, and/or research in favor of the spectrum of bipolarity.57-68 The material reviewed in this article refers to the phenomenology, course, and familial aspects of the spectrum. It is likely that genetic heterogeneity exists, underlying the bipolar spectrum.69-71 This does not rule out the possibility that biological commonalities may be shared by the spectrum.

Although the concept of bipolar spectrum has been criticized on methodologic grounds,72 the evidence reviewed herein has documented that the spectrum and its comorbidities are prevalent conditions in both psychiatric and general medical settings. In the differential diagnosis of depressive, anxious-phobic, and panic states, the clinician must consider bipolar II and its variants. Comorbidity is high with addictive, bulimic, and borderline conditions. Migraine73 can also coexist with soft bipolar disorders, as can other psychophysiological disorders61 beyond the scope of this review. This means that bipolarity can present clinically with the foregoing nonaffective features. Given emerging data on the link between bipolarity and suicidality,74 the recognition and proper management of the bipolar spectrum and its comorbidities is relevant to suicide prevention.75,76

The emerging literature on the bipolar spectrum is beginning to impact psychiatric practice worldwide,77 as well as pathophysiologic understanding of putative common temperamental and molecular genetic mechanisms underlying the spectrum and its comorbidities.78 The bipolar spectrum is also relevant to family and general medical practice,79-82 which represents the de facto field for prevalent affective disorders, ADHD, and substance and alcohol use disorders.

Conclusion

It has not been the purpose of this overview on the bipolar spectrum concept and its adjoining conditions to demolish the edifice of the diagnostic prototypes embodied in the DSM-IV. The clinician should use these prototypic descriptions as a guide to identify the most likely diagnosis that best fits a patient presenting with an elusive and complex array of affective manifestations subthreshold to the classical bipolar type. In adults, these manifestations are typically comorbid with anxious, migrainous, addictive, bulimic, and erratic personality disturbances. The DSM-IV provides no guidance as to why these disorders often coexist with bipolar illness, nor does it provide any rationale for prioritizing one diagnosis over another. To focus on the presenting condition exhorted by the DSM-IV, while sensible, is not necessarily always the best diagnostic solution. Because of its therapeutic and prognostic implications, it is important not to miss a bipolar spectrum diagnosis in the patients described in this review. Early age of onset, episodic or cyclic course, marked seasonality, mixity, and bipolar family history can serve as markers for a bipolar diathesis in such patients.

It is meaningful to consider that this illness, while operationally distinct from its commonly co-occurring disorders, may nonetheless share underlying neurobiologic mechanisms with them. This style of thinking is an incentive to contemporary molecular oligogenic studies in the field of bipolar and related disorders.78 This model postulates various combinations of shared genes among the adjoining disorders of bipolarity and the bipolar spectrum itself.

Taking these factors into account, the concept of the bipolar spectrum can serve to bridge practice, clinical research, and more basic research in psychiatry.83 In fact, spectrum concepts of mental illness may represent a promising alternative to the DSM-IV.84 PP

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35. Simpson SG, Folstein SE, Meyers DA, McMahon FJ, Brusco DM, DePaulo JR Jr. Bipolar II: the most common bipolar phenotype? Am J Psychiatry. 1993;150(6):901-903.

36. Jamison KR, Gerner RH, Hammen C, Padesky C. Clouds and silver linings: positive experiences associated with primary affective disorders. Am J Psychiatry. 1980;137(2):198-202.

37. Akiskal HS, Mendlowicz MV, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL. TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord. In press.

38. Akiskal HS. Delineating irritable and hyperthymic variants of the cyclothymic temperament. J Personal Disord. 1992;6:326-342.

39. Akiskal HS, Maser JD, Zeller PJ, et al. Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry. 1995;52(2):114-123.

40. International Statistical Classification of Diseases and Related Health Problems. 10 rev. Geneva, Switzerland: World Health Organization; 1992.

41. Akiskal HS. The distinctive mixed states of bipolar I, II, and III. Clin Neuropharmacol. 1992;15(suppl 1 pt A):632A-633A.

42. Akiskal HS, Benazzi F. Delineating depressive mixed states: their therapeutic significance. Clin Approaches Bipolar Disord. 2003;2:41-47.

43. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Diagnostic and treatment challenges. Psychiatr Clin North Am. 1999;22(3):565-583.

44. Deltito J, Martin L, Riefkohl J, et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord. 2001;67(1-3):221-228.

45. Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry. 1998;39(2):63-71.

46. Wilens TE, Biederman J, Wozniak J, Gunawardene S, Wong J, Monuteaux M. Can adults with attention-deficit/hyperactivity disorder be distinguished from those with comorbid bipolar disorder? Findings from a sample of clinically referred adults. Biol Psychiatry. 2003;54(1):1-8.

47. Masi G, Toni C, Perugi G, et al. Externalizing disorders in consecutively referred children and adolescents with bipolar disorder. Compr Psychiatry. 2003;44(3):184-189.

48. Dilsaver SC, Henderson-Fuller S, Akiskal HS. Occult mood disorders in 104 consecutively presenting children referred for the treatment of attention-deficit/hyperactivity disorder in a community mental health clinic. J Clin Psychiatry. 2003;64(10):1170-1176.

49. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Add Relat Clin Probl. 2003;5:7-98.

50. Camacho A, Akiskal HS. Proposal for a bipolar stimulant spectrum. Temperament, diagnostic validation and therapeutic outcomes with mood stabilizers. J Affect Disord. In press.

51. McElroy SL, Keck PE Jr, Phillips KA. Kleptomania, compulsive buying, and binge-eating disorder. J Clin Psychiatry. 1995;56(suppl 4):14-26. Discussion in: J Clin Psychiatry. 1995;56(suppl 4):27

52. Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol. 1980;13(4):156-167.

53. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411.

54. Akiskal HS, Akiskal K. Re-assessing the prevalence of bipolar disorders: clinical significance and artistic creativity. Psychiatrie Psychobiologie. 1998;3:29-36.

55. Coryell W, Endicott J, Keller M, et al. Bipolar affective disorder and high achievement: a familial association. Am J Psychiatry. 1989;146(8):983-988.

56. Richards R, Kinney DK, Lunde I, Benet M, Merzel AP. Creativity in manic-depressives, cyclothymes, their normal relatives, and control subjects. J Abnorm Psychol. 1988;97(3):281-288.

57. Taylor MA, Abrams R. Reassessing the bipolar-unipolar dichotomy. J Affect Disord. 1980;2(3):195-217.

58. Klerman GL. The spectrum of mania. Compr Psychiatry. 1981;22(1):11-20.

59. Egeland JA. Bipolarity: the iceberg of affective disorders? Compr Psychiatry. 1983;24(4):337-344.

60. Tsuang MT, Faraone SV, Fleming JA. Familial transmission of major affective disorders. Is there evidence supporting the distinction between unipolar and bipolar disorders? Br J Psychiatry. 1985;146:268-271.

61. Endicott NA. Psychophysiological correlates of ‘bipolarity’. J Affect Disord. 1989;17(1):47-56.

62. Himmelhoch JM. Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J Affect Disord. 1998;50(2-3):203-213.

63. Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47(2):125-134.

64. Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord. 2002;4(suppl 1):11-14.

65. Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder. Bipolar Disord. 2003;5(6):456-463.

66. Benazzi F. High frequency of bipolar spectrum in outpatients with depression. Can J Psychiatry. 2004;49(4):279-280.

67. Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. J Clin Psychiatry. 2001;62(suppl 14):5-9.

68. Cassano GB, Rucci P, Frank E, et al. The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry. 2004;161(7):1264-1269.

69. Gershon ES. Bipolar illness and schizophrenia as oligogenic diseases: implications for the future. Biol Psychiatry. 2000;47(3):240-244.

70. MacKinnon DF, Xu J, McMahon FJ, et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry. 1998;155(6):829-831.

71. Alda M. The phenotypic spectra of bipolar disorder. Eur Neuropsychopharmacol. 2004;14(suppl 2):S94-S99.

72. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord. 2000;2(1):3-7.

73. Oedegaard KJ, Fasmer OB. Is migraine in unipolar depressed patients a bipolar spectrum trait? J Affect Disord. 2004.

74. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am. 1999;22(3):667-673.

75. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467-1473.

76. Yerevanian BI, Koek RJ, Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder. J Affect Disord. 2003;73(3):223-228.

77. Akiskal HS. Classification, diagnosis and boundaries of bipolar disorders. In: Maj M, Akiskal HS, Lopez-Ibor JJ, Sartorius N, eds. Bipolar Disorder. London, UK: John Wiley & Sons; 2002:1-52.

78. Kelsoe JR. Arguments for the genetic basis of the bipolar spectrum. J Affect Disord. 2003;73(1-2):183-197.

79. Manning JS, Conner PD, Sahai A. The bipolar spectrum. A review of current concepts and implications for the management of depression in primary care. Arch Fam Med. 1998;7:63-71.

80. Manning JS, Haykal RF, Akiskal HS. The role of bipolarity in depression in the family practice setting. Psychiatr Clin North Am. 1999;22(3):689-703.

81. Manning JS, Ahmed S, McGuire HC, Hay DP. Mood disorders in family practice: beyond unipolarity to bipolarity. Prim Care Companion J Clin Psychiatry. 2002;4(4):142-150.

82. Piver A, Yatham LN, Lam RW. Bipolar spectrum disorders. New perspectives. Can Fam Physician. 2002;48:896-904. Erratum in: Can Fam Physician. 2002;48:1190.

83. Akiskal HS. From dysthymia to the bipolar spectrum: bridging practice and research (Jean Delay Prize Paper). Paper presented at: XII World Congress of Psychiatry; August 24–29, 2002; Yokahama, Japan.

84. Maser JD, Akiskal HS. Spectrum concepts in major mental disorders. Psychiatr Clin North Am. 2002;25(4):xi-xiii.


Dr. Akiskal is director of the International Mood Center in the Department of Psychiatry at the University of California, and chief of the Mood Disorders Program in the Veterans Administration Healthcare System, both in San Diego.

Disclosure: Dr. Akiskal is a consultant for and is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi-Synthelabo.

Please direct all correspondence to: Hagop S. Akiskal, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 3350 La Jolla Village Dr, La Jolla, CA 92161-0603; Tel: 619-552-8585; Fax: 619-534-8598; E-mail: hakiskal@ucsd.edu.


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 e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City. Dr. Nelson is Leon J Epstein Professor of Psychiatry and director of Geriatric Psychiatry at the University of California, San Francisco.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Nelson is a consultant to Bristol-Myers Squibb, Corcept, Merck, Orexigen, and Sierra Neuropharmaceuticals; is on the advisory boards of Bristol-Myers Squibb, Eli Lilly, and Shire; is on the Data, Safety Monitoring Boards of Medtronics, the National Institute of Mental Health (NIMH), and Orexigen; and receives grant support from the Health Resources and Services Administration and the NIMH.


 

Both clinicians and researchers have long known that the majority of depressed patients do not achieve or sustain a complete recovery from their disorders on most therapies. This has led to anecdotal reports and to clinical trials that suggest a broad range of interventions involving some combination of medications. The Sequenced Treatment Alternatives to Relieve Depression study1 examined response to treatment in a large sample of 3,671 patients with major depressive disorder. The patients were those typically encountered in primary care and psychiatry settings. The study found that even after 12–14 weeks of adequately dosed citalopram, only 37% of the patients achieved remission. The study indicates that most patients will require additional treatments. The common choices after initial treatment failure are to switch to another antidepressant, add a second antidepressant, start psychotherapy, or augment with a compound not approved for use as an antidepressant. Many different compounds have been used for augmentation including stimulants, modafinil, buspirone, pindolol, estrogen, and testosterone.2,3 Few controlled studies of these agents have been performed, and with the exception of a single modafinil study,4 the controlled studies have failed to show an advantage for augmentation with these agents. Thyroid augmentation has been more extensively studied. Reviews and meta-analyses indicate thyroid augmentation does accelerate response but the placebo-controlled trials in resistant depression fail to show an advantage.5,6

Lithium augmentation also has a long history. The idea for lithium augmentation was suggested by the observation in animal studies that the tricyclic antidepressants (TCAs) increased post-synaptic serotonin receptor sensitivity.4 Because lithium increases serotonin turnover, the thought was that lithium might have rapid effects when added to an ongoing TCA. In fact, the first study of lithium augmentation in depressed human subjects did report improvement within 48 hours in several patients.7 The other observation that supported the idea of a synergistic effect was the induction of mania after the addition of lithium noted in a few case reports.8 This effect would not be expected if lithium were acting independently. In this issue, Lawrence Price, MD, and colleagues provide a comprehensive and critical review of the lithium augmentation literature.

The use of atypical antipsychotics as adjunctive treatments for treatment-resistant depression has a relatively recent history. The use of adjunctive risperidone was first reported in eight patients who had failed selective serotonin reuptake inhibitor treatment in 1999.9 Since 2003, more than a dozen placebo-controlled augmentation trials of atypical antipsychotics in treatment-resistant non-psychotic depression have been reported or presented at meetings. George Papakostas, MD, provides an up-to-date and thoughtful review of this literature, which clinicians will find useful.

A brief case report by Anna Yusim, MD, describes a patient with phantom testicular pain. Like any form of phantom sensation, symptoms involving the genitalia are distressing to patients and difficult for the physician to both explain and treat. As Dr. Yusim notes, <10% of phantom pain patients receive relief with prescribed medication. There is clearly a need for additional research into the psychology and neurobiology of sensory disturbances. This additional information might lead to improved interventions.

Richard H. Weisler, MD, and David W. Goodman, MD, contribute an article on the assessment and diagnosis of adult attention-deficit/hyperactivity disorder (ADHD). They emphasize the need to rule out and factor into treatment decisions the presence of medical conditions and especially to consider cardiovascular risks before initiating treatment of adults with this disorder. Nevertheless, they note that adult ADHD remains under-recognized, underdiagnosed, and undertreated. Improved recognition and treatment should result in improved productivity in school and work as well as lead to better interpersonal relations, especially among family members.

Nadeem Bhanji, MD, and colleagues share the results of a survey of psychiatric physicians about direct-to-consumer (DTC) marketing. They report that surveyed psychiatrists believed that DTC had little significant effect on their prescribing practices, but that over 80% of respondents said they had prescribed medications specifically requested by their patients, often the result of their having seen a DTC advertisement. Among their conclusions is that there is a continued need for clinicians to play an active role about disease states and available treatments. PP

References

1.     Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients who required one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
2.    Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.
3.    Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom. 2006;75(3):139-153.
4.    de Montigny C, Aghajanian GK. Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science. 1978; 202(4374):1303-1306.
5.    Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
6.    Aronson R, Offman HJ, Joffe RT, et al. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-848.
7.    de Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138(3):252-256.
8.    Nelson JC. Use of lithium augmentation in refractory depression. In: Treatment Strategies in Refractory Depression. S. Roose and A. Glassman eds. Washington, DC: American Psychiatric Press, Inc.; 1990;35-49.
9.    Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60(4):256-259.

 

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