Sheldon H. Preskorn, MD

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.^1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”⁴

To help you “hit” the anxiety instead of the patient,¹ we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.

Box

Benzodiazepines

Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.⁵ As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.

Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).^6-8

Table 1

Benzodiazepines: How metabolized and half-lives

Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.

Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).

Table 2

Clinical effects of drug-drug interactions with benzodiazepines

Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.

At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.¹⁰ The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.

Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:

• A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.¹¹
  
• Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.¹²
  
• Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.¹³
  
• In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.¹⁴
  

Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.¹⁵

Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.³

Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.

As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.¹⁶ Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,^15,17 increasing the concentration of other drugs such as phenytoin.

Buspirone: Complicated pharmacology

One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.^18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:

• If 5-HT concentration is low, buspirone will act as an agonist.
  
• If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
  

Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.⁶

1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.

Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.

Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.²¹

Table 3

Clinical effects of drug-drug interactions with buspirone

• buspirone affects 5-HT mechanisms
  
• drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.²⁰
  

Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.⁶ Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.²⁰

Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.²²

As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff²³ added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.

Huang et al²⁴ found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.

Propranolol: Beta-blocking anxiolytic

Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.

Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.

Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.⁶ Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).

Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.²¹ Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.²¹ Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.²⁵

In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.

Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.⁶

Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity⁶ (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.

Table 4

How to avoid drug interactions with three common anxiolytics*

As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.²⁶

Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).

Table 5

Clinical effects of drug-drug interactions with propranolol

• Cytochrome P450 interactions. www.drug-interaction.com.
  
• FDA. Food and drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  

• Alprazolam • Xanax
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Carbatrol, others
  
• Chlordiazepoxide • Librium
  
• Cimetidine • Tagamet
  
• Clonazepam • Klonopin
  
• Clorazepate • Tranxene
  
• Clozapine • Clozaril
  
• Diazepam • Valium
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Haloperidol • Haldol
  
• Itraconazole • Sporanox
  
• Lorazepam • Ativan
  
• Midazolam • Versed
  
• Mirtazapine • Remeron
  
• Oxazepam • Serax
  
• Paroxetine • Paxil
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Rifampin • Rifadin, Rimactane
  
• Triazolam • Halcion
  
• Valproate • various
  
• Verapamil • Calan, Isoptin
  

Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

Box 2

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

LISTEN: 6 tips to minimize DDI risk

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

Box 2

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

LISTEN: 6 tips to minimize DDI risk

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

Drug-drug interactions (DDIs) can be viewed as physiologic combat wherein a “perpetrator” drug affects a “victim” drug’s pharmacokinetics or pharmacodynamics. Your challenge is to deter that interaction in patients taking two or more medications.

This article—first in a series—discusses polypharmacy risk factors that increase the likelihood of detrimental DDIs, then focuses on DDIs in patients taking mood stabilizers for bipolar disorder. We also offer practical tips to reduce DDI risk. Future articles will discuss DDI risks with antidepressants, antipsychotics, and anxiolytics.

To predict DDIs, you need to know psychotropics’ mechanism of action, metabolism, and effects on cytochrome P-450 (CYP) enzymes. Our discussion is not exhaustive because the data base is massive and new interactions continue to be discovered. Our aim is to equip you to anticipate and prevent DDIs when prescribing.

WHAT ARE ADVERSE DDIs?

An adverse event (AE) is any undesirable experience that occurs when a patient uses a medical product, whether or not the product caused the event. The FDA says an “undesirable experience” may be:

• an unfavorable and unintended symptom or sign
  
• an abnormal lab or radiographic finding
  
• a disease that is temporarily associated with the medical product.
  

An AE becomes “serious” (an SAE) when its duration, intensity, and/or frequency leads to death, a life-threatening condition, initial or prolonged hospitalization, disability, or congenital anomaly. Reporting is voluntary, but we strongly recommend that you report all SAEs to the FDA.

These definitions can help you confirm that a patient has experienced an SAE, but the task becomes more complicated when you try to attribute an SAE to a drug interaction. In the absence of an FDA definition, we assert that DDIs are responsible for SAEs when a perpetrator drug affects the pharmacokinetics or pharmacodynamics of a victim drug and exacerbates a known untoward event of the victim drug (Box 1).^1-5 Which drug is the perpetrator and which is the victim is not always clear, and sometimes a medication—such as carbamazepine—can be both at once.

Box 1

RISKS OF POLYPHARMACY

Individuals with psychiatric illnesses are at particular risk for DDIs (Box 2). Patients seen by psychiatrists, for example, are six times more likely than patients seen by primary care physicians to be taking multiple medications.⁶

Polypharmacy increases the risk of adverse events, nonadherence, medication errors, and drug interactions.⁷ FDA’s MedWatch Web site lists more than 630 DDI warnings.⁸ The more medications a patient is taking, the greater the risk for detrimental DDIs and cumulative toxicity,⁹ which often lead to DDI-induced AEs.¹⁰

A study of DDIs in 5,125 mostly older outpatients¹¹ found that:

• 1,594 (31%) had at least one interacting drug combination (average 1.6)
  
• subjects with one or more DDIs were taking an average 8.1 drugs, compared with 5.2 drugs in those without DDIs—a significant difference
  
• 155 (3%) had interactions of “major clinical significance.”
  

• Although drug interactions are responsible for only 3.8% of emergency department visits, patients with DDIs are usually admitted to the hospital.¹³
  
• Preventable drug interactions cause approximately one-third of all AEs in hospitalized patients and account for one-half of all AE costs.¹⁴
  

Box 2

HOW TO MINIMIZE DDI RISK

Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.¹⁶ The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.

We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.¹⁷ Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.¹⁶ For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.¹⁸

Keep in mind that systemic conditions may require a dosage change:

• Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
  
• Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.¹⁹
  

LISTEN: 6 tips to minimize DDI risk

DDIsWITH MOOD STABILIZERS

Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.²⁰ DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.²¹

Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).^17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.

Table 2

Some drug-drug interactions with mood stabilizers

LITHIUM: TOXICITY RISK

Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.^17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.¹⁷

Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.¹⁷ An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.

Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.²⁶ Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.²⁵

For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,¹⁷ and calcium channel blockers may increase the neurotoxicity risk.^17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.

VALPROIC ACID: MONITOR CLEARANCE

Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.

On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.¹⁷

Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.²²

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. http://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: http://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: http://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.

HISTORY: WINTER WOES

Mrs. A, age 64, lives alone in an old farmhouse. For approximately 8 months, she had complained of depressed mood, decreased interest, difficulty sleeping, low energy, decreased concentration, and feelings of hopelessness. She met DSM-IV-TR criteria for major depressive disorder with underlying anxiety.

Mrs. A also reported having sinus headaches throughout the fall and winter. Blood chemistry, CBC with differential, thyroid profile including T₄& TSH, urine drug screen, urine analysis, and ECG results were normal.

In April, Mrs. A was enrolled in an outpatient study of depression relapse prevention treatment. After taking the active study drug for 2 months, she reported continued low mood, low energy, difficulty concentrating, poor sleep and worsening headaches. Because her depression did not improve sufficiently, she was dropped from the study.

In July, Mrs. A saw a psychiatrist and was started on sertraline, 50 mg/d. By November, the dosage had been increased to 150 mg/d. At this time, she reported unsteadiness, dizziness, frequent falls, and intolerable headaches in addition to her depressive symptoms. She was referred to a neurologist to rule out a neurologic disorder.

Table 1

Symptoms that suggest major depression and/or chronic CO poisoning

The authors’ observations

Chronic fatigue syndrome is characterized by severe unexplained fatigue that persists for >6 months. The new-onset fatigue is not abated with rest. Other symptoms include impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, headaches, pain in several joints, and disturbed sleep.¹

Mrs. A, however, never complained of sore throat or joint or muscle pain, and her laboratory findings were normal.

Seasonal affective disorder (SAD) is characterized by a temporal relationship between onset of depressive symptoms and a particular time of year (eg, symptoms emerge each winter) for at least 2 years. Full remission also occurs at a characteristic time (eg, each summer).²

Mrs. A’s headaches, frequent falls, dizziness, and difficulties with balance do not suggest SAD. Also, these symptoms have not persisted long enough for an SAD diagnosis.

Thyroid disorder. Hypothyroidism symptoms—particularly low mood, decreased energy, fatigue, psychomotor retardation, and lack of motivation—can mimic depression. Mrs. A’s T₄ and TSH readings were normal, however.

Metabolic dysfunction. Symptoms secondary to decreased serum concentrations of sodium, potassium, magnesium, or calcium can mimic depression, but blood tests showed Mrs. A has normal electrolyte levels.

Brain tumor. Patients with a brain tumor can present with mood symptoms, psychosis, headaches, mania, cognitive impairments, seizure problems, and other symptoms depending on the tumor’s size and location.

FURTHER TREATMENT: SUDDEN RELIEF

By late November Mrs. A’s fatigue, once present only mornings, plagued her throughout the day. We considered changing antidepressants because of her complaints and sertraline’s lack of efficacy.

The following month, however, Mrs. A told us that her fatigue and headaches were gone. Mood, sleep, and concentration were also improved. Her Hamilton Rating Scale for Depression score had improved from 21 when she entered the study—indicating moderate severity—to 6, indicating remission. Her neurologic referral was cancelled.

Mrs. A then mentioned that her home’s water heater had been malfunctioning for several months. She said she could not afford to get it repaired during the summer but finally hired plumbers to fix it in late November.

After working all day in Mrs. A’s basement, two workers suffered acute headaches and nausea. The symptoms prompted the workers to search the basement for a carbon monoxide leak; they found a small leak in the water heater, which they replaced.

The next morning, Mrs. A said, her headache disappeared. Her other symptoms were gone within 4 days.

The authors’ observations

The sudden disappearance of Mrs. A’s symptoms after her water heater was replaced and emergence of severe physical symptoms in the two plumbers suggest carbon monoxide (CO) poisoning, a common and potentially lethal medical problem.

Low-level CO poisoning usually results from repeated exposure to incomplete combustion in a defective heating appliance, such as a water heater (Box 1).^3,4 Symptoms usually surface in the winter, when heating appliance use peaks and windows are left closed, allowing indoor CO to accumulate in high concentrations.⁷

Box 1

Whereas severe, acute CO poisoning typically is detected immediately after exposure, symptoms of chronic low-level CO exposure are easily mistaken for a primary depressive (Table 1) or other neuropsychiatric disorder—or overlooked altogether. Some cases persist for months before CO exposure is diagnosed. Clinicians often give unnecessary—sometimes costly—medical treatment while ignoring the underlying poisoning.

Mechanism of action. CO binds with hemoglobin (with an affinity >200 times that of oxygen) to form carboxyhemoglobin (COHb), which causes cellular anoxia by blocking transport of oxygen to the tissues, including the brain.^4,6,8

CO poisoning symptoms vary depending on COHb concentration (Table 2). COHb >5% in a symptomatic nonsmoker may indicate chronic low-level CO poisoning and require further evaluation.⁹ Levels >10% are common in heavy smokers (2 to 4 packs/day). It should be noted that Mrs. A does not smoke.

Presentation. Patients with chronic low-level CO poisoning often present with vague, nonspecific symptoms, such as weakness and fatigue, abdominal pain, nausea, vomiting, diarrhea, decreased concentration, diminished cognitive abilities, persistent headaches, and trouble sleeping.^4,8,10,11 Patients age >65 especially may present with multiple cognitive and somatic complaints that suggest Parkinson’s disease, chronic fatigue syndrome, dementia, or—in Mrs. A’s case—depression.^5,10,12

Table 2

Signs, symptoms of CO poisoning that emerge at different carboxyhemoglobin levels

Health effects of CO exposure range from subtle cardiovascular and neurobehavioral sequelae at low concentrations to loss of consciousness and death after acute exposure to higher concentrations.^3,5

Hypoxia of the brain and other organs resulting from low-level CO poisoning can cause a range of physiologic effects, including mental status changes.^10,11 Low-level CO exposure is particularly dangerous to pregnant women and to patients with a pre-existing ischemic illness.

Pregnancy. Chronic low-level CO exposure during pregnancy can harm the fetus, leading to low birth weight, short neonatal length, prematurity, perinatal death, and increased risk of developmental dysfunction.¹³

Ischemic illnesses. Because COHb cannot transport oxygen, the tissues that demand the most oxygen—such as the brain, heart, and skeletal muscles—are most affected. Because cardiac muscles extract approximately 75% of available oxygen from blood, patients with cardiac and pulmonary ischemic illnesses face a high risk for tissue injury with CO poisoning. At COHb levels >10%, patients with pre-existing cardiac disease experience increased severity and duration of angina; concentrations >15% place them at risk of myocardial infarction.⁶

Length of recovery from chronic CO exposure varies widely depending on severity of exposure and the patient’s general health.^3,5 CO has a 4- to 6-hour half-life and is excreted via the lungs fairly rapidly, so recovery can be swift once CO exposure is stopped. Emergency room referral depends upon severity of symptoms and CO exposure duration and nature (accidental or intentional).

The authors’ observations

CO poisoning can lead to long-term mental status changes. In a 3-year follow-up of patients repeatedly exposed to low CO levels:

• 43% developed neurologic sequelae including memory impairment
• 33% experienced personality changes including irritability, verbal aggression, violence and impulsivity, moodiness, distractibility, and sexual promiscuity
• 11% suffered gross neuropsychological effects, including psychosis, disorientation, and blindness.⁴

Primary care physicians and psychiatrists should monitor patients who have recovered from CO poisoning for symptoms of these disorders.

DETECTING CHRONIC CO EXPOSURE

Mrs. A’s case illustrates the seriousness and diagnostic complexity of chronic low-level CO exposure in older patients, especially during the fall and winter with increased home heating appliance use.⁷ CO exposure was not considered as a cause of Mrs. A’s symptoms until heating contractors found the water heater leak.

Watch for patients whose neuropsychiatric symptoms do not respond to treatment. Ask them about possible environmental, seasonal, or diurnal variations in symptoms. Also ask if the patient’s home heating system or water heater is ≥10 years old or has been malfunctioning (Box 2).

Checking COHb blood levels is the simplest way to confirm CO poisoning.^6,14

Box 2

FOLLOW-UP: ANXIOUS MOMENTS

Mrs. A’s depressive symptoms, headaches, dizziness, and balance problems have not returned. Her underlying anxiety symptoms worsened, however, when the psychiatrist tried to taper sertraline. She was diagnosed with generalized anxiety disorder and continued on sertraline, 100 mg/d.

The psychiatrist sees her every 4 to 6 weeks, and she routinely sees her primary care physician. No long-term effects of CO poisoning have been found.

Related resources

• U.S. Centers for Disease Control and Prevention. Enter “carbon monoxide poisoning” in search field. http://www.cdc.gov.
• Kao LW, Nanagas KA. Carbon monoxide poisoning. Emerg Med Clin North America 2004;22:985-1018.

Drug brand names

• Sertraline • Zoloft

Disclosure

Drs. Khan and D’Empaire report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has been a speaker for, consultant to, or principal investigator for several antidepressant manufacturers, including Pfizer Inc.

HISTORY: WINTER WOES

Mrs. A, age 64, lives alone in an old farmhouse. For approximately 8 months, she had complained of depressed mood, decreased interest, difficulty sleeping, low energy, decreased concentration, and feelings of hopelessness. She met DSM-IV-TR criteria for major depressive disorder with underlying anxiety.

Mrs. A also reported having sinus headaches throughout the fall and winter. Blood chemistry, CBC with differential, thyroid profile including T₄& TSH, urine drug screen, urine analysis, and ECG results were normal.

In April, Mrs. A was enrolled in an outpatient study of depression relapse prevention treatment. After taking the active study drug for 2 months, she reported continued low mood, low energy, difficulty concentrating, poor sleep and worsening headaches. Because her depression did not improve sufficiently, she was dropped from the study.

In July, Mrs. A saw a psychiatrist and was started on sertraline, 50 mg/d. By November, the dosage had been increased to 150 mg/d. At this time, she reported unsteadiness, dizziness, frequent falls, and intolerable headaches in addition to her depressive symptoms. She was referred to a neurologist to rule out a neurologic disorder.

Table 1

Symptoms that suggest major depression and/or chronic CO poisoning

The authors’ observations

Chronic fatigue syndrome is characterized by severe unexplained fatigue that persists for >6 months. The new-onset fatigue is not abated with rest. Other symptoms include impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, headaches, pain in several joints, and disturbed sleep.¹

Mrs. A, however, never complained of sore throat or joint or muscle pain, and her laboratory findings were normal.

Seasonal affective disorder (SAD) is characterized by a temporal relationship between onset of depressive symptoms and a particular time of year (eg, symptoms emerge each winter) for at least 2 years. Full remission also occurs at a characteristic time (eg, each summer).²

Mrs. A’s headaches, frequent falls, dizziness, and difficulties with balance do not suggest SAD. Also, these symptoms have not persisted long enough for an SAD diagnosis.

Thyroid disorder. Hypothyroidism symptoms—particularly low mood, decreased energy, fatigue, psychomotor retardation, and lack of motivation—can mimic depression. Mrs. A’s T₄ and TSH readings were normal, however.

Metabolic dysfunction. Symptoms secondary to decreased serum concentrations of sodium, potassium, magnesium, or calcium can mimic depression, but blood tests showed Mrs. A has normal electrolyte levels.

Brain tumor. Patients with a brain tumor can present with mood symptoms, psychosis, headaches, mania, cognitive impairments, seizure problems, and other symptoms depending on the tumor’s size and location.

FURTHER TREATMENT: SUDDEN RELIEF

By late November Mrs. A’s fatigue, once present only mornings, plagued her throughout the day. We considered changing antidepressants because of her complaints and sertraline’s lack of efficacy.

The following month, however, Mrs. A told us that her fatigue and headaches were gone. Mood, sleep, and concentration were also improved. Her Hamilton Rating Scale for Depression score had improved from 21 when she entered the study—indicating moderate severity—to 6, indicating remission. Her neurologic referral was cancelled.

Mrs. A then mentioned that her home’s water heater had been malfunctioning for several months. She said she could not afford to get it repaired during the summer but finally hired plumbers to fix it in late November.

After working all day in Mrs. A’s basement, two workers suffered acute headaches and nausea. The symptoms prompted the workers to search the basement for a carbon monoxide leak; they found a small leak in the water heater, which they replaced.

The next morning, Mrs. A said, her headache disappeared. Her other symptoms were gone within 4 days.

The authors’ observations

The sudden disappearance of Mrs. A’s symptoms after her water heater was replaced and emergence of severe physical symptoms in the two plumbers suggest carbon monoxide (CO) poisoning, a common and potentially lethal medical problem.

Low-level CO poisoning usually results from repeated exposure to incomplete combustion in a defective heating appliance, such as a water heater (Box 1).^3,4 Symptoms usually surface in the winter, when heating appliance use peaks and windows are left closed, allowing indoor CO to accumulate in high concentrations.⁷

Box 1

Whereas severe, acute CO poisoning typically is detected immediately after exposure, symptoms of chronic low-level CO exposure are easily mistaken for a primary depressive (Table 1) or other neuropsychiatric disorder—or overlooked altogether. Some cases persist for months before CO exposure is diagnosed. Clinicians often give unnecessary—sometimes costly—medical treatment while ignoring the underlying poisoning.

Mechanism of action. CO binds with hemoglobin (with an affinity >200 times that of oxygen) to form carboxyhemoglobin (COHb), which causes cellular anoxia by blocking transport of oxygen to the tissues, including the brain.^4,6,8

CO poisoning symptoms vary depending on COHb concentration (Table 2). COHb >5% in a symptomatic nonsmoker may indicate chronic low-level CO poisoning and require further evaluation.⁹ Levels >10% are common in heavy smokers (2 to 4 packs/day). It should be noted that Mrs. A does not smoke.

Presentation. Patients with chronic low-level CO poisoning often present with vague, nonspecific symptoms, such as weakness and fatigue, abdominal pain, nausea, vomiting, diarrhea, decreased concentration, diminished cognitive abilities, persistent headaches, and trouble sleeping.^4,8,10,11 Patients age >65 especially may present with multiple cognitive and somatic complaints that suggest Parkinson’s disease, chronic fatigue syndrome, dementia, or—in Mrs. A’s case—depression.^5,10,12

Table 2

Signs, symptoms of CO poisoning that emerge at different carboxyhemoglobin levels

Health effects of CO exposure range from subtle cardiovascular and neurobehavioral sequelae at low concentrations to loss of consciousness and death after acute exposure to higher concentrations.^3,5

Hypoxia of the brain and other organs resulting from low-level CO poisoning can cause a range of physiologic effects, including mental status changes.^10,11 Low-level CO exposure is particularly dangerous to pregnant women and to patients with a pre-existing ischemic illness.

Pregnancy. Chronic low-level CO exposure during pregnancy can harm the fetus, leading to low birth weight, short neonatal length, prematurity, perinatal death, and increased risk of developmental dysfunction.¹³

Ischemic illnesses. Because COHb cannot transport oxygen, the tissues that demand the most oxygen—such as the brain, heart, and skeletal muscles—are most affected. Because cardiac muscles extract approximately 75% of available oxygen from blood, patients with cardiac and pulmonary ischemic illnesses face a high risk for tissue injury with CO poisoning. At COHb levels >10%, patients with pre-existing cardiac disease experience increased severity and duration of angina; concentrations >15% place them at risk of myocardial infarction.⁶

Length of recovery from chronic CO exposure varies widely depending on severity of exposure and the patient’s general health.^3,5 CO has a 4- to 6-hour half-life and is excreted via the lungs fairly rapidly, so recovery can be swift once CO exposure is stopped. Emergency room referral depends upon severity of symptoms and CO exposure duration and nature (accidental or intentional).

The authors’ observations

CO poisoning can lead to long-term mental status changes. In a 3-year follow-up of patients repeatedly exposed to low CO levels:

• 43% developed neurologic sequelae including memory impairment
• 33% experienced personality changes including irritability, verbal aggression, violence and impulsivity, moodiness, distractibility, and sexual promiscuity
• 11% suffered gross neuropsychological effects, including psychosis, disorientation, and blindness.⁴

Primary care physicians and psychiatrists should monitor patients who have recovered from CO poisoning for symptoms of these disorders.

DETECTING CHRONIC CO EXPOSURE

Mrs. A’s case illustrates the seriousness and diagnostic complexity of chronic low-level CO exposure in older patients, especially during the fall and winter with increased home heating appliance use.⁷ CO exposure was not considered as a cause of Mrs. A’s symptoms until heating contractors found the water heater leak.

Watch for patients whose neuropsychiatric symptoms do not respond to treatment. Ask them about possible environmental, seasonal, or diurnal variations in symptoms. Also ask if the patient’s home heating system or water heater is ≥10 years old or has been malfunctioning (Box 2).

Checking COHb blood levels is the simplest way to confirm CO poisoning.^6,14

Box 2

FOLLOW-UP: ANXIOUS MOMENTS

Mrs. A’s depressive symptoms, headaches, dizziness, and balance problems have not returned. Her underlying anxiety symptoms worsened, however, when the psychiatrist tried to taper sertraline. She was diagnosed with generalized anxiety disorder and continued on sertraline, 100 mg/d.

The psychiatrist sees her every 4 to 6 weeks, and she routinely sees her primary care physician. No long-term effects of CO poisoning have been found.

Related resources

• U.S. Centers for Disease Control and Prevention. Enter “carbon monoxide poisoning” in search field. http://www.cdc.gov.
• Kao LW, Nanagas KA. Carbon monoxide poisoning. Emerg Med Clin North America 2004;22:985-1018.

Drug brand names

• Sertraline • Zoloft

Disclosure

Drs. Khan and D’Empaire report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has been a speaker for, consultant to, or principal investigator for several antidepressant manufacturers, including Pfizer Inc.

HISTORY: WINTER WOES

Mrs. A, age 64, lives alone in an old farmhouse. For approximately 8 months, she had complained of depressed mood, decreased interest, difficulty sleeping, low energy, decreased concentration, and feelings of hopelessness. She met DSM-IV-TR criteria for major depressive disorder with underlying anxiety.

Mrs. A also reported having sinus headaches throughout the fall and winter. Blood chemistry, CBC with differential, thyroid profile including T₄& TSH, urine drug screen, urine analysis, and ECG results were normal.

In April, Mrs. A was enrolled in an outpatient study of depression relapse prevention treatment. After taking the active study drug for 2 months, she reported continued low mood, low energy, difficulty concentrating, poor sleep and worsening headaches. Because her depression did not improve sufficiently, she was dropped from the study.

In July, Mrs. A saw a psychiatrist and was started on sertraline, 50 mg/d. By November, the dosage had been increased to 150 mg/d. At this time, she reported unsteadiness, dizziness, frequent falls, and intolerable headaches in addition to her depressive symptoms. She was referred to a neurologist to rule out a neurologic disorder.

Table 1

Symptoms that suggest major depression and/or chronic CO poisoning

The authors’ observations

Chronic fatigue syndrome is characterized by severe unexplained fatigue that persists for >6 months. The new-onset fatigue is not abated with rest. Other symptoms include impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, headaches, pain in several joints, and disturbed sleep.¹

Mrs. A, however, never complained of sore throat or joint or muscle pain, and her laboratory findings were normal.

Seasonal affective disorder (SAD) is characterized by a temporal relationship between onset of depressive symptoms and a particular time of year (eg, symptoms emerge each winter) for at least 2 years. Full remission also occurs at a characteristic time (eg, each summer).²

Mrs. A’s headaches, frequent falls, dizziness, and difficulties with balance do not suggest SAD. Also, these symptoms have not persisted long enough for an SAD diagnosis.

Thyroid disorder. Hypothyroidism symptoms—particularly low mood, decreased energy, fatigue, psychomotor retardation, and lack of motivation—can mimic depression. Mrs. A’s T₄ and TSH readings were normal, however.

Metabolic dysfunction. Symptoms secondary to decreased serum concentrations of sodium, potassium, magnesium, or calcium can mimic depression, but blood tests showed Mrs. A has normal electrolyte levels.

Brain tumor. Patients with a brain tumor can present with mood symptoms, psychosis, headaches, mania, cognitive impairments, seizure problems, and other symptoms depending on the tumor’s size and location.

FURTHER TREATMENT: SUDDEN RELIEF

By late November Mrs. A’s fatigue, once present only mornings, plagued her throughout the day. We considered changing antidepressants because of her complaints and sertraline’s lack of efficacy.

The following month, however, Mrs. A told us that her fatigue and headaches were gone. Mood, sleep, and concentration were also improved. Her Hamilton Rating Scale for Depression score had improved from 21 when she entered the study—indicating moderate severity—to 6, indicating remission. Her neurologic referral was cancelled.

Mrs. A then mentioned that her home’s water heater had been malfunctioning for several months. She said she could not afford to get it repaired during the summer but finally hired plumbers to fix it in late November.

After working all day in Mrs. A’s basement, two workers suffered acute headaches and nausea. The symptoms prompted the workers to search the basement for a carbon monoxide leak; they found a small leak in the water heater, which they replaced.

The next morning, Mrs. A said, her headache disappeared. Her other symptoms were gone within 4 days.

The authors’ observations

The sudden disappearance of Mrs. A’s symptoms after her water heater was replaced and emergence of severe physical symptoms in the two plumbers suggest carbon monoxide (CO) poisoning, a common and potentially lethal medical problem.

Low-level CO poisoning usually results from repeated exposure to incomplete combustion in a defective heating appliance, such as a water heater (Box 1).^3,4 Symptoms usually surface in the winter, when heating appliance use peaks and windows are left closed, allowing indoor CO to accumulate in high concentrations.⁷

Box 1

Whereas severe, acute CO poisoning typically is detected immediately after exposure, symptoms of chronic low-level CO exposure are easily mistaken for a primary depressive (Table 1) or other neuropsychiatric disorder—or overlooked altogether. Some cases persist for months before CO exposure is diagnosed. Clinicians often give unnecessary—sometimes costly—medical treatment while ignoring the underlying poisoning.

Mechanism of action. CO binds with hemoglobin (with an affinity >200 times that of oxygen) to form carboxyhemoglobin (COHb), which causes cellular anoxia by blocking transport of oxygen to the tissues, including the brain.^4,6,8

CO poisoning symptoms vary depending on COHb concentration (Table 2). COHb >5% in a symptomatic nonsmoker may indicate chronic low-level CO poisoning and require further evaluation.⁹ Levels >10% are common in heavy smokers (2 to 4 packs/day). It should be noted that Mrs. A does not smoke.

Presentation. Patients with chronic low-level CO poisoning often present with vague, nonspecific symptoms, such as weakness and fatigue, abdominal pain, nausea, vomiting, diarrhea, decreased concentration, diminished cognitive abilities, persistent headaches, and trouble sleeping.^4,8,10,11 Patients age >65 especially may present with multiple cognitive and somatic complaints that suggest Parkinson’s disease, chronic fatigue syndrome, dementia, or—in Mrs. A’s case—depression.^5,10,12

Table 2

Signs, symptoms of CO poisoning that emerge at different carboxyhemoglobin levels

Health effects of CO exposure range from subtle cardiovascular and neurobehavioral sequelae at low concentrations to loss of consciousness and death after acute exposure to higher concentrations.^3,5

Hypoxia of the brain and other organs resulting from low-level CO poisoning can cause a range of physiologic effects, including mental status changes.^10,11 Low-level CO exposure is particularly dangerous to pregnant women and to patients with a pre-existing ischemic illness.

Pregnancy. Chronic low-level CO exposure during pregnancy can harm the fetus, leading to low birth weight, short neonatal length, prematurity, perinatal death, and increased risk of developmental dysfunction.¹³

Ischemic illnesses. Because COHb cannot transport oxygen, the tissues that demand the most oxygen—such as the brain, heart, and skeletal muscles—are most affected. Because cardiac muscles extract approximately 75% of available oxygen from blood, patients with cardiac and pulmonary ischemic illnesses face a high risk for tissue injury with CO poisoning. At COHb levels >10%, patients with pre-existing cardiac disease experience increased severity and duration of angina; concentrations >15% place them at risk of myocardial infarction.⁶

Length of recovery from chronic CO exposure varies widely depending on severity of exposure and the patient’s general health.^3,5 CO has a 4- to 6-hour half-life and is excreted via the lungs fairly rapidly, so recovery can be swift once CO exposure is stopped. Emergency room referral depends upon severity of symptoms and CO exposure duration and nature (accidental or intentional).

The authors’ observations

CO poisoning can lead to long-term mental status changes. In a 3-year follow-up of patients repeatedly exposed to low CO levels:

• 43% developed neurologic sequelae including memory impairment
• 33% experienced personality changes including irritability, verbal aggression, violence and impulsivity, moodiness, distractibility, and sexual promiscuity
• 11% suffered gross neuropsychological effects, including psychosis, disorientation, and blindness.⁴

Primary care physicians and psychiatrists should monitor patients who have recovered from CO poisoning for symptoms of these disorders.

DETECTING CHRONIC CO EXPOSURE

Mrs. A’s case illustrates the seriousness and diagnostic complexity of chronic low-level CO exposure in older patients, especially during the fall and winter with increased home heating appliance use.⁷ CO exposure was not considered as a cause of Mrs. A’s symptoms until heating contractors found the water heater leak.

Watch for patients whose neuropsychiatric symptoms do not respond to treatment. Ask them about possible environmental, seasonal, or diurnal variations in symptoms. Also ask if the patient’s home heating system or water heater is ≥10 years old or has been malfunctioning (Box 2).

Checking COHb blood levels is the simplest way to confirm CO poisoning.^6,14

Box 2

FOLLOW-UP: ANXIOUS MOMENTS

Mrs. A’s depressive symptoms, headaches, dizziness, and balance problems have not returned. Her underlying anxiety symptoms worsened, however, when the psychiatrist tried to taper sertraline. She was diagnosed with generalized anxiety disorder and continued on sertraline, 100 mg/d.

The psychiatrist sees her every 4 to 6 weeks, and she routinely sees her primary care physician. No long-term effects of CO poisoning have been found.

Related resources

• U.S. Centers for Disease Control and Prevention. Enter “carbon monoxide poisoning” in search field. http://www.cdc.gov.
• Kao LW, Nanagas KA. Carbon monoxide poisoning. Emerg Med Clin North America 2004;22:985-1018.

Drug brand names

• Sertraline • Zoloft

Disclosure

Drs. Khan and D’Empaire report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has been a speaker for, consultant to, or principal investigator for several antidepressant manufacturers, including Pfizer Inc.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1

What is polypharmacy?

Many definitions have been used to describe polypharmacy (Box 1).^3-6 The most common definition is the use of five or more drugs at the same time in the same patient.⁷ Although polypharmacy often has a pejorative connotation, using five or more drugs may be therapeutic or contratherapeutic.

Therapeutic polypharmacy occurs, for example, when expert panels or researchers in carefully controlled clinical trials recommend using multiple medications to treat specific diseases. For example, the five-drug combination of isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine is therapeutic in initial tuberculosis treatment. More is better in this case because four antibiotics are needed to prevent the development of multiple drug-resistant Mycobacterium tuberculosis, and adding pyridoxine prevents isoniazid-induced neurotoxicity. This example illustrates two prescribing principles:

• using multiple drugs can help achieve an intended therapeutic goal
• adding one drug can prevent a known side effect of another drug.

Another example is the therapeutic management of congestive heart failure, in which five drug classes—an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, a digitalis glycoside, a beta blocker, and an aldosterone antagonist—are used in various combinations. All play a role in improving cardiac function and reducing morbidity and mortality.

Using combination drug therapy can also generate cost benefits, such as by adding a drug to delay or inhibit the metabolism of an expensive principal drug. For example, adding diltiazem—a cytochrome P450 (CYP) 3A4 inhibitor—to cyclosporine—which is metabolized by CYP 3A4 enzymes—reduces the dosage of cyclosporine needed to achieve a desired serum level, thereby reducing the cost of this drug. (Some have abandoned this strategy because of cyclosporine’s narrow therapeutic index.)

Contratherapeutic polypharmacy occurs when a patient taking multiple drugs experiences an unexpected or unintended adverse outcome.

Settings for polypharmacy

Polypharmacy occurs in five principal prescribing situations:

• treatment of symptoms
• treatment of multiple illnesses
• treatment of phasic illnesses, such as many affective, anxiety, seizure, and neurodegenerative disorders
• preventing or treating adverse effects of other drugs
• attempting to accelerate the onset of action or augment the effects of a preceding drug.

As described above, diseases such as tuberculosis and congestive heart failure, with well-understood causes and pathophysiologies, are often treated with multiple therapeutic drug combinations. However, the causes of many psychiatric disorders and syndromes are less well-understood, which makes prescribing drug combinations more difficult. It may be that treating less well-understood diseases is a risk factor for contratherapeutic polypharmacy.

Most individuals who are prescribed five or more drugs are taking unique drug combinations.⁸ These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.⁹Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.¹⁰ Here is why this combination may be dangerous:

• Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
• In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
• However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.

Table 1

POLYPHARMACY WITH TWO OR MORE MEDICATIONS

Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.

Drug-drug interactions

In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.

Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.

Table 2

HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.

How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.¹¹ This relationship can be represented by the formula:

effect = potency at the site of action × concentration at the site of action

Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:

effect = pharmacodynamics × pharmacokinetics

These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes:

effect = potency at the site of action × concentration at site of action × inter-individual variance

In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:

effect = pharmacodynamics × pharmacokinetics × inter-individual variance

Table 3

HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS

This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.

Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.

Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.¹²

In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.

Table 4

RISK FACTORS FOR POLYPHARMACY

The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:

drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)

In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.

Consequences, prevalence of polypharmacy

Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,^2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.

The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,⁶ compared with approximately 7% in the United States.²⁴ Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.²⁵ Polypharmacy is especially problematic in patients age 65 and older (Box 2),^26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.³² Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.³⁰

Box 2

Psychiatric disorders including schizophrenia, bipolar disorder, depression, personality disorders, and substance abuse place patients at higher risk for polypharmacy, as do certain demographic, psychosocial, medication, medical, and neurologic factors (Table 4). Other factors that increase the risk for polypharmacy include:

• institutional factors (recent hospitalization, admission to a surgical ward, nursing home placement, home health care, increased number of pharmacies used, increased number of clinics attended, client-centered psychiatric treatment compared with non-client-centered psychiatric treatment)
• provider factors (visit to a physician, treatment by general practitioners compared with specialists, increased number of providers, undocumented rationale or diagnosis supporting multiple medication use)
• having medical insurance.

Steps to avoiding polypharmacy

By identifying polypharmacy’s risk factors, we may decrease its associated morbidity, mortality, and cost. Steps to follow while prescribing—as represented by the mnemonics SAIL³³ and TIDE—may help you avoid polypharmacy’s negative consequences.

SAIL. Keep the drug regimen as simple as possible. Aim for once-daily or twice daily dosing. Try to simplify complex drug regimens by discontinuing any drug that does not achieve its defined therapeutic goal. For diseases and syndromes with less clear-cut causes, subtracting drugs from a complicated regimen may be more therapeutic than adding another drug. Try to treat multiple symptoms and syndromes with a single drug that may have multiple beneficial effects, rather than treating each symptom or syndrome with individual drugs.

Understand the potential adverse effects of each drug and potential drug-drug interactions. Whenever practical, choose drugs with broad rather than narrow therapeutic indices.

Each prescribed drug should have a clear indication and a well-defined therapeutic goal. Prescribe using evidence-based medicine as much as is practical.

List the name and dosage of each drug in the patient’s chart, and provide this information to the patient.³³ Consider adopting computer data entry and feedback procedures, which have been shown to decrease polypharmacy³⁴ and drug-drug interactions.³⁵

TIDE. In the busy medical practice, writing a prescription signals to the patient that his or her time with the doctor is almost finished. Allow time to address medication issues.

Apply the understanding of individual variability, pharmacokinetics, and pharmacodynamics when prescribing. Review with the patient all prescription and nonprescription drugs and dietary supplements being taken.

Be careful to avoid potentially dangerous drug-drug interactions, especially those associated with serious adverse events such as torsades de pointes.

Educate patients regarding drug and non-drug treatments. Explain potential adverse effects of each drug and potential drug-drug interactions.

Related resources

• Applied Clinical Psychopharmacology. www.Preskorn.com
• Hansten and Horn’s drug interactions. http://hanstenandhorn.com
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/index.html
• Arizona Center for Education and Research on Therapeutics. http://www.arizonacert.org

Disclosure

Drs. Werder and Preskorn have served on the speakers bureau of, as consultants to, or as principal investigators for Abbott Laboratories, AstraZeneca Pharmaceuticals, Biovail Corp., Bristol-Meyers Squibb Co., Merck and Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Hoffman-LaRoche, Janssen Pharmaceutica, Lundbeck, Novartis Pharmaceuticals Corp., Organon, Pfizer Inc., Solvay, Wyeth Pharmaceuticals, and Yamanouchi Pharmaceuticals Co., Ltd.

“Do no harm” is the first rule of medicine, yet 106,000 Americans die each year from properly prescribed and correctly taken medications.¹ In some cases, the cause of death is known and can be attributed to a drug-drug interaction. The likelihood of death or hospitalization is directly proportional to the number of medications a patient is taking, even after controlling for underlying diseases.²

In psychiatry, it is not unusual for us to prescribe more than one psychotropic agent to manage a patient’s symptoms:

• Patients with affective and psychotic disorders are commonly prescribed combinations of antipsychotics, mood stabilizers, antidepressants (often from more than one class), anxiolytics, antihistamines, and anticholinergics.
• Patients with posttraumatic stress disorder may take selective serotonin reuptake inhibitors, buspirone, trazodone, antipsychotics, mood stabilizers, benzodiazepines, beta blockers, and opiates.
• Multiple-drug regimens are used in treating other medical and psychiatric disorders, including chronic pain, fibromyalgia, chronic fatigue syndrome, sleep disorders, and epilepsy.

The greater the number of drugs used, the greater the likelihood that adverse events are emerging and are being treated, sometimes while being mistaken for patient psychopathology. As a prescriber, you are in a unique position to recognize and prevent interactions that can occur when patients are treated with two or more medications. This article defines polypharmacy, describes its consequences, prevalence, and risk factors, and offers an eight-step strategy with two mnemonics to help you avoid adverse events when prescribing multiple-drug regimens.

Box 1