Current Psychiatry

Mr. B, age 78, has a long history of well-controlled bipolar disorder and was diagnosed with Alzheimer’s dementia 6 months ago. He is living at home and has been taking donepezil, 10 mg/d, and lamotrigine, 100 mg bid.

This morning Mr. B’s wife calls and reports that he is experiencing sudden difficulty walking, dizziness, and “feeling drunk.” When you ask about Mr. B’s medications, his wife says that her husband’s internist had prescribed itraconazole, 200 mg/d, for onychomycosis, and Mr. B has taken 1 dose. You promptly discontinue the itraconazole, and Mr. B’s symptoms resolve.

Drug-drug interactions (DDIs) in Alzheimer’s disease (AD) patients such as Mr. B can be serious and even life-threatening. On average, persons age ≥65 use 4.5 prescription agents and 2 over-the-counter preparations per day,¹ and the number of concurrently used medications is a significant predictor of adverse drug reactions.²

Cognitive enhancers, including acetylcholinesterase inhibitors (AChEIs) and memantine, are the most widely prescribed agents for AD patients. The FDA has approved galantamine and rivastigmine for mild to moderate dementia, memantine for moderate to severe dementia, and donepezil for mild to severe dementia (Table 1).^3-5

To help you minimize adverse DDIs in AD patients, this article describes:

• pharmacokinetic and pharmacodynamic effects of cognitive enhancers used in AD management
  
• DDIs with medications commonly prescribed to AD patients
  
• how to avoid adverse events related to antipsychotics, antidepressants, and benzodiazepines.
  

Table 1

Pharmacokinetic features of cognitive enhancers

Pharmacologic changes with aging

Pharmacokinetics is the study of the time course of drugs and their metabolites through the body. Pharmacokinetic interactions involve alterations in the plasma concentration of a drug by a second agent.³

Absorption of medications is decreased in the elderly because of reduced intestinal blood flow and motility. Absorption further decreases if patients concomitantly take antacids, high-fiber supplements, or anticholinergic medications.

In plasma, drugs circulate freely or bound to proteins—mainly albumin and α1-acid glycoprotein. Aging can cause decreased plasma albumin and increased α1-acid glycoprotein.⁶ Additionally, malnutrition, diabetes mellitus, and hepatic and renal disease—all more common with advancing age—may cause hypoalbuminemia, which increases the free fraction of drugs bound to albumin.⁶Table 1 includes information about cognitive enhancers’ protein binding.

When 2 or more highly protein-bound drugs are coadministered, mutual displacement occurs and the free fraction of each drug increases. A recent case report described valproate toxicity with dizziness, ataxia, and falling in a 76-year-old man after aspirin was added to his regimen.⁷ The mechanism appeared to be mutual displacement from albumin combined with metabolism of valproate inhibited by aspirin.⁷

Metabolism. Liver size and hepatic blood flow decrease with aging.⁶ Cytochrome P-450 3A4 pathway activity slows, but the 2D6 pathway is not affected.⁴ Oxidative metabolism through CYP pathways is slower, but conjugation reactions are not.⁶Table 2^3,5,7,8 lists major substrates and inhibitors of CYP enzymes.

Azole antifungals are potent inhibitors of CYP 3A4,⁴ of which both donepezil and lamotrigine are substrates (Table 2). In Mr. B’s case, lamotrigine and donepezil levels increased because of this pharmacokinetic interaction. Because donepezil also is metabolized by the CYP 2D6 pathway, the increase in concentration is unlikely to modify the drug effect. Mr. B experienced symptoms consistent with lamotrigine toxicity.

Pharmacokinetics of AChEIs. AChEIs have relatively few pharmacokinetic interactions, although donepezil and galantamine are metabolized through the liver’s CYP 2D6 and 3A4 pathways.

Because rivastigmine does not undergo hepatic metabolism, it is least likely of the cognitive enhancers to have pharmacokinetic interactions with other medications. Rivastigmine did not lead to increased adverse events when administered concomitantly with 22 different classes of medications—including antidiabetics, cardiovascular drugs, gastrointestinal agents, and NSAIDs.⁹

Table 2

DDIs in AD patients: CYP-450 substrates and inhibitors*

Memantine, an amantadine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is a weak dopaminergic agonist with atropinic effects.¹¹ Because memantine is not metabolized by the CYP-450 pathway, it lacks pharmacokinetic DDIs.¹² However, combining memantine with other NMDA antagonists—such as amantadine or dextromethorphan—could cause hallucinations, dizziness, headache, fatigue, and confusion.¹¹ Concurrent use with drugs that lower seizure threshold, such as tricyclic antidepressants, may increase the risk of seizures.

Table 3

Potential drug-drug interactions in AD patients taking cognitive enhancers

DDIs with cognitive enhancers

Anticholinergics. Because anticholinergic drugs can worsen cognitive impairment and cause delirium they are contraindicated in older patients—especially those with AD. Antihistamines, histamine H2 blockers, low-potency first-generation antipsychotics (FGAs), and tricyclic antidepressants are common medications with anticholinergic effects (Table 4).^5,13,14

• 33% of those taking donepezil also were receiving anticholinergics, compared with 23% of controls
  
• 26% of all patients in the study used multiple anticholinergic medications.
  

Antiparkinsonian agents. Interaction of antiparkinsonian medications with AChEIs could limit the efficacy of either drug when treating comorbid AD and Parkinson’s disease (PD),⁵ although in practice, clinical deterioration of parkinsonism has not been reported.¹⁵ In one study, 25 PD patients stabilized on levodopa/carbidopa were given donepezil, 5 mg/d, or placebo for two 2-week courses separated by a washout of at least 2 weeks. At steady state, pharmacokinetic parameters were unchanged and no clinically significant DDIs were observed.¹⁶

Cardiovascular agents. Concurrent use of AChEIs and beta blockers, calcium channel inhibitors, or digoxin could worsen bradycardia and cause syncope. The risk is higher in patients:

• with sick sinus syndrome or other bradyarrhythmias
  
• taking antipsychotics that could induce torsades de pointes,¹¹ such as ziprasidone or haloperidol.
  

Other agents. AChEIs inhibit the metabolism of succinylcholine and therefore augment and prolong this drug’s neuromuscular blockade. Discontinue AChEIs before administering succinylcholine for anesthesia, such as for electroconvulsive treatment.

AChEIs may lead to toxicity when added to cholinergic agents such as bethanechol.¹¹ Similarly, AChEIs may precipitate a cholinergic crisis—with increasing weakness, hypersalivation, abdominal pains, and diarrhea—when used in conjunction with peripheral acetylcholinesterase inhibitors such as the myasthenia gravis agents pyridostigmine and neostigmine. The mechanism is increased acetylcholine available at the neuromuscular junction.

Table 4

Medications with moderate to strong anticholinergic activity

DDIs with other psychotropics

Antipsychotics. Nearly one-half of AD patients experience delusions, often in the middle stage of the disease, and many are prescribed second-generation antipsychotics (SGAs) to control delusions, hallucinations, sundowning, agitation, or aggression. Concomitant use of AChEIs and antipsychotics may increase the risk of extrapyramidal symptoms by disrupting the acetylcholine/dopamine balance in the striatum.⁵

In AD patients taking donepezil and risperidone, case reports describe parkinsonian syndrome and rigidity with immobility, which resolved after the antipsychotic was discontinued.^5,11 When rivastigmine and risperidone were coadministered, however, no clinically relevant adverse interactions were noted in a 20-week, open-label trial of 65 patients with AD, 10 with vascular dementia, and 10 with both.¹⁷

The FDA has warned of increased risk of death when SGAs are used to treat behavioral disturbances in dementia patients. In a recent meta-analysis of 15 placebo-controlled trials, cognitive tests scores worsened when AD patients took aripiprazole, olanzapine, quetiapine, or risperidone. A significant risk for cerebrovascular events was seen, especially with risperidone, although no clear causal relationship was established.¹⁸ Falls, injury, and syncope were not increased, and patients with less severe dementia, outpatients, and those selected for psychosis were less affected. Thus, provide careful follow-up and avoid long-term unwarranted antipsychotic use in AD patients.

Highly anticholinergic FGAs such as chlorpromazine are not recommended for AD patients (Table 4).

Antidepressants. Up to 30% of AD patients experience major depression.¹⁹ SSRIs are the antidepressants most often used to treat depression and anxiety in AD patients.

Citalopram, escitalopram, or venlafaxine are good choices for patients with AD because of minimal CYP inhibitory activity.⁴ Fluvoxamine, fluoxetine, and paroxetine inhibit CYP 2C9, through which warfarin and some other drugs with a narrow therapeutic index are metabolized.⁶

Herbal supplements. Ginkgo biloba and huperzine A (Chinese club moss) are the herbal supplements used most commonly by dementia patients. Ginkgo inhibits platelet aggregation and can cause bleeding complications, with or without concomitant antiplatelet or anticoagulant therapy such as aspirin, warfarin, and NSAIDs. Enzyme induction of CYP 2C19 by ginkgo, leading to subtherapeutic levels of anticonvulsants, has been implicated in a report of fatal seizures. Huperzine A is a natural cholinesterase inhibitor and should not be combined with AChEIs because of the risk of additive adverse effects.¹⁰

Related resources

• Jacobson SA, Pies RW, Greenblatt DJ. Handbook of geriatric psychopharmacology. Washington, DC: American Psychiatric Publishing; 2002.
  
• Sandson, NB. Drug-drug interaction primer. Washington, DC: American Psychiatric Publishing; 2007.
  

• Amantadine • Symmetrel
  
• Amitriptyline • Elavil
  
• Amoxapine • Asendin
  
• Aripiprazole • Abilify
  
• Atropine • Sal-Tropine
  
• Benztropine • Cogentin
  
• Bethanechol • Urecholine
  
• Biperiden • Akineton
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Tegretol
  
• Celecoxib • Celebrex
  
• Chlorpheniramine • Chlor-Trimeton
  
• Chlorpromazine • Thorazine
  
• Cimetidine • Tagamet
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Clozapine • Clozaril
  
• Cyclobenzaprine • Flexeril
  
• Cyproheptadine • Periactin
  
• Dextromethorphan • Benylin, Delsym, others
  
• Dicyclomine • Bentyl
  
• Digoxin • Lanoxin
  
• Diphenhydramine • Benadryl
  
• Disopyramide • Norpace
  
• Donepezil • Aricept
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Erythromycin • E-Mycin
  
• Fluconazole • Diflucan
  
• Fluvoxamine • Luvox
  
• Fluoxetine • Prozac
  
• Galantamine • Reminyl, Razadyne
  
• Haloperidol • Haldol
  
• Hydroxyzine • Vistaril
  
• Hyoscyamine • Anaspaz, Levbid, Levsin
  
• Imipramine • Tofranil
  
• Itraconazole • Sporanox
  
• Lamotrigine • Lamictal
  
• Levodopa/carbidopa • Sinemet
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Meclizine • Antivert
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Nefazodone • Serzone
  
• Neostigmine • Prostigmin
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Oxybutynin • Ditropan
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Promethazine • Phenergan
  
• Protriptyline • Vivactil
  
• Pyridostigmine • Mestinon
  
• Quetiapine • Seroquel
  
• Ranitidine • Zantac
  
• Risperidone • Risperdal
  
• Rivastigmine • Exelon
  
• Scopolamine • Scopace
  
• Sertraline • Zoloft
  
• Succinylcholine • Anectine
  
• Temazepam • Restoril
  
• Thioridazine • Mellaril
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Trihexyphenidyl • Artane
  
• Valproate • Depakote
  
• Venlafaxine • Effexor
  
• Warfarin • Coumadin
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. B, age 78, has a long history of well-controlled bipolar disorder and was diagnosed with Alzheimer’s dementia 6 months ago. He is living at home and has been taking donepezil, 10 mg/d, and lamotrigine, 100 mg bid.

This morning Mr. B’s wife calls and reports that he is experiencing sudden difficulty walking, dizziness, and “feeling drunk.” When you ask about Mr. B’s medications, his wife says that her husband’s internist had prescribed itraconazole, 200 mg/d, for onychomycosis, and Mr. B has taken 1 dose. You promptly discontinue the itraconazole, and Mr. B’s symptoms resolve.

Drug-drug interactions (DDIs) in Alzheimer’s disease (AD) patients such as Mr. B can be serious and even life-threatening. On average, persons age ≥65 use 4.5 prescription agents and 2 over-the-counter preparations per day,¹ and the number of concurrently used medications is a significant predictor of adverse drug reactions.²

Cognitive enhancers, including acetylcholinesterase inhibitors (AChEIs) and memantine, are the most widely prescribed agents for AD patients. The FDA has approved galantamine and rivastigmine for mild to moderate dementia, memantine for moderate to severe dementia, and donepezil for mild to severe dementia (Table 1).^3-5

To help you minimize adverse DDIs in AD patients, this article describes:

• pharmacokinetic and pharmacodynamic effects of cognitive enhancers used in AD management
  
• DDIs with medications commonly prescribed to AD patients
  
• how to avoid adverse events related to antipsychotics, antidepressants, and benzodiazepines.
  

Table 1

Pharmacokinetic features of cognitive enhancers

Pharmacologic changes with aging

Pharmacokinetics is the study of the time course of drugs and their metabolites through the body. Pharmacokinetic interactions involve alterations in the plasma concentration of a drug by a second agent.³

Absorption of medications is decreased in the elderly because of reduced intestinal blood flow and motility. Absorption further decreases if patients concomitantly take antacids, high-fiber supplements, or anticholinergic medications.

In plasma, drugs circulate freely or bound to proteins—mainly albumin and α1-acid glycoprotein. Aging can cause decreased plasma albumin and increased α1-acid glycoprotein.⁶ Additionally, malnutrition, diabetes mellitus, and hepatic and renal disease—all more common with advancing age—may cause hypoalbuminemia, which increases the free fraction of drugs bound to albumin.⁶Table 1 includes information about cognitive enhancers’ protein binding.

When 2 or more highly protein-bound drugs are coadministered, mutual displacement occurs and the free fraction of each drug increases. A recent case report described valproate toxicity with dizziness, ataxia, and falling in a 76-year-old man after aspirin was added to his regimen.⁷ The mechanism appeared to be mutual displacement from albumin combined with metabolism of valproate inhibited by aspirin.⁷

Metabolism. Liver size and hepatic blood flow decrease with aging.⁶ Cytochrome P-450 3A4 pathway activity slows, but the 2D6 pathway is not affected.⁴ Oxidative metabolism through CYP pathways is slower, but conjugation reactions are not.⁶Table 2^3,5,7,8 lists major substrates and inhibitors of CYP enzymes.

Azole antifungals are potent inhibitors of CYP 3A4,⁴ of which both donepezil and lamotrigine are substrates (Table 2). In Mr. B’s case, lamotrigine and donepezil levels increased because of this pharmacokinetic interaction. Because donepezil also is metabolized by the CYP 2D6 pathway, the increase in concentration is unlikely to modify the drug effect. Mr. B experienced symptoms consistent with lamotrigine toxicity.

Pharmacokinetics of AChEIs. AChEIs have relatively few pharmacokinetic interactions, although donepezil and galantamine are metabolized through the liver’s CYP 2D6 and 3A4 pathways.

Because rivastigmine does not undergo hepatic metabolism, it is least likely of the cognitive enhancers to have pharmacokinetic interactions with other medications. Rivastigmine did not lead to increased adverse events when administered concomitantly with 22 different classes of medications—including antidiabetics, cardiovascular drugs, gastrointestinal agents, and NSAIDs.⁹

Table 2

DDIs in AD patients: CYP-450 substrates and inhibitors*

Memantine, an amantadine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is a weak dopaminergic agonist with atropinic effects.¹¹ Because memantine is not metabolized by the CYP-450 pathway, it lacks pharmacokinetic DDIs.¹² However, combining memantine with other NMDA antagonists—such as amantadine or dextromethorphan—could cause hallucinations, dizziness, headache, fatigue, and confusion.¹¹ Concurrent use with drugs that lower seizure threshold, such as tricyclic antidepressants, may increase the risk of seizures.

Table 3

Potential drug-drug interactions in AD patients taking cognitive enhancers

DDIs with cognitive enhancers

Anticholinergics. Because anticholinergic drugs can worsen cognitive impairment and cause delirium they are contraindicated in older patients—especially those with AD. Antihistamines, histamine H2 blockers, low-potency first-generation antipsychotics (FGAs), and tricyclic antidepressants are common medications with anticholinergic effects (Table 4).^5,13,14

• 33% of those taking donepezil also were receiving anticholinergics, compared with 23% of controls
  
• 26% of all patients in the study used multiple anticholinergic medications.
  

Antiparkinsonian agents. Interaction of antiparkinsonian medications with AChEIs could limit the efficacy of either drug when treating comorbid AD and Parkinson’s disease (PD),⁵ although in practice, clinical deterioration of parkinsonism has not been reported.¹⁵ In one study, 25 PD patients stabilized on levodopa/carbidopa were given donepezil, 5 mg/d, or placebo for two 2-week courses separated by a washout of at least 2 weeks. At steady state, pharmacokinetic parameters were unchanged and no clinically significant DDIs were observed.¹⁶

Cardiovascular agents. Concurrent use of AChEIs and beta blockers, calcium channel inhibitors, or digoxin could worsen bradycardia and cause syncope. The risk is higher in patients:

• with sick sinus syndrome or other bradyarrhythmias
  
• taking antipsychotics that could induce torsades de pointes,¹¹ such as ziprasidone or haloperidol.
  

Other agents. AChEIs inhibit the metabolism of succinylcholine and therefore augment and prolong this drug’s neuromuscular blockade. Discontinue AChEIs before administering succinylcholine for anesthesia, such as for electroconvulsive treatment.

AChEIs may lead to toxicity when added to cholinergic agents such as bethanechol.¹¹ Similarly, AChEIs may precipitate a cholinergic crisis—with increasing weakness, hypersalivation, abdominal pains, and diarrhea—when used in conjunction with peripheral acetylcholinesterase inhibitors such as the myasthenia gravis agents pyridostigmine and neostigmine. The mechanism is increased acetylcholine available at the neuromuscular junction.

Table 4

Medications with moderate to strong anticholinergic activity

DDIs with other psychotropics

Antipsychotics. Nearly one-half of AD patients experience delusions, often in the middle stage of the disease, and many are prescribed second-generation antipsychotics (SGAs) to control delusions, hallucinations, sundowning, agitation, or aggression. Concomitant use of AChEIs and antipsychotics may increase the risk of extrapyramidal symptoms by disrupting the acetylcholine/dopamine balance in the striatum.⁵

In AD patients taking donepezil and risperidone, case reports describe parkinsonian syndrome and rigidity with immobility, which resolved after the antipsychotic was discontinued.^5,11 When rivastigmine and risperidone were coadministered, however, no clinically relevant adverse interactions were noted in a 20-week, open-label trial of 65 patients with AD, 10 with vascular dementia, and 10 with both.¹⁷

The FDA has warned of increased risk of death when SGAs are used to treat behavioral disturbances in dementia patients. In a recent meta-analysis of 15 placebo-controlled trials, cognitive tests scores worsened when AD patients took aripiprazole, olanzapine, quetiapine, or risperidone. A significant risk for cerebrovascular events was seen, especially with risperidone, although no clear causal relationship was established.¹⁸ Falls, injury, and syncope were not increased, and patients with less severe dementia, outpatients, and those selected for psychosis were less affected. Thus, provide careful follow-up and avoid long-term unwarranted antipsychotic use in AD patients.

Highly anticholinergic FGAs such as chlorpromazine are not recommended for AD patients (Table 4).

Antidepressants. Up to 30% of AD patients experience major depression.¹⁹ SSRIs are the antidepressants most often used to treat depression and anxiety in AD patients.

Citalopram, escitalopram, or venlafaxine are good choices for patients with AD because of minimal CYP inhibitory activity.⁴ Fluvoxamine, fluoxetine, and paroxetine inhibit CYP 2C9, through which warfarin and some other drugs with a narrow therapeutic index are metabolized.⁶

Herbal supplements. Ginkgo biloba and huperzine A (Chinese club moss) are the herbal supplements used most commonly by dementia patients. Ginkgo inhibits platelet aggregation and can cause bleeding complications, with or without concomitant antiplatelet or anticoagulant therapy such as aspirin, warfarin, and NSAIDs. Enzyme induction of CYP 2C19 by ginkgo, leading to subtherapeutic levels of anticonvulsants, has been implicated in a report of fatal seizures. Huperzine A is a natural cholinesterase inhibitor and should not be combined with AChEIs because of the risk of additive adverse effects.¹⁰

Related resources

• Jacobson SA, Pies RW, Greenblatt DJ. Handbook of geriatric psychopharmacology. Washington, DC: American Psychiatric Publishing; 2002.
  
• Sandson, NB. Drug-drug interaction primer. Washington, DC: American Psychiatric Publishing; 2007.
  

• Amantadine • Symmetrel
  
• Amitriptyline • Elavil
  
• Amoxapine • Asendin
  
• Aripiprazole • Abilify
  
• Atropine • Sal-Tropine
  
• Benztropine • Cogentin
  
• Bethanechol • Urecholine
  
• Biperiden • Akineton
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Tegretol
  
• Celecoxib • Celebrex
  
• Chlorpheniramine • Chlor-Trimeton
  
• Chlorpromazine • Thorazine
  
• Cimetidine • Tagamet
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Clozapine • Clozaril
  
• Cyclobenzaprine • Flexeril
  
• Cyproheptadine • Periactin
  
• Dextromethorphan • Benylin, Delsym, others
  
• Dicyclomine • Bentyl
  
• Digoxin • Lanoxin
  
• Diphenhydramine • Benadryl
  
• Disopyramide • Norpace
  
• Donepezil • Aricept
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Erythromycin • E-Mycin
  
• Fluconazole • Diflucan
  
• Fluvoxamine • Luvox
  
• Fluoxetine • Prozac
  
• Galantamine • Reminyl, Razadyne
  
• Haloperidol • Haldol
  
• Hydroxyzine • Vistaril
  
• Hyoscyamine • Anaspaz, Levbid, Levsin
  
• Imipramine • Tofranil
  
• Itraconazole • Sporanox
  
• Lamotrigine • Lamictal
  
• Levodopa/carbidopa • Sinemet
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Meclizine • Antivert
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Nefazodone • Serzone
  
• Neostigmine • Prostigmin
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Oxybutynin • Ditropan
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Promethazine • Phenergan
  
• Protriptyline • Vivactil
  
• Pyridostigmine • Mestinon
  
• Quetiapine • Seroquel
  
• Ranitidine • Zantac
  
• Risperidone • Risperdal
  
• Rivastigmine • Exelon
  
• Scopolamine • Scopace
  
• Sertraline • Zoloft
  
• Succinylcholine • Anectine
  
• Temazepam • Restoril
  
• Thioridazine • Mellaril
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Trihexyphenidyl • Artane
  
• Valproate • Depakote
  
• Venlafaxine • Effexor
  
• Warfarin • Coumadin
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. B, age 78, has a long history of well-controlled bipolar disorder and was diagnosed with Alzheimer’s dementia 6 months ago. He is living at home and has been taking donepezil, 10 mg/d, and lamotrigine, 100 mg bid.

This morning Mr. B’s wife calls and reports that he is experiencing sudden difficulty walking, dizziness, and “feeling drunk.” When you ask about Mr. B’s medications, his wife says that her husband’s internist had prescribed itraconazole, 200 mg/d, for onychomycosis, and Mr. B has taken 1 dose. You promptly discontinue the itraconazole, and Mr. B’s symptoms resolve.

Drug-drug interactions (DDIs) in Alzheimer’s disease (AD) patients such as Mr. B can be serious and even life-threatening. On average, persons age ≥65 use 4.5 prescription agents and 2 over-the-counter preparations per day,¹ and the number of concurrently used medications is a significant predictor of adverse drug reactions.²

Cognitive enhancers, including acetylcholinesterase inhibitors (AChEIs) and memantine, are the most widely prescribed agents for AD patients. The FDA has approved galantamine and rivastigmine for mild to moderate dementia, memantine for moderate to severe dementia, and donepezil for mild to severe dementia (Table 1).^3-5

To help you minimize adverse DDIs in AD patients, this article describes:

• pharmacokinetic and pharmacodynamic effects of cognitive enhancers used in AD management
  
• DDIs with medications commonly prescribed to AD patients
  
• how to avoid adverse events related to antipsychotics, antidepressants, and benzodiazepines.
  

Table 1

Pharmacokinetic features of cognitive enhancers

Pharmacologic changes with aging

Pharmacokinetics is the study of the time course of drugs and their metabolites through the body. Pharmacokinetic interactions involve alterations in the plasma concentration of a drug by a second agent.³

Absorption of medications is decreased in the elderly because of reduced intestinal blood flow and motility. Absorption further decreases if patients concomitantly take antacids, high-fiber supplements, or anticholinergic medications.

In plasma, drugs circulate freely or bound to proteins—mainly albumin and α1-acid glycoprotein. Aging can cause decreased plasma albumin and increased α1-acid glycoprotein.⁶ Additionally, malnutrition, diabetes mellitus, and hepatic and renal disease—all more common with advancing age—may cause hypoalbuminemia, which increases the free fraction of drugs bound to albumin.⁶Table 1 includes information about cognitive enhancers’ protein binding.

When 2 or more highly protein-bound drugs are coadministered, mutual displacement occurs and the free fraction of each drug increases. A recent case report described valproate toxicity with dizziness, ataxia, and falling in a 76-year-old man after aspirin was added to his regimen.⁷ The mechanism appeared to be mutual displacement from albumin combined with metabolism of valproate inhibited by aspirin.⁷

Metabolism. Liver size and hepatic blood flow decrease with aging.⁶ Cytochrome P-450 3A4 pathway activity slows, but the 2D6 pathway is not affected.⁴ Oxidative metabolism through CYP pathways is slower, but conjugation reactions are not.⁶Table 2^3,5,7,8 lists major substrates and inhibitors of CYP enzymes.

Azole antifungals are potent inhibitors of CYP 3A4,⁴ of which both donepezil and lamotrigine are substrates (Table 2). In Mr. B’s case, lamotrigine and donepezil levels increased because of this pharmacokinetic interaction. Because donepezil also is metabolized by the CYP 2D6 pathway, the increase in concentration is unlikely to modify the drug effect. Mr. B experienced symptoms consistent with lamotrigine toxicity.

Pharmacokinetics of AChEIs. AChEIs have relatively few pharmacokinetic interactions, although donepezil and galantamine are metabolized through the liver’s CYP 2D6 and 3A4 pathways.

Because rivastigmine does not undergo hepatic metabolism, it is least likely of the cognitive enhancers to have pharmacokinetic interactions with other medications. Rivastigmine did not lead to increased adverse events when administered concomitantly with 22 different classes of medications—including antidiabetics, cardiovascular drugs, gastrointestinal agents, and NSAIDs.⁹

Table 2

DDIs in AD patients: CYP-450 substrates and inhibitors*

Memantine, an amantadine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is a weak dopaminergic agonist with atropinic effects.¹¹ Because memantine is not metabolized by the CYP-450 pathway, it lacks pharmacokinetic DDIs.¹² However, combining memantine with other NMDA antagonists—such as amantadine or dextromethorphan—could cause hallucinations, dizziness, headache, fatigue, and confusion.¹¹ Concurrent use with drugs that lower seizure threshold, such as tricyclic antidepressants, may increase the risk of seizures.

Table 3

Potential drug-drug interactions in AD patients taking cognitive enhancers

DDIs with cognitive enhancers

Anticholinergics. Because anticholinergic drugs can worsen cognitive impairment and cause delirium they are contraindicated in older patients—especially those with AD. Antihistamines, histamine H2 blockers, low-potency first-generation antipsychotics (FGAs), and tricyclic antidepressants are common medications with anticholinergic effects (Table 4).^5,13,14

• 33% of those taking donepezil also were receiving anticholinergics, compared with 23% of controls
  
• 26% of all patients in the study used multiple anticholinergic medications.
  

Antiparkinsonian agents. Interaction of antiparkinsonian medications with AChEIs could limit the efficacy of either drug when treating comorbid AD and Parkinson’s disease (PD),⁵ although in practice, clinical deterioration of parkinsonism has not been reported.¹⁵ In one study, 25 PD patients stabilized on levodopa/carbidopa were given donepezil, 5 mg/d, or placebo for two 2-week courses separated by a washout of at least 2 weeks. At steady state, pharmacokinetic parameters were unchanged and no clinically significant DDIs were observed.¹⁶

Cardiovascular agents. Concurrent use of AChEIs and beta blockers, calcium channel inhibitors, or digoxin could worsen bradycardia and cause syncope. The risk is higher in patients:

• with sick sinus syndrome or other bradyarrhythmias
  
• taking antipsychotics that could induce torsades de pointes,¹¹ such as ziprasidone or haloperidol.
  

Other agents. AChEIs inhibit the metabolism of succinylcholine and therefore augment and prolong this drug’s neuromuscular blockade. Discontinue AChEIs before administering succinylcholine for anesthesia, such as for electroconvulsive treatment.

AChEIs may lead to toxicity when added to cholinergic agents such as bethanechol.¹¹ Similarly, AChEIs may precipitate a cholinergic crisis—with increasing weakness, hypersalivation, abdominal pains, and diarrhea—when used in conjunction with peripheral acetylcholinesterase inhibitors such as the myasthenia gravis agents pyridostigmine and neostigmine. The mechanism is increased acetylcholine available at the neuromuscular junction.

Table 4

Medications with moderate to strong anticholinergic activity

DDIs with other psychotropics

Antipsychotics. Nearly one-half of AD patients experience delusions, often in the middle stage of the disease, and many are prescribed second-generation antipsychotics (SGAs) to control delusions, hallucinations, sundowning, agitation, or aggression. Concomitant use of AChEIs and antipsychotics may increase the risk of extrapyramidal symptoms by disrupting the acetylcholine/dopamine balance in the striatum.⁵

In AD patients taking donepezil and risperidone, case reports describe parkinsonian syndrome and rigidity with immobility, which resolved after the antipsychotic was discontinued.^5,11 When rivastigmine and risperidone were coadministered, however, no clinically relevant adverse interactions were noted in a 20-week, open-label trial of 65 patients with AD, 10 with vascular dementia, and 10 with both.¹⁷

The FDA has warned of increased risk of death when SGAs are used to treat behavioral disturbances in dementia patients. In a recent meta-analysis of 15 placebo-controlled trials, cognitive tests scores worsened when AD patients took aripiprazole, olanzapine, quetiapine, or risperidone. A significant risk for cerebrovascular events was seen, especially with risperidone, although no clear causal relationship was established.¹⁸ Falls, injury, and syncope were not increased, and patients with less severe dementia, outpatients, and those selected for psychosis were less affected. Thus, provide careful follow-up and avoid long-term unwarranted antipsychotic use in AD patients.

Highly anticholinergic FGAs such as chlorpromazine are not recommended for AD patients (Table 4).

Antidepressants. Up to 30% of AD patients experience major depression.¹⁹ SSRIs are the antidepressants most often used to treat depression and anxiety in AD patients.

Citalopram, escitalopram, or venlafaxine are good choices for patients with AD because of minimal CYP inhibitory activity.⁴ Fluvoxamine, fluoxetine, and paroxetine inhibit CYP 2C9, through which warfarin and some other drugs with a narrow therapeutic index are metabolized.⁶

Herbal supplements. Ginkgo biloba and huperzine A (Chinese club moss) are the herbal supplements used most commonly by dementia patients. Ginkgo inhibits platelet aggregation and can cause bleeding complications, with or without concomitant antiplatelet or anticoagulant therapy such as aspirin, warfarin, and NSAIDs. Enzyme induction of CYP 2C19 by ginkgo, leading to subtherapeutic levels of anticonvulsants, has been implicated in a report of fatal seizures. Huperzine A is a natural cholinesterase inhibitor and should not be combined with AChEIs because of the risk of additive adverse effects.¹⁰

Related resources

• Jacobson SA, Pies RW, Greenblatt DJ. Handbook of geriatric psychopharmacology. Washington, DC: American Psychiatric Publishing; 2002.
  
• Sandson, NB. Drug-drug interaction primer. Washington, DC: American Psychiatric Publishing; 2007.
  

• Amantadine • Symmetrel
  
• Amitriptyline • Elavil
  
• Amoxapine • Asendin
  
• Aripiprazole • Abilify
  
• Atropine • Sal-Tropine
  
• Benztropine • Cogentin
  
• Bethanechol • Urecholine
  
• Biperiden • Akineton
  
• Bupropion • Wellbutrin
  
• Buspirone • BuSpar
  
• Carbamazepine • Tegretol
  
• Celecoxib • Celebrex
  
• Chlorpheniramine • Chlor-Trimeton
  
• Chlorpromazine • Thorazine
  
• Cimetidine • Tagamet
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Clozapine • Clozaril
  
• Cyclobenzaprine • Flexeril
  
• Cyproheptadine • Periactin
  
• Dextromethorphan • Benylin, Delsym, others
  
• Dicyclomine • Bentyl
  
• Digoxin • Lanoxin
  
• Diphenhydramine • Benadryl
  
• Disopyramide • Norpace
  
• Donepezil • Aricept
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Erythromycin • E-Mycin
  
• Fluconazole • Diflucan
  
• Fluvoxamine • Luvox
  
• Fluoxetine • Prozac
  
• Galantamine • Reminyl, Razadyne
  
• Haloperidol • Haldol
  
• Hydroxyzine • Vistaril
  
• Hyoscyamine • Anaspaz, Levbid, Levsin
  
• Imipramine • Tofranil
  
• Itraconazole • Sporanox
  
• Lamotrigine • Lamictal
  
• Levodopa/carbidopa • Sinemet
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Meclizine • Antivert
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Nefazodone • Serzone
  
• Neostigmine • Prostigmin
  
• Olanzapine • Zyprexa
  
• Oxazepam • Serax
  
• Oxybutynin • Ditropan
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Promethazine • Phenergan
  
• Protriptyline • Vivactil
  
• Pyridostigmine • Mestinon
  
• Quetiapine • Seroquel
  
• Ranitidine • Zantac
  
• Risperidone • Risperdal
  
• Rivastigmine • Exelon
  
• Scopolamine • Scopace
  
• Sertraline • Zoloft
  
• Succinylcholine • Anectine
  
• Temazepam • Restoril
  
• Thioridazine • Mellaril
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Trihexyphenidyl • Artane
  
• Valproate • Depakote
  
• Venlafaxine • Effexor
  
• Warfarin • Coumadin
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Life in the womb is fraught with hazards. Any deviation from a healthy pregnancy can damage a major organ system (first trimester), impair brain structural/functional development (second trimester), or cause prematurity and low birth weight (third trimester).

So many things can go wrong in the intrauterine environment that it is miraculous most babies are born with no apparent physical malformations. But behavioral teratogenesis is more subtle than physical defects and might not manifest until years later. Numerous studies have linked prenatal and obstetric complications to serious psychiatric disorders later in childhood or adulthood.

No wonder, then, that the pharmacologic management of mentally ill pregnant women is a high-stakes challenge. Consider the article in this issue by Louann Brizendine et al on treating anxiety during pregnancy with selective serotonin reuptake inhibitors vs benzodiazepines (page 38).

Risk vs benefit. Psychotropics can have unpredictable, serious effects on fetal growth and development, but fetal repercussions may be equally devastating if we do not stabilize the mentally ill mother and guard her against self-neglect, nonadherence to prenatal care, suicide, or infanticide. Thus, the benefit: risk ratio is sufficiently high to justify pharmacologic intervention during pregnancy—with the requisite caution this treatment deserves.

The greatest risk to the fetus is teratogenicity, which 1 review article¹ defined as “the dysgenesis of fetal organs as evidenced either structurally or functionally (eg, brain functions). The typical manifestations of teratogenesis are restricted growth or death of the fetus, carcinogenesis, and malformations, defined as defects in organ structure or function. These abnormalities vary in severity (eg, hypospadias that is mild and may be missed, or is severe, necessitating several corrective operations). Major malformations may be life-threatening and require major surgery or may have serious cosmetic or functional effects.”

Because of teratogenicity concerns, pregnant women are excluded from clinical trials of investigational drugs. Thus, new drugs are not approved for use in these patients, and FDA rankings of drugs’ teratogenic potential (Table) are guided by nonblinded, noncontrolled, naturalistic, after-the-fact observations—the lowest tier of evidence-based medicine.

Table

FDA classification of medications’ teratogenic potential

Proceed with caution. Against this background, I follow these principles when treating pregnant patients:

• Counsel all mentally ill women about the potential risks of conceiving while receiving a psychotropic before they consider pregnancy. Counseling should include all prescription and nonprescription drugs.
• Obtain a family history of psychiatric disorders from all pregnant patients.
• Make an accurate psychiatric diagnosis in pregnant patients, and assess the risks of providing vs withholding needed pharmacotherapy.
• Use nondrug treatments (if evidence-based) before medications. Options include behavioral therapies, interpersonal therapy, supportive therapy, and somatic treatments such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and light therapy.
• When using psychotropics, select the lowest-risk agents (Category A) first, and use the lowest efficacious dose.
• Collaborate with the patient’s obstetrician. I coined the term “psychiatric dystocia” to describe the complicating potential of mental illness on pregnancy.
• Completely avoid drugs with established teratogenicity, and educate the patient not to take these drugs if another physician prescribes them to her.
• Prescribe high-dose folate (4 to 5 mg/d) for psychotic, bipolar, or depressed pregnant patients to protect against neural tube defects and enhance fetal CNS development.
• Regularly check the patient’s nutrition, sleep hygiene, substance use (smoking, alcohol, coffee, illicit drugs), and use of over-the-counter supplements.
• Use stress-reduction techniques to reduce potential deleterious effects of stress-induced hypercortisolemia on the fetus, and involve the patient’s partner.
• See the mentally ill pregnant patient frequently for check-ups on response and/or side effects.
• Arrange for a child psychiatrist to examine the infant of a seriously mentally ill patient shortly after birth. A newborn’s irritability, crankiness, or insomnia may be perceived as withdrawal symptoms or behavioral teratogenesis, whereas it could very well be a genetically inherited temperament instability from a mother suffering from anxiety, depression, or psychosis.

Helping the mother without harming the child is like walking a tightrope: it calls upon all our skills, experience, and sound judgment.

P.S. To help you manage potential medico-legal issues such as prescribing during pregnancy, Current Psychiatry welcomes Douglas Mossman, MD, as editor of Malpractice Rx. This month, Dr. Mossman discusses documentation and invites you to submit questions about liability.

Life in the womb is fraught with hazards. Any deviation from a healthy pregnancy can damage a major organ system (first trimester), impair brain structural/functional development (second trimester), or cause prematurity and low birth weight (third trimester).

So many things can go wrong in the intrauterine environment that it is miraculous most babies are born with no apparent physical malformations. But behavioral teratogenesis is more subtle than physical defects and might not manifest until years later. Numerous studies have linked prenatal and obstetric complications to serious psychiatric disorders later in childhood or adulthood.

No wonder, then, that the pharmacologic management of mentally ill pregnant women is a high-stakes challenge. Consider the article in this issue by Louann Brizendine et al on treating anxiety during pregnancy with selective serotonin reuptake inhibitors vs benzodiazepines (page 38).

Risk vs benefit. Psychotropics can have unpredictable, serious effects on fetal growth and development, but fetal repercussions may be equally devastating if we do not stabilize the mentally ill mother and guard her against self-neglect, nonadherence to prenatal care, suicide, or infanticide. Thus, the benefit: risk ratio is sufficiently high to justify pharmacologic intervention during pregnancy—with the requisite caution this treatment deserves.

The greatest risk to the fetus is teratogenicity, which 1 review article¹ defined as “the dysgenesis of fetal organs as evidenced either structurally or functionally (eg, brain functions). The typical manifestations of teratogenesis are restricted growth or death of the fetus, carcinogenesis, and malformations, defined as defects in organ structure or function. These abnormalities vary in severity (eg, hypospadias that is mild and may be missed, or is severe, necessitating several corrective operations). Major malformations may be life-threatening and require major surgery or may have serious cosmetic or functional effects.”

Because of teratogenicity concerns, pregnant women are excluded from clinical trials of investigational drugs. Thus, new drugs are not approved for use in these patients, and FDA rankings of drugs’ teratogenic potential (Table) are guided by nonblinded, noncontrolled, naturalistic, after-the-fact observations—the lowest tier of evidence-based medicine.

Table

FDA classification of medications’ teratogenic potential

Proceed with caution. Against this background, I follow these principles when treating pregnant patients:

• Counsel all mentally ill women about the potential risks of conceiving while receiving a psychotropic before they consider pregnancy. Counseling should include all prescription and nonprescription drugs.
• Obtain a family history of psychiatric disorders from all pregnant patients.
• Make an accurate psychiatric diagnosis in pregnant patients, and assess the risks of providing vs withholding needed pharmacotherapy.
• Use nondrug treatments (if evidence-based) before medications. Options include behavioral therapies, interpersonal therapy, supportive therapy, and somatic treatments such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and light therapy.
• When using psychotropics, select the lowest-risk agents (Category A) first, and use the lowest efficacious dose.
• Collaborate with the patient’s obstetrician. I coined the term “psychiatric dystocia” to describe the complicating potential of mental illness on pregnancy.
• Completely avoid drugs with established teratogenicity, and educate the patient not to take these drugs if another physician prescribes them to her.
• Prescribe high-dose folate (4 to 5 mg/d) for psychotic, bipolar, or depressed pregnant patients to protect against neural tube defects and enhance fetal CNS development.
• Regularly check the patient’s nutrition, sleep hygiene, substance use (smoking, alcohol, coffee, illicit drugs), and use of over-the-counter supplements.
• Use stress-reduction techniques to reduce potential deleterious effects of stress-induced hypercortisolemia on the fetus, and involve the patient’s partner.
• See the mentally ill pregnant patient frequently for check-ups on response and/or side effects.
• Arrange for a child psychiatrist to examine the infant of a seriously mentally ill patient shortly after birth. A newborn’s irritability, crankiness, or insomnia may be perceived as withdrawal symptoms or behavioral teratogenesis, whereas it could very well be a genetically inherited temperament instability from a mother suffering from anxiety, depression, or psychosis.

Helping the mother without harming the child is like walking a tightrope: it calls upon all our skills, experience, and sound judgment.

P.S. To help you manage potential medico-legal issues such as prescribing during pregnancy, Current Psychiatry welcomes Douglas Mossman, MD, as editor of Malpractice Rx. This month, Dr. Mossman discusses documentation and invites you to submit questions about liability.

Life in the womb is fraught with hazards. Any deviation from a healthy pregnancy can damage a major organ system (first trimester), impair brain structural/functional development (second trimester), or cause prematurity and low birth weight (third trimester).

So many things can go wrong in the intrauterine environment that it is miraculous most babies are born with no apparent physical malformations. But behavioral teratogenesis is more subtle than physical defects and might not manifest until years later. Numerous studies have linked prenatal and obstetric complications to serious psychiatric disorders later in childhood or adulthood.

No wonder, then, that the pharmacologic management of mentally ill pregnant women is a high-stakes challenge. Consider the article in this issue by Louann Brizendine et al on treating anxiety during pregnancy with selective serotonin reuptake inhibitors vs benzodiazepines (page 38).

Risk vs benefit. Psychotropics can have unpredictable, serious effects on fetal growth and development, but fetal repercussions may be equally devastating if we do not stabilize the mentally ill mother and guard her against self-neglect, nonadherence to prenatal care, suicide, or infanticide. Thus, the benefit: risk ratio is sufficiently high to justify pharmacologic intervention during pregnancy—with the requisite caution this treatment deserves.

The greatest risk to the fetus is teratogenicity, which 1 review article¹ defined as “the dysgenesis of fetal organs as evidenced either structurally or functionally (eg, brain functions). The typical manifestations of teratogenesis are restricted growth or death of the fetus, carcinogenesis, and malformations, defined as defects in organ structure or function. These abnormalities vary in severity (eg, hypospadias that is mild and may be missed, or is severe, necessitating several corrective operations). Major malformations may be life-threatening and require major surgery or may have serious cosmetic or functional effects.”

Because of teratogenicity concerns, pregnant women are excluded from clinical trials of investigational drugs. Thus, new drugs are not approved for use in these patients, and FDA rankings of drugs’ teratogenic potential (Table) are guided by nonblinded, noncontrolled, naturalistic, after-the-fact observations—the lowest tier of evidence-based medicine.

Table

FDA classification of medications’ teratogenic potential

Proceed with caution. Against this background, I follow these principles when treating pregnant patients:

• Counsel all mentally ill women about the potential risks of conceiving while receiving a psychotropic before they consider pregnancy. Counseling should include all prescription and nonprescription drugs.
• Obtain a family history of psychiatric disorders from all pregnant patients.
• Make an accurate psychiatric diagnosis in pregnant patients, and assess the risks of providing vs withholding needed pharmacotherapy.
• Use nondrug treatments (if evidence-based) before medications. Options include behavioral therapies, interpersonal therapy, supportive therapy, and somatic treatments such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and light therapy.
• When using psychotropics, select the lowest-risk agents (Category A) first, and use the lowest efficacious dose.
• Collaborate with the patient’s obstetrician. I coined the term “psychiatric dystocia” to describe the complicating potential of mental illness on pregnancy.
• Completely avoid drugs with established teratogenicity, and educate the patient not to take these drugs if another physician prescribes them to her.
• Prescribe high-dose folate (4 to 5 mg/d) for psychotic, bipolar, or depressed pregnant patients to protect against neural tube defects and enhance fetal CNS development.
• Regularly check the patient’s nutrition, sleep hygiene, substance use (smoking, alcohol, coffee, illicit drugs), and use of over-the-counter supplements.
• Use stress-reduction techniques to reduce potential deleterious effects of stress-induced hypercortisolemia on the fetus, and involve the patient’s partner.
• See the mentally ill pregnant patient frequently for check-ups on response and/or side effects.
• Arrange for a child psychiatrist to examine the infant of a seriously mentally ill patient shortly after birth. A newborn’s irritability, crankiness, or insomnia may be perceived as withdrawal symptoms or behavioral teratogenesis, whereas it could very well be a genetically inherited temperament instability from a mother suffering from anxiety, depression, or psychosis.

Helping the mother without harming the child is like walking a tightrope: it calls upon all our skills, experience, and sound judgment.

P.S. To help you manage potential medico-legal issues such as prescribing during pregnancy, Current Psychiatry welcomes Douglas Mossman, MD, as editor of Malpractice Rx. This month, Dr. Mossman discusses documentation and invites you to submit questions about liability.

CASE: A ‘purification’

Mr. B, age 61, is in the ICU after shooting himself in the abdomen. The trauma team asks our psychiatry consultation/liaison service to determine if he needs special observation to prevent further self-harm.

Two days ago, Mr. B stood in the parking lot of a nearby hospital, aimed his rifle toward the left upper part of his abdomen, and fired. Bleeding profusely, he dragged himself to the hospital’s emergency room. ER staff stabilized him hemodynamically, then transferred him to our hospital’s regional trauma center, where surgeons performed an emergency laparotomy and found 2 sigmoid colon perforations, with feces floating outside the bowel.

After a partial colectomy and colostomy, Mr. B received broad-spectrum antibiotics, narcotic pain medication, and bowel rest in the ICU. When the trauma team called us, the patient’s condition was stable and he had awakened enough to communicate, although he still needed frequent monitoring.

We visit Mr. B in the ICU and ask him why he shot himself. He denies he was attempting suicide but adds that for months he has been feeling depressed, stressed, and guilty about “all the bad things I’ve done in my life.” Shooting himself helped him forget these negative thoughts.

A devout Roman Catholic, Mr. B has been researching flagellation and other forms of physical penance and considers the shooting a purification. He says he shot himself in the abdomen 2 previous times and felt better for months or years after each shooting.

Four years ago, Mr. B donated his left kidney to an unknown recipient. He does not equate the kidney donation with the shootings but says he felt happy while recuperating. He was later disappointed, however, because the procedure did not help him attract the “attention” he had hoped for.

Mr. B says he had been considering the latest shooting for at least 8 months and had carefully planned it. After studying anatomy textbooks, he figured he could fire into the left upper portion of his abdomen without striking a vital organ.

For several evenings, Mr. B aimed his rifle toward his abdomen but could not bring himself to pull the trigger. On the night of the shooting, he said, he “accidentally” fired at a more damaging angle than he had planned.

Cognitive examination results are mostly normal, although Mr. B has trouble interpreting similarities and proverbs. He appears pale but well-nourished, well-groomed, and serene. He speaks softly, often closing his eyes or staring into the distance. He says he feels “relieved” and “happy” after the shooting but did not anticipate such a severe injury. He denies suicidal thoughts and—because of his current euphoric mood—he hopes he never “needs” to shoot himself again.

The authors’ observations

We first considered delusional disorder and major depressive disorder with psychotic features. Mr. B’s belief that shooting himself would solve his problems seemed delusional, although he did not appear psychotic otherwise. Confusingly, Mr. B’s pre-admission symptoms seemed to suggest major depressive disorder, but he was happy in the ICU.

We explored other diagnoses, such as an odd form of OCD and a personality disorder (especially cluster A, given his strange beliefs), though at this point we had too little information for either diagnosis.

The authors’ observations

Mr. B was recovering from major abdominal surgery, was taking nothing orally, and claimed to feel fine psychologically. Because he was not grossly psychotic and did not endorse anxiety or depression, we decided against medication but recommended a chaplain consult and planned to visit Mr. B daily to gather more history.

We considered Mr. B a low suicide risk—especially while hospitalized—after he said his “need” to shoot himself had dissipated. He also endorsed no suicidal thoughts or other depressive symptoms, and the nursing staff viewed him as pleasant and compliant. We noted this evidence in the chart and continued to reassess him daily.

HISTORY: Dreams, nightmares

Over the next week, Mr. B shares his life story. He says his parents divorced when he was age 5, and around that time he spent approximately 2 weeks in the hospital after being hit by a truck. He considers those 2 weeks a bright spot in an otherwise turbulent childhood because his parents did not fight and he was showered with gifts and attention.

Soon after, Mr. B lived with his mother. When he was 9, he heard his divorced parents arguing during a family gathering and prayed for his own death.

Throughout his childhood, Mr. B dreamed of becoming a priest and a war hero. In his early teens, he attended a church youth program where he and other youths were taught that masturbation is a mortal sin. Through high school, Mr. B’s inability to stop masturbating shook his faith and discouraged him from pursuing the priesthood.

In high school, Mr. B did not use alcohol or drugs and excelled academically but had few friends. After graduating, he enlisted in the U.S. Army and hoped to serve in Vietnam, but basic training became too stressful. The relentless harangues from drill instructors reminded him of his parents’ frequent shouting matches during his childhood.

Approximately 2 weeks into basic training, Mr. B shot himself in the abdomen and injured his liver. He underwent laparotomy and cholecystectomy and was discharged from the military. His anxiety dissipated as he recovered, though he later regretted not serving in Vietnam.

Mr. B married at age 44 and was divorced 13 years later. Throughout the marriage, he says, he verbally abused his wife and was emotionally unsupportive. After the divorce, he felt remorse over having mistreated her. His guilt disappeared after he donated his left kidney to an unknown recipient, but the guilt soon returned and drove him to shoot himself a second time in 2005.

Mr. B worked as a special education teacher for 20 years before retiring 4 years ago and has since been pursuing a similar position because he misses going to work. His inability to find a permanent job has led to anxiety, insomnia, increased guilt, and decreased appetite. He says these feelings fueled his desire to shoot himself a third time.

Since his divorce, Mr. B has lived alone and has no family or friends nearby. He feels isolated and is hurt that his family has not acknowledged the cards and notes he sent to them but adds that he did not include his return address on the mailings.

FOLLOW-UP: No relief

Eleven days after admission, Mr. B says shooting himself has not relieved his negative feelings, and his impending discharge makes him feel anxious with some suicidal thoughts. The surgical team delays discharge after Mr. B develops ileus with nausea and vomiting. The trauma team’s attending physician prescribes an antiemetic, and ileus resolves after 4 days. Mr. B then is discharged in stable condition after he denies intention to harm himself.

Box 1

The authors’ observations

Some of Mr. B’s symptoms suggested OCD, including thought-related anxiety that is relieved after performing an action—in his case shooting himself. Whereas obsessions and/or compulsions occur daily in OCD, Mr. B would perform the action and then feel fine for months to years before his anxiety resurfaced. Also, he did not consider his thoughts wrong or obtrusive.

Box 2

• cluster A (odd ideas, solitary lifestyle)
  
• cluster B (self-harm, narcissistic tendencies)
  
• and cluster C (avoiding his relatives, dependence on others to meet his needs).
  

Mr. B’s intentional production of physical symptoms strongly suggested malingering, but we instead diagnosed factitious disorder because he was clearly motivated to play the sick role despite lack of a secondary gain (Box 2). The patient admitted causing the gunshot wound and clearly connected his subsequent emotional relief with both his positive childhood experience in the hospital and his satisfaction after donating a kidney.

Researchers have tried to distinguish between factitious disorder and other types of self-harm. Claes and Vandereycken⁴ would consider Mr. B’s behavior “self-mutilation” rather than factitious. Turner calls DSM-IV-TR criteria for factitious disorder nebulous and says that lying about symptoms or their origin should be a necessary criterion.⁵ If so, then Mr. B’s condition might fit no DSM diagnosis.⁶

The authors’ observations

Although Mr. B’s diagnosis remained elusive, he needed a treatment plan before discharge to prevent another shooting and save his life.

Although we did not diagnose a major depressive or anxiety-spectrum disorder, we felt an SSRI such as citalopram could help. According to some investigators, SSRIs might benefit patients with over-valued ideas that are not as persistent as delusions.^7,8

Additionally, we felt supportive therapy could help Mr. B establish a therapeutic relationship with a provider to whom he could turn during future crises. Should Mr. B contemplate self-harm, the therapist could suggest medications, hospitalization, or other interventions. We also recommended pastoral counseling to increase his support within his faith.

OUTCOME Another shot?

Before discharge, we start citalopram, 10 mg/d, and schedule a follow-up appointment within 2 weeks. We also suggest that Mr. B:

• move into an apartment near his outpatient doctors
  
• get involved with the local Catholic community to build his support network.
  

Mr. B calls his recent hospitalization upsetting because “I did not get the attention I wanted.” He endorses no immediate plan to shoot himself but voices concern that when his physical problems resolve, he might shoot Himself in the liver—as he had done 40 years ago—to bring himself full circle. “There’s still something attractive about this,” he says.

The authors’ observations

Patients with factitious illness commonly refuse mental health treatment.⁹

We feel Mr. B needs frequent ongoing appointments in a medical clinic where doctors can provide sufficient attention to counter his persistent self-harm urges. Regular appointments with a primary care physician—regardless of whether Mr. B is medically ill—could help him feel supported.

Related resources

• Feldman MD, Eisendrath SJ, eds. The spectrum of factitious disorders. Washington, DC: American Psychiatric Press; 1996.
  
• Sutton J, Martinson D. Self-injury Web site: What self-injury is.www.palace.net/~llama/psych/fwhat.html.
  

• Citalopram • Celexa
  
• Omeprazole • Prilosec
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: A ‘purification’

Mr. B, age 61, is in the ICU after shooting himself in the abdomen. The trauma team asks our psychiatry consultation/liaison service to determine if he needs special observation to prevent further self-harm.

Two days ago, Mr. B stood in the parking lot of a nearby hospital, aimed his rifle toward the left upper part of his abdomen, and fired. Bleeding profusely, he dragged himself to the hospital’s emergency room. ER staff stabilized him hemodynamically, then transferred him to our hospital’s regional trauma center, where surgeons performed an emergency laparotomy and found 2 sigmoid colon perforations, with feces floating outside the bowel.

After a partial colectomy and colostomy, Mr. B received broad-spectrum antibiotics, narcotic pain medication, and bowel rest in the ICU. When the trauma team called us, the patient’s condition was stable and he had awakened enough to communicate, although he still needed frequent monitoring.

We visit Mr. B in the ICU and ask him why he shot himself. He denies he was attempting suicide but adds that for months he has been feeling depressed, stressed, and guilty about “all the bad things I’ve done in my life.” Shooting himself helped him forget these negative thoughts.

A devout Roman Catholic, Mr. B has been researching flagellation and other forms of physical penance and considers the shooting a purification. He says he shot himself in the abdomen 2 previous times and felt better for months or years after each shooting.

Four years ago, Mr. B donated his left kidney to an unknown recipient. He does not equate the kidney donation with the shootings but says he felt happy while recuperating. He was later disappointed, however, because the procedure did not help him attract the “attention” he had hoped for.

Mr. B says he had been considering the latest shooting for at least 8 months and had carefully planned it. After studying anatomy textbooks, he figured he could fire into the left upper portion of his abdomen without striking a vital organ.

For several evenings, Mr. B aimed his rifle toward his abdomen but could not bring himself to pull the trigger. On the night of the shooting, he said, he “accidentally” fired at a more damaging angle than he had planned.

Cognitive examination results are mostly normal, although Mr. B has trouble interpreting similarities and proverbs. He appears pale but well-nourished, well-groomed, and serene. He speaks softly, often closing his eyes or staring into the distance. He says he feels “relieved” and “happy” after the shooting but did not anticipate such a severe injury. He denies suicidal thoughts and—because of his current euphoric mood—he hopes he never “needs” to shoot himself again.

The authors’ observations

We first considered delusional disorder and major depressive disorder with psychotic features. Mr. B’s belief that shooting himself would solve his problems seemed delusional, although he did not appear psychotic otherwise. Confusingly, Mr. B’s pre-admission symptoms seemed to suggest major depressive disorder, but he was happy in the ICU.

We explored other diagnoses, such as an odd form of OCD and a personality disorder (especially cluster A, given his strange beliefs), though at this point we had too little information for either diagnosis.

The authors’ observations

Mr. B was recovering from major abdominal surgery, was taking nothing orally, and claimed to feel fine psychologically. Because he was not grossly psychotic and did not endorse anxiety or depression, we decided against medication but recommended a chaplain consult and planned to visit Mr. B daily to gather more history.

We considered Mr. B a low suicide risk—especially while hospitalized—after he said his “need” to shoot himself had dissipated. He also endorsed no suicidal thoughts or other depressive symptoms, and the nursing staff viewed him as pleasant and compliant. We noted this evidence in the chart and continued to reassess him daily.

HISTORY: Dreams, nightmares

Over the next week, Mr. B shares his life story. He says his parents divorced when he was age 5, and around that time he spent approximately 2 weeks in the hospital after being hit by a truck. He considers those 2 weeks a bright spot in an otherwise turbulent childhood because his parents did not fight and he was showered with gifts and attention.

Soon after, Mr. B lived with his mother. When he was 9, he heard his divorced parents arguing during a family gathering and prayed for his own death.

Throughout his childhood, Mr. B dreamed of becoming a priest and a war hero. In his early teens, he attended a church youth program where he and other youths were taught that masturbation is a mortal sin. Through high school, Mr. B’s inability to stop masturbating shook his faith and discouraged him from pursuing the priesthood.

In high school, Mr. B did not use alcohol or drugs and excelled academically but had few friends. After graduating, he enlisted in the U.S. Army and hoped to serve in Vietnam, but basic training became too stressful. The relentless harangues from drill instructors reminded him of his parents’ frequent shouting matches during his childhood.

Approximately 2 weeks into basic training, Mr. B shot himself in the abdomen and injured his liver. He underwent laparotomy and cholecystectomy and was discharged from the military. His anxiety dissipated as he recovered, though he later regretted not serving in Vietnam.

Mr. B married at age 44 and was divorced 13 years later. Throughout the marriage, he says, he verbally abused his wife and was emotionally unsupportive. After the divorce, he felt remorse over having mistreated her. His guilt disappeared after he donated his left kidney to an unknown recipient, but the guilt soon returned and drove him to shoot himself a second time in 2005.

Mr. B worked as a special education teacher for 20 years before retiring 4 years ago and has since been pursuing a similar position because he misses going to work. His inability to find a permanent job has led to anxiety, insomnia, increased guilt, and decreased appetite. He says these feelings fueled his desire to shoot himself a third time.

Since his divorce, Mr. B has lived alone and has no family or friends nearby. He feels isolated and is hurt that his family has not acknowledged the cards and notes he sent to them but adds that he did not include his return address on the mailings.

FOLLOW-UP: No relief

Eleven days after admission, Mr. B says shooting himself has not relieved his negative feelings, and his impending discharge makes him feel anxious with some suicidal thoughts. The surgical team delays discharge after Mr. B develops ileus with nausea and vomiting. The trauma team’s attending physician prescribes an antiemetic, and ileus resolves after 4 days. Mr. B then is discharged in stable condition after he denies intention to harm himself.

Box 1

The authors’ observations

Some of Mr. B’s symptoms suggested OCD, including thought-related anxiety that is relieved after performing an action—in his case shooting himself. Whereas obsessions and/or compulsions occur daily in OCD, Mr. B would perform the action and then feel fine for months to years before his anxiety resurfaced. Also, he did not consider his thoughts wrong or obtrusive.

Box 2

• cluster A (odd ideas, solitary lifestyle)
  
• cluster B (self-harm, narcissistic tendencies)
  
• and cluster C (avoiding his relatives, dependence on others to meet his needs).
  

Mr. B’s intentional production of physical symptoms strongly suggested malingering, but we instead diagnosed factitious disorder because he was clearly motivated to play the sick role despite lack of a secondary gain (Box 2). The patient admitted causing the gunshot wound and clearly connected his subsequent emotional relief with both his positive childhood experience in the hospital and his satisfaction after donating a kidney.

Researchers have tried to distinguish between factitious disorder and other types of self-harm. Claes and Vandereycken⁴ would consider Mr. B’s behavior “self-mutilation” rather than factitious. Turner calls DSM-IV-TR criteria for factitious disorder nebulous and says that lying about symptoms or their origin should be a necessary criterion.⁵ If so, then Mr. B’s condition might fit no DSM diagnosis.⁶

The authors’ observations

Although Mr. B’s diagnosis remained elusive, he needed a treatment plan before discharge to prevent another shooting and save his life.

Although we did not diagnose a major depressive or anxiety-spectrum disorder, we felt an SSRI such as citalopram could help. According to some investigators, SSRIs might benefit patients with over-valued ideas that are not as persistent as delusions.^7,8

Additionally, we felt supportive therapy could help Mr. B establish a therapeutic relationship with a provider to whom he could turn during future crises. Should Mr. B contemplate self-harm, the therapist could suggest medications, hospitalization, or other interventions. We also recommended pastoral counseling to increase his support within his faith.

OUTCOME Another shot?

Before discharge, we start citalopram, 10 mg/d, and schedule a follow-up appointment within 2 weeks. We also suggest that Mr. B:

• move into an apartment near his outpatient doctors
  
• get involved with the local Catholic community to build his support network.
  

Mr. B calls his recent hospitalization upsetting because “I did not get the attention I wanted.” He endorses no immediate plan to shoot himself but voices concern that when his physical problems resolve, he might shoot Himself in the liver—as he had done 40 years ago—to bring himself full circle. “There’s still something attractive about this,” he says.

The authors’ observations

Patients with factitious illness commonly refuse mental health treatment.⁹

We feel Mr. B needs frequent ongoing appointments in a medical clinic where doctors can provide sufficient attention to counter his persistent self-harm urges. Regular appointments with a primary care physician—regardless of whether Mr. B is medically ill—could help him feel supported.

Related resources

• Feldman MD, Eisendrath SJ, eds. The spectrum of factitious disorders. Washington, DC: American Psychiatric Press; 1996.
  
• Sutton J, Martinson D. Self-injury Web site: What self-injury is.www.palace.net/~llama/psych/fwhat.html.
  

• Citalopram • Celexa
  
• Omeprazole • Prilosec
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: A ‘purification’

Mr. B, age 61, is in the ICU after shooting himself in the abdomen. The trauma team asks our psychiatry consultation/liaison service to determine if he needs special observation to prevent further self-harm.

Two days ago, Mr. B stood in the parking lot of a nearby hospital, aimed his rifle toward the left upper part of his abdomen, and fired. Bleeding profusely, he dragged himself to the hospital’s emergency room. ER staff stabilized him hemodynamically, then transferred him to our hospital’s regional trauma center, where surgeons performed an emergency laparotomy and found 2 sigmoid colon perforations, with feces floating outside the bowel.

After a partial colectomy and colostomy, Mr. B received broad-spectrum antibiotics, narcotic pain medication, and bowel rest in the ICU. When the trauma team called us, the patient’s condition was stable and he had awakened enough to communicate, although he still needed frequent monitoring.

We visit Mr. B in the ICU and ask him why he shot himself. He denies he was attempting suicide but adds that for months he has been feeling depressed, stressed, and guilty about “all the bad things I’ve done in my life.” Shooting himself helped him forget these negative thoughts.

A devout Roman Catholic, Mr. B has been researching flagellation and other forms of physical penance and considers the shooting a purification. He says he shot himself in the abdomen 2 previous times and felt better for months or years after each shooting.

Four years ago, Mr. B donated his left kidney to an unknown recipient. He does not equate the kidney donation with the shootings but says he felt happy while recuperating. He was later disappointed, however, because the procedure did not help him attract the “attention” he had hoped for.

Mr. B says he had been considering the latest shooting for at least 8 months and had carefully planned it. After studying anatomy textbooks, he figured he could fire into the left upper portion of his abdomen without striking a vital organ.

For several evenings, Mr. B aimed his rifle toward his abdomen but could not bring himself to pull the trigger. On the night of the shooting, he said, he “accidentally” fired at a more damaging angle than he had planned.

Cognitive examination results are mostly normal, although Mr. B has trouble interpreting similarities and proverbs. He appears pale but well-nourished, well-groomed, and serene. He speaks softly, often closing his eyes or staring into the distance. He says he feels “relieved” and “happy” after the shooting but did not anticipate such a severe injury. He denies suicidal thoughts and—because of his current euphoric mood—he hopes he never “needs” to shoot himself again.

The authors’ observations

We first considered delusional disorder and major depressive disorder with psychotic features. Mr. B’s belief that shooting himself would solve his problems seemed delusional, although he did not appear psychotic otherwise. Confusingly, Mr. B’s pre-admission symptoms seemed to suggest major depressive disorder, but he was happy in the ICU.

We explored other diagnoses, such as an odd form of OCD and a personality disorder (especially cluster A, given his strange beliefs), though at this point we had too little information for either diagnosis.

The authors’ observations

Mr. B was recovering from major abdominal surgery, was taking nothing orally, and claimed to feel fine psychologically. Because he was not grossly psychotic and did not endorse anxiety or depression, we decided against medication but recommended a chaplain consult and planned to visit Mr. B daily to gather more history.

We considered Mr. B a low suicide risk—especially while hospitalized—after he said his “need” to shoot himself had dissipated. He also endorsed no suicidal thoughts or other depressive symptoms, and the nursing staff viewed him as pleasant and compliant. We noted this evidence in the chart and continued to reassess him daily.

HISTORY: Dreams, nightmares

Over the next week, Mr. B shares his life story. He says his parents divorced when he was age 5, and around that time he spent approximately 2 weeks in the hospital after being hit by a truck. He considers those 2 weeks a bright spot in an otherwise turbulent childhood because his parents did not fight and he was showered with gifts and attention.

Soon after, Mr. B lived with his mother. When he was 9, he heard his divorced parents arguing during a family gathering and prayed for his own death.

Throughout his childhood, Mr. B dreamed of becoming a priest and a war hero. In his early teens, he attended a church youth program where he and other youths were taught that masturbation is a mortal sin. Through high school, Mr. B’s inability to stop masturbating shook his faith and discouraged him from pursuing the priesthood.

In high school, Mr. B did not use alcohol or drugs and excelled academically but had few friends. After graduating, he enlisted in the U.S. Army and hoped to serve in Vietnam, but basic training became too stressful. The relentless harangues from drill instructors reminded him of his parents’ frequent shouting matches during his childhood.

Approximately 2 weeks into basic training, Mr. B shot himself in the abdomen and injured his liver. He underwent laparotomy and cholecystectomy and was discharged from the military. His anxiety dissipated as he recovered, though he later regretted not serving in Vietnam.

Mr. B married at age 44 and was divorced 13 years later. Throughout the marriage, he says, he verbally abused his wife and was emotionally unsupportive. After the divorce, he felt remorse over having mistreated her. His guilt disappeared after he donated his left kidney to an unknown recipient, but the guilt soon returned and drove him to shoot himself a second time in 2005.

Mr. B worked as a special education teacher for 20 years before retiring 4 years ago and has since been pursuing a similar position because he misses going to work. His inability to find a permanent job has led to anxiety, insomnia, increased guilt, and decreased appetite. He says these feelings fueled his desire to shoot himself a third time.

Since his divorce, Mr. B has lived alone and has no family or friends nearby. He feels isolated and is hurt that his family has not acknowledged the cards and notes he sent to them but adds that he did not include his return address on the mailings.

FOLLOW-UP: No relief

Eleven days after admission, Mr. B says shooting himself has not relieved his negative feelings, and his impending discharge makes him feel anxious with some suicidal thoughts. The surgical team delays discharge after Mr. B develops ileus with nausea and vomiting. The trauma team’s attending physician prescribes an antiemetic, and ileus resolves after 4 days. Mr. B then is discharged in stable condition after he denies intention to harm himself.

Box 1

The authors’ observations

Some of Mr. B’s symptoms suggested OCD, including thought-related anxiety that is relieved after performing an action—in his case shooting himself. Whereas obsessions and/or compulsions occur daily in OCD, Mr. B would perform the action and then feel fine for months to years before his anxiety resurfaced. Also, he did not consider his thoughts wrong or obtrusive.

Box 2

• cluster A (odd ideas, solitary lifestyle)
  
• cluster B (self-harm, narcissistic tendencies)
  
• and cluster C (avoiding his relatives, dependence on others to meet his needs).
  

Mr. B’s intentional production of physical symptoms strongly suggested malingering, but we instead diagnosed factitious disorder because he was clearly motivated to play the sick role despite lack of a secondary gain (Box 2). The patient admitted causing the gunshot wound and clearly connected his subsequent emotional relief with both his positive childhood experience in the hospital and his satisfaction after donating a kidney.

Researchers have tried to distinguish between factitious disorder and other types of self-harm. Claes and Vandereycken⁴ would consider Mr. B’s behavior “self-mutilation” rather than factitious. Turner calls DSM-IV-TR criteria for factitious disorder nebulous and says that lying about symptoms or their origin should be a necessary criterion.⁵ If so, then Mr. B’s condition might fit no DSM diagnosis.⁶

The authors’ observations

Although Mr. B’s diagnosis remained elusive, he needed a treatment plan before discharge to prevent another shooting and save his life.

Although we did not diagnose a major depressive or anxiety-spectrum disorder, we felt an SSRI such as citalopram could help. According to some investigators, SSRIs might benefit patients with over-valued ideas that are not as persistent as delusions.^7,8

Additionally, we felt supportive therapy could help Mr. B establish a therapeutic relationship with a provider to whom he could turn during future crises. Should Mr. B contemplate self-harm, the therapist could suggest medications, hospitalization, or other interventions. We also recommended pastoral counseling to increase his support within his faith.

OUTCOME Another shot?

Before discharge, we start citalopram, 10 mg/d, and schedule a follow-up appointment within 2 weeks. We also suggest that Mr. B:

• move into an apartment near his outpatient doctors
  
• get involved with the local Catholic community to build his support network.
  

Mr. B calls his recent hospitalization upsetting because “I did not get the attention I wanted.” He endorses no immediate plan to shoot himself but voices concern that when his physical problems resolve, he might shoot Himself in the liver—as he had done 40 years ago—to bring himself full circle. “There’s still something attractive about this,” he says.

The authors’ observations

Patients with factitious illness commonly refuse mental health treatment.⁹

We feel Mr. B needs frequent ongoing appointments in a medical clinic where doctors can provide sufficient attention to counter his persistent self-harm urges. Regular appointments with a primary care physician—regardless of whether Mr. B is medically ill—could help him feel supported.

Related resources

• Feldman MD, Eisendrath SJ, eds. The spectrum of factitious disorders. Washington, DC: American Psychiatric Press; 1996.
  
• Sutton J, Martinson D. Self-injury Web site: What self-injury is.www.palace.net/~llama/psych/fwhat.html.
  

• Citalopram • Celexa
  
• Omeprazole • Prilosec
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Alysha, age 15, is an “A” student and top athlete who feels her parents push her to be perfect. After getting a B on a test, she feels overwhelmed by shame and guilt. She locks herself in the bathroom and begins cutting her arm with a razor blade.

Self-injurious behavior (SIB) in adolescents can be associated with internalizing, externalizing, and substance abuse disorders (Table 1). For most practitioners, such as Alysha, a major goal of SIB is to relieve intolerable stress and negative affect.¹

Although this secretive, highly addictive, learned behavior can be difficult to control, some clinical approaches can help these distressed teens and their parents. This article examines the dynamics of SIB, the association between suicidal ideation and SIB, and recommended treatments such as substitute behaviors and dialectic behavioral therapy.

Table 1

Common Axis I disorders among teens with SIB

Growing problem in adolescents

SIB is the deliberate infliction of harm to oneself, either internally or externally, without suicidal intent.¹ This behavior is also known as impulsive self-injury, non-suicidal self-injury, self-mutilation, cutting, and self-harm. Once reported primarily in adults with borderline personality disorder, SIB is becoming common among adolescents:

• Among 663 teens in community-sample survey, 46% engaged in some form of SIB in the past year, and 28% engaged in serious, repetitive behaviors.²
  
• 13% to 23% of teenagers have engaged in SIB, according to literature review.³
  
• Children as young as 9 have presented with SIB.
  

• burning
  
• swallowing objects or substances
  
• hitting oneself with the fist or against an object
  
• cutting circulation to a digit
  
• picking at skin
  
• pulling out hair.
  

Despite increasing prevalence among adolescents, SIB remains a solitary behavior. Based on my clinical experience, teens may share ideas about SIB, but they generally don’t practice it in groups.

SIB psychodynamics

Adults and adolescents with SIB frequently have:

• difficulty regulating emotions
  
• unstable interpersonal relations
  
• limited coping strategies.¹
  

Shame is also common and can be a major barrier to diagnosing SIB. Adolescents who are ashamed of the behavior will go to great lengths to hide it from others, including clinicians. Despite the shame, many adolescents feel unable to stop engaging in SIB because it fulfills a powerful need.

Adults and adolescents who practice SIB most often report their behavior is motivated by affect regulation and tension release.⁴ Some adolescents engage in a different, manipulative form of SIB not to relieve tension but as a threat to prevent loss (Box).⁴

Behavioral reinforcement. An acute stressor—such as parental limits on behavior, feelings of rejection or abandonment by peers, or failing to achieve an unrealistic goal—triggers an escalating, intolerable affect. By experimentation or accident, an adolescent discovers that SIB provides rapid relief of the intolerable state—a calmness that may last for minutes, hours, or days. This relief reinforces the behavior, and the adolescent repeats SIB when faced with the next stressor.

Most individuals with SIB report a similar sequence of events. There is a trigger event, usually involving a real or perceived feeling of loss, rejection, or abandonment. The adolescent tries to resist the impulse to self-harm, feels escalating emotional distress, engages in SIB, and feels immediate relief.⁵

Inducing pain or bleeding as a means of relieving intolerable stress may be an attempt to:

• turn emotional pain into more manageable physical pain
  
• direct anger that cannot be expressed at others onto oneself
  
• punish oneself for perceived misdeeds.⁴
  

Box

CASE 2: Lingering effects of trauma

Melissa, age 13, has been sexually abused by her foster brother. She briefly returns to the home where her foster brother still resides. He has torn up her room, and her mother—who supports the foster brother—has left the room that way for her to find. Melissa returns to her current residence, cuts her arm 15 times, and pierces her tongue.

In therapy, she denies being angry or upset and does not know why she cut her arm or pierced her tongue.

Even an adolescent who experienced neglect or loss of attachment object without overt physical or sexual abuse might have trouble establishing a therapeutic alliance because of difficulty with trust.⁶ He or she may have little or no capacity to identify emotional states, which limits insight into the behavior.⁵

Dissociation. Some adolescents use SIB to try to feel something or to bring themselves back from a dissociative state. They report feeling lost, alone, and disconnected from others and themselves. Some report seeing blood as a way of reconnecting with being alive.

Dissociation may occur in adolescents with a history of trauma, particularly in childhood. Abused individuals who engage in SIB may be identifying with the aggressor, attempting to cut away internalized negative images of the abuser or to control anger they are unable to acknowledge.⁶

Clues prompt further assessment

SIB assessment begins with screening for the behavior. If you find any indicators that suggest SIB (Table 2), question the adolescent about self-injury. Many adolescents want help—and will respond accurately to questions about self-injury—but need to be asked. They usually won’t volunteer the information during an initial evaluation.

• number, location, and age of injuries
  
• depth of cuts (if applicable)
  
• signs of infection.
  

Suicide screening. By definition, SIB does not include an intention to die, and most teenagers with SIB will deny suicidal intent. However, because the line between SIB and passive suicide can be thin, careful screening and ongoing monitoring for suicidal ideation and behavior in teens with SIB is essential. In one study:

• 70% of adolescents who engaged in SIB had made one suicide attempt
  
• 55% had made multiple attempts.⁷
  

Address the parents’ concerns. During your assessment, also focus on the adolescent’s parents. They often are highly distressed, confused, and angry. They typically learn about the SIB from their child’s school counselors or peers and feel betrayed and guilty. They may want to be excessively intrusive and punitive and need support, information, and guidance to address their child’s safety.

Table 2

SIB: Spotting behavioral clues

Treatment recommendations

Always take SIB in adolescents seriously, and not as something they will “outgrow.” Adolescents with SIB need help modulating affect, stabilizing interpersonal relationships, and developing more adaptive coping strategies and problem-solving skills. Underlying dynamics—especially childhood trauma—must be explored and resolved.

Few evidence-based studies have evaluated SIB treatment in adolescents. Clinicians have extrapolated suggested interventions from the adult literature; however, much of this data was obtained from treating adult women with borderline personality disorder.

No medications are FDA-approved for treating SIB. Use pharmacologic interventions to treat underlying disorders, such as depression or anxiety, so that patients are better able to participate in other therapeutic interventions.

Dialectical behavioral therapy (DBT) is the only therapeutic entity shown in controlled trials to successfully treat SIB. Weekly individual psychotherapy and skills training groups focus on:

• regulating emotions
  
• tolerating distress
  
• improving interpersonal relationships
  
• reducing identity confusion and maladaptive cognitions.⁹
  

Prevention. Although SIB can be done with any object, most adolescents have a preferred method for causing self-injury and may have a “kit” of equipment. Identify and remove any tools the adolescent uses for self-injury. Because SIB is a highly ritualistic behavior, denying access to the preferred tools can help reduce self-injury frequency and convey that the behavior is unacceptable.

One individual should be designated to monitor the adolescent for SIB. Adolescents are seeking trust and do not respond well to constant questions about their behavior. Because some parents can become intrusive, monitoring may be best assigned to the adolescent’s therapist or a less emotional parent.

CASE 3: Scars provoke relapse

Claudia, a musically talented teen with SIB, withdraws from her choir when they choose costumes with short sleeves. She had not engaged in SIB in >1 year but has scarring and cheloid from the cuts. Years later she starts cutting again after laser treatments fail to remove the scars. She is frustrated because she will always have to wear long sleeves.

Treatment is essential, however, because this behavior can last for decades and leave scars that might interfere with future goals. The longer the adolescent has been dependent on the behavior, the more difficult it is to treat.

Related resources

• Levenkron S. Cutting: understanding and overcoming self-mutilation. New York: W.W. Norton & Company; 1998.
  
• Favazza AR. Bodies under siege: self-mutilation and body modification in culture and psychiatry. 2nd ed. Baltimore: The Johns Hopkins University Press; 1996.
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Alysha, age 15, is an “A” student and top athlete who feels her parents push her to be perfect. After getting a B on a test, she feels overwhelmed by shame and guilt. She locks herself in the bathroom and begins cutting her arm with a razor blade.

Self-injurious behavior (SIB) in adolescents can be associated with internalizing, externalizing, and substance abuse disorders (Table 1). For most practitioners, such as Alysha, a major goal of SIB is to relieve intolerable stress and negative affect.¹

Although this secretive, highly addictive, learned behavior can be difficult to control, some clinical approaches can help these distressed teens and their parents. This article examines the dynamics of SIB, the association between suicidal ideation and SIB, and recommended treatments such as substitute behaviors and dialectic behavioral therapy.

Table 1

Common Axis I disorders among teens with SIB

Growing problem in adolescents

SIB is the deliberate infliction of harm to oneself, either internally or externally, without suicidal intent.¹ This behavior is also known as impulsive self-injury, non-suicidal self-injury, self-mutilation, cutting, and self-harm. Once reported primarily in adults with borderline personality disorder, SIB is becoming common among adolescents:

• Among 663 teens in community-sample survey, 46% engaged in some form of SIB in the past year, and 28% engaged in serious, repetitive behaviors.²
  
• 13% to 23% of teenagers have engaged in SIB, according to literature review.³
  
• Children as young as 9 have presented with SIB.
  

• burning
  
• swallowing objects or substances
  
• hitting oneself with the fist or against an object
  
• cutting circulation to a digit
  
• picking at skin
  
• pulling out hair.
  

Despite increasing prevalence among adolescents, SIB remains a solitary behavior. Based on my clinical experience, teens may share ideas about SIB, but they generally don’t practice it in groups.

SIB psychodynamics

Adults and adolescents with SIB frequently have:

• difficulty regulating emotions
  
• unstable interpersonal relations
  
• limited coping strategies.¹
  

Shame is also common and can be a major barrier to diagnosing SIB. Adolescents who are ashamed of the behavior will go to great lengths to hide it from others, including clinicians. Despite the shame, many adolescents feel unable to stop engaging in SIB because it fulfills a powerful need.

Adults and adolescents who practice SIB most often report their behavior is motivated by affect regulation and tension release.⁴ Some adolescents engage in a different, manipulative form of SIB not to relieve tension but as a threat to prevent loss (Box).⁴

Behavioral reinforcement. An acute stressor—such as parental limits on behavior, feelings of rejection or abandonment by peers, or failing to achieve an unrealistic goal—triggers an escalating, intolerable affect. By experimentation or accident, an adolescent discovers that SIB provides rapid relief of the intolerable state—a calmness that may last for minutes, hours, or days. This relief reinforces the behavior, and the adolescent repeats SIB when faced with the next stressor.

Most individuals with SIB report a similar sequence of events. There is a trigger event, usually involving a real or perceived feeling of loss, rejection, or abandonment. The adolescent tries to resist the impulse to self-harm, feels escalating emotional distress, engages in SIB, and feels immediate relief.⁵

Inducing pain or bleeding as a means of relieving intolerable stress may be an attempt to:

• turn emotional pain into more manageable physical pain
  
• direct anger that cannot be expressed at others onto oneself
  
• punish oneself for perceived misdeeds.⁴
  

Box

CASE 2: Lingering effects of trauma

Melissa, age 13, has been sexually abused by her foster brother. She briefly returns to the home where her foster brother still resides. He has torn up her room, and her mother—who supports the foster brother—has left the room that way for her to find. Melissa returns to her current residence, cuts her arm 15 times, and pierces her tongue.

In therapy, she denies being angry or upset and does not know why she cut her arm or pierced her tongue.

Even an adolescent who experienced neglect or loss of attachment object without overt physical or sexual abuse might have trouble establishing a therapeutic alliance because of difficulty with trust.⁶ He or she may have little or no capacity to identify emotional states, which limits insight into the behavior.⁵

Dissociation. Some adolescents use SIB to try to feel something or to bring themselves back from a dissociative state. They report feeling lost, alone, and disconnected from others and themselves. Some report seeing blood as a way of reconnecting with being alive.

Dissociation may occur in adolescents with a history of trauma, particularly in childhood. Abused individuals who engage in SIB may be identifying with the aggressor, attempting to cut away internalized negative images of the abuser or to control anger they are unable to acknowledge.⁶

Clues prompt further assessment

SIB assessment begins with screening for the behavior. If you find any indicators that suggest SIB (Table 2), question the adolescent about self-injury. Many adolescents want help—and will respond accurately to questions about self-injury—but need to be asked. They usually won’t volunteer the information during an initial evaluation.

• number, location, and age of injuries
  
• depth of cuts (if applicable)
  
• signs of infection.
  

Suicide screening. By definition, SIB does not include an intention to die, and most teenagers with SIB will deny suicidal intent. However, because the line between SIB and passive suicide can be thin, careful screening and ongoing monitoring for suicidal ideation and behavior in teens with SIB is essential. In one study:

• 70% of adolescents who engaged in SIB had made one suicide attempt
  
• 55% had made multiple attempts.⁷
  

Address the parents’ concerns. During your assessment, also focus on the adolescent’s parents. They often are highly distressed, confused, and angry. They typically learn about the SIB from their child’s school counselors or peers and feel betrayed and guilty. They may want to be excessively intrusive and punitive and need support, information, and guidance to address their child’s safety.

Table 2

SIB: Spotting behavioral clues

Treatment recommendations

Always take SIB in adolescents seriously, and not as something they will “outgrow.” Adolescents with SIB need help modulating affect, stabilizing interpersonal relationships, and developing more adaptive coping strategies and problem-solving skills. Underlying dynamics—especially childhood trauma—must be explored and resolved.

Few evidence-based studies have evaluated SIB treatment in adolescents. Clinicians have extrapolated suggested interventions from the adult literature; however, much of this data was obtained from treating adult women with borderline personality disorder.

No medications are FDA-approved for treating SIB. Use pharmacologic interventions to treat underlying disorders, such as depression or anxiety, so that patients are better able to participate in other therapeutic interventions.

Dialectical behavioral therapy (DBT) is the only therapeutic entity shown in controlled trials to successfully treat SIB. Weekly individual psychotherapy and skills training groups focus on:

• regulating emotions
  
• tolerating distress
  
• improving interpersonal relationships
  
• reducing identity confusion and maladaptive cognitions.⁹
  

Prevention. Although SIB can be done with any object, most adolescents have a preferred method for causing self-injury and may have a “kit” of equipment. Identify and remove any tools the adolescent uses for self-injury. Because SIB is a highly ritualistic behavior, denying access to the preferred tools can help reduce self-injury frequency and convey that the behavior is unacceptable.

One individual should be designated to monitor the adolescent for SIB. Adolescents are seeking trust and do not respond well to constant questions about their behavior. Because some parents can become intrusive, monitoring may be best assigned to the adolescent’s therapist or a less emotional parent.

CASE 3: Scars provoke relapse

Claudia, a musically talented teen with SIB, withdraws from her choir when they choose costumes with short sleeves. She had not engaged in SIB in >1 year but has scarring and cheloid from the cuts. Years later she starts cutting again after laser treatments fail to remove the scars. She is frustrated because she will always have to wear long sleeves.

Treatment is essential, however, because this behavior can last for decades and leave scars that might interfere with future goals. The longer the adolescent has been dependent on the behavior, the more difficult it is to treat.

Related resources

• Levenkron S. Cutting: understanding and overcoming self-mutilation. New York: W.W. Norton & Company; 1998.
  
• Favazza AR. Bodies under siege: self-mutilation and body modification in culture and psychiatry. 2nd ed. Baltimore: The Johns Hopkins University Press; 1996.
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Alysha, age 15, is an “A” student and top athlete who feels her parents push her to be perfect. After getting a B on a test, she feels overwhelmed by shame and guilt. She locks herself in the bathroom and begins cutting her arm with a razor blade.

Self-injurious behavior (SIB) in adolescents can be associated with internalizing, externalizing, and substance abuse disorders (Table 1). For most practitioners, such as Alysha, a major goal of SIB is to relieve intolerable stress and negative affect.¹

Although this secretive, highly addictive, learned behavior can be difficult to control, some clinical approaches can help these distressed teens and their parents. This article examines the dynamics of SIB, the association between suicidal ideation and SIB, and recommended treatments such as substitute behaviors and dialectic behavioral therapy.

Table 1

Common Axis I disorders among teens with SIB

Growing problem in adolescents

SIB is the deliberate infliction of harm to oneself, either internally or externally, without suicidal intent.¹ This behavior is also known as impulsive self-injury, non-suicidal self-injury, self-mutilation, cutting, and self-harm. Once reported primarily in adults with borderline personality disorder, SIB is becoming common among adolescents:

• Among 663 teens in community-sample survey, 46% engaged in some form of SIB in the past year, and 28% engaged in serious, repetitive behaviors.²
  
• 13% to 23% of teenagers have engaged in SIB, according to literature review.³
  
• Children as young as 9 have presented with SIB.
  

• burning
  
• swallowing objects or substances
  
• hitting oneself with the fist or against an object
  
• cutting circulation to a digit
  
• picking at skin
  
• pulling out hair.
  

Despite increasing prevalence among adolescents, SIB remains a solitary behavior. Based on my clinical experience, teens may share ideas about SIB, but they generally don’t practice it in groups.

SIB psychodynamics

Adults and adolescents with SIB frequently have:

• difficulty regulating emotions
  
• unstable interpersonal relations
  
• limited coping strategies.¹
  

Shame is also common and can be a major barrier to diagnosing SIB. Adolescents who are ashamed of the behavior will go to great lengths to hide it from others, including clinicians. Despite the shame, many adolescents feel unable to stop engaging in SIB because it fulfills a powerful need.

Adults and adolescents who practice SIB most often report their behavior is motivated by affect regulation and tension release.⁴ Some adolescents engage in a different, manipulative form of SIB not to relieve tension but as a threat to prevent loss (Box).⁴

Behavioral reinforcement. An acute stressor—such as parental limits on behavior, feelings of rejection or abandonment by peers, or failing to achieve an unrealistic goal—triggers an escalating, intolerable affect. By experimentation or accident, an adolescent discovers that SIB provides rapid relief of the intolerable state—a calmness that may last for minutes, hours, or days. This relief reinforces the behavior, and the adolescent repeats SIB when faced with the next stressor.

Most individuals with SIB report a similar sequence of events. There is a trigger event, usually involving a real or perceived feeling of loss, rejection, or abandonment. The adolescent tries to resist the impulse to self-harm, feels escalating emotional distress, engages in SIB, and feels immediate relief.⁵

Inducing pain or bleeding as a means of relieving intolerable stress may be an attempt to:

• turn emotional pain into more manageable physical pain
  
• direct anger that cannot be expressed at others onto oneself
  
• punish oneself for perceived misdeeds.⁴
  

Box

CASE 2: Lingering effects of trauma

Melissa, age 13, has been sexually abused by her foster brother. She briefly returns to the home where her foster brother still resides. He has torn up her room, and her mother—who supports the foster brother—has left the room that way for her to find. Melissa returns to her current residence, cuts her arm 15 times, and pierces her tongue.

In therapy, she denies being angry or upset and does not know why she cut her arm or pierced her tongue.

Even an adolescent who experienced neglect or loss of attachment object without overt physical or sexual abuse might have trouble establishing a therapeutic alliance because of difficulty with trust.⁶ He or she may have little or no capacity to identify emotional states, which limits insight into the behavior.⁵

Dissociation. Some adolescents use SIB to try to feel something or to bring themselves back from a dissociative state. They report feeling lost, alone, and disconnected from others and themselves. Some report seeing blood as a way of reconnecting with being alive.

Dissociation may occur in adolescents with a history of trauma, particularly in childhood. Abused individuals who engage in SIB may be identifying with the aggressor, attempting to cut away internalized negative images of the abuser or to control anger they are unable to acknowledge.⁶

Clues prompt further assessment

SIB assessment begins with screening for the behavior. If you find any indicators that suggest SIB (Table 2), question the adolescent about self-injury. Many adolescents want help—and will respond accurately to questions about self-injury—but need to be asked. They usually won’t volunteer the information during an initial evaluation.

• number, location, and age of injuries
  
• depth of cuts (if applicable)
  
• signs of infection.
  

Suicide screening. By definition, SIB does not include an intention to die, and most teenagers with SIB will deny suicidal intent. However, because the line between SIB and passive suicide can be thin, careful screening and ongoing monitoring for suicidal ideation and behavior in teens with SIB is essential. In one study:

• 70% of adolescents who engaged in SIB had made one suicide attempt
  
• 55% had made multiple attempts.⁷
  

Address the parents’ concerns. During your assessment, also focus on the adolescent’s parents. They often are highly distressed, confused, and angry. They typically learn about the SIB from their child’s school counselors or peers and feel betrayed and guilty. They may want to be excessively intrusive and punitive and need support, information, and guidance to address their child’s safety.

Table 2

SIB: Spotting behavioral clues

Treatment recommendations

Always take SIB in adolescents seriously, and not as something they will “outgrow.” Adolescents with SIB need help modulating affect, stabilizing interpersonal relationships, and developing more adaptive coping strategies and problem-solving skills. Underlying dynamics—especially childhood trauma—must be explored and resolved.

Few evidence-based studies have evaluated SIB treatment in adolescents. Clinicians have extrapolated suggested interventions from the adult literature; however, much of this data was obtained from treating adult women with borderline personality disorder.

No medications are FDA-approved for treating SIB. Use pharmacologic interventions to treat underlying disorders, such as depression or anxiety, so that patients are better able to participate in other therapeutic interventions.

Dialectical behavioral therapy (DBT) is the only therapeutic entity shown in controlled trials to successfully treat SIB. Weekly individual psychotherapy and skills training groups focus on:

• regulating emotions
  
• tolerating distress
  
• improving interpersonal relationships
  
• reducing identity confusion and maladaptive cognitions.⁹
  

Prevention. Although SIB can be done with any object, most adolescents have a preferred method for causing self-injury and may have a “kit” of equipment. Identify and remove any tools the adolescent uses for self-injury. Because SIB is a highly ritualistic behavior, denying access to the preferred tools can help reduce self-injury frequency and convey that the behavior is unacceptable.

One individual should be designated to monitor the adolescent for SIB. Adolescents are seeking trust and do not respond well to constant questions about their behavior. Because some parents can become intrusive, monitoring may be best assigned to the adolescent’s therapist or a less emotional parent.

CASE 3: Scars provoke relapse

Claudia, a musically talented teen with SIB, withdraws from her choir when they choose costumes with short sleeves. She had not engaged in SIB in >1 year but has scarring and cheloid from the cuts. Years later she starts cutting again after laser treatments fail to remove the scars. She is frustrated because she will always have to wear long sleeves.

Treatment is essential, however, because this behavior can last for decades and leave scars that might interfere with future goals. The longer the adolescent has been dependent on the behavior, the more difficult it is to treat.

Related resources

• Levenkron S. Cutting: understanding and overcoming self-mutilation. New York: W.W. Norton & Company; 1998.
  
• Favazza AR. Bodies under siege: self-mutilation and body modification in culture and psychiatry. 2nd ed. Baltimore: The Johns Hopkins University Press; 1996.
  

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. K, age 25, is 6 weeks pregnant and is taking medications for generalized anxiety disorder (GAD). When she was diagnosed with GAD at age 19, her symptoms included 6 months of excessive anxiety—insomnia, fatigue, difficulty with concentration, and psychomotor agitation—without mood symptoms. These symptoms interfered greatly with her schoolwork and other daily activities.

For 6 years Ms. K has been taking the selective serotonin reuptake inhibitor (SSRI) paroxetine, 15 mg/d, and the benzodiazepine clonazepam, 0.5 mg as needed, with good symptom control. Now that she is pregnant and her primary care doctor has refused to continue these medications, she is seeking treatment and advice.

Not enough is known about how to safely treat anxiety disorders during pregnancy, and physicians are not sure what to do with patients such as Ms. K. Without evidence-based guidelines, we feel anxious about potential risks to mother and fetus as we try to provide appropriate drug therapy.

To help you and your patients weigh the risks and benefits of perinatal treatments for anxiety disorders, this article briefly summarizes the evidence on:

• anxiety disorders’ natural history during pregnancy
  
• how untreated maternal anxiety affects the fetus
  
• nonpharmacologic therapies for anxiety disorders
  
• a plan to manage fetal risks by staggering SSRI and benzodiazepine use during the first and third trimesters.
  

Anxiety during pregnancy

Nearly one-third of women experience an anxiety disorder during their lives, with peak onset during childbearing years.^1,2 Compared with research on perinatal depression, far fewer studies have examined anxiety disorders’ onset, presentation, prevalence, and treatment.¹

The literature includes no studies of the course of preexisting GAD or posttraumatic stress disorder (PTSD) and no evidence that symptoms of preexisting obsessive-compulsive disorder (OCD) change during pregnancy. Some studies of panic disorder show symptoms improving during pregnancy, whereas others do not (Table 1).¹

One small study done in late pregnancy found a significant association between the prevalence of an anxiety disorder, maternal primiparity, and comorbid medical conditions. Thus, a woman in her first pregnancy may be at increased risk to develop an anxiety disorder if she has a comorbid medical condition.³ As in the case of Ms. K, however, continuation of preexisting anxiety appears more likely than onset of a new anxiety disorder during pregnancy.

Table 1

How pregnancy affects the course of 4 anxiety disorders

Fetal risks from maternal anxiety

Fetal risk from severe maternal anxiety is not zero. Offspring born to high-anxiety mothers exhibit neurobehavioral differences compared with offspring of calmer mothers. Changes in high-anxiety mothers’ offspring include:

• altered EEG activation and vagal tone
  
• increased time in deep sleep and less time in active alert states
  
• lower performance on the Brazelton Neonatal Behavior Assessment Scale.⁴
  

Exposure to maternal high anxiety has been associated with mental developmental delays in infants and increased risk for behavioral and emotional problems in young children.^7-10 Anxiety may not directly cause intrauterine growth retardation and preterm delivery, but it is significantly associated with prenatal tobacco, alcohol, and narcotics use—which predicts these and other negative neonatal outcomes.¹¹

CASE CONTINUED: ‘Stay the course’

Ms. K worries that she could not tolerate recurrence of her anxiety symptoms and wishes to continue both medications. Her husband concurs, but they want to minimize potential risks to their baby. You discuss the options for treating anxiety symptoms during pregnancy, including medications, psychotherapy, and behavioral treatments.

Treatment decisions

Ideally you’ll begin treating anxiety disorders in women of childbearing age with preconception psychoeducation. Explaining the risks of medications if she were to become pregnant and asking about the contraception she is using are de rigueur. Psychotherapy is low risk to the fetus and is considered first choice for treating mild to moderate anxiety in women of childbearing age who plan to become pregnant (Box).^1,14-17

Box

Because Ms. K wishes to continue taking paroxetine and clonazepam, what can you tell her about the risks and benefits of SSRIs and benzodiazepines during pregnancy?

SSRIs in pregnancy

Teratogenicity. Compared with benzodiazepines, SSRIs have been considered agents of choice for use during pregnancy because of a lower risk of teratogenic effects.¹⁵ Paroxetine, however, appears to pose a greater risk for teratogenicity than other SSRIs.

The overall rate of fetal malformations from SSRIs appears to be low, although most studies have examined only fluoxetine or paroxetine. Some studies have reported various malformations with fluoxetine or sertraline, but others have not. In Finland, a population-based study found no increase in rate of major congenital malformations in offspring of 1,782 women who filled prescriptions for SSRIs during pregnancy, compared with the general population rate of 1% to 3%.²¹

Neurobehavioral effects. SSRI exposure during fetal life has shown no long-term neurobehavioral effects. A blinded prospective study by Nulman et al²² found no differences in global IQ scores, language development, or behavioral development among children age ≤5 who were exposed in utero to fluoxetine (n=40) or a tricyclic antidepressant (n=46), compared with unexposed children of nondepressed mothers (n=36). Similarly, using reports from teachers and clinical measures of internalizing behaviors, Misri et al¹⁰ found no increase in depression, anxiety, or withdrawal in 4-year-olds with prenatal exposure to SSRIs (n=22), compared with nonexposed children (n=14).

Pulmonary hypertension. SSRI exposure in later pregnancy may increase the rate of persistent pulmonary hypertension of the newborn (PPHN), which occurs in 1 to 2 infants per 1,000 live births. PPHN showed a statistically significant association with late prenatal SSRI exposure (OR 6.1) in a study that controlled for maternal smoking, body mass index, and diabetes.²³ PPHN occurred in approximately 1% of infants exposed to SSRIs in late pregnancy. PPHN rates were not affected by maternal depression/anxiety, non-SSRI antidepressant exposure throughout pregnancy, or SSRI exposure during early pregnancy only.

Toxicity and withdrawal syndromes. Infants of women who continue to take SSRIs just before delivery can develop toxicity or withdrawal syndromes. Occurrence of either syndrome depends on SSRI half-life, serum concentration, and the pharmacodynamics of other medications given during pregnancy and labor.²⁴

Discontinuation syndromes can occur in SSRI-exposed neonates within a few hours or days after birth and last up to 1 month after delivery, depending on the infant’s susceptibility.²⁵ Nearly two-thirds of suspected SSRI-induced neonatal withdrawal syndromes have been associated with paroxetine, although all SSRIs appear be associated with some risk.²⁶ Several trials, including a recent prospective study, found prenatal antidepressant use associated with lower gestational age at birth and increased risk of preterm birth.²⁷

• greater tremulousness
  
• less flexible and dampened state regulation
  
• more time in uninterrupted REM sleep
  
• more frequent startles or sudden arousals
  
• greater generalized motor activity
  
• greater autonomic dysregulation.²⁸
  

• tremor (37/60)
  
• GI disturbances (34/60)—including exaggerated sucking, poor feeding, regurgitation, vomiting, and loose stools
  
• sleep disturbance (21/60).
  

Recommendations. The perception that SSRIs have low fetal toxicity has guided prescribing practices in recent years. Newer evidence shows, however, that fetal exposure to SSRIs may have some adverse effects, including lower birth weight and early delivery. First-trimester paroxetine use has been associated with increased risk for fetal ventricular and/or atrial septal defects.

Discuss these risks with the patient when you consider starting or continuing SSRI use during pregnancy.²⁴ If you prescribe an SSRI, use the minimum effective dosage and avoid paroxetine during pregnancy.¹⁸

To reduce the risk for PPHN, early delivery, and neonatal withdrawal syndromes, taper and discontinue the SSRI during the third trimester. Restarting the SSRI soon after delivery is the most effective way to prevent recurrence of anxiety symptoms or postpartum depression.

Benzodiazepines

Teratogenicity. Like SSRIs, benzodiazepines cross the placenta to the fetus.²⁹ Benzodiazepine teratogenicity remains controversial.⁸ Some—but not all—data show a small but significant increased risk for major malformations/oral cleft malformations with first-trimester benzodiazepine exposure.

A Medline literature search from 1966 to 2000 found not enough information to determine whether potential benefits of benzodiazepines to the mother outweigh risks to the fetus.²⁹ An ambitious meta-analysis of >1,400 studies by Dolovich et al³⁰ found a small association between fetal exposure to benzodiazepines and major malformations/cleft palate, but only in pooled data from case-controlled studies. No association was found between fetal exposure to benzodiazepines and malformations/cleft palate in pooled data from cohort studies.

A 32-month, hospital-based surveillance program of 28,565 births found no increase in the rate of major malformations in 43 infants exposed to clonazepam monotherapy—33 (77%) in the first trimester.³¹ Thus, the risk of major malformations/cleft palate with the use of benzodiazepines in the first trimester appears to be low.

• Neonatal toxicity (“floppy infant syndrome”)—characterized by hypothermia, lethargy, poor respiratory effort, and feeding difficulties—occurs after maternal benzodiazepine use just before delivery.⁸
  
• Neonatal withdrawal may be caused by very late, third trimester exposure to benzodiazepines. Symptoms—which can persist ≤3 months after delivery—include restlessness, irritability, abnormal sleep patterns, suckling difficulties, growth retardation, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting.^8,29
  

To minimize neonatal withdrawal, gradually taper the mother’s benzodiazepine before delivery.²⁹ Because the baby’s due date is calculated to be ±2 weeks before delivery, begin this taper 3 to 4 weeks before the due date and discontinue at least 1 week before delivery. Breastfeeding while taking benzodiazepines is not recommended because of the risk of over-sedating the infant.

A rational approach

Both benzodiazepines and SSRIs are associated with low but demonstrated risks to the fetus when used during pregnancy (Table 2).^{19,20,23,25,30,33} Use these medications to manage a patient’s anxiety only if the clinical benefit to the mother justifies the potential risks to the fetus.²⁹

A staggered combination of SSRIs during the first 2 trimesters and benzodiazepines during the last 2 trimesters can help balance the risks and benefits of pharmacotherapy of anxiety disorders during pregnancy (Table 3).

Frankly discuss with your patient the risks and benefits in the context of her perceived need for symptom control to sustain her level of functioning. You could document this discussion in the progress note as “R, B, A, and pt C,” signifying that risks, benefits, and alternatives were discussed, and the patient consented. If possible, include the patient’s husband, partner, or parent in this discussion.

Table 2

Risks of SSRIs vs benzodiazepines during pregnancy stages

Staggered, combination therapy for anxiety disorders during pregnancy

CASE CONTINUED: CBT plus medication

Ms. K and her husband are open to adding weekly cognitive-behavioral therapy (CBT) for anxiety as long as she can continue her medications. You discuss the evidence regarding potential neonatal risks with paroxetine and clonazepam treatment. Because Ms. K is 6 weeks pregnant, you outline a plan for a rapid cross-taper off paroxetine and onto fluoxetine, 10 to 30 mg/d, explaining that paroxetine might pose a greater first-trimester risk of major congenital malformations and cardiac malformations. You discuss possible side effects of fluoxetine and explain a plan to taper off fluoxetine during the third trimester to reduce the risk of PPHN, early delivery, and withdrawal in the newborn.

Because Ms. K has been taking clonazepam at only 0.5 mg 1 to 2 times per week, you instruct her to stop taking the benzodiazepine for the next 6 weeks until she is through her first trimester. You also reassure her that she can use clonazepam after the first trimester, if necessary, as long as she agrees to taper off completely 1 to 2 weeks before to her due date.

You refer her to a CBT therapist and emphasize the importance of CBT, relaxation, and sleep hygiene—as well as support from her husband, family, and friends—to reduce her stress and facilitate the medication taper during her third trimester. You plan to see her monthly and co-manage her care with the CBT therapist and Ob/Gyn. You document this discussion in her medical record as evidence of informed consent.

Related resources

• Baby Center. Managing stress and anxiety during pregnancy. Patient information. www.babycenter.com/0_managing-stress-and-anxiety-during-pregnancy_1683.bc.
  
• Organization of Teratology Information Specialists (OTIS). www.otispregnancy.org.
  

Drug brand names

• Clonazepam • Klonopin
  
• Paroxetine • Paxil
  
• Fluoxetine • Prozac
  
• Sertraline • Zoloft
  

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. K, age 25, is 6 weeks pregnant and is taking medications for generalized anxiety disorder (GAD). When she was diagnosed with GAD at age 19, her symptoms included 6 months of excessive anxiety—insomnia, fatigue, difficulty with concentration, and psychomotor agitation—without mood symptoms. These symptoms interfered greatly with her schoolwork and other daily activities.

For 6 years Ms. K has been taking the selective serotonin reuptake inhibitor (SSRI) paroxetine, 15 mg/d, and the benzodiazepine clonazepam, 0.5 mg as needed, with good symptom control. Now that she is pregnant and her primary care doctor has refused to continue these medications, she is seeking treatment and advice.

Not enough is known about how to safely treat anxiety disorders during pregnancy, and physicians are not sure what to do with patients such as Ms. K. Without evidence-based guidelines, we feel anxious about potential risks to mother and fetus as we try to provide appropriate drug therapy.

To help you and your patients weigh the risks and benefits of perinatal treatments for anxiety disorders, this article briefly summarizes the evidence on:

• anxiety disorders’ natural history during pregnancy
  
• how untreated maternal anxiety affects the fetus
  
• nonpharmacologic therapies for anxiety disorders
  
• a plan to manage fetal risks by staggering SSRI and benzodiazepine use during the first and third trimesters.
  

Anxiety during pregnancy

Nearly one-third of women experience an anxiety disorder during their lives, with peak onset during childbearing years.^1,2 Compared with research on perinatal depression, far fewer studies have examined anxiety disorders’ onset, presentation, prevalence, and treatment.¹

The literature includes no studies of the course of preexisting GAD or posttraumatic stress disorder (PTSD) and no evidence that symptoms of preexisting obsessive-compulsive disorder (OCD) change during pregnancy. Some studies of panic disorder show symptoms improving during pregnancy, whereas others do not (Table 1).¹

One small study done in late pregnancy found a significant association between the prevalence of an anxiety disorder, maternal primiparity, and comorbid medical conditions. Thus, a woman in her first pregnancy may be at increased risk to develop an anxiety disorder if she has a comorbid medical condition.³ As in the case of Ms. K, however, continuation of preexisting anxiety appears more likely than onset of a new anxiety disorder during pregnancy.

Table 1

How pregnancy affects the course of 4 anxiety disorders

Fetal risks from maternal anxiety

Fetal risk from severe maternal anxiety is not zero. Offspring born to high-anxiety mothers exhibit neurobehavioral differences compared with offspring of calmer mothers. Changes in high-anxiety mothers’ offspring include:

• altered EEG activation and vagal tone
  
• increased time in deep sleep and less time in active alert states
  
• lower performance on the Brazelton Neonatal Behavior Assessment Scale.⁴
  

Exposure to maternal high anxiety has been associated with mental developmental delays in infants and increased risk for behavioral and emotional problems in young children.^7-10 Anxiety may not directly cause intrauterine growth retardation and preterm delivery, but it is significantly associated with prenatal tobacco, alcohol, and narcotics use—which predicts these and other negative neonatal outcomes.¹¹

CASE CONTINUED: ‘Stay the course’

Ms. K worries that she could not tolerate recurrence of her anxiety symptoms and wishes to continue both medications. Her husband concurs, but they want to minimize potential risks to their baby. You discuss the options for treating anxiety symptoms during pregnancy, including medications, psychotherapy, and behavioral treatments.

Treatment decisions

Ideally you’ll begin treating anxiety disorders in women of childbearing age with preconception psychoeducation. Explaining the risks of medications if she were to become pregnant and asking about the contraception she is using are de rigueur. Psychotherapy is low risk to the fetus and is considered first choice for treating mild to moderate anxiety in women of childbearing age who plan to become pregnant (Box).^1,14-17

Box

Because Ms. K wishes to continue taking paroxetine and clonazepam, what can you tell her about the risks and benefits of SSRIs and benzodiazepines during pregnancy?

SSRIs in pregnancy

Teratogenicity. Compared with benzodiazepines, SSRIs have been considered agents of choice for use during pregnancy because of a lower risk of teratogenic effects.¹⁵ Paroxetine, however, appears to pose a greater risk for teratogenicity than other SSRIs.

The overall rate of fetal malformations from SSRIs appears to be low, although most studies have examined only fluoxetine or paroxetine. Some studies have reported various malformations with fluoxetine or sertraline, but others have not. In Finland, a population-based study found no increase in rate of major congenital malformations in offspring of 1,782 women who filled prescriptions for SSRIs during pregnancy, compared with the general population rate of 1% to 3%.²¹

Neurobehavioral effects. SSRI exposure during fetal life has shown no long-term neurobehavioral effects. A blinded prospective study by Nulman et al²² found no differences in global IQ scores, language development, or behavioral development among children age ≤5 who were exposed in utero to fluoxetine (n=40) or a tricyclic antidepressant (n=46), compared with unexposed children of nondepressed mothers (n=36). Similarly, using reports from teachers and clinical measures of internalizing behaviors, Misri et al¹⁰ found no increase in depression, anxiety, or withdrawal in 4-year-olds with prenatal exposure to SSRIs (n=22), compared with nonexposed children (n=14).

Pulmonary hypertension. SSRI exposure in later pregnancy may increase the rate of persistent pulmonary hypertension of the newborn (PPHN), which occurs in 1 to 2 infants per 1,000 live births. PPHN showed a statistically significant association with late prenatal SSRI exposure (OR 6.1) in a study that controlled for maternal smoking, body mass index, and diabetes.²³ PPHN occurred in approximately 1% of infants exposed to SSRIs in late pregnancy. PPHN rates were not affected by maternal depression/anxiety, non-SSRI antidepressant exposure throughout pregnancy, or SSRI exposure during early pregnancy only.

Toxicity and withdrawal syndromes. Infants of women who continue to take SSRIs just before delivery can develop toxicity or withdrawal syndromes. Occurrence of either syndrome depends on SSRI half-life, serum concentration, and the pharmacodynamics of other medications given during pregnancy and labor.²⁴

Discontinuation syndromes can occur in SSRI-exposed neonates within a few hours or days after birth and last up to 1 month after delivery, depending on the infant’s susceptibility.²⁵ Nearly two-thirds of suspected SSRI-induced neonatal withdrawal syndromes have been associated with paroxetine, although all SSRIs appear be associated with some risk.²⁶ Several trials, including a recent prospective study, found prenatal antidepressant use associated with lower gestational age at birth and increased risk of preterm birth.²⁷

• greater tremulousness
  
• less flexible and dampened state regulation
  
• more time in uninterrupted REM sleep
  
• more frequent startles or sudden arousals
  
• greater generalized motor activity
  
• greater autonomic dysregulation.²⁸
  

• tremor (37/60)
  
• GI disturbances (34/60)—including exaggerated sucking, poor feeding, regurgitation, vomiting, and loose stools
  
• sleep disturbance (21/60).
  

Recommendations. The perception that SSRIs have low fetal toxicity has guided prescribing practices in recent years. Newer evidence shows, however, that fetal exposure to SSRIs may have some adverse effects, including lower birth weight and early delivery. First-trimester paroxetine use has been associated with increased risk for fetal ventricular and/or atrial septal defects.

Discuss these risks with the patient when you consider starting or continuing SSRI use during pregnancy.²⁴ If you prescribe an SSRI, use the minimum effective dosage and avoid paroxetine during pregnancy.¹⁸

To reduce the risk for PPHN, early delivery, and neonatal withdrawal syndromes, taper and discontinue the SSRI during the third trimester. Restarting the SSRI soon after delivery is the most effective way to prevent recurrence of anxiety symptoms or postpartum depression.

Benzodiazepines

Teratogenicity. Like SSRIs, benzodiazepines cross the placenta to the fetus.²⁹ Benzodiazepine teratogenicity remains controversial.⁸ Some—but not all—data show a small but significant increased risk for major malformations/oral cleft malformations with first-trimester benzodiazepine exposure.

A Medline literature search from 1966 to 2000 found not enough information to determine whether potential benefits of benzodiazepines to the mother outweigh risks to the fetus.²⁹ An ambitious meta-analysis of >1,400 studies by Dolovich et al³⁰ found a small association between fetal exposure to benzodiazepines and major malformations/cleft palate, but only in pooled data from case-controlled studies. No association was found between fetal exposure to benzodiazepines and malformations/cleft palate in pooled data from cohort studies.

A 32-month, hospital-based surveillance program of 28,565 births found no increase in the rate of major malformations in 43 infants exposed to clonazepam monotherapy—33 (77%) in the first trimester.³¹ Thus, the risk of major malformations/cleft palate with the use of benzodiazepines in the first trimester appears to be low.

• Neonatal toxicity (“floppy infant syndrome”)—characterized by hypothermia, lethargy, poor respiratory effort, and feeding difficulties—occurs after maternal benzodiazepine use just before delivery.⁸
  
• Neonatal withdrawal may be caused by very late, third trimester exposure to benzodiazepines. Symptoms—which can persist ≤3 months after delivery—include restlessness, irritability, abnormal sleep patterns, suckling difficulties, growth retardation, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting.^8,29
  

To minimize neonatal withdrawal, gradually taper the mother’s benzodiazepine before delivery.²⁹ Because the baby’s due date is calculated to be ±2 weeks before delivery, begin this taper 3 to 4 weeks before the due date and discontinue at least 1 week before delivery. Breastfeeding while taking benzodiazepines is not recommended because of the risk of over-sedating the infant.

A rational approach

Both benzodiazepines and SSRIs are associated with low but demonstrated risks to the fetus when used during pregnancy (Table 2).^{19,20,23,25,30,33} Use these medications to manage a patient’s anxiety only if the clinical benefit to the mother justifies the potential risks to the fetus.²⁹

A staggered combination of SSRIs during the first 2 trimesters and benzodiazepines during the last 2 trimesters can help balance the risks and benefits of pharmacotherapy of anxiety disorders during pregnancy (Table 3).

Frankly discuss with your patient the risks and benefits in the context of her perceived need for symptom control to sustain her level of functioning. You could document this discussion in the progress note as “R, B, A, and pt C,” signifying that risks, benefits, and alternatives were discussed, and the patient consented. If possible, include the patient’s husband, partner, or parent in this discussion.

Table 2

Risks of SSRIs vs benzodiazepines during pregnancy stages

Staggered, combination therapy for anxiety disorders during pregnancy