Andreea L. Seritan, MD

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

Agent	Protein binding	CYP-450 activity	Other features
AChEIs
Donepezil	96%	CYP 2D6, 3A4 substrate	Once-daily dosing
Rivastigmine	40%	None	Metabolized by cholinesterases
Galantamine	18%	CYP 2D6, 3A4 substrate	Nicotinic cholinergic receptor modulation
NMDA receptor antagonist
Memantine	45%	None	No hepatic metabolism
CYP-450: cytochrome P-450; AChEIs: acetylcholinesterase inhibitors; NMDA: N-methyl-D-aspartate
Source: References 3-5

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.

Distribution. With aging, lean body mass typically decreases and adipose tissue increases. Because most psychotropics are lipid-soluble, their volume of distribution increases with age. This leads to drug accumulation and longer half-lives. On the other hand, water-soluble medications such as lithium distribute in a smaller volume and pose a higher risk of toxicity.

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.

Excretion. The age-associated decline in renal clearance related to a diminished glomerular filtration rate leads to decreased excretion of active metabolites and lithium, making older patients more susceptible to lithium toxicity. The magnitude of the decline in renal clearance varies among patients and is exacerbated by concomitant conditions—such as diabetes and hypertension—and medications—such as nonsteroidal anti-inflammatory drugs (NSAIDs).⁴ Thiazide diuretics, angiotensin-converting enzyme inhibitors, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib may elevate lithium levels.³

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*

	CYP 2D6	CYP 3A4
Substrates (substances metabolized by enzyme)	Second-generation antipsychotics Citalopram Donepezil Duloxetine Galantamine Haloperidol Tricyclic antidepressants Trazodone Venlafaxine	Second-generation antipsychotics Benzodiazepines Buspirone Carbamazepine Donepezil Galantamine Haloperidol Lamotrigine Mirtazapine Nefazodone Sertraline Tricyclic antidepressants Trazodone Zolpidem
Inhibitors	Bupropion Cimetidine Duloxetine Fluoxetine Paroxetine Sertraline	Erythromycin Fluconazole Fluvoxamine Grapefruit juice Itraconazole Nefazodone
*All cytochrome P (CYP) 450 enzymes are induced by barbiturates, phenytoin, carbamazepine, and rifampicin. Smoking also induces CYP 1A2.
DDIs: drug-drug interactions; AD: Alzheimer’s disease
Source: References 3,5,7,8

Pharmacodynamics is the study of the time course and intensity of drugs’ pharmacologic effects. Pharmacodynamic interactions involve changes in a drug’s action at a receptor or biologically active site.³ Pharmacodynamic interactions may result from an antagonistic or synergistic mechanism (Table 3).^3,5,10 Dopamine neurons degenerate with aging, particularly after age 70, and the number of cholinergic receptors decreases in AD patients. As a result, these patients may become more sensitive to antipsychotics, selective serotonin reuptake inhibitors (SSRIs)—which indirectly reduce dopamine outflow—and medications with anticholinergic effects.⁴

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

Interaction	Mechanism	Potential sequela(e)
AChEIs + anticholinergics	↓ Acetylcholine in CNS	Cognitive worsening, delirium
AChEIs + beta blockers	Vagal stimulation and sympathetic blockade	Bradycardia, syncope
AChEIs + cholinergics	↑ Acetylcholine in PNS	Cholinergic crisis: hypersalivation, abdominal pain, diarrhea
AChEIs + antipsychotics (rare)	↑ Acetylcholine/↓ dopamine in striatum	Parkinsonian syndrome, rigidity
Ginkgo biloba + warfarin	Antiplatelet aggregation and anticoagulation	Gastrointestinal bleeding, hematuria, subcutaneous ecchymosis
AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system
Source: References 3,5,10

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

Anticholinergics can counteract AChEIs’ beneficial effect. Concurrent use of anticholinergics and AChEIs is fairly common in clinical practice but is rarely appropriate because of pharmacologic antagonism. In a retrospective study of 836 community-living older adults (age ≥65) with probable dementia, Roe et al¹³ compared anticholinergic use in 418 who were taking donepezil with 418 matched controls who were not taking donepezil. They found:

• 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.
  

Similarly, a study of pharmacy claims for AChEIs among 557 Medicaid beneficiaries aged ≥50 found that 35% of patients taking AChEIs also received at least 1 anticholinergic drug.¹⁴

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.
  

In patients taking these cardiovascular drugs, make sure that heart rate is >60 bpm before AChEI treatment, and monitor regularly.

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

Class	Examples
Antiarrhythmics	Disopyramide
Antiemetics	Meclizine
Antiparkinsonians	Benztropine, biperiden, trihexyphenidyl
Antipsychotics	Chlorpromazine, clozapine, olanzapine, pimozide, thioridazine
Antihistamines	Chlorpheniramine, cyproheptadine, diphenhydramine, hydroxyzine, Promethazine
Gastrointestinal/urinary antispasmodics	Atropine, belladonna alkaloids, dicyclomine, hyoscyamine, oxybutynin, scopolamine, tolterodine
H2 histamine	Cimetidine, ranitidine
Muscle relaxants	Cyclobenzaprine
Tricyclic antidepressants	Amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline
Source: References 5,13,14

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

Benzodiazepines are contraindicated in elderly patients (especially those with AD) because of the high risk of delirium, worsened cognitive function, paradoxical disinhibition, and falls.²⁰ If benzodiazepines are necessary to control anxiety, use intermediate-duration agents that do not undergo oxidative metabolism and have no active metabolites, such as lorazepam, oxazepam, or temazepam.¹⁹ See Table 2 for more information on benzodiazepine DDIs.

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.
  

Drug brand names

• 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
  

Disclosure

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

Agent	Protein binding	CYP-450 activity	Other features
AChEIs
Donepezil	96%	CYP 2D6, 3A4 substrate	Once-daily dosing
Rivastigmine	40%	None	Metabolized by cholinesterases
Galantamine	18%	CYP 2D6, 3A4 substrate	Nicotinic cholinergic receptor modulation
NMDA receptor antagonist
Memantine	45%	None	No hepatic metabolism
CYP-450: cytochrome P-450; AChEIs: acetylcholinesterase inhibitors; NMDA: N-methyl-D-aspartate
Source: References 3-5

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.

Distribution. With aging, lean body mass typically decreases and adipose tissue increases. Because most psychotropics are lipid-soluble, their volume of distribution increases with age. This leads to drug accumulation and longer half-lives. On the other hand, water-soluble medications such as lithium distribute in a smaller volume and pose a higher risk of toxicity.

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.

Excretion. The age-associated decline in renal clearance related to a diminished glomerular filtration rate leads to decreased excretion of active metabolites and lithium, making older patients more susceptible to lithium toxicity. The magnitude of the decline in renal clearance varies among patients and is exacerbated by concomitant conditions—such as diabetes and hypertension—and medications—such as nonsteroidal anti-inflammatory drugs (NSAIDs).⁴ Thiazide diuretics, angiotensin-converting enzyme inhibitors, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib may elevate lithium levels.³

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*

	CYP 2D6	CYP 3A4
Substrates (substances metabolized by enzyme)	Second-generation antipsychotics Citalopram Donepezil Duloxetine Galantamine Haloperidol Tricyclic antidepressants Trazodone Venlafaxine	Second-generation antipsychotics Benzodiazepines Buspirone Carbamazepine Donepezil Galantamine Haloperidol Lamotrigine Mirtazapine Nefazodone Sertraline Tricyclic antidepressants Trazodone Zolpidem
Inhibitors	Bupropion Cimetidine Duloxetine Fluoxetine Paroxetine Sertraline	Erythromycin Fluconazole Fluvoxamine Grapefruit juice Itraconazole Nefazodone
*All cytochrome P (CYP) 450 enzymes are induced by barbiturates, phenytoin, carbamazepine, and rifampicin. Smoking also induces CYP 1A2.
DDIs: drug-drug interactions; AD: Alzheimer’s disease
Source: References 3,5,7,8

Pharmacodynamics is the study of the time course and intensity of drugs’ pharmacologic effects. Pharmacodynamic interactions involve changes in a drug’s action at a receptor or biologically active site.³ Pharmacodynamic interactions may result from an antagonistic or synergistic mechanism (Table 3).^3,5,10 Dopamine neurons degenerate with aging, particularly after age 70, and the number of cholinergic receptors decreases in AD patients. As a result, these patients may become more sensitive to antipsychotics, selective serotonin reuptake inhibitors (SSRIs)—which indirectly reduce dopamine outflow—and medications with anticholinergic effects.⁴

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

Interaction	Mechanism	Potential sequela(e)
AChEIs + anticholinergics	↓ Acetylcholine in CNS	Cognitive worsening, delirium
AChEIs + beta blockers	Vagal stimulation and sympathetic blockade	Bradycardia, syncope
AChEIs + cholinergics	↑ Acetylcholine in PNS	Cholinergic crisis: hypersalivation, abdominal pain, diarrhea
AChEIs + antipsychotics (rare)	↑ Acetylcholine/↓ dopamine in striatum	Parkinsonian syndrome, rigidity
Ginkgo biloba + warfarin	Antiplatelet aggregation and anticoagulation	Gastrointestinal bleeding, hematuria, subcutaneous ecchymosis
AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system
Source: References 3,5,10

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

Anticholinergics can counteract AChEIs’ beneficial effect. Concurrent use of anticholinergics and AChEIs is fairly common in clinical practice but is rarely appropriate because of pharmacologic antagonism. In a retrospective study of 836 community-living older adults (age ≥65) with probable dementia, Roe et al¹³ compared anticholinergic use in 418 who were taking donepezil with 418 matched controls who were not taking donepezil. They found:

• 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.
  

Similarly, a study of pharmacy claims for AChEIs among 557 Medicaid beneficiaries aged ≥50 found that 35% of patients taking AChEIs also received at least 1 anticholinergic drug.¹⁴

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.
  

In patients taking these cardiovascular drugs, make sure that heart rate is >60 bpm before AChEI treatment, and monitor regularly.

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

Class	Examples
Antiarrhythmics	Disopyramide
Antiemetics	Meclizine
Antiparkinsonians	Benztropine, biperiden, trihexyphenidyl
Antipsychotics	Chlorpromazine, clozapine, olanzapine, pimozide, thioridazine
Antihistamines	Chlorpheniramine, cyproheptadine, diphenhydramine, hydroxyzine, Promethazine
Gastrointestinal/urinary antispasmodics	Atropine, belladonna alkaloids, dicyclomine, hyoscyamine, oxybutynin, scopolamine, tolterodine
H2 histamine	Cimetidine, ranitidine
Muscle relaxants	Cyclobenzaprine
Tricyclic antidepressants	Amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline
Source: References 5,13,14

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

Benzodiazepines are contraindicated in elderly patients (especially those with AD) because of the high risk of delirium, worsened cognitive function, paradoxical disinhibition, and falls.²⁰ If benzodiazepines are necessary to control anxiety, use intermediate-duration agents that do not undergo oxidative metabolism and have no active metabolites, such as lorazepam, oxazepam, or temazepam.¹⁹ See Table 2 for more information on benzodiazepine DDIs.

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.
  

Drug brand names

• 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
  

Disclosure

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

Agent	Protein binding	CYP-450 activity	Other features
AChEIs
Donepezil	96%	CYP 2D6, 3A4 substrate	Once-daily dosing
Rivastigmine	40%	None	Metabolized by cholinesterases
Galantamine	18%	CYP 2D6, 3A4 substrate	Nicotinic cholinergic receptor modulation
NMDA receptor antagonist
Memantine	45%	None	No hepatic metabolism
CYP-450: cytochrome P-450; AChEIs: acetylcholinesterase inhibitors; NMDA: N-methyl-D-aspartate
Source: References 3-5

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.

Distribution. With aging, lean body mass typically decreases and adipose tissue increases. Because most psychotropics are lipid-soluble, their volume of distribution increases with age. This leads to drug accumulation and longer half-lives. On the other hand, water-soluble medications such as lithium distribute in a smaller volume and pose a higher risk of toxicity.

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.

Excretion. The age-associated decline in renal clearance related to a diminished glomerular filtration rate leads to decreased excretion of active metabolites and lithium, making older patients more susceptible to lithium toxicity. The magnitude of the decline in renal clearance varies among patients and is exacerbated by concomitant conditions—such as diabetes and hypertension—and medications—such as nonsteroidal anti-inflammatory drugs (NSAIDs).⁴ Thiazide diuretics, angiotensin-converting enzyme inhibitors, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib may elevate lithium levels.³

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*

	CYP 2D6	CYP 3A4
Substrates (substances metabolized by enzyme)	Second-generation antipsychotics Citalopram Donepezil Duloxetine Galantamine Haloperidol Tricyclic antidepressants Trazodone Venlafaxine	Second-generation antipsychotics Benzodiazepines Buspirone Carbamazepine Donepezil Galantamine Haloperidol Lamotrigine Mirtazapine Nefazodone Sertraline Tricyclic antidepressants Trazodone Zolpidem
Inhibitors	Bupropion Cimetidine Duloxetine Fluoxetine Paroxetine Sertraline	Erythromycin Fluconazole Fluvoxamine Grapefruit juice Itraconazole Nefazodone
*All cytochrome P (CYP) 450 enzymes are induced by barbiturates, phenytoin, carbamazepine, and rifampicin. Smoking also induces CYP 1A2.
DDIs: drug-drug interactions; AD: Alzheimer’s disease
Source: References 3,5,7,8

Pharmacodynamics is the study of the time course and intensity of drugs’ pharmacologic effects. Pharmacodynamic interactions involve changes in a drug’s action at a receptor or biologically active site.³ Pharmacodynamic interactions may result from an antagonistic or synergistic mechanism (Table 3).^3,5,10 Dopamine neurons degenerate with aging, particularly after age 70, and the number of cholinergic receptors decreases in AD patients. As a result, these patients may become more sensitive to antipsychotics, selective serotonin reuptake inhibitors (SSRIs)—which indirectly reduce dopamine outflow—and medications with anticholinergic effects.⁴

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

Interaction	Mechanism	Potential sequela(e)
AChEIs + anticholinergics	↓ Acetylcholine in CNS	Cognitive worsening, delirium
AChEIs + beta blockers	Vagal stimulation and sympathetic blockade	Bradycardia, syncope
AChEIs + cholinergics	↑ Acetylcholine in PNS	Cholinergic crisis: hypersalivation, abdominal pain, diarrhea
AChEIs + antipsychotics (rare)	↑ Acetylcholine/↓ dopamine in striatum	Parkinsonian syndrome, rigidity
Ginkgo biloba + warfarin	Antiplatelet aggregation and anticoagulation	Gastrointestinal bleeding, hematuria, subcutaneous ecchymosis
AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system
Source: References 3,5,10

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

Anticholinergics can counteract AChEIs’ beneficial effect. Concurrent use of anticholinergics and AChEIs is fairly common in clinical practice but is rarely appropriate because of pharmacologic antagonism. In a retrospective study of 836 community-living older adults (age ≥65) with probable dementia, Roe et al¹³ compared anticholinergic use in 418 who were taking donepezil with 418 matched controls who were not taking donepezil. They found:

• 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.
  

Similarly, a study of pharmacy claims for AChEIs among 557 Medicaid beneficiaries aged ≥50 found that 35% of patients taking AChEIs also received at least 1 anticholinergic drug.¹⁴

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.
  

In patients taking these cardiovascular drugs, make sure that heart rate is >60 bpm before AChEI treatment, and monitor regularly.

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

Class	Examples
Antiarrhythmics	Disopyramide
Antiemetics	Meclizine
Antiparkinsonians	Benztropine, biperiden, trihexyphenidyl
Antipsychotics	Chlorpromazine, clozapine, olanzapine, pimozide, thioridazine
Antihistamines	Chlorpheniramine, cyproheptadine, diphenhydramine, hydroxyzine, Promethazine
Gastrointestinal/urinary antispasmodics	Atropine, belladonna alkaloids, dicyclomine, hyoscyamine, oxybutynin, scopolamine, tolterodine
H2 histamine	Cimetidine, ranitidine
Muscle relaxants	Cyclobenzaprine
Tricyclic antidepressants	Amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline
Source: References 5,13,14

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

Benzodiazepines are contraindicated in elderly patients (especially those with AD) because of the high risk of delirium, worsened cognitive function, paradoxical disinhibition, and falls.²⁰ If benzodiazepines are necessary to control anxiety, use intermediate-duration agents that do not undergo oxidative metabolism and have no active metabolites, such as lorazepam, oxazepam, or temazepam.¹⁹ See Table 2 for more information on benzodiazepine DDIs.

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.
  

Drug brand names

• 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
  

Disclosure

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

History: a lovelorn life

Ms. F, age 33, presents with one complaint: “I want to know how to maintain a relationship.” Problem is, social situations have made her feel anxious since childhood. She has trouble keeping a boyfriend; she left two intimate, extended relationships at different times.

She says she is too ashamed to invite people over because she cannot keep her apartment neat. She is also sick of her job as a filing clerk and wants a new career.

Ms. F reports no other anxiety symptoms or mood changes but often cannot concentrate. She denies impulsivity or poor judgment but admits that she makes decisions without getting important facts. For example, she enrolled at a community college without knowing what skills her new career would require. About 6 months ago, she left her boyfriend after realizing—18 months into the relationship—that he does not share her interests.

poll here

The authors’ observations

Information on all the above factors is crucial to diagnosing a socialization problem. Outline your differential diagnosis as the interview progresses.

Ask the patient:

How did you fare in school? A childhood history of pervasive inattention or impulsivity in at least two settings (at home and in school, for example) can signal attention-deficit/hyperactivity disorder (ADHD).^{fragile X syndrome). Boys with the fragile X premutation have a higher rate of ADHD symptoms and autism spectrum disorders than do boys without this premutation.3 Ms. F’s test showed two normal alleles, thus ruling out fragile X premutation.}

Table 1

Mental status examination signs that suggest a PDD

Little direct or sustained eye contact   Eyes flit around the room   Patient talks without looking at anyone
Few facial expressions   Flat affect
Impaired speech production   Although prosody (intonation) is normal, rate is rapid, with cluttered bursts followed by long pauses and occasional unusual emphasis on certain words
Tangential thought process   Patient changes topics quickly without transition   Non-sequitur responses
Brief responses to questions, offering little spontaneous information
Very detailed answers that include irrelevant information
Pedantic phrasing
Repetitive use of language
Does not pick up on nonquestions
Concrete answers to questions about emotion   Patient cannot describe how emotions “feel”
Appears uncomfortable during conversation with examiner   Rapport strained; patient does not seem to enjoy interaction
PDD: pervasive developmental disorder

Treatment: medication and exploration

Ms. F agrees to an ADOS test. Her total score of 9 (7 in social, 2 in communication, and 0 in stereotyped/repetitive behavior) suggest a moderate PDD. We rule out autism based on the test score and Asperger’s syndrome because of her early language development delays (Table 2).

We start escitalopram, 10 mg/d, to address Ms. F’s anxiety. We see her weekly for medication management and start weekly psychotherapy to explore her two previous relationships and her desire to find a partner.

Ms. F, however, reacts anxiously to the therapist’s exploratory techniques. She has difficulty taking the lead and becomes extremely uncomfortable with silences in the conversation. The therapist tries cognitive-behavioral tactics to engage her, but Ms. F does not respond.

The therapist then conceptualizes her role as “coach” and tries a more-direct, problem-solving approach. She addresses specific challenges, such as an overwhelming class assignment, but Ms. F does not discuss or follow through on the problem.

After 6 months, Ms. F asks to stop psychotherapy because she has made little progress. She also asks to reduce medication checks to monthly, saying that weekly sessions interfere with her schoolwork. She says she would consider resuming psychotherapy.

At this point, Ms. F’s anxiety is significantly improved based on clinical impression. She continues to do well 6 months after stopping psychotherapy, though she is still without a boyfriend.

poll hereTable 2

Autism or Asperger’s? Watch for these distinguishing features

Clinical feature	Autism	Asperger’s syndrome
Impaired nonverbal behavior	+	+
Language delay	+	–
Stereotyped behavior (routines, mannerisms)	+	+
Impaired social relationships	+	+
Cognitive delay	±	–
+: Present –: absent ±: Might be present

The authors’ observations

The ability to possess a theory of mind—or “mentalize”—helps us understand others’ beliefs, desires, thoughts, intentions, and knowledge. Attributing mental states to self and others helps explain and predict behavior, which is critical to social interaction.

A therapeutic relationship can help teach patients to handle social situations.⁴ In autism or PDD,^5,6 however, theory of mind deficits typically frustrate relationship building.⁴ Because ability to mentalize is critical to psychodynamic psychotherapy,⁷ exploration does not help patients with PDD. By contrast, therapists can be more successful by being active in sessions and giving directions, suggestions, and information.

Which psychotherapy models work? Limited data address psychotherapy for adults with PDD; most studies have followed children.

CBT for persons with autism or PDD is directive, problem-focused, and targets automatic reactions.⁸ Social skills groups and CBT focusing on day-to-day problem solving can help older children and adolescents.⁹ A 20-week social skills intervention employing a CBT approach, paired with psychoeducation for parents, has helped boys ages 8 to 12 with autism, PDD, or Asperger’s syndrome.¹⁰

 

Other interventions use pictures, cartoons, and other visuals to help patients identify and correct misperceptions and determine how different responses might affect people’s thoughts and feelings.^9,11 Role play allows the patient to practice social interaction but requires make-believe,¹¹ so getting a PDD patient to participate can be challenging.

Medication can help manage comorbid anxiety, obsessive-compulsive, and mood symptoms in PDD. Limited data support using selective serotonin reuptake inhibitors for this purpose.¹²

Related resources

• Ozonoff S, Dawson G, McPartland J. A parent’s guide to Asperger syndrome & high-functioning autism: how to meet the challenges and help your child thrive. New York: Guilford Press; 2002.
  
• MAAP Services. A global information and support network for more advanced persons with autism and Asperger syndrome. www.asperger.org.
  

Drug brand name

• Escitalopram • Lexapro
  

Disclosures

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

History: a lovelorn life

Ms. F, age 33, presents with one complaint: “I want to know how to maintain a relationship.” Problem is, social situations have made her feel anxious since childhood. She has trouble keeping a boyfriend; she left two intimate, extended relationships at different times.

She says she is too ashamed to invite people over because she cannot keep her apartment neat. She is also sick of her job as a filing clerk and wants a new career.

Ms. F reports no other anxiety symptoms or mood changes but often cannot concentrate. She denies impulsivity or poor judgment but admits that she makes decisions without getting important facts. For example, she enrolled at a community college without knowing what skills her new career would require. About 6 months ago, she left her boyfriend after realizing—18 months into the relationship—that he does not share her interests.

poll here

The authors’ observations

Information on all the above factors is crucial to diagnosing a socialization problem. Outline your differential diagnosis as the interview progresses.

Ask the patient:

How did you fare in school? A childhood history of pervasive inattention or impulsivity in at least two settings (at home and in school, for example) can signal attention-deficit/hyperactivity disorder (ADHD).^{fragile X syndrome). Boys with the fragile X premutation have a higher rate of ADHD symptoms and autism spectrum disorders than do boys without this premutation.3 Ms. F’s test showed two normal alleles, thus ruling out fragile X premutation.}

Table 1

Mental status examination signs that suggest a PDD

Little direct or sustained eye contact   Eyes flit around the room   Patient talks without looking at anyone
Few facial expressions   Flat affect
Impaired speech production   Although prosody (intonation) is normal, rate is rapid, with cluttered bursts followed by long pauses and occasional unusual emphasis on certain words
Tangential thought process   Patient changes topics quickly without transition   Non-sequitur responses
Brief responses to questions, offering little spontaneous information
Very detailed answers that include irrelevant information
Pedantic phrasing
Repetitive use of language
Does not pick up on nonquestions
Concrete answers to questions about emotion   Patient cannot describe how emotions “feel”
Appears uncomfortable during conversation with examiner   Rapport strained; patient does not seem to enjoy interaction
PDD: pervasive developmental disorder

Treatment: medication and exploration

Ms. F agrees to an ADOS test. Her total score of 9 (7 in social, 2 in communication, and 0 in stereotyped/repetitive behavior) suggest a moderate PDD. We rule out autism based on the test score and Asperger’s syndrome because of her early language development delays (Table 2).

We start escitalopram, 10 mg/d, to address Ms. F’s anxiety. We see her weekly for medication management and start weekly psychotherapy to explore her two previous relationships and her desire to find a partner.

Ms. F, however, reacts anxiously to the therapist’s exploratory techniques. She has difficulty taking the lead and becomes extremely uncomfortable with silences in the conversation. The therapist tries cognitive-behavioral tactics to engage her, but Ms. F does not respond.

The therapist then conceptualizes her role as “coach” and tries a more-direct, problem-solving approach. She addresses specific challenges, such as an overwhelming class assignment, but Ms. F does not discuss or follow through on the problem.

After 6 months, Ms. F asks to stop psychotherapy because she has made little progress. She also asks to reduce medication checks to monthly, saying that weekly sessions interfere with her schoolwork. She says she would consider resuming psychotherapy.

At this point, Ms. F’s anxiety is significantly improved based on clinical impression. She continues to do well 6 months after stopping psychotherapy, though she is still without a boyfriend.

poll hereTable 2

Autism or Asperger’s? Watch for these distinguishing features

Clinical feature	Autism	Asperger’s syndrome
Impaired nonverbal behavior	+	+
Language delay	+	–
Stereotyped behavior (routines, mannerisms)	+	+
Impaired social relationships	+	+
Cognitive delay	±	–
+: Present –: absent ±: Might be present

The authors’ observations

The ability to possess a theory of mind—or “mentalize”—helps us understand others’ beliefs, desires, thoughts, intentions, and knowledge. Attributing mental states to self and others helps explain and predict behavior, which is critical to social interaction.

A therapeutic relationship can help teach patients to handle social situations.⁴ In autism or PDD,^5,6 however, theory of mind deficits typically frustrate relationship building.⁴ Because ability to mentalize is critical to psychodynamic psychotherapy,⁷ exploration does not help patients with PDD. By contrast, therapists can be more successful by being active in sessions and giving directions, suggestions, and information.

Which psychotherapy models work? Limited data address psychotherapy for adults with PDD; most studies have followed children.

CBT for persons with autism or PDD is directive, problem-focused, and targets automatic reactions.⁸ Social skills groups and CBT focusing on day-to-day problem solving can help older children and adolescents.⁹ A 20-week social skills intervention employing a CBT approach, paired with psychoeducation for parents, has helped boys ages 8 to 12 with autism, PDD, or Asperger’s syndrome.¹⁰

 

Other interventions use pictures, cartoons, and other visuals to help patients identify and correct misperceptions and determine how different responses might affect people’s thoughts and feelings.^9,11 Role play allows the patient to practice social interaction but requires make-believe,¹¹ so getting a PDD patient to participate can be challenging.

Medication can help manage comorbid anxiety, obsessive-compulsive, and mood symptoms in PDD. Limited data support using selective serotonin reuptake inhibitors for this purpose.¹²

Related resources

• Ozonoff S, Dawson G, McPartland J. A parent’s guide to Asperger syndrome & high-functioning autism: how to meet the challenges and help your child thrive. New York: Guilford Press; 2002.
  
• MAAP Services. A global information and support network for more advanced persons with autism and Asperger syndrome. www.asperger.org.
  

Drug brand name

• Escitalopram • Lexapro
  

Disclosures

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

History: a lovelorn life

Ms. F, age 33, presents with one complaint: “I want to know how to maintain a relationship.” Problem is, social situations have made her feel anxious since childhood. She has trouble keeping a boyfriend; she left two intimate, extended relationships at different times.

She says she is too ashamed to invite people over because she cannot keep her apartment neat. She is also sick of her job as a filing clerk and wants a new career.

Ms. F reports no other anxiety symptoms or mood changes but often cannot concentrate. She denies impulsivity or poor judgment but admits that she makes decisions without getting important facts. For example, she enrolled at a community college without knowing what skills her new career would require. About 6 months ago, she left her boyfriend after realizing—18 months into the relationship—that he does not share her interests.

poll here

The authors’ observations

Information on all the above factors is crucial to diagnosing a socialization problem. Outline your differential diagnosis as the interview progresses.

Ask the patient:

How did you fare in school? A childhood history of pervasive inattention or impulsivity in at least two settings (at home and in school, for example) can signal attention-deficit/hyperactivity disorder (ADHD).^{fragile X syndrome). Boys with the fragile X premutation have a higher rate of ADHD symptoms and autism spectrum disorders than do boys without this premutation.3 Ms. F’s test showed two normal alleles, thus ruling out fragile X premutation.}

Table 1

Mental status examination signs that suggest a PDD

Little direct or sustained eye contact   Eyes flit around the room   Patient talks without looking at anyone
Few facial expressions   Flat affect
Impaired speech production   Although prosody (intonation) is normal, rate is rapid, with cluttered bursts followed by long pauses and occasional unusual emphasis on certain words
Tangential thought process   Patient changes topics quickly without transition   Non-sequitur responses
Brief responses to questions, offering little spontaneous information
Very detailed answers that include irrelevant information
Pedantic phrasing
Repetitive use of language
Does not pick up on nonquestions
Concrete answers to questions about emotion   Patient cannot describe how emotions “feel”
Appears uncomfortable during conversation with examiner   Rapport strained; patient does not seem to enjoy interaction
PDD: pervasive developmental disorder

Treatment: medication and exploration

Ms. F agrees to an ADOS test. Her total score of 9 (7 in social, 2 in communication, and 0 in stereotyped/repetitive behavior) suggest a moderate PDD. We rule out autism based on the test score and Asperger’s syndrome because of her early language development delays (Table 2).

We start escitalopram, 10 mg/d, to address Ms. F’s anxiety. We see her weekly for medication management and start weekly psychotherapy to explore her two previous relationships and her desire to find a partner.

Ms. F, however, reacts anxiously to the therapist’s exploratory techniques. She has difficulty taking the lead and becomes extremely uncomfortable with silences in the conversation. The therapist tries cognitive-behavioral tactics to engage her, but Ms. F does not respond.

The therapist then conceptualizes her role as “coach” and tries a more-direct, problem-solving approach. She addresses specific challenges, such as an overwhelming class assignment, but Ms. F does not discuss or follow through on the problem.

After 6 months, Ms. F asks to stop psychotherapy because she has made little progress. She also asks to reduce medication checks to monthly, saying that weekly sessions interfere with her schoolwork. She says she would consider resuming psychotherapy.

At this point, Ms. F’s anxiety is significantly improved based on clinical impression. She continues to do well 6 months after stopping psychotherapy, though she is still without a boyfriend.

poll hereTable 2

Autism or Asperger’s? Watch for these distinguishing features

Clinical feature	Autism	Asperger’s syndrome
Impaired nonverbal behavior	+	+
Language delay	+	–
Stereotyped behavior (routines, mannerisms)	+	+
Impaired social relationships	+	+
Cognitive delay	±	–
+: Present –: absent ±: Might be present

The authors’ observations

The ability to possess a theory of mind—or “mentalize”—helps us understand others’ beliefs, desires, thoughts, intentions, and knowledge. Attributing mental states to self and others helps explain and predict behavior, which is critical to social interaction.

A therapeutic relationship can help teach patients to handle social situations.⁴ In autism or PDD,^5,6 however, theory of mind deficits typically frustrate relationship building.⁴ Because ability to mentalize is critical to psychodynamic psychotherapy,⁷ exploration does not help patients with PDD. By contrast, therapists can be more successful by being active in sessions and giving directions, suggestions, and information.

Which psychotherapy models work? Limited data address psychotherapy for adults with PDD; most studies have followed children.

CBT for persons with autism or PDD is directive, problem-focused, and targets automatic reactions.⁸ Social skills groups and CBT focusing on day-to-day problem solving can help older children and adolescents.⁹ A 20-week social skills intervention employing a CBT approach, paired with psychoeducation for parents, has helped boys ages 8 to 12 with autism, PDD, or Asperger’s syndrome.¹⁰

 

Other interventions use pictures, cartoons, and other visuals to help patients identify and correct misperceptions and determine how different responses might affect people’s thoughts and feelings.^9,11 Role play allows the patient to practice social interaction but requires make-believe,¹¹ so getting a PDD patient to participate can be challenging.

Medication can help manage comorbid anxiety, obsessive-compulsive, and mood symptoms in PDD. Limited data support using selective serotonin reuptake inhibitors for this purpose.¹²

Related resources

• Ozonoff S, Dawson G, McPartland J. A parent’s guide to Asperger syndrome & high-functioning autism: how to meet the challenges and help your child thrive. New York: Guilford Press; 2002.
  
• MAAP Services. A global information and support network for more advanced persons with autism and Asperger syndrome. www.asperger.org.
  

Drug brand name

• Escitalopram • Lexapro
  

Disclosures

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

Many medical conditions common among new mothers can cause depressed mood, fatigue, and other symptoms that suggest postpartum depression. To help you quickly pinpoint the source of a new mother’s depressive symptoms and plan treatment, this article reviews:

• new-onset or pre-existing neurologic, cardiovascular, thyroid, and other conditions that mimic postpartum depression
  
• risk factors and clinical features that distinguish postpartum depression from other psychiatric disorders
  
• laboratory tests that confirm or rule out medical problems.
  

Case: ‘I can’t sleep’

Mrs. A, age 40, sleeps 2 hours nightly at most. Awakened by her 3-month-old daughter’s overnight crying, she lies awake and ruminates over the day’s events. Throughout the day, she fears she cannot care for her baby and 2-year-old son, and she depends on a family member to stay home with her. Financial concerns force her back to work 3 months after giving birth, but she is so despondent that she can barely function.

Mrs. A’s primary care physician diagnoses primary insomnia and prescribes mirtazapine and zolpidem, 15 and 10 mg each night, respectively, but her sleep disturbance persists after 6 weeks. The physician adds the hypnotic temazepam, 15 mg at night, and the sedating anticonvulsant gabapentin, 300 mg at bedtime. Both are titrated over 6 months to 45 mg and 1,800 mg at bedtime, respectively, but Mrs. A continues to lose sleep.

After 6 months, the doctor stops mirtazapine because Mrs. A has gained 20 lb. A switch to sertraline, 25 mg/d, has no effect.

Eighteen months after symptom onset, Mrs. A still sleeps poorly, even though her daughter—now age 2—sleeps through the night. Her depressed mood—undiagnosed by the physician—continues to worsen. She sees a psychiatrist after routine blood tests and a sleep study reveal no medical cause for her insomnia.

Is it postpartum depression?

Mrs. A’s despondent mood, sleep disturbances, feelings of inadequacy as a parent, and impaired concentration suggest postpartum depression. Ego-dystonic obsessive thoughts of harming the infant might emerge, although nonpsychotic patients rarely act upon them.¹

Finding risk factors for postpartum depression can clarify the diagnosis. Ask the patient:

• When did you first notice symptoms? DSMIV-TR says postpartum depression usually begins within 4 weeks of giving birth,² but most researchers define the postpartum period as ≤6 months after delivery.^1,3 Mrs. A’s depression and insomnia started 3 months after childbirth.
  
• Have you been depressed before? Women with past postpartum or other depressive episodes face a high risk of recurrence after subsequent pregnancies.^1,3 Active eating disorder during pregnancy⁴ and past premenstrual dysphoric disorder also are risk factors.^1,3
  
• Has anyone in your family had depression? This increases postpartum depression risk.⁵
  
• Who is helping you? Psychosocial stress and lack of social support can fuel postpartum depression.^1,3 Mrs. A gets practical help from family members, but life’s pressures are taking their toll.
  

Is it another mental illness?

Screen women with postpartum depressive symptoms for anxiety, which is highly comorbid with depression.⁶

Include bipolar disorder in the differential diagnosis. Ask new mothers with depressive symptoms if they feel inexplicably happy, irritable, or unusually energetic at times. Also screen for postpartum psychosis, which can progress to bipolar disorder⁷ and—worse—greatly increase the risk of infanticide.

The Edinburgh Postnatal Depression Scale,⁸ a 10-item self-report screening tool that takes about 5 minutes to complete, can help identify postpartum depression (see Related resources).

Case continued: A postpartum headache

During our initial interview, Mrs. A denies thoughts of harming herself or her children, and psychotic symptoms are not apparent. She reports no past depressive or anxiety episodes and does not use alcohol or illicit drugs. Her sister has a history of depression (not postpartum).

During review of systems, Mrs. A complains of persistent headaches. Brain MRI reveals a 4.5×5 mm microadenoma in the pituitary gland. We refer her to an endocrinologist, who obtains prolactin readings of 92 and 122.4 ng/mL (normal range, 2.8 to 29.2 ng/mL).

Discussion. Mrs. A had few predictive factors for postpartum depression, an atypical presentation with insomnia as the main symptom, and incomplete response after 18 months of treatment. These findings—plus her elevated prolactin and brain MRI results—suggest a medical cause.

Is it a medical problem?

Pre-existing or new-onset postpartum medical conditions can confound the diagnosis.

• Fatigue can mimic depression’s neurovegetative signs (poor energy, decreased appetite, sleep). Common causes include sleep deprivation, thyroid disorders, anemia, cardiomyopathy, and infections (Table 1).⁹
  
• Weight change could signal a medical condition whose symptoms resemble postpartum depression—such as diabetes or human immunodeficiency virus (HIV) (Table 2).
  
• Other disorders—including neurologic diseases, prolactinomas, systemic lupus erythematosus, diabetes, and rheumatoid arthritis—can cause depressive and other psychiatric symptoms (Table 3).
  

 

Recognizing the following disorders’ physical signs is key to uncovering a medical cause for postpartum depressive symptoms.

Thyroid disease. Postpartum thyroiditis (PPT) can occur 1 to 3 months after delivery,¹⁰ often recurs after subsequent pregnancies,¹¹ and can progress to permanent hypothyroidism within 5 years.¹⁰ Hypothyroidism can cause cognitive slowing, depression, and psychosis, and acute mania has been reported with severe hypothyroidism secondary to PPT.¹²

Find out if the patient tested positive early in gestation for thyroid antibodies, as this may predict postpartum depression.

Multiple sclerosis (MS) can cause anxiety, mania, depression, and cognitive impairment.¹³ Drugs used to treat MS—such as steroids or interferon—can induce depression.

Relapses are infrequent during pregnancy but increase significantly within 3 months after giving birth¹⁴ in about one-third of women with active MS before pregnancy.¹⁵ Gait ataxia, sensory loss, numbness, hyperactive reflexes or spasticity, bladder dysfunction, visual impairment, disordered ocular motility, and fatigue are prominent clinical signs of MS.¹⁶

Myasthenia gravis (MG). Women who become pregnant within 1 year after diagnosis run a high risk of MG exacerbation.¹⁷

Fatigue and muscular weakness caused by MG can mimic depression, and adjusting to this debilitating illness can cause depression. Double vision, droopy eyelids, and muscle weakness alleviated by rest but worsened by activity are pathognomonic signs.¹⁶

Other neurologic diseases. Pre-existing seizure disorders can worsen after giving birth and cause depression.¹⁴

Subtle presentations of brain tumors include cognitive deficits, mood disturbance, and personality change. A left frontal lobe tumor can cause depression.

Ask the patient if she has had headaches, visual symptoms, vomiting, seizures, or focal neurologic deficits—any of these could signal a primary brain tumor or intracranial hemorrhage.

Prolactinomas, the most common pituitary tumor in pregnant and postpartum women, enlarge during pregnancy and regress after delivery.¹⁴ Depression, anxiety, apathy, and personality changes may stem from the pituitary tumor, its treatment, or changes in the hypothalamic-pituitary-end organ axis.¹⁸ Typical amenorrhea-galactorrhea syndrome resembles postpartum physiologic changes.

Headaches are common, and compression of the optic chiasm with macrodenomas causes visual field changes.

Systemic lupus erythematosus (SLE), most prevalent in young women, might flare during pregnancy and within 6 weeks after giving birth.¹¹ Headaches, seizures, or cerebrovascular events with comorbid mood disorders, delirium, dementia, psychosis, or anxiety can signal SLE.¹³

Suspect SLE if the patient presents with fatigue, “butterfly” face rash, or joint pain. Test for renal or cardiopulmonary involvement.

Rheumatoid arthritis (RA). Because inflammatory activity is heightened after childbirth, postpartum women—particularly after bearing a first child—face a five-fold risk of RA compared with other women.¹¹ Breast-feeding might worsen RA, presumably by increasing prolactin production.

Physical limitations caused by RA can cause depression. Symmetric joint pain associated with morning stiffness—especially in the fingers, hands, or knees—might signal RA.

Anemia. Increased need for iron and folic acid during pregnancy can lead to anemia. Neuropsychiatric manifestations of folate deficiency range from mild irritability to severe depression, dementia, psychosis, and confusion.¹⁹ Vitamin B12 deficiency can lead to megaloblastic anemia or neurologic problems such as peripheral neuropathy, as well as depression, delirium, or dementia.¹⁹

Ask the patient about:

• alcohol dependence, malnourishment, chronic illness, inflammatory bowel disease, gastric bypass or other gastric surgery, which can impair vitamin B12 absorption
  
• use of anticonvulsants such as carbamazepine or valproic acid, which can decrease folate.
  

Hypotension mimics anergia. Postpartum hypotension can cause partial or total necrosis of the anterior pituitary gland. This leads to panhypopituitarism (Sheehan’s syndrome)—a rare complication characterized by failure to lactate, amenorrhea, hypothyroidism, and adrenal insufficiency.

When not in hypotensive circulatory shock, patients with adrenal insufficiency might present with depression, delirium, or psychosis.¹³ Ask the patient if she is having lactation problems and irregular periods, which could signal a pituitary problem.

Peripartum cardiomyopathy—an acute dilated cardiomyopathy— appears ≤6 months after delivery and may cause fatigue.^10,20 Check for shortness of breath at night and with exertion, palpitations, and extremity swelling.

Gestational diabetes. Pregnancy-induced insulin resistance leads to gestational diabetes mellitus. Women with gestational diabetes can develop type 2 diabetes after giving birth.¹⁰

Blood sugar fluctuations can cause depression, irritability, or memory problems. Depression can sabotage adherence to diet and treatment, leading to poor glycemic control.

Ask the patient if she was diagnosed with gestational diabetes and if she is experiencing fatigue, excessive thirst, frequent urination, blurred vision, headaches, excessive hunger, or unexplainable weight loss.

Primary biliary cirrhosis is most prevalent in women ages 35 to 60 and may cause depression.²⁰ Pruritus, fatigue, jaundice, and liver abnormalities point to this autoimmune disease, and postpartum exacerbations have been reported.²¹

HIV infection often leads to cognitive loss and depression with suicidal thoughts.¹³ Highly active antiretroviral medications commonly cause agitation, pain, mood changes, and insomnia.

 

Ask the patient is she is HIV positive. Watch for weight loss, fever, anorexia, and recurrent infections.

Substance abuse. Intoxication, withdrawal, or long-term alcohol or drug use can contribute to depression. Women at high risk for substance abuse disorder might not adhere to psychiatric treatment and may be prone to sexually transmitted diseases. If possible, see the patient every 3 to 4 weeks during the postpartum period.

Pain—if not adequately controlled—can fuel depression. Ask the patient if she has chronic pain or suffered a severe injury.

Table 1

Possible tests if postpartum patient is constantly fatigued

Laboratory test	Confirms or rules out	Order if patient also presents with:
Acetylcholine receptor antibodies	Myasthenia gravis	Double vision, droopy eyelids, muscle weakness
Alkaline phosphatase	Primary biliary cirrhosis	Jaundice, pruritus
Antimitochondrial antibody	Primary biliary cirrhosis	Jaundice, pruritus
Antinuclear antibody	Systemic lupus erythematosus	‘Butterfly’ facial rash, joint pain, morning stiffness
CBC	Microcytic anemia, megaloblastic anemia	Pallor, low energy, peripheral neuropathy, shortness of breath
Electrolytes	Adrenal insufficiency, renal disease	Low blood pressure, seizures, skin pigmentation
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, headaches, frequent urination, unexplainable weight loss
HIV	HIV infection/AIDS	Anorexia, recurrent infections, weight loss
Liver function tests	Alcohol abuse, hepatitis, primary biliary cirrhosis	Asterixis (flapping tremor), easy bruising, jaundice, pruritus, spider telangiectasias
Lumbar puncture	Multiple sclerosis	Bladder dysfunction, gait ataxia, ocular signs, sensory loss, spasticity

Table 2

Possible tests if postpartum patient has lost or gained weight

Laboratory test	Confirms or rules out	Order if patient also presents with:
Antithyroid antibody	Postpartum thyroiditis	Constipation, dry skin, hair loss, lethargy, memory loss
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, fatigue, frequent urination, headaches
HIV	HIV infection/AIDS	Anorexia, fatigue, recurrent infections
TSH±thyroid panel	Hypothyroidism	Constipation, dry skin, hair loss, lethargy
TSH±thyroid panel	Hyperthyroidism	Agitation, anxiety, heat intolerance, palpitations

Table 3

Possible tests if postpartum patient has other physical symptoms

Laboratory test	Confirms or rules out	Order if patient presents with:
Blood urea nitrogen/creatinine	Renal disease, dehydration	Back pain, frequent urination or oliguria, low blood pressure
Brain MRI	Brain tumors, white matter disease	Focal deficits, headaches, seizures, vision problems, vomiting
C-reactive protein	Rheumatoid arthritis	Joint pain, morning stiffness
ECG	Cardiomyopathy	Extremity swelling, palpitations, shortness of breath at night and with exertion
Erythrocyte sedimentation rate	Rheumatoid arthritis, SLE	‘Butterfly’ facial rash, joint pain
Folate	Folate deficiency	Ataxia, loss of vibration and position sense, peripheral neuropathy, weakness
Prolactin	Prolactinoma, hypopituitarism	Amenorrhea/galactorrhea, headache, visual field loss
Rapid plasma reagin	Syphilis	Ataxic wide-based gait, loss of position, deep pain and temperature sensation, palmar/plantar rash
Rheumatoid factor	Rheumatoid arthritis	Morning stiffness, symmetric joint pain
Urinalysis	Urinary infection, diabetes, renal disease	Burning or difficulty with voiding, dark-colored urine, frequent urination
Urine drug screen	Substance abuse disorder	Erratic behavior, irritability or aggression; violence, mental status changes
Vitamin B12	Anemia, malnutrition, inflammatory bowel disease	Loss of position or vibratory sensation, mood and cognitive changes, tingling and numbness in hands and feet
SLE: Systemic lupus erythematosus

Determining a medical cause

Laboratory and neuroimaging findings—obtained in concert with the patient’s primary care physician—will help confirm or rule out a medical problem (Table 4). Consult with a neurologist, endocrinologist or rheumatologist if indicated.

Table 4

Findings that signal a possible postpartum medical problem

Laboratory finding	Could signal …
Low hemoglobin, hematocrit and mean cell volume (MCV) values	Microcytic anemia
MCV >100 mm3	Megaloblastic anemia
Positive anticardiolipin or antinuclear antibody	Systemic lupus erythematosus
Blood urea nitrogen >20 mg/dL, creatinine >1.5 mg/dL	Acute or chronic renal failure
Low specific gravity on urinalysis	Diabetes insipidus or renal tubular abnormalities
Proteinuria with glycosuria	Diabetes mellitus
Proteinuria with protein or cellular casts	Systemic lupus erythematosus
Hyponatremia and hyperkalemia	Adrenocortical insufficiency
Hypo/hypernatremia	Seizures
Albumin	Malnutrition
SGOT/SGPT >35 u/L (each)	Alcohol abuse disorder, hepatitis, hepatic encephalopathy
Alkaline phosphatase >120 u/L, positive antimitochondrial antibody	Primary biliary cirrhosis
Erythrocyte sedimentation rate >20 mm/hr	Systemic lupus erythematosus, rheumatoid arthritis
Positive rheumatoid factor	Rheumatoid arthritis
Prolactin >24 ng/mL	Prolactinoma
TSH >5 µu/mL	Hypothyroidism
TSH	Hyperthyroidism
IgG >1.4 mg/dL, oligoclonal bands, myelin basic protein in CSF	Multiple sclerosis
White matter hyperintensities in brain MRI	Multiple sclerosis, CNS vasculitis, tumors
Source: Reference 5

Case: will the tumor resolve?

Mrs. A’s endocrinologist prescribes bromocriptine to manage her hyperprolactinemia, but she refuses to start the dopamine agonist after the doctor explains that it might cause psychosis.

Working closely, the psychiatrist and endocrinologist postpone bromocriptine therapy to see if the prolactinoma will resolve without treatment. They order brain MRIs every 6 months to track the tumor.

Mrs. A starts weekly psychodynamic therapy, during which she explores her fear of failure as a mother. Within 2 months, she recognizes that she has set unrealistically high expectations for herself. Adopting a supportive approach, the therapist encourages her to go on dates with her husband and run errands or relax alone for 2 hours each weekend.

The psychiatrist discusses sleep hygiene and adds quetiapine, 25 mg at bedtime; reduces gabapentin over 3 months to 300 mg nightly; and titrates sertraline to 100 mg/d. The psychiatrist also weans Mrs. A off temazepam over 3 months, watching closely for withdrawal symptoms.

At the psychiatrist’s suggestion, Mrs. A. resumes exercising at a gym four to five times a week. Mrs. A reduces zolpidem use—taking it only as needed for insomnia—then tapers off gabapentin. Quetiapine is discontinued.

 

After 4 months, psychotherapy sessions are decreased to biweekly. Prolactin is 66.6 ng/mL at 3 months, then normalizes to 23.4 ng/mL at 6 months. Six months later, brain MRI shows no change in baseline tumor size. The endocrinologist continues semiannual brain MRI and prolactin testing to see if the tumor will shrink without surgery.

Nearly 1 year after presentation, Mrs. A’s depression is in remission.

Related resources

• Edinburgh Postnatal Depression Scale. http://www.drgrelling.com/Downloads.htm (click on “Edinburgh Postnatal Depression Scale” under “Resources for professionals”).
  
• Postpartum Support International. www.postpartum.net.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol, others
  
• Gabapentin • Neurontin
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Temazepam • Restoril
  
• Valproic acid • Depakene
  
• Zolpidem • Ambien
  

Disclosures

Dr. Seritan reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Many medical conditions common among new mothers can cause depressed mood, fatigue, and other symptoms that suggest postpartum depression. To help you quickly pinpoint the source of a new mother’s depressive symptoms and plan treatment, this article reviews:

• new-onset or pre-existing neurologic, cardiovascular, thyroid, and other conditions that mimic postpartum depression
  
• risk factors and clinical features that distinguish postpartum depression from other psychiatric disorders
  
• laboratory tests that confirm or rule out medical problems.
  

Case: ‘I can’t sleep’

Mrs. A, age 40, sleeps 2 hours nightly at most. Awakened by her 3-month-old daughter’s overnight crying, she lies awake and ruminates over the day’s events. Throughout the day, she fears she cannot care for her baby and 2-year-old son, and she depends on a family member to stay home with her. Financial concerns force her back to work 3 months after giving birth, but she is so despondent that she can barely function.

Mrs. A’s primary care physician diagnoses primary insomnia and prescribes mirtazapine and zolpidem, 15 and 10 mg each night, respectively, but her sleep disturbance persists after 6 weeks. The physician adds the hypnotic temazepam, 15 mg at night, and the sedating anticonvulsant gabapentin, 300 mg at bedtime. Both are titrated over 6 months to 45 mg and 1,800 mg at bedtime, respectively, but Mrs. A continues to lose sleep.

After 6 months, the doctor stops mirtazapine because Mrs. A has gained 20 lb. A switch to sertraline, 25 mg/d, has no effect.

Eighteen months after symptom onset, Mrs. A still sleeps poorly, even though her daughter—now age 2—sleeps through the night. Her depressed mood—undiagnosed by the physician—continues to worsen. She sees a psychiatrist after routine blood tests and a sleep study reveal no medical cause for her insomnia.

Is it postpartum depression?

Mrs. A’s despondent mood, sleep disturbances, feelings of inadequacy as a parent, and impaired concentration suggest postpartum depression. Ego-dystonic obsessive thoughts of harming the infant might emerge, although nonpsychotic patients rarely act upon them.¹

Finding risk factors for postpartum depression can clarify the diagnosis. Ask the patient:

• When did you first notice symptoms? DSMIV-TR says postpartum depression usually begins within 4 weeks of giving birth,² but most researchers define the postpartum period as ≤6 months after delivery.^1,3 Mrs. A’s depression and insomnia started 3 months after childbirth.
  
• Have you been depressed before? Women with past postpartum or other depressive episodes face a high risk of recurrence after subsequent pregnancies.^1,3 Active eating disorder during pregnancy⁴ and past premenstrual dysphoric disorder also are risk factors.^1,3
  
• Has anyone in your family had depression? This increases postpartum depression risk.⁵
  
• Who is helping you? Psychosocial stress and lack of social support can fuel postpartum depression.^1,3 Mrs. A gets practical help from family members, but life’s pressures are taking their toll.
  

Is it another mental illness?

Screen women with postpartum depressive symptoms for anxiety, which is highly comorbid with depression.⁶

Include bipolar disorder in the differential diagnosis. Ask new mothers with depressive symptoms if they feel inexplicably happy, irritable, or unusually energetic at times. Also screen for postpartum psychosis, which can progress to bipolar disorder⁷ and—worse—greatly increase the risk of infanticide.

The Edinburgh Postnatal Depression Scale,⁸ a 10-item self-report screening tool that takes about 5 minutes to complete, can help identify postpartum depression (see Related resources).

Case continued: A postpartum headache

During our initial interview, Mrs. A denies thoughts of harming herself or her children, and psychotic symptoms are not apparent. She reports no past depressive or anxiety episodes and does not use alcohol or illicit drugs. Her sister has a history of depression (not postpartum).

During review of systems, Mrs. A complains of persistent headaches. Brain MRI reveals a 4.5×5 mm microadenoma in the pituitary gland. We refer her to an endocrinologist, who obtains prolactin readings of 92 and 122.4 ng/mL (normal range, 2.8 to 29.2 ng/mL).

Discussion. Mrs. A had few predictive factors for postpartum depression, an atypical presentation with insomnia as the main symptom, and incomplete response after 18 months of treatment. These findings—plus her elevated prolactin and brain MRI results—suggest a medical cause.

Is it a medical problem?

Pre-existing or new-onset postpartum medical conditions can confound the diagnosis.

• Fatigue can mimic depression’s neurovegetative signs (poor energy, decreased appetite, sleep). Common causes include sleep deprivation, thyroid disorders, anemia, cardiomyopathy, and infections (Table 1).⁹
  
• Weight change could signal a medical condition whose symptoms resemble postpartum depression—such as diabetes or human immunodeficiency virus (HIV) (Table 2).
  
• Other disorders—including neurologic diseases, prolactinomas, systemic lupus erythematosus, diabetes, and rheumatoid arthritis—can cause depressive and other psychiatric symptoms (Table 3).
  

 

Recognizing the following disorders’ physical signs is key to uncovering a medical cause for postpartum depressive symptoms.

Thyroid disease. Postpartum thyroiditis (PPT) can occur 1 to 3 months after delivery,¹⁰ often recurs after subsequent pregnancies,¹¹ and can progress to permanent hypothyroidism within 5 years.¹⁰ Hypothyroidism can cause cognitive slowing, depression, and psychosis, and acute mania has been reported with severe hypothyroidism secondary to PPT.¹²

Find out if the patient tested positive early in gestation for thyroid antibodies, as this may predict postpartum depression.

Multiple sclerosis (MS) can cause anxiety, mania, depression, and cognitive impairment.¹³ Drugs used to treat MS—such as steroids or interferon—can induce depression.

Relapses are infrequent during pregnancy but increase significantly within 3 months after giving birth¹⁴ in about one-third of women with active MS before pregnancy.¹⁵ Gait ataxia, sensory loss, numbness, hyperactive reflexes or spasticity, bladder dysfunction, visual impairment, disordered ocular motility, and fatigue are prominent clinical signs of MS.¹⁶

Myasthenia gravis (MG). Women who become pregnant within 1 year after diagnosis run a high risk of MG exacerbation.¹⁷

Fatigue and muscular weakness caused by MG can mimic depression, and adjusting to this debilitating illness can cause depression. Double vision, droopy eyelids, and muscle weakness alleviated by rest but worsened by activity are pathognomonic signs.¹⁶

Other neurologic diseases. Pre-existing seizure disorders can worsen after giving birth and cause depression.¹⁴

Subtle presentations of brain tumors include cognitive deficits, mood disturbance, and personality change. A left frontal lobe tumor can cause depression.

Ask the patient if she has had headaches, visual symptoms, vomiting, seizures, or focal neurologic deficits—any of these could signal a primary brain tumor or intracranial hemorrhage.

Prolactinomas, the most common pituitary tumor in pregnant and postpartum women, enlarge during pregnancy and regress after delivery.¹⁴ Depression, anxiety, apathy, and personality changes may stem from the pituitary tumor, its treatment, or changes in the hypothalamic-pituitary-end organ axis.¹⁸ Typical amenorrhea-galactorrhea syndrome resembles postpartum physiologic changes.

Headaches are common, and compression of the optic chiasm with macrodenomas causes visual field changes.

Systemic lupus erythematosus (SLE), most prevalent in young women, might flare during pregnancy and within 6 weeks after giving birth.¹¹ Headaches, seizures, or cerebrovascular events with comorbid mood disorders, delirium, dementia, psychosis, or anxiety can signal SLE.¹³

Suspect SLE if the patient presents with fatigue, “butterfly” face rash, or joint pain. Test for renal or cardiopulmonary involvement.

Rheumatoid arthritis (RA). Because inflammatory activity is heightened after childbirth, postpartum women—particularly after bearing a first child—face a five-fold risk of RA compared with other women.¹¹ Breast-feeding might worsen RA, presumably by increasing prolactin production.

Physical limitations caused by RA can cause depression. Symmetric joint pain associated with morning stiffness—especially in the fingers, hands, or knees—might signal RA.

Anemia. Increased need for iron and folic acid during pregnancy can lead to anemia. Neuropsychiatric manifestations of folate deficiency range from mild irritability to severe depression, dementia, psychosis, and confusion.¹⁹ Vitamin B12 deficiency can lead to megaloblastic anemia or neurologic problems such as peripheral neuropathy, as well as depression, delirium, or dementia.¹⁹

Ask the patient about:

• alcohol dependence, malnourishment, chronic illness, inflammatory bowel disease, gastric bypass or other gastric surgery, which can impair vitamin B12 absorption
  
• use of anticonvulsants such as carbamazepine or valproic acid, which can decrease folate.
  

Hypotension mimics anergia. Postpartum hypotension can cause partial or total necrosis of the anterior pituitary gland. This leads to panhypopituitarism (Sheehan’s syndrome)—a rare complication characterized by failure to lactate, amenorrhea, hypothyroidism, and adrenal insufficiency.

When not in hypotensive circulatory shock, patients with adrenal insufficiency might present with depression, delirium, or psychosis.¹³ Ask the patient if she is having lactation problems and irregular periods, which could signal a pituitary problem.

Peripartum cardiomyopathy—an acute dilated cardiomyopathy— appears ≤6 months after delivery and may cause fatigue.^10,20 Check for shortness of breath at night and with exertion, palpitations, and extremity swelling.

Gestational diabetes. Pregnancy-induced insulin resistance leads to gestational diabetes mellitus. Women with gestational diabetes can develop type 2 diabetes after giving birth.¹⁰

Blood sugar fluctuations can cause depression, irritability, or memory problems. Depression can sabotage adherence to diet and treatment, leading to poor glycemic control.

Ask the patient if she was diagnosed with gestational diabetes and if she is experiencing fatigue, excessive thirst, frequent urination, blurred vision, headaches, excessive hunger, or unexplainable weight loss.

Primary biliary cirrhosis is most prevalent in women ages 35 to 60 and may cause depression.²⁰ Pruritus, fatigue, jaundice, and liver abnormalities point to this autoimmune disease, and postpartum exacerbations have been reported.²¹

HIV infection often leads to cognitive loss and depression with suicidal thoughts.¹³ Highly active antiretroviral medications commonly cause agitation, pain, mood changes, and insomnia.

 

Ask the patient is she is HIV positive. Watch for weight loss, fever, anorexia, and recurrent infections.

Substance abuse. Intoxication, withdrawal, or long-term alcohol or drug use can contribute to depression. Women at high risk for substance abuse disorder might not adhere to psychiatric treatment and may be prone to sexually transmitted diseases. If possible, see the patient every 3 to 4 weeks during the postpartum period.

Pain—if not adequately controlled—can fuel depression. Ask the patient if she has chronic pain or suffered a severe injury.

Table 1

Possible tests if postpartum patient is constantly fatigued

Laboratory test	Confirms or rules out	Order if patient also presents with:
Acetylcholine receptor antibodies	Myasthenia gravis	Double vision, droopy eyelids, muscle weakness
Alkaline phosphatase	Primary biliary cirrhosis	Jaundice, pruritus
Antimitochondrial antibody	Primary biliary cirrhosis	Jaundice, pruritus
Antinuclear antibody	Systemic lupus erythematosus	‘Butterfly’ facial rash, joint pain, morning stiffness
CBC	Microcytic anemia, megaloblastic anemia	Pallor, low energy, peripheral neuropathy, shortness of breath
Electrolytes	Adrenal insufficiency, renal disease	Low blood pressure, seizures, skin pigmentation
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, headaches, frequent urination, unexplainable weight loss
HIV	HIV infection/AIDS	Anorexia, recurrent infections, weight loss
Liver function tests	Alcohol abuse, hepatitis, primary biliary cirrhosis	Asterixis (flapping tremor), easy bruising, jaundice, pruritus, spider telangiectasias
Lumbar puncture	Multiple sclerosis	Bladder dysfunction, gait ataxia, ocular signs, sensory loss, spasticity

Table 2

Possible tests if postpartum patient has lost or gained weight

Laboratory test	Confirms or rules out	Order if patient also presents with:
Antithyroid antibody	Postpartum thyroiditis	Constipation, dry skin, hair loss, lethargy, memory loss
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, fatigue, frequent urination, headaches
HIV	HIV infection/AIDS	Anorexia, fatigue, recurrent infections
TSH±thyroid panel	Hypothyroidism	Constipation, dry skin, hair loss, lethargy
TSH±thyroid panel	Hyperthyroidism	Agitation, anxiety, heat intolerance, palpitations

Table 3

Possible tests if postpartum patient has other physical symptoms

Laboratory test	Confirms or rules out	Order if patient presents with:
Blood urea nitrogen/creatinine	Renal disease, dehydration	Back pain, frequent urination or oliguria, low blood pressure
Brain MRI	Brain tumors, white matter disease	Focal deficits, headaches, seizures, vision problems, vomiting
C-reactive protein	Rheumatoid arthritis	Joint pain, morning stiffness
ECG	Cardiomyopathy	Extremity swelling, palpitations, shortness of breath at night and with exertion
Erythrocyte sedimentation rate	Rheumatoid arthritis, SLE	‘Butterfly’ facial rash, joint pain
Folate	Folate deficiency	Ataxia, loss of vibration and position sense, peripheral neuropathy, weakness
Prolactin	Prolactinoma, hypopituitarism	Amenorrhea/galactorrhea, headache, visual field loss
Rapid plasma reagin	Syphilis	Ataxic wide-based gait, loss of position, deep pain and temperature sensation, palmar/plantar rash
Rheumatoid factor	Rheumatoid arthritis	Morning stiffness, symmetric joint pain
Urinalysis	Urinary infection, diabetes, renal disease	Burning or difficulty with voiding, dark-colored urine, frequent urination
Urine drug screen	Substance abuse disorder	Erratic behavior, irritability or aggression; violence, mental status changes
Vitamin B12	Anemia, malnutrition, inflammatory bowel disease	Loss of position or vibratory sensation, mood and cognitive changes, tingling and numbness in hands and feet
SLE: Systemic lupus erythematosus

Determining a medical cause

Laboratory and neuroimaging findings—obtained in concert with the patient’s primary care physician—will help confirm or rule out a medical problem (Table 4). Consult with a neurologist, endocrinologist or rheumatologist if indicated.

Table 4

Findings that signal a possible postpartum medical problem

Laboratory finding	Could signal …
Low hemoglobin, hematocrit and mean cell volume (MCV) values	Microcytic anemia
MCV >100 mm3	Megaloblastic anemia
Positive anticardiolipin or antinuclear antibody	Systemic lupus erythematosus
Blood urea nitrogen >20 mg/dL, creatinine >1.5 mg/dL	Acute or chronic renal failure
Low specific gravity on urinalysis	Diabetes insipidus or renal tubular abnormalities
Proteinuria with glycosuria	Diabetes mellitus
Proteinuria with protein or cellular casts	Systemic lupus erythematosus
Hyponatremia and hyperkalemia	Adrenocortical insufficiency
Hypo/hypernatremia	Seizures
Albumin	Malnutrition
SGOT/SGPT >35 u/L (each)	Alcohol abuse disorder, hepatitis, hepatic encephalopathy
Alkaline phosphatase >120 u/L, positive antimitochondrial antibody	Primary biliary cirrhosis
Erythrocyte sedimentation rate >20 mm/hr	Systemic lupus erythematosus, rheumatoid arthritis
Positive rheumatoid factor	Rheumatoid arthritis
Prolactin >24 ng/mL	Prolactinoma
TSH >5 µu/mL	Hypothyroidism
TSH	Hyperthyroidism
IgG >1.4 mg/dL, oligoclonal bands, myelin basic protein in CSF	Multiple sclerosis
White matter hyperintensities in brain MRI	Multiple sclerosis, CNS vasculitis, tumors
Source: Reference 5

Case: will the tumor resolve?

Mrs. A’s endocrinologist prescribes bromocriptine to manage her hyperprolactinemia, but she refuses to start the dopamine agonist after the doctor explains that it might cause psychosis.

Working closely, the psychiatrist and endocrinologist postpone bromocriptine therapy to see if the prolactinoma will resolve without treatment. They order brain MRIs every 6 months to track the tumor.

Mrs. A starts weekly psychodynamic therapy, during which she explores her fear of failure as a mother. Within 2 months, she recognizes that she has set unrealistically high expectations for herself. Adopting a supportive approach, the therapist encourages her to go on dates with her husband and run errands or relax alone for 2 hours each weekend.

The psychiatrist discusses sleep hygiene and adds quetiapine, 25 mg at bedtime; reduces gabapentin over 3 months to 300 mg nightly; and titrates sertraline to 100 mg/d. The psychiatrist also weans Mrs. A off temazepam over 3 months, watching closely for withdrawal symptoms.

At the psychiatrist’s suggestion, Mrs. A. resumes exercising at a gym four to five times a week. Mrs. A reduces zolpidem use—taking it only as needed for insomnia—then tapers off gabapentin. Quetiapine is discontinued.

 

After 4 months, psychotherapy sessions are decreased to biweekly. Prolactin is 66.6 ng/mL at 3 months, then normalizes to 23.4 ng/mL at 6 months. Six months later, brain MRI shows no change in baseline tumor size. The endocrinologist continues semiannual brain MRI and prolactin testing to see if the tumor will shrink without surgery.

Nearly 1 year after presentation, Mrs. A’s depression is in remission.

Related resources

• Edinburgh Postnatal Depression Scale. http://www.drgrelling.com/Downloads.htm (click on “Edinburgh Postnatal Depression Scale” under “Resources for professionals”).
  
• Postpartum Support International. www.postpartum.net.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol, others
  
• Gabapentin • Neurontin
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Temazepam • Restoril
  
• Valproic acid • Depakene
  
• Zolpidem • Ambien
  

Disclosures

Dr. Seritan reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Many medical conditions common among new mothers can cause depressed mood, fatigue, and other symptoms that suggest postpartum depression. To help you quickly pinpoint the source of a new mother’s depressive symptoms and plan treatment, this article reviews:

• new-onset or pre-existing neurologic, cardiovascular, thyroid, and other conditions that mimic postpartum depression
  
• risk factors and clinical features that distinguish postpartum depression from other psychiatric disorders
  
• laboratory tests that confirm or rule out medical problems.
  

Case: ‘I can’t sleep’

Mrs. A, age 40, sleeps 2 hours nightly at most. Awakened by her 3-month-old daughter’s overnight crying, she lies awake and ruminates over the day’s events. Throughout the day, she fears she cannot care for her baby and 2-year-old son, and she depends on a family member to stay home with her. Financial concerns force her back to work 3 months after giving birth, but she is so despondent that she can barely function.

Mrs. A’s primary care physician diagnoses primary insomnia and prescribes mirtazapine and zolpidem, 15 and 10 mg each night, respectively, but her sleep disturbance persists after 6 weeks. The physician adds the hypnotic temazepam, 15 mg at night, and the sedating anticonvulsant gabapentin, 300 mg at bedtime. Both are titrated over 6 months to 45 mg and 1,800 mg at bedtime, respectively, but Mrs. A continues to lose sleep.

After 6 months, the doctor stops mirtazapine because Mrs. A has gained 20 lb. A switch to sertraline, 25 mg/d, has no effect.

Eighteen months after symptom onset, Mrs. A still sleeps poorly, even though her daughter—now age 2—sleeps through the night. Her depressed mood—undiagnosed by the physician—continues to worsen. She sees a psychiatrist after routine blood tests and a sleep study reveal no medical cause for her insomnia.

Is it postpartum depression?

Mrs. A’s despondent mood, sleep disturbances, feelings of inadequacy as a parent, and impaired concentration suggest postpartum depression. Ego-dystonic obsessive thoughts of harming the infant might emerge, although nonpsychotic patients rarely act upon them.¹

Finding risk factors for postpartum depression can clarify the diagnosis. Ask the patient:

• When did you first notice symptoms? DSMIV-TR says postpartum depression usually begins within 4 weeks of giving birth,² but most researchers define the postpartum period as ≤6 months after delivery.^1,3 Mrs. A’s depression and insomnia started 3 months after childbirth.
  
• Have you been depressed before? Women with past postpartum or other depressive episodes face a high risk of recurrence after subsequent pregnancies.^1,3 Active eating disorder during pregnancy⁴ and past premenstrual dysphoric disorder also are risk factors.^1,3
  
• Has anyone in your family had depression? This increases postpartum depression risk.⁵
  
• Who is helping you? Psychosocial stress and lack of social support can fuel postpartum depression.^1,3 Mrs. A gets practical help from family members, but life’s pressures are taking their toll.
  

Is it another mental illness?

Screen women with postpartum depressive symptoms for anxiety, which is highly comorbid with depression.⁶

Include bipolar disorder in the differential diagnosis. Ask new mothers with depressive symptoms if they feel inexplicably happy, irritable, or unusually energetic at times. Also screen for postpartum psychosis, which can progress to bipolar disorder⁷ and—worse—greatly increase the risk of infanticide.

The Edinburgh Postnatal Depression Scale,⁸ a 10-item self-report screening tool that takes about 5 minutes to complete, can help identify postpartum depression (see Related resources).

Case continued: A postpartum headache

During our initial interview, Mrs. A denies thoughts of harming herself or her children, and psychotic symptoms are not apparent. She reports no past depressive or anxiety episodes and does not use alcohol or illicit drugs. Her sister has a history of depression (not postpartum).

During review of systems, Mrs. A complains of persistent headaches. Brain MRI reveals a 4.5×5 mm microadenoma in the pituitary gland. We refer her to an endocrinologist, who obtains prolactin readings of 92 and 122.4 ng/mL (normal range, 2.8 to 29.2 ng/mL).

Discussion. Mrs. A had few predictive factors for postpartum depression, an atypical presentation with insomnia as the main symptom, and incomplete response after 18 months of treatment. These findings—plus her elevated prolactin and brain MRI results—suggest a medical cause.

Is it a medical problem?

Pre-existing or new-onset postpartum medical conditions can confound the diagnosis.

• Fatigue can mimic depression’s neurovegetative signs (poor energy, decreased appetite, sleep). Common causes include sleep deprivation, thyroid disorders, anemia, cardiomyopathy, and infections (Table 1).⁹
  
• Weight change could signal a medical condition whose symptoms resemble postpartum depression—such as diabetes or human immunodeficiency virus (HIV) (Table 2).
  
• Other disorders—including neurologic diseases, prolactinomas, systemic lupus erythematosus, diabetes, and rheumatoid arthritis—can cause depressive and other psychiatric symptoms (Table 3).
  

 

Recognizing the following disorders’ physical signs is key to uncovering a medical cause for postpartum depressive symptoms.

Thyroid disease. Postpartum thyroiditis (PPT) can occur 1 to 3 months after delivery,¹⁰ often recurs after subsequent pregnancies,¹¹ and can progress to permanent hypothyroidism within 5 years.¹⁰ Hypothyroidism can cause cognitive slowing, depression, and psychosis, and acute mania has been reported with severe hypothyroidism secondary to PPT.¹²

Find out if the patient tested positive early in gestation for thyroid antibodies, as this may predict postpartum depression.

Multiple sclerosis (MS) can cause anxiety, mania, depression, and cognitive impairment.¹³ Drugs used to treat MS—such as steroids or interferon—can induce depression.

Relapses are infrequent during pregnancy but increase significantly within 3 months after giving birth¹⁴ in about one-third of women with active MS before pregnancy.¹⁵ Gait ataxia, sensory loss, numbness, hyperactive reflexes or spasticity, bladder dysfunction, visual impairment, disordered ocular motility, and fatigue are prominent clinical signs of MS.¹⁶

Myasthenia gravis (MG). Women who become pregnant within 1 year after diagnosis run a high risk of MG exacerbation.¹⁷

Fatigue and muscular weakness caused by MG can mimic depression, and adjusting to this debilitating illness can cause depression. Double vision, droopy eyelids, and muscle weakness alleviated by rest but worsened by activity are pathognomonic signs.¹⁶

Other neurologic diseases. Pre-existing seizure disorders can worsen after giving birth and cause depression.¹⁴

Subtle presentations of brain tumors include cognitive deficits, mood disturbance, and personality change. A left frontal lobe tumor can cause depression.

Ask the patient if she has had headaches, visual symptoms, vomiting, seizures, or focal neurologic deficits—any of these could signal a primary brain tumor or intracranial hemorrhage.

Prolactinomas, the most common pituitary tumor in pregnant and postpartum women, enlarge during pregnancy and regress after delivery.¹⁴ Depression, anxiety, apathy, and personality changes may stem from the pituitary tumor, its treatment, or changes in the hypothalamic-pituitary-end organ axis.¹⁸ Typical amenorrhea-galactorrhea syndrome resembles postpartum physiologic changes.

Headaches are common, and compression of the optic chiasm with macrodenomas causes visual field changes.

Systemic lupus erythematosus (SLE), most prevalent in young women, might flare during pregnancy and within 6 weeks after giving birth.¹¹ Headaches, seizures, or cerebrovascular events with comorbid mood disorders, delirium, dementia, psychosis, or anxiety can signal SLE.¹³

Suspect SLE if the patient presents with fatigue, “butterfly” face rash, or joint pain. Test for renal or cardiopulmonary involvement.

Rheumatoid arthritis (RA). Because inflammatory activity is heightened after childbirth, postpartum women—particularly after bearing a first child—face a five-fold risk of RA compared with other women.¹¹ Breast-feeding might worsen RA, presumably by increasing prolactin production.

Physical limitations caused by RA can cause depression. Symmetric joint pain associated with morning stiffness—especially in the fingers, hands, or knees—might signal RA.

Anemia. Increased need for iron and folic acid during pregnancy can lead to anemia. Neuropsychiatric manifestations of folate deficiency range from mild irritability to severe depression, dementia, psychosis, and confusion.¹⁹ Vitamin B12 deficiency can lead to megaloblastic anemia or neurologic problems such as peripheral neuropathy, as well as depression, delirium, or dementia.¹⁹

Ask the patient about:

• alcohol dependence, malnourishment, chronic illness, inflammatory bowel disease, gastric bypass or other gastric surgery, which can impair vitamin B12 absorption
  
• use of anticonvulsants such as carbamazepine or valproic acid, which can decrease folate.
  

Hypotension mimics anergia. Postpartum hypotension can cause partial or total necrosis of the anterior pituitary gland. This leads to panhypopituitarism (Sheehan’s syndrome)—a rare complication characterized by failure to lactate, amenorrhea, hypothyroidism, and adrenal insufficiency.

When not in hypotensive circulatory shock, patients with adrenal insufficiency might present with depression, delirium, or psychosis.¹³ Ask the patient if she is having lactation problems and irregular periods, which could signal a pituitary problem.

Peripartum cardiomyopathy—an acute dilated cardiomyopathy— appears ≤6 months after delivery and may cause fatigue.^10,20 Check for shortness of breath at night and with exertion, palpitations, and extremity swelling.

Gestational diabetes. Pregnancy-induced insulin resistance leads to gestational diabetes mellitus. Women with gestational diabetes can develop type 2 diabetes after giving birth.¹⁰

Blood sugar fluctuations can cause depression, irritability, or memory problems. Depression can sabotage adherence to diet and treatment, leading to poor glycemic control.

Ask the patient if she was diagnosed with gestational diabetes and if she is experiencing fatigue, excessive thirst, frequent urination, blurred vision, headaches, excessive hunger, or unexplainable weight loss.

Primary biliary cirrhosis is most prevalent in women ages 35 to 60 and may cause depression.²⁰ Pruritus, fatigue, jaundice, and liver abnormalities point to this autoimmune disease, and postpartum exacerbations have been reported.²¹

HIV infection often leads to cognitive loss and depression with suicidal thoughts.¹³ Highly active antiretroviral medications commonly cause agitation, pain, mood changes, and insomnia.

 

Ask the patient is she is HIV positive. Watch for weight loss, fever, anorexia, and recurrent infections.

Substance abuse. Intoxication, withdrawal, or long-term alcohol or drug use can contribute to depression. Women at high risk for substance abuse disorder might not adhere to psychiatric treatment and may be prone to sexually transmitted diseases. If possible, see the patient every 3 to 4 weeks during the postpartum period.

Pain—if not adequately controlled—can fuel depression. Ask the patient if she has chronic pain or suffered a severe injury.

Table 1

Possible tests if postpartum patient is constantly fatigued

Laboratory test	Confirms or rules out	Order if patient also presents with:
Acetylcholine receptor antibodies	Myasthenia gravis	Double vision, droopy eyelids, muscle weakness
Alkaline phosphatase	Primary biliary cirrhosis	Jaundice, pruritus
Antimitochondrial antibody	Primary biliary cirrhosis	Jaundice, pruritus
Antinuclear antibody	Systemic lupus erythematosus	‘Butterfly’ facial rash, joint pain, morning stiffness
CBC	Microcytic anemia, megaloblastic anemia	Pallor, low energy, peripheral neuropathy, shortness of breath
Electrolytes	Adrenal insufficiency, renal disease	Low blood pressure, seizures, skin pigmentation
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, headaches, frequent urination, unexplainable weight loss
HIV	HIV infection/AIDS	Anorexia, recurrent infections, weight loss
Liver function tests	Alcohol abuse, hepatitis, primary biliary cirrhosis	Asterixis (flapping tremor), easy bruising, jaundice, pruritus, spider telangiectasias
Lumbar puncture	Multiple sclerosis	Bladder dysfunction, gait ataxia, ocular signs, sensory loss, spasticity

Table 2

Possible tests if postpartum patient has lost or gained weight

Laboratory test	Confirms or rules out	Order if patient also presents with:
Antithyroid antibody	Postpartum thyroiditis	Constipation, dry skin, hair loss, lethargy, memory loss
Glucose (fasting or glucose tolerance)	Type 1 or 2 diabetes mellitus	Blurred vision, excessive thirst/hunger, fatigue, frequent urination, headaches
HIV	HIV infection/AIDS	Anorexia, fatigue, recurrent infections
TSH±thyroid panel	Hypothyroidism	Constipation, dry skin, hair loss, lethargy
TSH±thyroid panel	Hyperthyroidism	Agitation, anxiety, heat intolerance, palpitations

Table 3

Possible tests if postpartum patient has other physical symptoms

Laboratory test	Confirms or rules out	Order if patient presents with:
Blood urea nitrogen/creatinine	Renal disease, dehydration	Back pain, frequent urination or oliguria, low blood pressure
Brain MRI	Brain tumors, white matter disease	Focal deficits, headaches, seizures, vision problems, vomiting
C-reactive protein	Rheumatoid arthritis	Joint pain, morning stiffness
ECG	Cardiomyopathy	Extremity swelling, palpitations, shortness of breath at night and with exertion
Erythrocyte sedimentation rate	Rheumatoid arthritis, SLE	‘Butterfly’ facial rash, joint pain
Folate	Folate deficiency	Ataxia, loss of vibration and position sense, peripheral neuropathy, weakness
Prolactin	Prolactinoma, hypopituitarism	Amenorrhea/galactorrhea, headache, visual field loss
Rapid plasma reagin	Syphilis	Ataxic wide-based gait, loss of position, deep pain and temperature sensation, palmar/plantar rash
Rheumatoid factor	Rheumatoid arthritis	Morning stiffness, symmetric joint pain
Urinalysis	Urinary infection, diabetes, renal disease	Burning or difficulty with voiding, dark-colored urine, frequent urination
Urine drug screen	Substance abuse disorder	Erratic behavior, irritability or aggression; violence, mental status changes
Vitamin B12	Anemia, malnutrition, inflammatory bowel disease	Loss of position or vibratory sensation, mood and cognitive changes, tingling and numbness in hands and feet
SLE: Systemic lupus erythematosus

Determining a medical cause

Laboratory and neuroimaging findings—obtained in concert with the patient’s primary care physician—will help confirm or rule out a medical problem (Table 4). Consult with a neurologist, endocrinologist or rheumatologist if indicated.

Table 4

Findings that signal a possible postpartum medical problem

Laboratory finding	Could signal …
Low hemoglobin, hematocrit and mean cell volume (MCV) values	Microcytic anemia
MCV >100 mm3	Megaloblastic anemia
Positive anticardiolipin or antinuclear antibody	Systemic lupus erythematosus
Blood urea nitrogen >20 mg/dL, creatinine >1.5 mg/dL	Acute or chronic renal failure
Low specific gravity on urinalysis	Diabetes insipidus or renal tubular abnormalities
Proteinuria with glycosuria	Diabetes mellitus
Proteinuria with protein or cellular casts	Systemic lupus erythematosus
Hyponatremia and hyperkalemia	Adrenocortical insufficiency
Hypo/hypernatremia	Seizures
Albumin	Malnutrition
SGOT/SGPT >35 u/L (each)	Alcohol abuse disorder, hepatitis, hepatic encephalopathy
Alkaline phosphatase >120 u/L, positive antimitochondrial antibody	Primary biliary cirrhosis
Erythrocyte sedimentation rate >20 mm/hr	Systemic lupus erythematosus, rheumatoid arthritis
Positive rheumatoid factor	Rheumatoid arthritis
Prolactin >24 ng/mL	Prolactinoma
TSH >5 µu/mL	Hypothyroidism
TSH	Hyperthyroidism
IgG >1.4 mg/dL, oligoclonal bands, myelin basic protein in CSF	Multiple sclerosis
White matter hyperintensities in brain MRI	Multiple sclerosis, CNS vasculitis, tumors
Source: Reference 5

Case: will the tumor resolve?

Mrs. A’s endocrinologist prescribes bromocriptine to manage her hyperprolactinemia, but she refuses to start the dopamine agonist after the doctor explains that it might cause psychosis.

Working closely, the psychiatrist and endocrinologist postpone bromocriptine therapy to see if the prolactinoma will resolve without treatment. They order brain MRIs every 6 months to track the tumor.

Mrs. A starts weekly psychodynamic therapy, during which she explores her fear of failure as a mother. Within 2 months, she recognizes that she has set unrealistically high expectations for herself. Adopting a supportive approach, the therapist encourages her to go on dates with her husband and run errands or relax alone for 2 hours each weekend.

The psychiatrist discusses sleep hygiene and adds quetiapine, 25 mg at bedtime; reduces gabapentin over 3 months to 300 mg nightly; and titrates sertraline to 100 mg/d. The psychiatrist also weans Mrs. A off temazepam over 3 months, watching closely for withdrawal symptoms.

At the psychiatrist’s suggestion, Mrs. A. resumes exercising at a gym four to five times a week. Mrs. A reduces zolpidem use—taking it only as needed for insomnia—then tapers off gabapentin. Quetiapine is discontinued.

 

After 4 months, psychotherapy sessions are decreased to biweekly. Prolactin is 66.6 ng/mL at 3 months, then normalizes to 23.4 ng/mL at 6 months. Six months later, brain MRI shows no change in baseline tumor size. The endocrinologist continues semiannual brain MRI and prolactin testing to see if the tumor will shrink without surgery.

Nearly 1 year after presentation, Mrs. A’s depression is in remission.

Related resources

• Edinburgh Postnatal Depression Scale. http://www.drgrelling.com/Downloads.htm (click on “Edinburgh Postnatal Depression Scale” under “Resources for professionals”).
  
• Postpartum Support International. www.postpartum.net.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Carbamazepine • Tegretol, others
  
• Gabapentin • Neurontin
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Temazepam • Restoril
  
• Valproic acid • Depakene
  
• Zolpidem • Ambien
  

Disclosures

Dr. Seritan reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.