Current Psychiatry

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

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

Delirium is the most common psychiatric disorder on medical/surgical units of general hospitals and is a major cause of consultations for consultation-liaison (C-L) psychiatrists in medical centers.

It primarily afflicts older patients and is characterized by a rapid onset of confusion with hallucinations, delusions, agitation (but sometimes hypoactivity), and fluctuating severity and outcomes. It can be triggered by multiple factors, including dehydration, electrolyte imbalance, upper respiratory infection, urinary tract infections, post-surgical state, and, very commonly, iatrogenic factors. Many medications, especially those with anticholinergic activity, can cause delirium in older patients. Delirium can lead to pronged hospital stays, functional decline, cognitive impairment, and accelerated mortality.¹

So what is the evidence-based treatment for this common and serious neuropsychiatric brain disorder? None exists! Delirium is managed by identifying and addressing underlying factors, as well as supportive medical care (hydration, nutrition, sleep, monitoring vital signs, preventing aspiration, quiet rooms, orientation, and ambulation). Physical restraints are undesirable but may be hard to avoid for severely disinhibited and agitated patients who try to rip out their IV or endotracheal tube or assault staff or family members who try to calm them during their psychotic confusional state.

Doesn’t this sound similar to dementia patients in nursing homes who develop psychosis and agitation and pose management problems for their family and staff? These 2 neuropsychiatric conditions are clinically similar, and the use of antipsychotic agents is not FDA-approved for either of them. Antipsychotics have not been found efficacious for delirium² or dementia with psychosis³ but their use continues. The paradox is that C-L psychiatrists use small doses of antipsychotics routinely for delirium and generally believe that such pharmacologic intervention works in many patients, although some older agents (eg, haloperidol) have been reported to be neurotoxic⁴ and associated with higher mortality in dementia patients with psychosis.^5,6

The relationship of antipsychotic treatment with delirium and dementia is complex, paradoxical, and unsettled. Consider the following:

• Antipsychotics are not approved for the psychosis of dementia despite 17 large, placebo-controlled trials with 4 different second-generation agents.
• The FDA issued a “black-box” warning on all first- and second-generation antipsychotics because of a 1.6-times higher mortality rate among older patients with dementia.
• No placebo-controlled, FDA trials of delirium have been conducted with any antipsychotic agents.
• Clinicians frequently use first- and second-generation antipsychotics for delirium despite the lack of evidence.
• The FDA has not issued a “black-box” warning on antipsychotics for use in delirium as they did for dementia, although typically both populations are older and may be susceptible to the same complications observed in Alzheimer’s disease trials (eg, strokes, transient ischemic attack, and aspiration pneumonia). This may be because of the absence of safety data of antipsychotics in delirium based on industry-sponsored registration clinical trials. No data means no warning, although the risk factors may be present for millions of older patients who have suffered from delirium and have been treated with first-or second-generation antipsychotics.

The current convoluted state of pharmacotherapy for delirium and dementia is likely to continue: dementia patients with psychosis may or may not receive antipsychotics because of the FDA’s “black-box” warning while delirium patients readily receive various antipsychotics based on long-term practice, although not a single antipsychotic has been FDA-approved for delirium. Until a pharmaceutical company decides to conduct a large placebo-controlled trial for delirium, the current widespread, off-label use of antipsychotics in delirium will continue and “black-box” warning will apply only to 1 clinical population of older persons (those with dementia) but not another (those with delirium). Go figure!

Delirium is the most common psychiatric disorder on medical/surgical units of general hospitals and is a major cause of consultations for consultation-liaison (C-L) psychiatrists in medical centers.

It primarily afflicts older patients and is characterized by a rapid onset of confusion with hallucinations, delusions, agitation (but sometimes hypoactivity), and fluctuating severity and outcomes. It can be triggered by multiple factors, including dehydration, electrolyte imbalance, upper respiratory infection, urinary tract infections, post-surgical state, and, very commonly, iatrogenic factors. Many medications, especially those with anticholinergic activity, can cause delirium in older patients. Delirium can lead to pronged hospital stays, functional decline, cognitive impairment, and accelerated mortality.¹

So what is the evidence-based treatment for this common and serious neuropsychiatric brain disorder? None exists! Delirium is managed by identifying and addressing underlying factors, as well as supportive medical care (hydration, nutrition, sleep, monitoring vital signs, preventing aspiration, quiet rooms, orientation, and ambulation). Physical restraints are undesirable but may be hard to avoid for severely disinhibited and agitated patients who try to rip out their IV or endotracheal tube or assault staff or family members who try to calm them during their psychotic confusional state.

Doesn’t this sound similar to dementia patients in nursing homes who develop psychosis and agitation and pose management problems for their family and staff? These 2 neuropsychiatric conditions are clinically similar, and the use of antipsychotic agents is not FDA-approved for either of them. Antipsychotics have not been found efficacious for delirium² or dementia with psychosis³ but their use continues. The paradox is that C-L psychiatrists use small doses of antipsychotics routinely for delirium and generally believe that such pharmacologic intervention works in many patients, although some older agents (eg, haloperidol) have been reported to be neurotoxic⁴ and associated with higher mortality in dementia patients with psychosis.^5,6

The relationship of antipsychotic treatment with delirium and dementia is complex, paradoxical, and unsettled. Consider the following:

• Antipsychotics are not approved for the psychosis of dementia despite 17 large, placebo-controlled trials with 4 different second-generation agents.
• The FDA issued a “black-box” warning on all first- and second-generation antipsychotics because of a 1.6-times higher mortality rate among older patients with dementia.
• No placebo-controlled, FDA trials of delirium have been conducted with any antipsychotic agents.
• Clinicians frequently use first- and second-generation antipsychotics for delirium despite the lack of evidence.
• The FDA has not issued a “black-box” warning on antipsychotics for use in delirium as they did for dementia, although typically both populations are older and may be susceptible to the same complications observed in Alzheimer’s disease trials (eg, strokes, transient ischemic attack, and aspiration pneumonia). This may be because of the absence of safety data of antipsychotics in delirium based on industry-sponsored registration clinical trials. No data means no warning, although the risk factors may be present for millions of older patients who have suffered from delirium and have been treated with first-or second-generation antipsychotics.

The current convoluted state of pharmacotherapy for delirium and dementia is likely to continue: dementia patients with psychosis may or may not receive antipsychotics because of the FDA’s “black-box” warning while delirium patients readily receive various antipsychotics based on long-term practice, although not a single antipsychotic has been FDA-approved for delirium. Until a pharmaceutical company decides to conduct a large placebo-controlled trial for delirium, the current widespread, off-label use of antipsychotics in delirium will continue and “black-box” warning will apply only to 1 clinical population of older persons (those with dementia) but not another (those with delirium). Go figure!

Delirium is the most common psychiatric disorder on medical/surgical units of general hospitals and is a major cause of consultations for consultation-liaison (C-L) psychiatrists in medical centers.

It primarily afflicts older patients and is characterized by a rapid onset of confusion with hallucinations, delusions, agitation (but sometimes hypoactivity), and fluctuating severity and outcomes. It can be triggered by multiple factors, including dehydration, electrolyte imbalance, upper respiratory infection, urinary tract infections, post-surgical state, and, very commonly, iatrogenic factors. Many medications, especially those with anticholinergic activity, can cause delirium in older patients. Delirium can lead to pronged hospital stays, functional decline, cognitive impairment, and accelerated mortality.¹

So what is the evidence-based treatment for this common and serious neuropsychiatric brain disorder? None exists! Delirium is managed by identifying and addressing underlying factors, as well as supportive medical care (hydration, nutrition, sleep, monitoring vital signs, preventing aspiration, quiet rooms, orientation, and ambulation). Physical restraints are undesirable but may be hard to avoid for severely disinhibited and agitated patients who try to rip out their IV or endotracheal tube or assault staff or family members who try to calm them during their psychotic confusional state.

Doesn’t this sound similar to dementia patients in nursing homes who develop psychosis and agitation and pose management problems for their family and staff? These 2 neuropsychiatric conditions are clinically similar, and the use of antipsychotic agents is not FDA-approved for either of them. Antipsychotics have not been found efficacious for delirium² or dementia with psychosis³ but their use continues. The paradox is that C-L psychiatrists use small doses of antipsychotics routinely for delirium and generally believe that such pharmacologic intervention works in many patients, although some older agents (eg, haloperidol) have been reported to be neurotoxic⁴ and associated with higher mortality in dementia patients with psychosis.^5,6

The relationship of antipsychotic treatment with delirium and dementia is complex, paradoxical, and unsettled. Consider the following:

• Antipsychotics are not approved for the psychosis of dementia despite 17 large, placebo-controlled trials with 4 different second-generation agents.
• The FDA issued a “black-box” warning on all first- and second-generation antipsychotics because of a 1.6-times higher mortality rate among older patients with dementia.
• No placebo-controlled, FDA trials of delirium have been conducted with any antipsychotic agents.
• Clinicians frequently use first- and second-generation antipsychotics for delirium despite the lack of evidence.
• The FDA has not issued a “black-box” warning on antipsychotics for use in delirium as they did for dementia, although typically both populations are older and may be susceptible to the same complications observed in Alzheimer’s disease trials (eg, strokes, transient ischemic attack, and aspiration pneumonia). This may be because of the absence of safety data of antipsychotics in delirium based on industry-sponsored registration clinical trials. No data means no warning, although the risk factors may be present for millions of older patients who have suffered from delirium and have been treated with first-or second-generation antipsychotics.

The current convoluted state of pharmacotherapy for delirium and dementia is likely to continue: dementia patients with psychosis may or may not receive antipsychotics because of the FDA’s “black-box” warning while delirium patients readily receive various antipsychotics based on long-term practice, although not a single antipsychotic has been FDA-approved for delirium. Until a pharmaceutical company decides to conduct a large placebo-controlled trial for delirium, the current widespread, off-label use of antipsychotics in delirium will continue and “black-box” warning will apply only to 1 clinical population of older persons (those with dementia) but not another (those with delirium). Go figure!

CASE: Behavioral changes

Mr. K, age 45, is brought to the emergency department (ED) by his wife for severe paranoia, combative behavior, confusion, and slowed cognition. Mr. K tells the ED staff that a chemical abrasion he sustained a few weeks earlier has spread to his penis, and insists that his penis is retracting into his body. He has tied a string around his penis to keep it from disappearing into his body. According to Mr. K’s wife, he went to an urgent care clinic 2 weeks ago after he sustained chemical abrasions from exposure to cleaning solution at home. The provider at the urgent care clinic started Mr. K on an unknown dose of oral prednisone.

Mr. K’s wife reports that her husband had a dysphoric episode approximately 6 months ago when his business was struggling but his mood improved without psychiatric care. Mr. K’s medical history includes episodic sarcoidosis of the eyes, skin, and lungs. In the past these symptoms remitted after he received oral prednisone.

ED clinicians consider neurosarcoidosis and substance-induced delirium in the differential diagnosis (Table).¹ A CT scan of the head fails to show lesions suggestive of neurosarcoidosis. Chest radiography does not reveal lesions suggestive of lung sarcoids and Mr. K has no skin lesions.

Table

DSM-IV-TR criteria for substance-induced delirium

Mr. K is admitted to the psychiatric inpatient unit for acute stabilization, where he remains aggressive and combative. He throws chairs at his peers and staff on the unit and is placed in physical restraints. He requires several doses of IM haloperidol, 5 mg, lorazepam, 2 mg, and diphenhydramine, 50 mg, for severe agitation. Mr. K is guarded, perseverative, and selectively mute. He avoids eye contact and has poor grooming. He has slow thought processing and displays concrete thought process. Prednisone is discontinued and olanzapine, titrated to 30 mg/d, and mirtazapine, titrated to 30 mg/d, are started for psychosis and depression.

Mr. K’s mood and behavior eventually return to baseline but slowed cognition persists. He is discharged from our facility.

The authors’ observations

Cortisone was first used to treat rheumatoid arthritis in 1948 and corticosteroids have been linked to multiple neuropsychiatric complications that have been broadly defined as steroid psychosis. This syndrome includes reversible behavioral manifestations such as hypomania, irritability, mood reactivity, anxiety, and insomnia in addition to more severe symptoms such as depression, mania, and psychosis.² Although mild cognitive deficits have been noted in patients taking corticosteroids, most published cases have focused on steroid-induced psychosis.

In 1984, Varney et al³ noted a phenomenon they called “steroid dementia” in 6 patients treated with corticosteroids. On first evaluation, these patients presented with symptoms similar to early Alzheimer’s dementia—impaired memory, attention, and concentration. Three patients initially were diagnosed first with Alzheimer’s dementia until their symptoms spontaneously improved when steroids were reduced or discontinued. Although their presentation resembled Alzheimer’s dementia, patients with steroid dementia had a specific cognitive presentation associated with corticosteroid use. Symptoms included impaired verbal memory and spatial thinking but normal procedural memory. These patients showed intact immediate recall but impaired delayed recall with difficulty tracking conversations and word finding. Overall, patients with steroid dementia showed a predominance of verbal declarative memory deficits out of proportion to other cognitive symptoms. These symptoms and recent corticosteroid exposure differentiated steroid dementia from other forms of dementia.

In a later article, Varney reviewed electroencephalography (EEG) and CT findings associated with steroid dementia, noting bilateral EEG abnormalities and acute cortical atrophy on CT.⁴ Steroid dementia largely was reversible, resolving 3 to 11 months after corticosteroid discontinuation. Additionally, Varney noted that patients who had psychosis and dementia had more severe and longer-lasting dementia.

TREATMENT: Progressive decline

Mr. K is college educated, has been married for 15 years, has 2 children, age 9 and 11, and owns a successful basketball coaching business. He has no history of substance abuse, legal issues, or violence. He reports a good childhood with normal developmental milestones and no history of trauma.

In the 6 months after his initial psychiatric admission, Mr. K sees various outpatient providers, who change his psychotropics multiple times. He also receives 4 courses of prednisone for ocular sarcoidosis. He is admitted twice to other psychiatric facilities. After he has paranoid interactions with colleagues and families of the youth he coaches, his business fails.

After his third psychiatric inpatient hospitalization, Mr. K becomes severely paranoid, believing his wife is having an affair. He becomes physically abusive to his wife, who obtains a restraining order and leaves with their children. Mr. K barely leaves his house and stops grooming. A friend notes that Mr. K’s home has become uninhabitable, and it goes into foreclosure. After Mr. K’s neighbors report combative behavior and paranoia, police bring him in on an involuntary hold for a fourth psychiatric hospitalization (the second in our facility).

During this hospitalization—6 months after the initial ED presentation—the neurology team conducts a repeat medical workup. EEG shows generalized slowing. Head CT and MRI show diffuse cortical atrophy that was not seen in previous imaging. Mr. K has ocular lesions characteristic of ocular sarcoidosis. His mental status examination is similar to his first presentation except that the psychosis and thought disorganization are considerably worse. His cognitive functioning also shows significant decline. Cognitive screening reveals intact remote memory with impaired recent memory. His thinking is concrete and his verbal memory is markedly impaired. His Mini-Mental State Examination score is 27/30, indicating functional capacity that is better than his clinical presentation. Because of difficulty with concentration and verbal processing, Mr. K is unable to complete the Minnesota Multiphasic Personality Inventory despite substantial assistance. On most days he cannot recall recent conversations with his wife, staff, or physicians. He is taking no medications at this time.

Mr. K is restarted on olanzapine, titrated to 30 mg/d, to control his psychosis; this medication was effective during his last stay in our facility. Oral prednisone is discontinued and methotrexate, 10 mg/week, is initiated for ocular sarcoidosis. Based on recommendations from a case series report,⁵ we start Mr. K on lithium, titrated to 600 mg twice a day, for steroid-induced mood symptoms, Mr. K’s psychosis and mood improve dramatically once he reaches a therapeutic lithium level; however, his cognition remains slowed and he is unable to care for his basic needs.

The authors’ observations

Steroid dementia may be the result of effects in the medial temporal lobe, specifically dorsolateral prefrontal cortex, which impairs working memory, and the parahippocampal gyrus.^6,7 The cognitive presentation of steroid dementia Varney et al³ described has been replicated in healthy volunteers who received corticosteroids.³ Patients with Cushing’s syndrome also have been noted to have diminished hippocampal volume and similar cognitive deficits. Cognitive impairment experienced by patients treated with corticosteroids may be caused by neuronal death in the hippocampus and dorsolateral prefrontal cortex. The etiology of cell death is multifactorial and includes glutamate-mediated excitotoxicity, activation of proinflammatory pathways, inhibited utilization of glucose in the hippocampus, telomere shortening, and diminished cell repair by brain-derived neurotrophic factor. The net result is significant, widespread damage that in some cases is irreversible.⁸

Because of the severity of Mr. K’s psychosis and personality change from baseline, his cognitive symptoms were largely overlooked during his first psychiatric hospitalization. The affective flattening, delayed verbal response, and markedly concrete thought process were considered within the spectrum of resolving psychosis. After further hospitalizations and abnormal results on cognitive testing, Mr. K’s cognitive impairment was fully noted. His symptoms match those of previously documented cases of steroid dementia, including verbal deficits out of proportion to other impairment, acute cerebral atrophy on CT after corticosteroid treatment, and gradual improvement of symptoms when corticosteroids were discontinued.

Management recommendations

Educate patients taking steroids about possible side effects of mood changes, psychosis, and cognitive deficits. Close monitoring of patients on corticosteroids is paramount. If psychiatric or cognitive symptoms develop, gradually discontinue the corticosteroid and seek other treatments.

Randomized, placebo-controlled trials of lamotrigine and memantine have shown these medications are cognitively protective for patients taking prednisone.⁹

OUTCOME: Long-term deficits

After a 33-day stay in our adult inpatient psychiatric facility, the county places Mr. K in a permanent conservatorship for severe grave disability. He is discharged to a long-term psychiatric care locked facility for ongoing management. Mr. K spends 20 months in the long-term care facility while his family remains hopeful for his recovery and return home. He is admitted to our facility for acute stabilization of psychotic symptoms after he is released from the locked facility. Although no imaging studies are conducted, he remains significantly forgetful. Additionally, his paranoia persists.

Mr. K is poorly compliant with his psychotropics, which include divalproex, 1,000 mg/d, and olanzapine, 30 mg/d. Although he is discharged home with his family, his functional capacity is less than expected and he requires continuous support. Insisting that Mr. K abstain from steroids after the first psychiatric hospitalization might have prevented this seemingly irreversible dementia.

Related Resources

• Sacks O, Shulman M. Steroid dementia: an overlooked diagnosis? Neurology. 2005;64(4):707-709.
• Cipriani G, Picchi L, Vedovello M, et al. Reversible dementia from corticosteroid therapy. Clinical Geriatrics. 2012;20(7):38-41.

Drug Brand Names

• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Memantine • Namenda
• Methotrexate • Rheumatrex, Trexall
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Prednisone • Deltasone, Meticorten, others

Disclosure

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

CASE: Behavioral changes

Mr. K, age 45, is brought to the emergency department (ED) by his wife for severe paranoia, combative behavior, confusion, and slowed cognition. Mr. K tells the ED staff that a chemical abrasion he sustained a few weeks earlier has spread to his penis, and insists that his penis is retracting into his body. He has tied a string around his penis to keep it from disappearing into his body. According to Mr. K’s wife, he went to an urgent care clinic 2 weeks ago after he sustained chemical abrasions from exposure to cleaning solution at home. The provider at the urgent care clinic started Mr. K on an unknown dose of oral prednisone.

Mr. K’s wife reports that her husband had a dysphoric episode approximately 6 months ago when his business was struggling but his mood improved without psychiatric care. Mr. K’s medical history includes episodic sarcoidosis of the eyes, skin, and lungs. In the past these symptoms remitted after he received oral prednisone.

ED clinicians consider neurosarcoidosis and substance-induced delirium in the differential diagnosis (Table).¹ A CT scan of the head fails to show lesions suggestive of neurosarcoidosis. Chest radiography does not reveal lesions suggestive of lung sarcoids and Mr. K has no skin lesions.

Table

DSM-IV-TR criteria for substance-induced delirium

Mr. K is admitted to the psychiatric inpatient unit for acute stabilization, where he remains aggressive and combative. He throws chairs at his peers and staff on the unit and is placed in physical restraints. He requires several doses of IM haloperidol, 5 mg, lorazepam, 2 mg, and diphenhydramine, 50 mg, for severe agitation. Mr. K is guarded, perseverative, and selectively mute. He avoids eye contact and has poor grooming. He has slow thought processing and displays concrete thought process. Prednisone is discontinued and olanzapine, titrated to 30 mg/d, and mirtazapine, titrated to 30 mg/d, are started for psychosis and depression.

Mr. K’s mood and behavior eventually return to baseline but slowed cognition persists. He is discharged from our facility.

The authors’ observations

Cortisone was first used to treat rheumatoid arthritis in 1948 and corticosteroids have been linked to multiple neuropsychiatric complications that have been broadly defined as steroid psychosis. This syndrome includes reversible behavioral manifestations such as hypomania, irritability, mood reactivity, anxiety, and insomnia in addition to more severe symptoms such as depression, mania, and psychosis.² Although mild cognitive deficits have been noted in patients taking corticosteroids, most published cases have focused on steroid-induced psychosis.

In 1984, Varney et al³ noted a phenomenon they called “steroid dementia” in 6 patients treated with corticosteroids. On first evaluation, these patients presented with symptoms similar to early Alzheimer’s dementia—impaired memory, attention, and concentration. Three patients initially were diagnosed first with Alzheimer’s dementia until their symptoms spontaneously improved when steroids were reduced or discontinued. Although their presentation resembled Alzheimer’s dementia, patients with steroid dementia had a specific cognitive presentation associated with corticosteroid use. Symptoms included impaired verbal memory and spatial thinking but normal procedural memory. These patients showed intact immediate recall but impaired delayed recall with difficulty tracking conversations and word finding. Overall, patients with steroid dementia showed a predominance of verbal declarative memory deficits out of proportion to other cognitive symptoms. These symptoms and recent corticosteroid exposure differentiated steroid dementia from other forms of dementia.

In a later article, Varney reviewed electroencephalography (EEG) and CT findings associated with steroid dementia, noting bilateral EEG abnormalities and acute cortical atrophy on CT.⁴ Steroid dementia largely was reversible, resolving 3 to 11 months after corticosteroid discontinuation. Additionally, Varney noted that patients who had psychosis and dementia had more severe and longer-lasting dementia.

TREATMENT: Progressive decline

Mr. K is college educated, has been married for 15 years, has 2 children, age 9 and 11, and owns a successful basketball coaching business. He has no history of substance abuse, legal issues, or violence. He reports a good childhood with normal developmental milestones and no history of trauma.

In the 6 months after his initial psychiatric admission, Mr. K sees various outpatient providers, who change his psychotropics multiple times. He also receives 4 courses of prednisone for ocular sarcoidosis. He is admitted twice to other psychiatric facilities. After he has paranoid interactions with colleagues and families of the youth he coaches, his business fails.

After his third psychiatric inpatient hospitalization, Mr. K becomes severely paranoid, believing his wife is having an affair. He becomes physically abusive to his wife, who obtains a restraining order and leaves with their children. Mr. K barely leaves his house and stops grooming. A friend notes that Mr. K’s home has become uninhabitable, and it goes into foreclosure. After Mr. K’s neighbors report combative behavior and paranoia, police bring him in on an involuntary hold for a fourth psychiatric hospitalization (the second in our facility).

During this hospitalization—6 months after the initial ED presentation—the neurology team conducts a repeat medical workup. EEG shows generalized slowing. Head CT and MRI show diffuse cortical atrophy that was not seen in previous imaging. Mr. K has ocular lesions characteristic of ocular sarcoidosis. His mental status examination is similar to his first presentation except that the psychosis and thought disorganization are considerably worse. His cognitive functioning also shows significant decline. Cognitive screening reveals intact remote memory with impaired recent memory. His thinking is concrete and his verbal memory is markedly impaired. His Mini-Mental State Examination score is 27/30, indicating functional capacity that is better than his clinical presentation. Because of difficulty with concentration and verbal processing, Mr. K is unable to complete the Minnesota Multiphasic Personality Inventory despite substantial assistance. On most days he cannot recall recent conversations with his wife, staff, or physicians. He is taking no medications at this time.

Mr. K is restarted on olanzapine, titrated to 30 mg/d, to control his psychosis; this medication was effective during his last stay in our facility. Oral prednisone is discontinued and methotrexate, 10 mg/week, is initiated for ocular sarcoidosis. Based on recommendations from a case series report,⁵ we start Mr. K on lithium, titrated to 600 mg twice a day, for steroid-induced mood symptoms, Mr. K’s psychosis and mood improve dramatically once he reaches a therapeutic lithium level; however, his cognition remains slowed and he is unable to care for his basic needs.

The authors’ observations

Steroid dementia may be the result of effects in the medial temporal lobe, specifically dorsolateral prefrontal cortex, which impairs working memory, and the parahippocampal gyrus.^6,7 The cognitive presentation of steroid dementia Varney et al³ described has been replicated in healthy volunteers who received corticosteroids.³ Patients with Cushing’s syndrome also have been noted to have diminished hippocampal volume and similar cognitive deficits. Cognitive impairment experienced by patients treated with corticosteroids may be caused by neuronal death in the hippocampus and dorsolateral prefrontal cortex. The etiology of cell death is multifactorial and includes glutamate-mediated excitotoxicity, activation of proinflammatory pathways, inhibited utilization of glucose in the hippocampus, telomere shortening, and diminished cell repair by brain-derived neurotrophic factor. The net result is significant, widespread damage that in some cases is irreversible.⁸

Because of the severity of Mr. K’s psychosis and personality change from baseline, his cognitive symptoms were largely overlooked during his first psychiatric hospitalization. The affective flattening, delayed verbal response, and markedly concrete thought process were considered within the spectrum of resolving psychosis. After further hospitalizations and abnormal results on cognitive testing, Mr. K’s cognitive impairment was fully noted. His symptoms match those of previously documented cases of steroid dementia, including verbal deficits out of proportion to other impairment, acute cerebral atrophy on CT after corticosteroid treatment, and gradual improvement of symptoms when corticosteroids were discontinued.

Management recommendations

Educate patients taking steroids about possible side effects of mood changes, psychosis, and cognitive deficits. Close monitoring of patients on corticosteroids is paramount. If psychiatric or cognitive symptoms develop, gradually discontinue the corticosteroid and seek other treatments.

Randomized, placebo-controlled trials of lamotrigine and memantine have shown these medications are cognitively protective for patients taking prednisone.⁹

OUTCOME: Long-term deficits

After a 33-day stay in our adult inpatient psychiatric facility, the county places Mr. K in a permanent conservatorship for severe grave disability. He is discharged to a long-term psychiatric care locked facility for ongoing management. Mr. K spends 20 months in the long-term care facility while his family remains hopeful for his recovery and return home. He is admitted to our facility for acute stabilization of psychotic symptoms after he is released from the locked facility. Although no imaging studies are conducted, he remains significantly forgetful. Additionally, his paranoia persists.

Mr. K is poorly compliant with his psychotropics, which include divalproex, 1,000 mg/d, and olanzapine, 30 mg/d. Although he is discharged home with his family, his functional capacity is less than expected and he requires continuous support. Insisting that Mr. K abstain from steroids after the first psychiatric hospitalization might have prevented this seemingly irreversible dementia.

Related Resources

• Sacks O, Shulman M. Steroid dementia: an overlooked diagnosis? Neurology. 2005;64(4):707-709.
• Cipriani G, Picchi L, Vedovello M, et al. Reversible dementia from corticosteroid therapy. Clinical Geriatrics. 2012;20(7):38-41.

Drug Brand Names

• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Memantine • Namenda
• Methotrexate • Rheumatrex, Trexall
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Prednisone • Deltasone, Meticorten, others

Disclosure

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

CASE: Behavioral changes

Mr. K, age 45, is brought to the emergency department (ED) by his wife for severe paranoia, combative behavior, confusion, and slowed cognition. Mr. K tells the ED staff that a chemical abrasion he sustained a few weeks earlier has spread to his penis, and insists that his penis is retracting into his body. He has tied a string around his penis to keep it from disappearing into his body. According to Mr. K’s wife, he went to an urgent care clinic 2 weeks ago after he sustained chemical abrasions from exposure to cleaning solution at home. The provider at the urgent care clinic started Mr. K on an unknown dose of oral prednisone.

Mr. K’s wife reports that her husband had a dysphoric episode approximately 6 months ago when his business was struggling but his mood improved without psychiatric care. Mr. K’s medical history includes episodic sarcoidosis of the eyes, skin, and lungs. In the past these symptoms remitted after he received oral prednisone.

ED clinicians consider neurosarcoidosis and substance-induced delirium in the differential diagnosis (Table).¹ A CT scan of the head fails to show lesions suggestive of neurosarcoidosis. Chest radiography does not reveal lesions suggestive of lung sarcoids and Mr. K has no skin lesions.

Table

DSM-IV-TR criteria for substance-induced delirium

Mr. K is admitted to the psychiatric inpatient unit for acute stabilization, where he remains aggressive and combative. He throws chairs at his peers and staff on the unit and is placed in physical restraints. He requires several doses of IM haloperidol, 5 mg, lorazepam, 2 mg, and diphenhydramine, 50 mg, for severe agitation. Mr. K is guarded, perseverative, and selectively mute. He avoids eye contact and has poor grooming. He has slow thought processing and displays concrete thought process. Prednisone is discontinued and olanzapine, titrated to 30 mg/d, and mirtazapine, titrated to 30 mg/d, are started for psychosis and depression.

Mr. K’s mood and behavior eventually return to baseline but slowed cognition persists. He is discharged from our facility.

The authors’ observations

Cortisone was first used to treat rheumatoid arthritis in 1948 and corticosteroids have been linked to multiple neuropsychiatric complications that have been broadly defined as steroid psychosis. This syndrome includes reversible behavioral manifestations such as hypomania, irritability, mood reactivity, anxiety, and insomnia in addition to more severe symptoms such as depression, mania, and psychosis.² Although mild cognitive deficits have been noted in patients taking corticosteroids, most published cases have focused on steroid-induced psychosis.

In 1984, Varney et al³ noted a phenomenon they called “steroid dementia” in 6 patients treated with corticosteroids. On first evaluation, these patients presented with symptoms similar to early Alzheimer’s dementia—impaired memory, attention, and concentration. Three patients initially were diagnosed first with Alzheimer’s dementia until their symptoms spontaneously improved when steroids were reduced or discontinued. Although their presentation resembled Alzheimer’s dementia, patients with steroid dementia had a specific cognitive presentation associated with corticosteroid use. Symptoms included impaired verbal memory and spatial thinking but normal procedural memory. These patients showed intact immediate recall but impaired delayed recall with difficulty tracking conversations and word finding. Overall, patients with steroid dementia showed a predominance of verbal declarative memory deficits out of proportion to other cognitive symptoms. These symptoms and recent corticosteroid exposure differentiated steroid dementia from other forms of dementia.

In a later article, Varney reviewed electroencephalography (EEG) and CT findings associated with steroid dementia, noting bilateral EEG abnormalities and acute cortical atrophy on CT.⁴ Steroid dementia largely was reversible, resolving 3 to 11 months after corticosteroid discontinuation. Additionally, Varney noted that patients who had psychosis and dementia had more severe and longer-lasting dementia.

TREATMENT: Progressive decline

Mr. K is college educated, has been married for 15 years, has 2 children, age 9 and 11, and owns a successful basketball coaching business. He has no history of substance abuse, legal issues, or violence. He reports a good childhood with normal developmental milestones and no history of trauma.

In the 6 months after his initial psychiatric admission, Mr. K sees various outpatient providers, who change his psychotropics multiple times. He also receives 4 courses of prednisone for ocular sarcoidosis. He is admitted twice to other psychiatric facilities. After he has paranoid interactions with colleagues and families of the youth he coaches, his business fails.

After his third psychiatric inpatient hospitalization, Mr. K becomes severely paranoid, believing his wife is having an affair. He becomes physically abusive to his wife, who obtains a restraining order and leaves with their children. Mr. K barely leaves his house and stops grooming. A friend notes that Mr. K’s home has become uninhabitable, and it goes into foreclosure. After Mr. K’s neighbors report combative behavior and paranoia, police bring him in on an involuntary hold for a fourth psychiatric hospitalization (the second in our facility).

During this hospitalization—6 months after the initial ED presentation—the neurology team conducts a repeat medical workup. EEG shows generalized slowing. Head CT and MRI show diffuse cortical atrophy that was not seen in previous imaging. Mr. K has ocular lesions characteristic of ocular sarcoidosis. His mental status examination is similar to his first presentation except that the psychosis and thought disorganization are considerably worse. His cognitive functioning also shows significant decline. Cognitive screening reveals intact remote memory with impaired recent memory. His thinking is concrete and his verbal memory is markedly impaired. His Mini-Mental State Examination score is 27/30, indicating functional capacity that is better than his clinical presentation. Because of difficulty with concentration and verbal processing, Mr. K is unable to complete the Minnesota Multiphasic Personality Inventory despite substantial assistance. On most days he cannot recall recent conversations with his wife, staff, or physicians. He is taking no medications at this time.

Mr. K is restarted on olanzapine, titrated to 30 mg/d, to control his psychosis; this medication was effective during his last stay in our facility. Oral prednisone is discontinued and methotrexate, 10 mg/week, is initiated for ocular sarcoidosis. Based on recommendations from a case series report,⁵ we start Mr. K on lithium, titrated to 600 mg twice a day, for steroid-induced mood symptoms, Mr. K’s psychosis and mood improve dramatically once he reaches a therapeutic lithium level; however, his cognition remains slowed and he is unable to care for his basic needs.

The authors’ observations

Steroid dementia may be the result of effects in the medial temporal lobe, specifically dorsolateral prefrontal cortex, which impairs working memory, and the parahippocampal gyrus.^6,7 The cognitive presentation of steroid dementia Varney et al³ described has been replicated in healthy volunteers who received corticosteroids.³ Patients with Cushing’s syndrome also have been noted to have diminished hippocampal volume and similar cognitive deficits. Cognitive impairment experienced by patients treated with corticosteroids may be caused by neuronal death in the hippocampus and dorsolateral prefrontal cortex. The etiology of cell death is multifactorial and includes glutamate-mediated excitotoxicity, activation of proinflammatory pathways, inhibited utilization of glucose in the hippocampus, telomere shortening, and diminished cell repair by brain-derived neurotrophic factor. The net result is significant, widespread damage that in some cases is irreversible.⁸

Because of the severity of Mr. K’s psychosis and personality change from baseline, his cognitive symptoms were largely overlooked during his first psychiatric hospitalization. The affective flattening, delayed verbal response, and markedly concrete thought process were considered within the spectrum of resolving psychosis. After further hospitalizations and abnormal results on cognitive testing, Mr. K’s cognitive impairment was fully noted. His symptoms match those of previously documented cases of steroid dementia, including verbal deficits out of proportion to other impairment, acute cerebral atrophy on CT after corticosteroid treatment, and gradual improvement of symptoms when corticosteroids were discontinued.

Management recommendations

Educate patients taking steroids about possible side effects of mood changes, psychosis, and cognitive deficits. Close monitoring of patients on corticosteroids is paramount. If psychiatric or cognitive symptoms develop, gradually discontinue the corticosteroid and seek other treatments.

Randomized, placebo-controlled trials of lamotrigine and memantine have shown these medications are cognitively protective for patients taking prednisone.⁹

OUTCOME: Long-term deficits

After a 33-day stay in our adult inpatient psychiatric facility, the county places Mr. K in a permanent conservatorship for severe grave disability. He is discharged to a long-term psychiatric care locked facility for ongoing management. Mr. K spends 20 months in the long-term care facility while his family remains hopeful for his recovery and return home. He is admitted to our facility for acute stabilization of psychotic symptoms after he is released from the locked facility. Although no imaging studies are conducted, he remains significantly forgetful. Additionally, his paranoia persists.

Mr. K is poorly compliant with his psychotropics, which include divalproex, 1,000 mg/d, and olanzapine, 30 mg/d. Although he is discharged home with his family, his functional capacity is less than expected and he requires continuous support. Insisting that Mr. K abstain from steroids after the first psychiatric hospitalization might have prevented this seemingly irreversible dementia.

Related Resources

• Sacks O, Shulman M. Steroid dementia: an overlooked diagnosis? Neurology. 2005;64(4):707-709.
• Cipriani G, Picchi L, Vedovello M, et al. Reversible dementia from corticosteroid therapy. Clinical Geriatrics. 2012;20(7):38-41.

Drug Brand Names

• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Memantine • Namenda
• Methotrexate • Rheumatrex, Trexall
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Prednisone • Deltasone, Meticorten, others

Disclosure

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