Amandeep Singh Bains, MD

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

Psychiatric patients smoke at a higher rate than the general population.² One study found that approximately 70% of patients with schizophrenia and as many as 45% of those with bipolar disorder smoke enough cigarettes (7 to 20 a day) to induce CYP1A2 and CYP2B6 activity.² Patients who smoke and are given clozapine, haloperidol, or olanzapine show a lower serum concen­tration than non-smokers; in fact, the clo­zapine level can be reduced as much as 2.4-fold.2-5 Subsequently, patients can expe­rience diminished clinical response to these 3 psychotropics.³

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

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

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

Psychiatric patients smoke at a higher rate than the general population.² One study found that approximately 70% of patients with schizophrenia and as many as 45% of those with bipolar disorder smoke enough cigarettes (7 to 20 a day) to induce CYP1A2 and CYP2B6 activity.² Patients who smoke and are given clozapine, haloperidol, or olanzapine show a lower serum concen­tration than non-smokers; in fact, the clo­zapine level can be reduced as much as 2.4-fold.2-5 Subsequently, patients can expe­rience diminished clinical response to these 3 psychotropics.³

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

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

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

Psychiatric patients smoke at a higher rate than the general population.² One study found that approximately 70% of patients with schizophrenia and as many as 45% of those with bipolar disorder smoke enough cigarettes (7 to 20 a day) to induce CYP1A2 and CYP2B6 activity.² Patients who smoke and are given clozapine, haloperidol, or olanzapine show a lower serum concen­tration than non-smokers; in fact, the clo­zapine level can be reduced as much as 2.4-fold.2-5 Subsequently, patients can expe­rience diminished clinical response to these 3 psychotropics.³

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

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

In some patients, symptoms of depres­sion, psychosis, delirium, or dementia exist concomitantly with, or as a result of, an abnormal (elevated or low) serum cal­cium concentration that has been precipi­tated by an unrecognized endocrinopathy. The apparent psychiatric presentations of such patients might reflect parathyroid pathology—not psychopathology.

Hypercalcemia and hypocalcemia often are related to a distinct spectrum of condi­tions, such as diseases of the parathyroid glands, kidneys, and various neoplasms including malignancies. Be alert to the pos­sibility of parathyroid disease in patients whose presentation suggests mental ill­ness concurrent with, or as a direct conse­quence of, an abnormal calcium level, and investigate appropriately.

The Table^1-9 illustrates how 3 clini­cal laboratory tests—serum calcium, serum parathyroid hormone (PTH), and phosphate—can narrow the differen­tial diagnosis when the clinical impres­sion is parathyroid-related illness. Seek endocrinology consultation whenever a parathyroid-associated ailment is discov­ered or suspected. Serum calcium is rou­tinely assayed in hospitalized patients; when managing a patient with treatment-refractory psychiatric illness, (1) always check the reported result of that test and (2) consider measuring PTH.

Case reports¹
Case 1: Woman with chronic depression. The patient was hospitalized while suicidal. Serial serum calcium levels were 12.5 mg/dL and 15.8 mg/dL (reference range, 8.2–10.2 mg/dL). The PTH level was elevated at 287 pg/mL (refer­ence range, 10–65 pg/mL).

After thyroid imaging, surgery revealed a parathyroid mass, which was resected. Histologic examination confirmed an adenoma.

The calcium concentration declined to 8.6 mg/dL postoperatively and stabilized at 9.2 mg/dL. Psychiatric symptoms resolved fully; she experienced a complete recovery.

Case 2: Man on long-term lithium mainte­nance. The patient was admitted in a delusional psychotic state. The serum calcium level was 14.3 mg/dL initially, decreasing to 11.5 mg/dL after lithium was discontinued. The PTH level was elevated at 97 pg/mL at admission, consis­tent with hyperparathyroidism.

A parathyroid adenoma was resected. Serum calcium level normalized at 10.7 mg/dL; psycho­sis resolved with striking, sustained improve­ment in mental status.

Full return to mental, physical health

The diagnosis of parathyroid adenoma in these 2 patients, which began with a psy­chiatric presentation, was properly made after an abnormal serum calcium level was documented. Surgical treatment of the endocrinopathy produced full remission and a return to normal mental and physi­cal health.

Although psychiatric manifestations are associated with an abnormal serum calcium concentration, the severity of those presen­tations does not correlate with the degree of abnormality of the calcium level.¹⁰

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

In some patients, symptoms of depres­sion, psychosis, delirium, or dementia exist concomitantly with, or as a result of, an abnormal (elevated or low) serum cal­cium concentration that has been precipi­tated by an unrecognized endocrinopathy. The apparent psychiatric presentations of such patients might reflect parathyroid pathology—not psychopathology.

Hypercalcemia and hypocalcemia often are related to a distinct spectrum of condi­tions, such as diseases of the parathyroid glands, kidneys, and various neoplasms including malignancies. Be alert to the pos­sibility of parathyroid disease in patients whose presentation suggests mental ill­ness concurrent with, or as a direct conse­quence of, an abnormal calcium level, and investigate appropriately.

The Table^1-9 illustrates how 3 clini­cal laboratory tests—serum calcium, serum parathyroid hormone (PTH), and phosphate—can narrow the differen­tial diagnosis when the clinical impres­sion is parathyroid-related illness. Seek endocrinology consultation whenever a parathyroid-associated ailment is discov­ered or suspected. Serum calcium is rou­tinely assayed in hospitalized patients; when managing a patient with treatment-refractory psychiatric illness, (1) always check the reported result of that test and (2) consider measuring PTH.

Case reports¹
Case 1: Woman with chronic depression. The patient was hospitalized while suicidal. Serial serum calcium levels were 12.5 mg/dL and 15.8 mg/dL (reference range, 8.2–10.2 mg/dL). The PTH level was elevated at 287 pg/mL (refer­ence range, 10–65 pg/mL).

After thyroid imaging, surgery revealed a parathyroid mass, which was resected. Histologic examination confirmed an adenoma.

The calcium concentration declined to 8.6 mg/dL postoperatively and stabilized at 9.2 mg/dL. Psychiatric symptoms resolved fully; she experienced a complete recovery.

Case 2: Man on long-term lithium mainte­nance. The patient was admitted in a delusional psychotic state. The serum calcium level was 14.3 mg/dL initially, decreasing to 11.5 mg/dL after lithium was discontinued. The PTH level was elevated at 97 pg/mL at admission, consis­tent with hyperparathyroidism.

A parathyroid adenoma was resected. Serum calcium level normalized at 10.7 mg/dL; psycho­sis resolved with striking, sustained improve­ment in mental status.

Full return to mental, physical health

The diagnosis of parathyroid adenoma in these 2 patients, which began with a psy­chiatric presentation, was properly made after an abnormal serum calcium level was documented. Surgical treatment of the endocrinopathy produced full remission and a return to normal mental and physi­cal health.

Although psychiatric manifestations are associated with an abnormal serum calcium concentration, the severity of those presen­tations does not correlate with the degree of abnormality of the calcium level.¹⁰

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

In some patients, symptoms of depres­sion, psychosis, delirium, or dementia exist concomitantly with, or as a result of, an abnormal (elevated or low) serum cal­cium concentration that has been precipi­tated by an unrecognized endocrinopathy. The apparent psychiatric presentations of such patients might reflect parathyroid pathology—not psychopathology.

Hypercalcemia and hypocalcemia often are related to a distinct spectrum of condi­tions, such as diseases of the parathyroid glands, kidneys, and various neoplasms including malignancies. Be alert to the pos­sibility of parathyroid disease in patients whose presentation suggests mental ill­ness concurrent with, or as a direct conse­quence of, an abnormal calcium level, and investigate appropriately.

The Table^1-9 illustrates how 3 clini­cal laboratory tests—serum calcium, serum parathyroid hormone (PTH), and phosphate—can narrow the differen­tial diagnosis when the clinical impres­sion is parathyroid-related illness. Seek endocrinology consultation whenever a parathyroid-associated ailment is discov­ered or suspected. Serum calcium is rou­tinely assayed in hospitalized patients; when managing a patient with treatment-refractory psychiatric illness, (1) always check the reported result of that test and (2) consider measuring PTH.

Case reports¹
Case 1: Woman with chronic depression. The patient was hospitalized while suicidal. Serial serum calcium levels were 12.5 mg/dL and 15.8 mg/dL (reference range, 8.2–10.2 mg/dL). The PTH level was elevated at 287 pg/mL (refer­ence range, 10–65 pg/mL).

After thyroid imaging, surgery revealed a parathyroid mass, which was resected. Histologic examination confirmed an adenoma.

The calcium concentration declined to 8.6 mg/dL postoperatively and stabilized at 9.2 mg/dL. Psychiatric symptoms resolved fully; she experienced a complete recovery.

Case 2: Man on long-term lithium mainte­nance. The patient was admitted in a delusional psychotic state. The serum calcium level was 14.3 mg/dL initially, decreasing to 11.5 mg/dL after lithium was discontinued. The PTH level was elevated at 97 pg/mL at admission, consis­tent with hyperparathyroidism.

A parathyroid adenoma was resected. Serum calcium level normalized at 10.7 mg/dL; psycho­sis resolved with striking, sustained improve­ment in mental status.

Full return to mental, physical health

The diagnosis of parathyroid adenoma in these 2 patients, which began with a psy­chiatric presentation, was properly made after an abnormal serum calcium level was documented. Surgical treatment of the endocrinopathy produced full remission and a return to normal mental and physi­cal health.

Although psychiatric manifestations are associated with an abnormal serum calcium concentration, the severity of those presen­tations does not correlate with the degree of abnormality of the calcium level.¹⁰

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