More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote

More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote

More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote

Anxiety disorders are the most common psychiatric illnesses in the United States, with a prevalence of nearly 29%.¹ These disorders typically are treated with pharmacotherapy, psychotherapy, or a combination of both. Pharmacotherapy for anxiety has evolved considerably during the last 30 years, but medications are not efficacious for or tolerated by all patients. For example, selective serotonin reuptake inhibitors, which are frequently used for treating anxiety, can cause sexual dysfunction,² weight gain,² drug interactions,² coagulopathies,³ and gastrointestinal disturbances.⁴ Psychotherapeutic techniques, such as cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), are efficacious for mild to moderate anxiety.^5-7

In addition to standard pharmacotherapy and psychotherapy, some evidence suggests that complementary therapies, such as yoga, massage, and relaxation techniques, may be beneficial as adjunctive treatments for anxiety. In placebo-controlled trials, several of these complementary therapies have been shown to decrease serum levels of the inflammatory biomarker cortisol. Anxiety is associated with inflammation,⁸ so therapies that reduce inflammation may help reduce symptoms of anxiety. Here, we describe the results of select positive randomized controlled trials (RCTs) of several complementary interventions for anxiety that might be useful as adjunctive treatments to psychotherapy or pharmacotherapy.

A look at RCTs that measured both anxiety and cortisol

We searched PubMed, Google Scholar, and Scopus to identify RCTs of complementary nonpharmacologic and nonpsychotherapeutic therapies for anxiety published from January 2010 to May 2017. We included only studies that:

• blindly assessed anxiety levels through a validated instrument (the State-Trait Anxiety Inventory [STAI])⁹
• measured cortisol concentrations before and after treatment.

Evaluating both STAI scores and cortisol levels is useful because doing so gives insight into both the clinical and biological efficacy of the therapies. Studies were excluded if they employed a pharmacologic agent in addition to the approach being evaluated.

We identified 26 studies, of which 14 met the inclusion/exclusion criteria. These studies found beneficial effects for yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Yoga

Yoga has become increasingly popular in the Western world during the last 2 decades.¹⁰ There are a variety of yoga practices; common forms include hatha yoga, power yoga, kripalu yoga, and forrest yoga.¹¹

A study of 92 depressed pregnant women monitored the effects of 20 minutes of yoga once a week for 12 weeks.¹² Half of the women were randomly assigned to the yoga intervention, which consisted of standing, kneeling, and seated poses, and half were assigned to a social support discussion group. After 12 weeks, both groups had significant decreases in STAI scores. Both groups also had statistically significant decreases in salivary cortisol levels immediately after each session.¹²

Hatha yoga consists of a combination of postural exercises, breathing techniques, relaxation, and meditation. In a 12-week study of 88 postmenopausal women, those who practiced hatha yoga for 75 minutes a day had significantly lower STAI scores compared with women who exercised for 75 minutes a day and those who performed no physical activity.¹³

Continue to: Massage therapy

Massage therapy

Receiving as little as 15 minutes of back massage has proven to be beneficial for individuals with anxiety. In an RCT conducted in Turkey, 44 caregivers of patients with cancer were assigned to receive a back massage or to rest quietly in a room for 15 minutes once each day for 1 week.¹⁴ By the end of the week, compared with those who quietly rested, those who received the back massage had a statistically significant reduction in serum cortisol levels and STAI scores.¹⁴

Aromatherapy massage

Aromatherapy is the use of essential oils from plants through distillation.¹⁵ The scent of the oils is purported to provide medical benefits. More than 60 essential oils are used therapeutically, including rose, lavender, lemon, and orange.¹⁶ These essential oils are frequently used in combination with a massage.

In South Korea, researchers investigated the effects of aromatherapy massage on 25 women who had children diagnosed with attention-deficit/hyperactivity disorder.¹⁷ Women assigned to the treatment group received a 40-minute aromatherapy massage using mixed essential oils that contained lavender and geranium twice a week for 4 weeks. Women in the control group received no treatment. Compared with those in the control group, women who received the aromatherapy massages had a statistically significant decrease in STAI scores and salivary cortisol levels. Plasma cortisol was not significantly different between groups.¹⁷

Pet therapy

The psychological benefits of animal-assisted therapy were not evident until World War II, when dogs were used to cheer up injured soldiers.¹⁸ Today, pet therapy has been used on many inpatient units.¹⁹

In a U.S. study, 48 healthy undergraduate students were assigned to a room with a dog, a room with a friend, or a room by themselves.²⁰ All participants were given the Trier Social Stress Test (TSST), a protocol that measures stress by having participants give a speech and perform mental arithmetic in front of an audience.The TSST is known to induce increases in cortisol levels. Although no differences in STAI scores were found among groups, students in the room with the dog had a lower spike in salivary cortisol after the TSST compared with participants who were in a room with a friend or in a room alone.²⁰

Continue to: Qigong

In Chinese medicine, Qi is known as a vital life force that flows through the body. The disruption of Qi is hypothesized to contri­bute to disease.²¹

Qigong is a medical therapy that focuses on uniting the body, breath, and mind to improve health.²¹ It consists of rhythmic, choreographed movements used to position the body into postures believed to help direct Qi to specific areas in the body. Qigong also uses sound exercises, in which an individual creates certain syllables while breathing. Six syllables are used, each of which is believed to affect a certain organ.²¹

Korean researchers randomly assigned 32 healthy men to a Qigong training group or a sham Qigong control group.²² Individuals in the training group performed 25 minutes of sound exercises, 20 minutes of meditation, and 15 minutes of movements. The control group learned the same movements as the experimental group, but without the conscious effort of moving Qi. After 3 sessions, those in the Qigong training group had significantly decreased STAI scores and serum cortisol levels compared with those in the sham group.²²

In a different Korean study, researchers randomly assigned 50 participants with elevated distress levels to a Qigong training group or a waitlist control group in which participants called a trainer to describe stressful events.²³ After 4 weeks, participants in the Qigong group had significant decreases in STAI scores compared with the control group. However, there were no changes in salivary cortisol levels.²³

Auricular acupressure

Auricular acupressure involves applying pressure on certain portions of the auricle (outer ear) to alleviate pain and disease.²⁴ Similar to Qigong, auricular acupressure focuses on reestablishing Qi in the body. Researchers randomly assigned 80 post-caesarean section women in Taiwan to 5 days of auricular acupressure or usual care.²⁵ The women who received auricular acupressure had significantly lower STAI scores and serum cortisol levels compared with women who received routine care.²⁵

Continue to: Reiki touch therapy

Reiki touch therapy originated in Japan. In this therapy, healers apply a light touch or hover their hands above an individual’s body to help direct energy.²⁶

The effects of reiki touch therapy were recently evaluated in a U.S. study.²⁷ Researchers randomly assigned 37 patients with human immunodeficiency virus to an experimental group that received 30 minutes of reiki touch therapy plus music therapy 6 times a week for 10 weeks, or to a music therapy–only control group. Patients who received reiki touch therapy had a significant decrease in STAI scores. Patients in this group also had a statistically significant drop in salivary cortisol levels after the first week.²⁷

Acupuncture

Acupuncture is the application of needles to specific areas on the body. Acupuncture has been proposed to activate pain receptors, thereby producing an analgesic response.²⁸

Researchers in Brazil randomly assigned 57 lactating women with preterm infants to an experimental group that received acupuncture or to a control group that received sham acupuncture.²⁹ Treatment was administered at 5 points on the ear unilaterally for 5 minutes once a week for 16 months. Custom-made needles that did not actually puncture the skin were used in the sham group; a toothpick was used to create the sensation of needle perforations. STAI scores were reduced in both groups, although there was no statistically significant difference in scores between the acupuncture and sham groups.²⁹

Music therapy

Music has been long believed to have beneficial psychological effects. In Turkey, researchers evaluated the effects of music therapy in 100 oncology patients who received port catheters.³⁰ Patients were randomly assigned to an experimental group that received music therapy throughout the procedure or to a control group that received normal care. Patients who listened to music during port catheter placement had significantly reduced STAI scores and serum cortisol levels compared with those in the control group.³⁰

Continue to: Relaxation techniques

A wide range of relaxation techniques are used for therapeutic purposes. In Switzerland, researchers evaluated the anxiolytic effects of 10 minutes of progressive muscle relaxation and guided imagery in 39 pregnant women.³¹ Women randomly assigned to progressive muscle relaxation were instructed to systematically tense and then release muscle groups throughout their body in sequential order. Women assigned to the guided imagery intervention were told to imagine a safe place and to think of someone who could confer security and reassurance. The remainder of the women were assigned to a control group, where they sat quietly without any formal instructions. Researchers found that each group had a decrease in STAI scores and salivary cortisol levels immediately after the intervention.³¹

The relaxation response was first described in 1975 by Herbert Benson, MD, as a deep meditative state characterized by a decrease in tension, heart rate, and breathing rate. Several techniques can induce this state, including hypnosis, progressive muscle relaxation, yoga, and transcendental meditation.³² In a study of 15 healthy older adults (age 65 to 80), researchers randomly assigned participants to a relaxation response training group or to a control group.³³ The relaxation response training included meditation, imagery, and relaxation techniques. After 5 weeks, participants who received the relaxation response training had marginally significant decreases in STAI scores compared with those in the control group.³³

Consider these therapies as adjuncts

Our review of select positive RCTs (Table^{12-14,17,20,22,23,25,27,29-31,33}) suggests that some nonpharmacologic/nonpsychotherapeutic adjunctive interventions may have beneficial effects for patients who have anxiety. Several of the controlled studies we reviewed demonstrated that these interventions are superior to placebo. The reductions in both anxiety severity as measured by the STAI and cortisol levels suggests that some of these complementary therapies deserve a second look as useful adjuncts to established anxiety treatments.

Bottom Line

A review of select randomized controlled trials suggests that some complementary therapies may be helpful as adjunctive therapy in patients with anxiety. These include yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Related Resources

• Bandelow B, Baldwin D, Abelli M, et al. Biological markers for anxiety disorders, OCD and PTSD: a consensus statement. Part II: neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry. 2017;18(3):162-214.
• National Institute of Mental Health. Anxiety disorders. https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml.

Anxiety disorders are the most common psychiatric illnesses in the United States, with a prevalence of nearly 29%.¹ These disorders typically are treated with pharmacotherapy, psychotherapy, or a combination of both. Pharmacotherapy for anxiety has evolved considerably during the last 30 years, but medications are not efficacious for or tolerated by all patients. For example, selective serotonin reuptake inhibitors, which are frequently used for treating anxiety, can cause sexual dysfunction,² weight gain,² drug interactions,² coagulopathies,³ and gastrointestinal disturbances.⁴ Psychotherapeutic techniques, such as cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), are efficacious for mild to moderate anxiety.^5-7

In addition to standard pharmacotherapy and psychotherapy, some evidence suggests that complementary therapies, such as yoga, massage, and relaxation techniques, may be beneficial as adjunctive treatments for anxiety. In placebo-controlled trials, several of these complementary therapies have been shown to decrease serum levels of the inflammatory biomarker cortisol. Anxiety is associated with inflammation,⁸ so therapies that reduce inflammation may help reduce symptoms of anxiety. Here, we describe the results of select positive randomized controlled trials (RCTs) of several complementary interventions for anxiety that might be useful as adjunctive treatments to psychotherapy or pharmacotherapy.

A look at RCTs that measured both anxiety and cortisol

We searched PubMed, Google Scholar, and Scopus to identify RCTs of complementary nonpharmacologic and nonpsychotherapeutic therapies for anxiety published from January 2010 to May 2017. We included only studies that:

• blindly assessed anxiety levels through a validated instrument (the State-Trait Anxiety Inventory [STAI])⁹
• measured cortisol concentrations before and after treatment.

Evaluating both STAI scores and cortisol levels is useful because doing so gives insight into both the clinical and biological efficacy of the therapies. Studies were excluded if they employed a pharmacologic agent in addition to the approach being evaluated.

We identified 26 studies, of which 14 met the inclusion/exclusion criteria. These studies found beneficial effects for yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Yoga

Yoga has become increasingly popular in the Western world during the last 2 decades.¹⁰ There are a variety of yoga practices; common forms include hatha yoga, power yoga, kripalu yoga, and forrest yoga.¹¹

A study of 92 depressed pregnant women monitored the effects of 20 minutes of yoga once a week for 12 weeks.¹² Half of the women were randomly assigned to the yoga intervention, which consisted of standing, kneeling, and seated poses, and half were assigned to a social support discussion group. After 12 weeks, both groups had significant decreases in STAI scores. Both groups also had statistically significant decreases in salivary cortisol levels immediately after each session.¹²

Hatha yoga consists of a combination of postural exercises, breathing techniques, relaxation, and meditation. In a 12-week study of 88 postmenopausal women, those who practiced hatha yoga for 75 minutes a day had significantly lower STAI scores compared with women who exercised for 75 minutes a day and those who performed no physical activity.¹³

Continue to: Massage therapy

Massage therapy

Receiving as little as 15 minutes of back massage has proven to be beneficial for individuals with anxiety. In an RCT conducted in Turkey, 44 caregivers of patients with cancer were assigned to receive a back massage or to rest quietly in a room for 15 minutes once each day for 1 week.¹⁴ By the end of the week, compared with those who quietly rested, those who received the back massage had a statistically significant reduction in serum cortisol levels and STAI scores.¹⁴

Aromatherapy massage

Aromatherapy is the use of essential oils from plants through distillation.¹⁵ The scent of the oils is purported to provide medical benefits. More than 60 essential oils are used therapeutically, including rose, lavender, lemon, and orange.¹⁶ These essential oils are frequently used in combination with a massage.

In South Korea, researchers investigated the effects of aromatherapy massage on 25 women who had children diagnosed with attention-deficit/hyperactivity disorder.¹⁷ Women assigned to the treatment group received a 40-minute aromatherapy massage using mixed essential oils that contained lavender and geranium twice a week for 4 weeks. Women in the control group received no treatment. Compared with those in the control group, women who received the aromatherapy massages had a statistically significant decrease in STAI scores and salivary cortisol levels. Plasma cortisol was not significantly different between groups.¹⁷

Pet therapy

The psychological benefits of animal-assisted therapy were not evident until World War II, when dogs were used to cheer up injured soldiers.¹⁸ Today, pet therapy has been used on many inpatient units.¹⁹

In a U.S. study, 48 healthy undergraduate students were assigned to a room with a dog, a room with a friend, or a room by themselves.²⁰ All participants were given the Trier Social Stress Test (TSST), a protocol that measures stress by having participants give a speech and perform mental arithmetic in front of an audience.The TSST is known to induce increases in cortisol levels. Although no differences in STAI scores were found among groups, students in the room with the dog had a lower spike in salivary cortisol after the TSST compared with participants who were in a room with a friend or in a room alone.²⁰

Continue to: Qigong

In Chinese medicine, Qi is known as a vital life force that flows through the body. The disruption of Qi is hypothesized to contri­bute to disease.²¹

Qigong is a medical therapy that focuses on uniting the body, breath, and mind to improve health.²¹ It consists of rhythmic, choreographed movements used to position the body into postures believed to help direct Qi to specific areas in the body. Qigong also uses sound exercises, in which an individual creates certain syllables while breathing. Six syllables are used, each of which is believed to affect a certain organ.²¹

Korean researchers randomly assigned 32 healthy men to a Qigong training group or a sham Qigong control group.²² Individuals in the training group performed 25 minutes of sound exercises, 20 minutes of meditation, and 15 minutes of movements. The control group learned the same movements as the experimental group, but without the conscious effort of moving Qi. After 3 sessions, those in the Qigong training group had significantly decreased STAI scores and serum cortisol levels compared with those in the sham group.²²

In a different Korean study, researchers randomly assigned 50 participants with elevated distress levels to a Qigong training group or a waitlist control group in which participants called a trainer to describe stressful events.²³ After 4 weeks, participants in the Qigong group had significant decreases in STAI scores compared with the control group. However, there were no changes in salivary cortisol levels.²³

Auricular acupressure

Auricular acupressure involves applying pressure on certain portions of the auricle (outer ear) to alleviate pain and disease.²⁴ Similar to Qigong, auricular acupressure focuses on reestablishing Qi in the body. Researchers randomly assigned 80 post-caesarean section women in Taiwan to 5 days of auricular acupressure or usual care.²⁵ The women who received auricular acupressure had significantly lower STAI scores and serum cortisol levels compared with women who received routine care.²⁵

Continue to: Reiki touch therapy

Reiki touch therapy originated in Japan. In this therapy, healers apply a light touch or hover their hands above an individual’s body to help direct energy.²⁶

The effects of reiki touch therapy were recently evaluated in a U.S. study.²⁷ Researchers randomly assigned 37 patients with human immunodeficiency virus to an experimental group that received 30 minutes of reiki touch therapy plus music therapy 6 times a week for 10 weeks, or to a music therapy–only control group. Patients who received reiki touch therapy had a significant decrease in STAI scores. Patients in this group also had a statistically significant drop in salivary cortisol levels after the first week.²⁷

Acupuncture

Acupuncture is the application of needles to specific areas on the body. Acupuncture has been proposed to activate pain receptors, thereby producing an analgesic response.²⁸

Researchers in Brazil randomly assigned 57 lactating women with preterm infants to an experimental group that received acupuncture or to a control group that received sham acupuncture.²⁹ Treatment was administered at 5 points on the ear unilaterally for 5 minutes once a week for 16 months. Custom-made needles that did not actually puncture the skin were used in the sham group; a toothpick was used to create the sensation of needle perforations. STAI scores were reduced in both groups, although there was no statistically significant difference in scores between the acupuncture and sham groups.²⁹

Music therapy

Music has been long believed to have beneficial psychological effects. In Turkey, researchers evaluated the effects of music therapy in 100 oncology patients who received port catheters.³⁰ Patients were randomly assigned to an experimental group that received music therapy throughout the procedure or to a control group that received normal care. Patients who listened to music during port catheter placement had significantly reduced STAI scores and serum cortisol levels compared with those in the control group.³⁰

Continue to: Relaxation techniques

A wide range of relaxation techniques are used for therapeutic purposes. In Switzerland, researchers evaluated the anxiolytic effects of 10 minutes of progressive muscle relaxation and guided imagery in 39 pregnant women.³¹ Women randomly assigned to progressive muscle relaxation were instructed to systematically tense and then release muscle groups throughout their body in sequential order. Women assigned to the guided imagery intervention were told to imagine a safe place and to think of someone who could confer security and reassurance. The remainder of the women were assigned to a control group, where they sat quietly without any formal instructions. Researchers found that each group had a decrease in STAI scores and salivary cortisol levels immediately after the intervention.³¹

The relaxation response was first described in 1975 by Herbert Benson, MD, as a deep meditative state characterized by a decrease in tension, heart rate, and breathing rate. Several techniques can induce this state, including hypnosis, progressive muscle relaxation, yoga, and transcendental meditation.³² In a study of 15 healthy older adults (age 65 to 80), researchers randomly assigned participants to a relaxation response training group or to a control group.³³ The relaxation response training included meditation, imagery, and relaxation techniques. After 5 weeks, participants who received the relaxation response training had marginally significant decreases in STAI scores compared with those in the control group.³³

Consider these therapies as adjuncts

Our review of select positive RCTs (Table^{12-14,17,20,22,23,25,27,29-31,33}) suggests that some nonpharmacologic/nonpsychotherapeutic adjunctive interventions may have beneficial effects for patients who have anxiety. Several of the controlled studies we reviewed demonstrated that these interventions are superior to placebo. The reductions in both anxiety severity as measured by the STAI and cortisol levels suggests that some of these complementary therapies deserve a second look as useful adjuncts to established anxiety treatments.

Bottom Line

A review of select randomized controlled trials suggests that some complementary therapies may be helpful as adjunctive therapy in patients with anxiety. These include yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Related Resources

• Bandelow B, Baldwin D, Abelli M, et al. Biological markers for anxiety disorders, OCD and PTSD: a consensus statement. Part II: neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry. 2017;18(3):162-214.
• National Institute of Mental Health. Anxiety disorders. https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml.

Anxiety disorders are the most common psychiatric illnesses in the United States, with a prevalence of nearly 29%.¹ These disorders typically are treated with pharmacotherapy, psychotherapy, or a combination of both. Pharmacotherapy for anxiety has evolved considerably during the last 30 years, but medications are not efficacious for or tolerated by all patients. For example, selective serotonin reuptake inhibitors, which are frequently used for treating anxiety, can cause sexual dysfunction,² weight gain,² drug interactions,² coagulopathies,³ and gastrointestinal disturbances.⁴ Psychotherapeutic techniques, such as cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), are efficacious for mild to moderate anxiety.^5-7

In addition to standard pharmacotherapy and psychotherapy, some evidence suggests that complementary therapies, such as yoga, massage, and relaxation techniques, may be beneficial as adjunctive treatments for anxiety. In placebo-controlled trials, several of these complementary therapies have been shown to decrease serum levels of the inflammatory biomarker cortisol. Anxiety is associated with inflammation,⁸ so therapies that reduce inflammation may help reduce symptoms of anxiety. Here, we describe the results of select positive randomized controlled trials (RCTs) of several complementary interventions for anxiety that might be useful as adjunctive treatments to psychotherapy or pharmacotherapy.

A look at RCTs that measured both anxiety and cortisol

We searched PubMed, Google Scholar, and Scopus to identify RCTs of complementary nonpharmacologic and nonpsychotherapeutic therapies for anxiety published from January 2010 to May 2017. We included only studies that:

• blindly assessed anxiety levels through a validated instrument (the State-Trait Anxiety Inventory [STAI])⁹
• measured cortisol concentrations before and after treatment.

Evaluating both STAI scores and cortisol levels is useful because doing so gives insight into both the clinical and biological efficacy of the therapies. Studies were excluded if they employed a pharmacologic agent in addition to the approach being evaluated.

We identified 26 studies, of which 14 met the inclusion/exclusion criteria. These studies found beneficial effects for yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Yoga

Yoga has become increasingly popular in the Western world during the last 2 decades.¹⁰ There are a variety of yoga practices; common forms include hatha yoga, power yoga, kripalu yoga, and forrest yoga.¹¹

A study of 92 depressed pregnant women monitored the effects of 20 minutes of yoga once a week for 12 weeks.¹² Half of the women were randomly assigned to the yoga intervention, which consisted of standing, kneeling, and seated poses, and half were assigned to a social support discussion group. After 12 weeks, both groups had significant decreases in STAI scores. Both groups also had statistically significant decreases in salivary cortisol levels immediately after each session.¹²

Hatha yoga consists of a combination of postural exercises, breathing techniques, relaxation, and meditation. In a 12-week study of 88 postmenopausal women, those who practiced hatha yoga for 75 minutes a day had significantly lower STAI scores compared with women who exercised for 75 minutes a day and those who performed no physical activity.¹³

Continue to: Massage therapy

Massage therapy

Receiving as little as 15 minutes of back massage has proven to be beneficial for individuals with anxiety. In an RCT conducted in Turkey, 44 caregivers of patients with cancer were assigned to receive a back massage or to rest quietly in a room for 15 minutes once each day for 1 week.¹⁴ By the end of the week, compared with those who quietly rested, those who received the back massage had a statistically significant reduction in serum cortisol levels and STAI scores.¹⁴

Aromatherapy massage

Aromatherapy is the use of essential oils from plants through distillation.¹⁵ The scent of the oils is purported to provide medical benefits. More than 60 essential oils are used therapeutically, including rose, lavender, lemon, and orange.¹⁶ These essential oils are frequently used in combination with a massage.

In South Korea, researchers investigated the effects of aromatherapy massage on 25 women who had children diagnosed with attention-deficit/hyperactivity disorder.¹⁷ Women assigned to the treatment group received a 40-minute aromatherapy massage using mixed essential oils that contained lavender and geranium twice a week for 4 weeks. Women in the control group received no treatment. Compared with those in the control group, women who received the aromatherapy massages had a statistically significant decrease in STAI scores and salivary cortisol levels. Plasma cortisol was not significantly different between groups.¹⁷

Pet therapy

The psychological benefits of animal-assisted therapy were not evident until World War II, when dogs were used to cheer up injured soldiers.¹⁸ Today, pet therapy has been used on many inpatient units.¹⁹

In a U.S. study, 48 healthy undergraduate students were assigned to a room with a dog, a room with a friend, or a room by themselves.²⁰ All participants were given the Trier Social Stress Test (TSST), a protocol that measures stress by having participants give a speech and perform mental arithmetic in front of an audience.The TSST is known to induce increases in cortisol levels. Although no differences in STAI scores were found among groups, students in the room with the dog had a lower spike in salivary cortisol after the TSST compared with participants who were in a room with a friend or in a room alone.²⁰

Continue to: Qigong

In Chinese medicine, Qi is known as a vital life force that flows through the body. The disruption of Qi is hypothesized to contri­bute to disease.²¹

Qigong is a medical therapy that focuses on uniting the body, breath, and mind to improve health.²¹ It consists of rhythmic, choreographed movements used to position the body into postures believed to help direct Qi to specific areas in the body. Qigong also uses sound exercises, in which an individual creates certain syllables while breathing. Six syllables are used, each of which is believed to affect a certain organ.²¹

Korean researchers randomly assigned 32 healthy men to a Qigong training group or a sham Qigong control group.²² Individuals in the training group performed 25 minutes of sound exercises, 20 minutes of meditation, and 15 minutes of movements. The control group learned the same movements as the experimental group, but without the conscious effort of moving Qi. After 3 sessions, those in the Qigong training group had significantly decreased STAI scores and serum cortisol levels compared with those in the sham group.²²

In a different Korean study, researchers randomly assigned 50 participants with elevated distress levels to a Qigong training group or a waitlist control group in which participants called a trainer to describe stressful events.²³ After 4 weeks, participants in the Qigong group had significant decreases in STAI scores compared with the control group. However, there were no changes in salivary cortisol levels.²³

Auricular acupressure

Auricular acupressure involves applying pressure on certain portions of the auricle (outer ear) to alleviate pain and disease.²⁴ Similar to Qigong, auricular acupressure focuses on reestablishing Qi in the body. Researchers randomly assigned 80 post-caesarean section women in Taiwan to 5 days of auricular acupressure or usual care.²⁵ The women who received auricular acupressure had significantly lower STAI scores and serum cortisol levels compared with women who received routine care.²⁵

Continue to: Reiki touch therapy

Reiki touch therapy originated in Japan. In this therapy, healers apply a light touch or hover their hands above an individual’s body to help direct energy.²⁶

The effects of reiki touch therapy were recently evaluated in a U.S. study.²⁷ Researchers randomly assigned 37 patients with human immunodeficiency virus to an experimental group that received 30 minutes of reiki touch therapy plus music therapy 6 times a week for 10 weeks, or to a music therapy–only control group. Patients who received reiki touch therapy had a significant decrease in STAI scores. Patients in this group also had a statistically significant drop in salivary cortisol levels after the first week.²⁷

Acupuncture

Acupuncture is the application of needles to specific areas on the body. Acupuncture has been proposed to activate pain receptors, thereby producing an analgesic response.²⁸

Researchers in Brazil randomly assigned 57 lactating women with preterm infants to an experimental group that received acupuncture or to a control group that received sham acupuncture.²⁹ Treatment was administered at 5 points on the ear unilaterally for 5 minutes once a week for 16 months. Custom-made needles that did not actually puncture the skin were used in the sham group; a toothpick was used to create the sensation of needle perforations. STAI scores were reduced in both groups, although there was no statistically significant difference in scores between the acupuncture and sham groups.²⁹

Music therapy

Music has been long believed to have beneficial psychological effects. In Turkey, researchers evaluated the effects of music therapy in 100 oncology patients who received port catheters.³⁰ Patients were randomly assigned to an experimental group that received music therapy throughout the procedure or to a control group that received normal care. Patients who listened to music during port catheter placement had significantly reduced STAI scores and serum cortisol levels compared with those in the control group.³⁰

Continue to: Relaxation techniques

A wide range of relaxation techniques are used for therapeutic purposes. In Switzerland, researchers evaluated the anxiolytic effects of 10 minutes of progressive muscle relaxation and guided imagery in 39 pregnant women.³¹ Women randomly assigned to progressive muscle relaxation were instructed to systematically tense and then release muscle groups throughout their body in sequential order. Women assigned to the guided imagery intervention were told to imagine a safe place and to think of someone who could confer security and reassurance. The remainder of the women were assigned to a control group, where they sat quietly without any formal instructions. Researchers found that each group had a decrease in STAI scores and salivary cortisol levels immediately after the intervention.³¹

The relaxation response was first described in 1975 by Herbert Benson, MD, as a deep meditative state characterized by a decrease in tension, heart rate, and breathing rate. Several techniques can induce this state, including hypnosis, progressive muscle relaxation, yoga, and transcendental meditation.³² In a study of 15 healthy older adults (age 65 to 80), researchers randomly assigned participants to a relaxation response training group or to a control group.³³ The relaxation response training included meditation, imagery, and relaxation techniques. After 5 weeks, participants who received the relaxation response training had marginally significant decreases in STAI scores compared with those in the control group.³³

Consider these therapies as adjuncts

Our review of select positive RCTs (Table^{12-14,17,20,22,23,25,27,29-31,33}) suggests that some nonpharmacologic/nonpsychotherapeutic adjunctive interventions may have beneficial effects for patients who have anxiety. Several of the controlled studies we reviewed demonstrated that these interventions are superior to placebo. The reductions in both anxiety severity as measured by the STAI and cortisol levels suggests that some of these complementary therapies deserve a second look as useful adjuncts to established anxiety treatments.

Bottom Line

A review of select randomized controlled trials suggests that some complementary therapies may be helpful as adjunctive therapy in patients with anxiety. These include yoga, massage therapy, aromatherapy massage, pet therapy, Qigong, auricular acupressure, reiki touch therapy, acupuncture, music therapy, and relaxation techniques.

Related Resources

• Bandelow B, Baldwin D, Abelli M, et al. Biological markers for anxiety disorders, OCD and PTSD: a consensus statement. Part II: neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry. 2017;18(3):162-214.
• National Institute of Mental Health. Anxiety disorders. https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml.

As evidence supporting the use of electroconvulsive therapy (ECT) to treat patients with depression and other psychiatric illnesses continues to grow, myths about this treatment persist. In light of these myths, patients might be reluctant to receive ECT. As clinicians, we need to educate patients about the safety and effectiveness of this treatment. Here are 10 of the most commonly held myths about ECT, and why each is a misconception.

1. It is a barbaric treatment. ECT is conducted in a controlled medical environment, either during a hospitalization or as an outpatient procedure, by a team consisting of a psychiatrist, anesthesiologist, and nurse. Patients receive a short-acting intravenous anesthetic to ensure that they are unaware of the procedure, and a muscle relaxant to help prevent physical injury. Vital signs and brain waves are monitored throughout the procedure, which typically lasts 15 to 20 minutes. Patients remain relaxed, are unaware that they are having a seizure, and experience no pain. Following ECT, the patient is taken to a recovery area, where he or she is closely monitored as the medications wear off.

2. It causes brain damage. Studies using MRI to look at the brain before and after ECT have found no evidence that ECT causes negative changes in the brain’s structural anatomy.¹ To the contrary, there is evidence that there is neuroplasticity in the brain in response to ECT, and the neurotrophin brain-derived neurotrophic factor also may be increased.^2,3

3. It causes permanent memory loss. ECT can result in both anterograde and retrograde memory impairment; however, anterograde amnesia typically lasts only days to weeks. Retrograde amnesia is much less common, but when it occurs, it tends to be loss of memory of events that took place in the weeks leading up to and during treatment. Using an ultrabrief (as opposed to standard brief) pulse, as well as right unilateral (as opposed to bilateral) electrode placement, substantially reduces the risk of cognitive and memory adverse effects.⁴

4. It is a treatment of last resort. Typically, ECT is used for patients who have not responded to other interventions. However, ECT can be used as a first-line treatment for patients if a rapid or higher likelihood of response is necessary, such as when a patient is suicidal, catatonic, or malnourished as a result of severe depression.⁵

5. It only works for depression. Evidence shows ECT is efficacious for several psychiatric conditions, not just unipolar depressive disorder. It can effectively treat bipolar depression, mania, catatonia, and acute psychosis associated with schizophrenia and schizoaffective disorders.⁶ ECT also has been demonstrated to be effective in acute and maintenance treatment of Parkinson’s disease.⁷

6. It is not safe. Death associated with ECT is extremely rare. A recent analysis estimated that the rate of ECT-related mortality is 2.1 deaths per 100,000 treatments. In comparison, the mortality rate of general anesthesia used during surgery has been reported as 3.4 deaths per 100,000 procedures.⁸ Evidence also suggests ECT can be safely administered to patients who are pregnant.⁹

Continue to: 7. It cannot be given to patients with epilepsy

7. It cannot be given to patients with epilepsy. There are no absolute contraindications to using ECT for these patients. Most patients with epilepsy can be successfully treated with ECT without requiring an adjustment to the dose of their antiepileptic medications.¹⁰

8. It will change one’s personality. ECT has not been found to cause any alterations in personality. Patients who are treated with ECT may describe feeling more like themselves once their chronic symptoms of depression have improved. However, ECT has not been shown to effectively treat the symptoms or underlying illness of personality disorders, and it may not be an effective treatment for depression associated with borderline personality disorder.¹¹

9. Its success rate is low. ECT has the highest response and remission rates of any form of treatment used for depression. An estimated 70% to 90% of patients with depression who are treated with ECT show improvement.¹²

10. It is a permanent cure. ECT is not likely a permanent solution for severe depression. The likelihood of relapse in patients with severe depression who are helped by ECT can be reduced by receiving ongoing antidepressant treatment, and some patients may require continuation or maintenance ECT.¹³

As evidence supporting the use of electroconvulsive therapy (ECT) to treat patients with depression and other psychiatric illnesses continues to grow, myths about this treatment persist. In light of these myths, patients might be reluctant to receive ECT. As clinicians, we need to educate patients about the safety and effectiveness of this treatment. Here are 10 of the most commonly held myths about ECT, and why each is a misconception.

1. It is a barbaric treatment. ECT is conducted in a controlled medical environment, either during a hospitalization or as an outpatient procedure, by a team consisting of a psychiatrist, anesthesiologist, and nurse. Patients receive a short-acting intravenous anesthetic to ensure that they are unaware of the procedure, and a muscle relaxant to help prevent physical injury. Vital signs and brain waves are monitored throughout the procedure, which typically lasts 15 to 20 minutes. Patients remain relaxed, are unaware that they are having a seizure, and experience no pain. Following ECT, the patient is taken to a recovery area, where he or she is closely monitored as the medications wear off.

2. It causes brain damage. Studies using MRI to look at the brain before and after ECT have found no evidence that ECT causes negative changes in the brain’s structural anatomy.¹ To the contrary, there is evidence that there is neuroplasticity in the brain in response to ECT, and the neurotrophin brain-derived neurotrophic factor also may be increased.^2,3

3. It causes permanent memory loss. ECT can result in both anterograde and retrograde memory impairment; however, anterograde amnesia typically lasts only days to weeks. Retrograde amnesia is much less common, but when it occurs, it tends to be loss of memory of events that took place in the weeks leading up to and during treatment. Using an ultrabrief (as opposed to standard brief) pulse, as well as right unilateral (as opposed to bilateral) electrode placement, substantially reduces the risk of cognitive and memory adverse effects.⁴

4. It is a treatment of last resort. Typically, ECT is used for patients who have not responded to other interventions. However, ECT can be used as a first-line treatment for patients if a rapid or higher likelihood of response is necessary, such as when a patient is suicidal, catatonic, or malnourished as a result of severe depression.⁵

5. It only works for depression. Evidence shows ECT is efficacious for several psychiatric conditions, not just unipolar depressive disorder. It can effectively treat bipolar depression, mania, catatonia, and acute psychosis associated with schizophrenia and schizoaffective disorders.⁶ ECT also has been demonstrated to be effective in acute and maintenance treatment of Parkinson’s disease.⁷

6. It is not safe. Death associated with ECT is extremely rare. A recent analysis estimated that the rate of ECT-related mortality is 2.1 deaths per 100,000 treatments. In comparison, the mortality rate of general anesthesia used during surgery has been reported as 3.4 deaths per 100,000 procedures.⁸ Evidence also suggests ECT can be safely administered to patients who are pregnant.⁹

Continue to: 7. It cannot be given to patients with epilepsy

7. It cannot be given to patients with epilepsy. There are no absolute contraindications to using ECT for these patients. Most patients with epilepsy can be successfully treated with ECT without requiring an adjustment to the dose of their antiepileptic medications.¹⁰

8. It will change one’s personality. ECT has not been found to cause any alterations in personality. Patients who are treated with ECT may describe feeling more like themselves once their chronic symptoms of depression have improved. However, ECT has not been shown to effectively treat the symptoms or underlying illness of personality disorders, and it may not be an effective treatment for depression associated with borderline personality disorder.¹¹

9. Its success rate is low. ECT has the highest response and remission rates of any form of treatment used for depression. An estimated 70% to 90% of patients with depression who are treated with ECT show improvement.¹²

10. It is a permanent cure. ECT is not likely a permanent solution for severe depression. The likelihood of relapse in patients with severe depression who are helped by ECT can be reduced by receiving ongoing antidepressant treatment, and some patients may require continuation or maintenance ECT.¹³

As evidence supporting the use of electroconvulsive therapy (ECT) to treat patients with depression and other psychiatric illnesses continues to grow, myths about this treatment persist. In light of these myths, patients might be reluctant to receive ECT. As clinicians, we need to educate patients about the safety and effectiveness of this treatment. Here are 10 of the most commonly held myths about ECT, and why each is a misconception.

1. It is a barbaric treatment. ECT is conducted in a controlled medical environment, either during a hospitalization or as an outpatient procedure, by a team consisting of a psychiatrist, anesthesiologist, and nurse. Patients receive a short-acting intravenous anesthetic to ensure that they are unaware of the procedure, and a muscle relaxant to help prevent physical injury. Vital signs and brain waves are monitored throughout the procedure, which typically lasts 15 to 20 minutes. Patients remain relaxed, are unaware that they are having a seizure, and experience no pain. Following ECT, the patient is taken to a recovery area, where he or she is closely monitored as the medications wear off.

2. It causes brain damage. Studies using MRI to look at the brain before and after ECT have found no evidence that ECT causes negative changes in the brain’s structural anatomy.¹ To the contrary, there is evidence that there is neuroplasticity in the brain in response to ECT, and the neurotrophin brain-derived neurotrophic factor also may be increased.^2,3

3. It causes permanent memory loss. ECT can result in both anterograde and retrograde memory impairment; however, anterograde amnesia typically lasts only days to weeks. Retrograde amnesia is much less common, but when it occurs, it tends to be loss of memory of events that took place in the weeks leading up to and during treatment. Using an ultrabrief (as opposed to standard brief) pulse, as well as right unilateral (as opposed to bilateral) electrode placement, substantially reduces the risk of cognitive and memory adverse effects.⁴

4. It is a treatment of last resort. Typically, ECT is used for patients who have not responded to other interventions. However, ECT can be used as a first-line treatment for patients if a rapid or higher likelihood of response is necessary, such as when a patient is suicidal, catatonic, or malnourished as a result of severe depression.⁵

5. It only works for depression. Evidence shows ECT is efficacious for several psychiatric conditions, not just unipolar depressive disorder. It can effectively treat bipolar depression, mania, catatonia, and acute psychosis associated with schizophrenia and schizoaffective disorders.⁶ ECT also has been demonstrated to be effective in acute and maintenance treatment of Parkinson’s disease.⁷

6. It is not safe. Death associated with ECT is extremely rare. A recent analysis estimated that the rate of ECT-related mortality is 2.1 deaths per 100,000 treatments. In comparison, the mortality rate of general anesthesia used during surgery has been reported as 3.4 deaths per 100,000 procedures.⁸ Evidence also suggests ECT can be safely administered to patients who are pregnant.⁹

Continue to: 7. It cannot be given to patients with epilepsy

7. It cannot be given to patients with epilepsy. There are no absolute contraindications to using ECT for these patients. Most patients with epilepsy can be successfully treated with ECT without requiring an adjustment to the dose of their antiepileptic medications.¹⁰

8. It will change one’s personality. ECT has not been found to cause any alterations in personality. Patients who are treated with ECT may describe feeling more like themselves once their chronic symptoms of depression have improved. However, ECT has not been shown to effectively treat the symptoms or underlying illness of personality disorders, and it may not be an effective treatment for depression associated with borderline personality disorder.¹¹

9. Its success rate is low. ECT has the highest response and remission rates of any form of treatment used for depression. An estimated 70% to 90% of patients with depression who are treated with ECT show improvement.¹²

10. It is a permanent cure. ECT is not likely a permanent solution for severe depression. The likelihood of relapse in patients with severe depression who are helped by ECT can be reduced by receiving ongoing antidepressant treatment, and some patients may require continuation or maintenance ECT.¹³

Telogen effluvium (TE)—temporary hair loss due to the shedding of telogen (resting phase of hair cycle) hair after exposure to some form of stress—is one of the most common causes of diffuse non-scarring hair loss from the scalp.¹ TE is more common than anagen (growing phase of hair cycle) hair loss.² Hair loss can be triggered by numerous factors, including certain psychotropic medications.^3,4 Mood stabilizers, such as valproic acid and lithium, are most commonly implicated. Hair loss also has been associated with the use of the first-generation antipsychotics haloperidol and chlorpromazine and the second-generation antipsychotics olanzapine, quetiapine, and risperidone.^5-7 We recently cared for a woman with bipolar I disorder and generalized anxiety disorder who was prescribed lurasidone and later developed TE. Her hair loss completely resolved 4 months after lurasidone was discontinued.

TE can be triggered by events that interrupt the normal hair growth cycle. Typically, it is observed approximately 3 months after a triggering event and is usually self-limiting, lasting approximately 6 months.⁷ Diagnostic features include a strongly positive hair-pull test, a trichogram showing >25% telogen hair, and a biopsy showing an increase in telogen follicles.^8,9 To conduct the hair-pull test, grasp approximately 40 to 60 hairs between the thumb and forefinger while slightly stretching the scalp to allow your fingers to slide along the length of the hair. Usually only 2 to 3 hairs in the telogen phase can be plucked via this method; if >10% of the hairs grasped can be plucked, this indicates a pathologic process.¹⁰

Significant hair loss, particularly among women, is a distressing adverse effect that can be an important moderator of compliance, treatment adherence, and relapse. To help clinicians narrow down the wide range of potential causes of a patient’s hair loss, we created the mnemonic NEED HAIR.

Nutritional: Iron deficiency anemia, a “crash” diet, zinc deficiency, vitamin B6 or B12 deficiency, chronic starvation, diarrhea, hypoproteinemia (metabolic or dietary origin), malabsorption, or heavy metal ingestion.¹

Endocrine: Thyroid disorders and the early stage of androgenic alopecia.^8,11

Environmental: Stress from a severe febrile illness, emotional stress, serious injuries, major surgery, large hemorrhage, and difficult labor.¹²

Drugs: Oral contraceptives, antithyroid drugs, retinoids (etretinate and acitretin), anticonvulsants, antidepressants, antipsychotics, hypolipidemic drugs, anticoagulants, antihypertensives (beta blockers, angiotensin-converting enzyme inhibitors), and cytotoxic drugs.^1,4-7

Continue to: Hormonal fluctuations

Hormonal fluctuations: Polycystic ovarian syndrome and postpartum hormonal changes.¹¹

Autoimmune: Lupus erythematosus, dermatomyositis, scleroderma, Hashimoto’s thyroiditis, Sjögren’s syndrome, inflammatory bowel disease, and autoimmune atrophic gastritis.^12,13

Infections and chronic illnesses: Fungal infections (eg, tinea capitis), human immunodeficiency virus, syphilis, typhoid, malaria, tuberculosis, malignancy, renal failure, hepatic failure, and other chronic illnesses.^1,9

Radiation: Radiation treatment and excessive UV exposure.^12,14,15

Treatment for hair loss depends on the specific cause or triggering event. If you suspect that your patient’s hair loss may be medication-induced, first rule out other possible causes by performing relevant investigations, such as a complete blood count, comprehensive metabolic panel, T3, T4, thyroid stimulating hormone, prolactin, and iron studies. If you determine the medication is the likely cause, safely taper and discontinue it, and consider an alternative agent.

Telogen effluvium (TE)—temporary hair loss due to the shedding of telogen (resting phase of hair cycle) hair after exposure to some form of stress—is one of the most common causes of diffuse non-scarring hair loss from the scalp.¹ TE is more common than anagen (growing phase of hair cycle) hair loss.² Hair loss can be triggered by numerous factors, including certain psychotropic medications.^3,4 Mood stabilizers, such as valproic acid and lithium, are most commonly implicated. Hair loss also has been associated with the use of the first-generation antipsychotics haloperidol and chlorpromazine and the second-generation antipsychotics olanzapine, quetiapine, and risperidone.^5-7 We recently cared for a woman with bipolar I disorder and generalized anxiety disorder who was prescribed lurasidone and later developed TE. Her hair loss completely resolved 4 months after lurasidone was discontinued.

TE can be triggered by events that interrupt the normal hair growth cycle. Typically, it is observed approximately 3 months after a triggering event and is usually self-limiting, lasting approximately 6 months.⁷ Diagnostic features include a strongly positive hair-pull test, a trichogram showing >25% telogen hair, and a biopsy showing an increase in telogen follicles.^8,9 To conduct the hair-pull test, grasp approximately 40 to 60 hairs between the thumb and forefinger while slightly stretching the scalp to allow your fingers to slide along the length of the hair. Usually only 2 to 3 hairs in the telogen phase can be plucked via this method; if >10% of the hairs grasped can be plucked, this indicates a pathologic process.¹⁰

Significant hair loss, particularly among women, is a distressing adverse effect that can be an important moderator of compliance, treatment adherence, and relapse. To help clinicians narrow down the wide range of potential causes of a patient’s hair loss, we created the mnemonic NEED HAIR.

Nutritional: Iron deficiency anemia, a “crash” diet, zinc deficiency, vitamin B6 or B12 deficiency, chronic starvation, diarrhea, hypoproteinemia (metabolic or dietary origin), malabsorption, or heavy metal ingestion.¹

Endocrine: Thyroid disorders and the early stage of androgenic alopecia.^8,11

Environmental: Stress from a severe febrile illness, emotional stress, serious injuries, major surgery, large hemorrhage, and difficult labor.¹²

Drugs: Oral contraceptives, antithyroid drugs, retinoids (etretinate and acitretin), anticonvulsants, antidepressants, antipsychotics, hypolipidemic drugs, anticoagulants, antihypertensives (beta blockers, angiotensin-converting enzyme inhibitors), and cytotoxic drugs.^1,4-7

Continue to: Hormonal fluctuations

Hormonal fluctuations: Polycystic ovarian syndrome and postpartum hormonal changes.¹¹

Autoimmune: Lupus erythematosus, dermatomyositis, scleroderma, Hashimoto’s thyroiditis, Sjögren’s syndrome, inflammatory bowel disease, and autoimmune atrophic gastritis.^12,13

Infections and chronic illnesses: Fungal infections (eg, tinea capitis), human immunodeficiency virus, syphilis, typhoid, malaria, tuberculosis, malignancy, renal failure, hepatic failure, and other chronic illnesses.^1,9

Radiation: Radiation treatment and excessive UV exposure.^12,14,15

Treatment for hair loss depends on the specific cause or triggering event. If you suspect that your patient’s hair loss may be medication-induced, first rule out other possible causes by performing relevant investigations, such as a complete blood count, comprehensive metabolic panel, T3, T4, thyroid stimulating hormone, prolactin, and iron studies. If you determine the medication is the likely cause, safely taper and discontinue it, and consider an alternative agent.

Telogen effluvium (TE)—temporary hair loss due to the shedding of telogen (resting phase of hair cycle) hair after exposure to some form of stress—is one of the most common causes of diffuse non-scarring hair loss from the scalp.¹ TE is more common than anagen (growing phase of hair cycle) hair loss.² Hair loss can be triggered by numerous factors, including certain psychotropic medications.^3,4 Mood stabilizers, such as valproic acid and lithium, are most commonly implicated. Hair loss also has been associated with the use of the first-generation antipsychotics haloperidol and chlorpromazine and the second-generation antipsychotics olanzapine, quetiapine, and risperidone.^5-7 We recently cared for a woman with bipolar I disorder and generalized anxiety disorder who was prescribed lurasidone and later developed TE. Her hair loss completely resolved 4 months after lurasidone was discontinued.

TE can be triggered by events that interrupt the normal hair growth cycle. Typically, it is observed approximately 3 months after a triggering event and is usually self-limiting, lasting approximately 6 months.⁷ Diagnostic features include a strongly positive hair-pull test, a trichogram showing >25% telogen hair, and a biopsy showing an increase in telogen follicles.^8,9 To conduct the hair-pull test, grasp approximately 40 to 60 hairs between the thumb and forefinger while slightly stretching the scalp to allow your fingers to slide along the length of the hair. Usually only 2 to 3 hairs in the telogen phase can be plucked via this method; if >10% of the hairs grasped can be plucked, this indicates a pathologic process.¹⁰

Significant hair loss, particularly among women, is a distressing adverse effect that can be an important moderator of compliance, treatment adherence, and relapse. To help clinicians narrow down the wide range of potential causes of a patient’s hair loss, we created the mnemonic NEED HAIR.

Nutritional: Iron deficiency anemia, a “crash” diet, zinc deficiency, vitamin B6 or B12 deficiency, chronic starvation, diarrhea, hypoproteinemia (metabolic or dietary origin), malabsorption, or heavy metal ingestion.¹

Endocrine: Thyroid disorders and the early stage of androgenic alopecia.^8,11

Environmental: Stress from a severe febrile illness, emotional stress, serious injuries, major surgery, large hemorrhage, and difficult labor.¹²

Drugs: Oral contraceptives, antithyroid drugs, retinoids (etretinate and acitretin), anticonvulsants, antidepressants, antipsychotics, hypolipidemic drugs, anticoagulants, antihypertensives (beta blockers, angiotensin-converting enzyme inhibitors), and cytotoxic drugs.^1,4-7

Continue to: Hormonal fluctuations

Hormonal fluctuations: Polycystic ovarian syndrome and postpartum hormonal changes.¹¹

Autoimmune: Lupus erythematosus, dermatomyositis, scleroderma, Hashimoto’s thyroiditis, Sjögren’s syndrome, inflammatory bowel disease, and autoimmune atrophic gastritis.^12,13

Infections and chronic illnesses: Fungal infections (eg, tinea capitis), human immunodeficiency virus, syphilis, typhoid, malaria, tuberculosis, malignancy, renal failure, hepatic failure, and other chronic illnesses.^1,9

Radiation: Radiation treatment and excessive UV exposure.^12,14,15

Treatment for hair loss depends on the specific cause or triggering event. If you suspect that your patient’s hair loss may be medication-induced, first rule out other possible causes by performing relevant investigations, such as a complete blood count, comprehensive metabolic panel, T3, T4, thyroid stimulating hormone, prolactin, and iron studies. If you determine the medication is the likely cause, safely taper and discontinue it, and consider an alternative agent.

Most patients who take psychotropic medications are at low risk for cardiovascular adverse effects from these medications, and require only routine monitoring. However, patients with severe mental illness, those with a personal or family history of cardiovascular disease, or those receiving high doses or multiple medications are considered at high risk for morbidity and mortality from cardiovascular adverse effects. Such patients may need more careful cardiovascular monitoring.

To help identify important cardiovascular-related adverse effects of various psychotropics, we summarize these risks, and offer guidance about what you can do when your patient experiences them (Table).¹

Antipsychotics and metabolic syndrome

Patients who take antipsychotics should be monitored for metabolic syndrome. The presence of 3 of the following 5 para­meters is considered positive for metabolic syndrome²:

• fasting glucose ≥100 mg/dL or hemoglobin A_1c ≥5.6%
• blood pressure ≥130/85 mm Hg
• triglycerides ≥150 mg/dL
• high-density lipoprotein cholesterol
• waist circumference ≥102 cm in men or ≥88 cm in women.

Stimulants and sudden cardiac death

Sudden cardiac death (SCD) in children and adolescents who take stimulants to treat attention-deficit/hyperactivity disorder is rare. For these patients, the risk of SCD is no higher than that of the general population.³ For patients who do not have any known cardiac risk factors, the American Academy of Pediatrics does not recommend performing any cardiac tests before starting stimulants.³

Most patients who take psychotropic medications are at low risk for cardiovascular adverse effects from these medications, and require only routine monitoring. However, patients with severe mental illness, those with a personal or family history of cardiovascular disease, or those receiving high doses or multiple medications are considered at high risk for morbidity and mortality from cardiovascular adverse effects. Such patients may need more careful cardiovascular monitoring.

To help identify important cardiovascular-related adverse effects of various psychotropics, we summarize these risks, and offer guidance about what you can do when your patient experiences them (Table).¹

Antipsychotics and metabolic syndrome

Patients who take antipsychotics should be monitored for metabolic syndrome. The presence of 3 of the following 5 para­meters is considered positive for metabolic syndrome²:

• fasting glucose ≥100 mg/dL or hemoglobin A_1c ≥5.6%
• blood pressure ≥130/85 mm Hg
• triglycerides ≥150 mg/dL
• high-density lipoprotein cholesterol
• waist circumference ≥102 cm in men or ≥88 cm in women.

Stimulants and sudden cardiac death

Sudden cardiac death (SCD) in children and adolescents who take stimulants to treat attention-deficit/hyperactivity disorder is rare. For these patients, the risk of SCD is no higher than that of the general population.³ For patients who do not have any known cardiac risk factors, the American Academy of Pediatrics does not recommend performing any cardiac tests before starting stimulants.³

Most patients who take psychotropic medications are at low risk for cardiovascular adverse effects from these medications, and require only routine monitoring. However, patients with severe mental illness, those with a personal or family history of cardiovascular disease, or those receiving high doses or multiple medications are considered at high risk for morbidity and mortality from cardiovascular adverse effects. Such patients may need more careful cardiovascular monitoring.

To help identify important cardiovascular-related adverse effects of various psychotropics, we summarize these risks, and offer guidance about what you can do when your patient experiences them (Table).¹

Antipsychotics and metabolic syndrome

Patients who take antipsychotics should be monitored for metabolic syndrome. The presence of 3 of the following 5 para­meters is considered positive for metabolic syndrome²:

• fasting glucose ≥100 mg/dL or hemoglobin A_1c ≥5.6%
• blood pressure ≥130/85 mm Hg
• triglycerides ≥150 mg/dL
• high-density lipoprotein cholesterol
• waist circumference ≥102 cm in men or ≥88 cm in women.

Stimulants and sudden cardiac death

Sudden cardiac death (SCD) in children and adolescents who take stimulants to treat attention-deficit/hyperactivity disorder is rare. For these patients, the risk of SCD is no higher than that of the general population.³ For patients who do not have any known cardiac risk factors, the American Academy of Pediatrics does not recommend performing any cardiac tests before starting stimulants.³

Recently, contemporary “culture” has capriciously confounded and confused our national community with a cringeworthy “C” word. Unfortunately, this was followed by only transient public consternation, reflecting the coarsening of our social communication and discourse and the cant of many. But the ripple effects continue.

As a psychiatrist who closely observes the human condition, I contemplated the current confrontational tone in the media, and wondered how corrosive language can confuse and cloud our sensibilities.

Then it occurred to me that there are many commendable clinical “C” words that describe what we psychiatrists do in daily practice. We stay calm while facing crises, and help our patients achieve certainty when stress makes them confused. We compassionately comfort and care for our suffering patients. We strive to engender courage and confidence when fragile patients are confronted with continuous criticism by callous and condescending people. We remain composed when we counsel patients with confrontational and crabby moods and help correct their confusing conflicts. We coordinate their care with courtesy, always aspiring for a cure for their corroded emotional condition.

But then I felt compelled to go further and call on my creativity to consider “C” words that describe severe psychiatric clinical disorders. I came up with the following cogent cascade of common characteristics of serious mental disorders:

• Cerebral pathology
• Circuit disruptions of neural connections
• Chemical imbalance
• Cytokine inflammatory con­flagration
• Cognitive impairment
• Chronic course
• Crippled functioning.

My compulsion continued. I decided to contemplate more “C” words that capture our therapeutic course of action to correct a patient whose cortico-limbic circuitry is being threatened with considerable, even calamitous collapse. My consideration led to clarity, and I came up with the following list of what we psychiatrists conform to in our clinical practice:

• Connect with patients
• Correct diagnosis
• Course-specific intervention
• Choose the appropriate medication
• Combine cognitive-behavioral therapy with medication
• Cognitive assessment at baseline
• Compliance/concordance with treatment
• Continuity of care
• Comorbidities, physical and psychiatric
• Collaborative care with other medical specialists
• Comprehensive treatment plan with other mental health professionals.

A book about dirty words written by a psychoanalyst called the “C” expletive the worst of all cuss words.¹ Its recent emergence in the national media compromised our civility and created a cesspool of contemptible conversations. Let’s transcend the contemptible “C” word of a caustic contemporary “culture” (which had its 15 minutes of infamy), and consider the many coherent and congenial “C” words of psych­iatric practice that bring peace of mind and contentment to those who suffer from psychiatric brain conditions. As for the compulsive or involuntary use of curse words that begin with a “C,” or any other letter, psychiatry has a clinical term for it: coprolalia.

Editor's note: How many C words are there in this editorial? Email answers to [email protected]

Recently, contemporary “culture” has capriciously confounded and confused our national community with a cringeworthy “C” word. Unfortunately, this was followed by only transient public consternation, reflecting the coarsening of our social communication and discourse and the cant of many. But the ripple effects continue.

As a psychiatrist who closely observes the human condition, I contemplated the current confrontational tone in the media, and wondered how corrosive language can confuse and cloud our sensibilities.

Then it occurred to me that there are many commendable clinical “C” words that describe what we psychiatrists do in daily practice. We stay calm while facing crises, and help our patients achieve certainty when stress makes them confused. We compassionately comfort and care for our suffering patients. We strive to engender courage and confidence when fragile patients are confronted with continuous criticism by callous and condescending people. We remain composed when we counsel patients with confrontational and crabby moods and help correct their confusing conflicts. We coordinate their care with courtesy, always aspiring for a cure for their corroded emotional condition.

But then I felt compelled to go further and call on my creativity to consider “C” words that describe severe psychiatric clinical disorders. I came up with the following cogent cascade of common characteristics of serious mental disorders:

• Cerebral pathology
• Circuit disruptions of neural connections
• Chemical imbalance
• Cytokine inflammatory con­flagration
• Cognitive impairment
• Chronic course
• Crippled functioning.

My compulsion continued. I decided to contemplate more “C” words that capture our therapeutic course of action to correct a patient whose cortico-limbic circuitry is being threatened with considerable, even calamitous collapse. My consideration led to clarity, and I came up with the following list of what we psychiatrists conform to in our clinical practice:

• Connect with patients
• Correct diagnosis
• Course-specific intervention
• Choose the appropriate medication
• Combine cognitive-behavioral therapy with medication
• Cognitive assessment at baseline
• Compliance/concordance with treatment
• Continuity of care
• Comorbidities, physical and psychiatric
• Collaborative care with other medical specialists
• Comprehensive treatment plan with other mental health professionals.

A book about dirty words written by a psychoanalyst called the “C” expletive the worst of all cuss words.¹ Its recent emergence in the national media compromised our civility and created a cesspool of contemptible conversations. Let’s transcend the contemptible “C” word of a caustic contemporary “culture” (which had its 15 minutes of infamy), and consider the many coherent and congenial “C” words of psych­iatric practice that bring peace of mind and contentment to those who suffer from psychiatric brain conditions. As for the compulsive or involuntary use of curse words that begin with a “C,” or any other letter, psychiatry has a clinical term for it: coprolalia.

Editor's note: How many C words are there in this editorial? Email answers to [email protected]

Recently, contemporary “culture” has capriciously confounded and confused our national community with a cringeworthy “C” word. Unfortunately, this was followed by only transient public consternation, reflecting the coarsening of our social communication and discourse and the cant of many. But the ripple effects continue.

As a psychiatrist who closely observes the human condition, I contemplated the current confrontational tone in the media, and wondered how corrosive language can confuse and cloud our sensibilities.

Then it occurred to me that there are many commendable clinical “C” words that describe what we psychiatrists do in daily practice. We stay calm while facing crises, and help our patients achieve certainty when stress makes them confused. We compassionately comfort and care for our suffering patients. We strive to engender courage and confidence when fragile patients are confronted with continuous criticism by callous and condescending people. We remain composed when we counsel patients with confrontational and crabby moods and help correct their confusing conflicts. We coordinate their care with courtesy, always aspiring for a cure for their corroded emotional condition.

But then I felt compelled to go further and call on my creativity to consider “C” words that describe severe psychiatric clinical disorders. I came up with the following cogent cascade of common characteristics of serious mental disorders:

• Cerebral pathology
• Circuit disruptions of neural connections
• Chemical imbalance
• Cytokine inflammatory con­flagration
• Cognitive impairment
• Chronic course
• Crippled functioning.

My compulsion continued. I decided to contemplate more “C” words that capture our therapeutic course of action to correct a patient whose cortico-limbic circuitry is being threatened with considerable, even calamitous collapse. My consideration led to clarity, and I came up with the following list of what we psychiatrists conform to in our clinical practice:

• Connect with patients
• Correct diagnosis
• Course-specific intervention
• Choose the appropriate medication
• Combine cognitive-behavioral therapy with medication
• Cognitive assessment at baseline
• Compliance/concordance with treatment
• Continuity of care
• Comorbidities, physical and psychiatric
• Collaborative care with other medical specialists
• Comprehensive treatment plan with other mental health professionals.

A book about dirty words written by a psychoanalyst called the “C” expletive the worst of all cuss words.¹ Its recent emergence in the national media compromised our civility and created a cesspool of contemptible conversations. Let’s transcend the contemptible “C” word of a caustic contemporary “culture” (which had its 15 minutes of infamy), and consider the many coherent and congenial “C” words of psych­iatric practice that bring peace of mind and contentment to those who suffer from psychiatric brain conditions. As for the compulsive or involuntary use of curse words that begin with a “C,” or any other letter, psychiatry has a clinical term for it: coprolalia.

Editor's note: How many C words are there in this editorial? Email answers to [email protected]

“Was this your first one?”

You might be asked this question in several circumstances. Was this your first 5K run? Was this your first time taking the MCAT? For me, I was asked if this was the first time a patient had died while in my care as a resident.

As it turns out, this was the first patient who died under my care. This seemed obvious to everyone around me because when I received the news, offhandedly, days after my patient’s discharge, I cried. My colleagues’ responses to my tears were kind and supportive. No one was callous or judgmental. I was given time to compose myself before continuing my rounds for the day. Yet, the most common question asked of me was, “Was this your first one?”

The implication of this question was that these situations would become easier and less emotional over time. Everyone believed my tears were a special response, privileged only to my first experience. This was conveyed to me as if it was a chance to explain my emotions. As if grieving alone was not sufficient to explain tears, I began to run through the reasons for my behavior, and my mind rapidly searched for answers. I thought:

• “I saw this patient daily for weeks, and I was close to him.”
• “There was an element of suicidality in this case, so it was different.”
• “After all, this was my first experience like this.”

In reality, these reasons were irrelevant and not needed to explain my tears. I was mourning the loss of a life—someone I had come to know well—and this was a life that ultimately could not be saved by the health care system.

These were my feelings during the July of my intern year. It is now a year later; I have since experienced an incredible number of moments that warranted mourning. There were oncology patients with advanced diseases who needed help disclosing their prognosis to family members. There were days when I was tasked with altering treatment courses from aggressive treatment to comfort measures only. There was the Christmas Eve when a pair of brothers dropped off their elderly father in the emergency department because no one was able or willing to care for him at home.

These moments can come fast, and they occur more frequently than one might imagine. Each is worthy of mourning. Each is worthy of tears, whether it is my first loss or my 50th. But the reality is that I could not function in my job and care for all my patients equally if I stopped every time to acknowledge my emotions. As much as it causes my stomach to turn, I understand the “Was this your first one?” phenomenon. To outwardly express your emotions and openly mourn in the moment, you need to have the time and allow yourself the vulnerability to do so. After your “first one,” you realize that mournful moments can occur regularly and you must choose to process emotions on your own time because you don’t have the luxury of processing a loss of life in the present moment.

Continue to: This is not to diminish...

This is not to diminish the importance of mourning or belittle the experience of processing one’s emotions. It simply highlights the importance of self-care. Emotions need to be processed outside of the hustle and bustle of the work day. There are other patients who require and deserve their clinician’s undivided attention. To truly provide patients with the highest quality of care, I find caring for myself and processing my reactions to daily events to be essential. Writing down my thoughts or talking to loved ones are ways that help me process my experiences. Taking a trip out of town, going for a hike, or watching a movie also are ways to help create balance in an emotionally charged career. I hope to use my new understanding of the “first one” phenomenon as a reminder to maintain my own well-being. In doing so, I can be attuned to my patients’ needs and provide them with empathic care. Even though my outward expression may change as I learn to process these moments differently, I want to treat each patient with the same level of empathy, value, and compassion as my first one.

“Was this your first one?”

You might be asked this question in several circumstances. Was this your first 5K run? Was this your first time taking the MCAT? For me, I was asked if this was the first time a patient had died while in my care as a resident.

As it turns out, this was the first patient who died under my care. This seemed obvious to everyone around me because when I received the news, offhandedly, days after my patient’s discharge, I cried. My colleagues’ responses to my tears were kind and supportive. No one was callous or judgmental. I was given time to compose myself before continuing my rounds for the day. Yet, the most common question asked of me was, “Was this your first one?”

The implication of this question was that these situations would become easier and less emotional over time. Everyone believed my tears were a special response, privileged only to my first experience. This was conveyed to me as if it was a chance to explain my emotions. As if grieving alone was not sufficient to explain tears, I began to run through the reasons for my behavior, and my mind rapidly searched for answers. I thought:

• “I saw this patient daily for weeks, and I was close to him.”
• “There was an element of suicidality in this case, so it was different.”
• “After all, this was my first experience like this.”

In reality, these reasons were irrelevant and not needed to explain my tears. I was mourning the loss of a life—someone I had come to know well—and this was a life that ultimately could not be saved by the health care system.

These were my feelings during the July of my intern year. It is now a year later; I have since experienced an incredible number of moments that warranted mourning. There were oncology patients with advanced diseases who needed help disclosing their prognosis to family members. There were days when I was tasked with altering treatment courses from aggressive treatment to comfort measures only. There was the Christmas Eve when a pair of brothers dropped off their elderly father in the emergency department because no one was able or willing to care for him at home.

These moments can come fast, and they occur more frequently than one might imagine. Each is worthy of mourning. Each is worthy of tears, whether it is my first loss or my 50th. But the reality is that I could not function in my job and care for all my patients equally if I stopped every time to acknowledge my emotions. As much as it causes my stomach to turn, I understand the “Was this your first one?” phenomenon. To outwardly express your emotions and openly mourn in the moment, you need to have the time and allow yourself the vulnerability to do so. After your “first one,” you realize that mournful moments can occur regularly and you must choose to process emotions on your own time because you don’t have the luxury of processing a loss of life in the present moment.

Continue to: This is not to diminish...

This is not to diminish the importance of mourning or belittle the experience of processing one’s emotions. It simply highlights the importance of self-care. Emotions need to be processed outside of the hustle and bustle of the work day. There are other patients who require and deserve their clinician’s undivided attention. To truly provide patients with the highest quality of care, I find caring for myself and processing my reactions to daily events to be essential. Writing down my thoughts or talking to loved ones are ways that help me process my experiences. Taking a trip out of town, going for a hike, or watching a movie also are ways to help create balance in an emotionally charged career. I hope to use my new understanding of the “first one” phenomenon as a reminder to maintain my own well-being. In doing so, I can be attuned to my patients’ needs and provide them with empathic care. Even though my outward expression may change as I learn to process these moments differently, I want to treat each patient with the same level of empathy, value, and compassion as my first one.

“Was this your first one?”

You might be asked this question in several circumstances. Was this your first 5K run? Was this your first time taking the MCAT? For me, I was asked if this was the first time a patient had died while in my care as a resident.

As it turns out, this was the first patient who died under my care. This seemed obvious to everyone around me because when I received the news, offhandedly, days after my patient’s discharge, I cried. My colleagues’ responses to my tears were kind and supportive. No one was callous or judgmental. I was given time to compose myself before continuing my rounds for the day. Yet, the most common question asked of me was, “Was this your first one?”

The implication of this question was that these situations would become easier and less emotional over time. Everyone believed my tears were a special response, privileged only to my first experience. This was conveyed to me as if it was a chance to explain my emotions. As if grieving alone was not sufficient to explain tears, I began to run through the reasons for my behavior, and my mind rapidly searched for answers. I thought:

• “I saw this patient daily for weeks, and I was close to him.”
• “There was an element of suicidality in this case, so it was different.”
• “After all, this was my first experience like this.”

In reality, these reasons were irrelevant and not needed to explain my tears. I was mourning the loss of a life—someone I had come to know well—and this was a life that ultimately could not be saved by the health care system.

These were my feelings during the July of my intern year. It is now a year later; I have since experienced an incredible number of moments that warranted mourning. There were oncology patients with advanced diseases who needed help disclosing their prognosis to family members. There were days when I was tasked with altering treatment courses from aggressive treatment to comfort measures only. There was the Christmas Eve when a pair of brothers dropped off their elderly father in the emergency department because no one was able or willing to care for him at home.

These moments can come fast, and they occur more frequently than one might imagine. Each is worthy of mourning. Each is worthy of tears, whether it is my first loss or my 50th. But the reality is that I could not function in my job and care for all my patients equally if I stopped every time to acknowledge my emotions. As much as it causes my stomach to turn, I understand the “Was this your first one?” phenomenon. To outwardly express your emotions and openly mourn in the moment, you need to have the time and allow yourself the vulnerability to do so. After your “first one,” you realize that mournful moments can occur regularly and you must choose to process emotions on your own time because you don’t have the luxury of processing a loss of life in the present moment.

Continue to: This is not to diminish...

This is not to diminish the importance of mourning or belittle the experience of processing one’s emotions. It simply highlights the importance of self-care. Emotions need to be processed outside of the hustle and bustle of the work day. There are other patients who require and deserve their clinician’s undivided attention. To truly provide patients with the highest quality of care, I find caring for myself and processing my reactions to daily events to be essential. Writing down my thoughts or talking to loved ones are ways that help me process my experiences. Taking a trip out of town, going for a hike, or watching a movie also are ways to help create balance in an emotionally charged career. I hope to use my new understanding of the “first one” phenomenon as a reminder to maintain my own well-being. In doing so, I can be attuned to my patients’ needs and provide them with empathic care. Even though my outward expression may change as I learn to process these moments differently, I want to treat each patient with the same level of empathy, value, and compassion as my first one.

I have often turned to yoga for my own reprieve; I find the heat, breath, and movement exhilarating. Training to become a yoga teacher has taught me that medicine, not unlike yoga, requires patience and resiliency.

It is 3 AM. I am an intern in psychiatry, 2 months out of medical school, and tonight I am on crash working the trauma bay. The attending is an uncompromising intellectual who graces the ER like Meryl Streep on the red carpet. She smiles at me with only a slight movement from the corner of her mouth, “You know you’re gonna have to do some sutures before you finish your rotation.”

4 AM. I am feeling gross, and I hate wearing scrubs. I scan the patient list, looking for more psychiatry cases. Three more hours. A nurse approaches me with a gravid look on her face. “Dr. Brown, we have a code blue coming in. I think he overdosed on something. We’re going to need all the hands we can get.” Less than 2 minutes later, I am running toward a man who had been rolled in. Clothes drenched in vomit, matted hair. And CPR starts. The attending runs the code like a ballad, her central nervous system bathed in adrenaline, crimson blood boiling in her veins. I’m observing in the corner of the room, praying that this guy does not die. I am so uncomfortable; this is not a comfortable feeling. “Dr. Brown, you’re up.”

Let me tell you, when you’re getting certified in Advanced Cardiac Life Support, you go to a class on a Saturday, there are snacks, and your instructor will probably be a paramedic who is earning side cash teaching CPR. You will watch funny videos—we even danced to the Bee Gees’ Stayin’ Alive. But this is not funny, nor is it fun. And my head is spinning so fast, the sound of the Bee Gees smears to silence.

I take off my white coat and trot to the center of the room. The lights are bright, I am hot, and people are moving really fast. I feel like I’m in a vignette. It seems like we’re in the fourth movement of a Shostakovich symphony, the attending is cueing, up and down, like Bernstein conducting the Philharmonic, her arms are flailing; this production is hers and everyone is in sync. The man’s skin is pale, almost gray, he smells like sweat and urine and vomit. His irises are blue, blue like the ocean. His beard is thick and opaque, speckled with premature dots of gray. He looks calm. Listless. Dead. He is looking at me, like the Mona Lisa, as if beckoning me to save him, to give him another chance. At life. I put my hands gently on his sternum and I start my round of chest compressions. His skin is rubbery. I feel like I’m breaking his ribs, am I? This is not like the class. The cardiac monitor flatlines. Was it like that before? I think so, I’m not really sure. The attending stops conducting and runs over. Someone taps me and says it’s time to switch. Shortly thereafter, time of death is pronounced. “Damn it,” I hear the attending exclaim quietly but deliberately. I am hot, and I have a headache. I take off my gloves. Where’s my cell phone? I’m going to check Facebook, maybe ESPN.com. I feel heavy. And then I’m sitting at the computer screen again, after the rain. The attending comes back to her seat. She has a green smoothie, she takes a sip, and is slow to return the oversized cup to the table.

This night 3 years ago remains vivid. I am looking at her now. The unabashed attending. We are all looking at her.

She pulls out a petite makeup case and opens an oval mirror. She applies 2 thin lines of lustrous lip gloss, smacks her lips, grounding herself, then places the mirror back in her bag. She takes one deep breath, pauses briefly, and, letting go, she sits up tall, her dignity restored, then looks at me and claps, “Come on, doctor, we’ve got more patients to see.”

That night in the ER, I experienced how troubling it is losing a life with the burden of responsibility, but also the beauty of Aparigraha, letting go, and moving forward. I learned this lesson, unspoken, from an admirable attending, and was reminded of it 3 years later as I pursued a deeper understanding of yoga.

I have often turned to yoga for my own reprieve; I find the heat, breath, and movement exhilarating. Training to become a yoga teacher has taught me that medicine, not unlike yoga, requires patience and resiliency.

It is 3 AM. I am an intern in psychiatry, 2 months out of medical school, and tonight I am on crash working the trauma bay. The attending is an uncompromising intellectual who graces the ER like Meryl Streep on the red carpet. She smiles at me with only a slight movement from the corner of her mouth, “You know you’re gonna have to do some sutures before you finish your rotation.”

4 AM. I am feeling gross, and I hate wearing scrubs. I scan the patient list, looking for more psychiatry cases. Three more hours. A nurse approaches me with a gravid look on her face. “Dr. Brown, we have a code blue coming in. I think he overdosed on something. We’re going to need all the hands we can get.” Less than 2 minutes later, I am running toward a man who had been rolled in. Clothes drenched in vomit, matted hair. And CPR starts. The attending runs the code like a ballad, her central nervous system bathed in adrenaline, crimson blood boiling in her veins. I’m observing in the corner of the room, praying that this guy does not die. I am so uncomfortable; this is not a comfortable feeling. “Dr. Brown, you’re up.”

Let me tell you, when you’re getting certified in Advanced Cardiac Life Support, you go to a class on a Saturday, there are snacks, and your instructor will probably be a paramedic who is earning side cash teaching CPR. You will watch funny videos—we even danced to the Bee Gees’ Stayin’ Alive. But this is not funny, nor is it fun. And my head is spinning so fast, the sound of the Bee Gees smears to silence.

I take off my white coat and trot to the center of the room. The lights are bright, I am hot, and people are moving really fast. I feel like I’m in a vignette. It seems like we’re in the fourth movement of a Shostakovich symphony, the attending is cueing, up and down, like Bernstein conducting the Philharmonic, her arms are flailing; this production is hers and everyone is in sync. The man’s skin is pale, almost gray, he smells like sweat and urine and vomit. His irises are blue, blue like the ocean. His beard is thick and opaque, speckled with premature dots of gray. He looks calm. Listless. Dead. He is looking at me, like the Mona Lisa, as if beckoning me to save him, to give him another chance. At life. I put my hands gently on his sternum and I start my round of chest compressions. His skin is rubbery. I feel like I’m breaking his ribs, am I? This is not like the class. The cardiac monitor flatlines. Was it like that before? I think so, I’m not really sure. The attending stops conducting and runs over. Someone taps me and says it’s time to switch. Shortly thereafter, time of death is pronounced. “Damn it,” I hear the attending exclaim quietly but deliberately. I am hot, and I have a headache. I take off my gloves. Where’s my cell phone? I’m going to check Facebook, maybe ESPN.com. I feel heavy. And then I’m sitting at the computer screen again, after the rain. The attending comes back to her seat. She has a green smoothie, she takes a sip, and is slow to return the oversized cup to the table.

This night 3 years ago remains vivid. I am looking at her now. The unabashed attending. We are all looking at her.

She pulls out a petite makeup case and opens an oval mirror. She applies 2 thin lines of lustrous lip gloss, smacks her lips, grounding herself, then places the mirror back in her bag. She takes one deep breath, pauses briefly, and, letting go, she sits up tall, her dignity restored, then looks at me and claps, “Come on, doctor, we’ve got more patients to see.”

That night in the ER, I experienced how troubling it is losing a life with the burden of responsibility, but also the beauty of Aparigraha, letting go, and moving forward. I learned this lesson, unspoken, from an admirable attending, and was reminded of it 3 years later as I pursued a deeper understanding of yoga.

I have often turned to yoga for my own reprieve; I find the heat, breath, and movement exhilarating. Training to become a yoga teacher has taught me that medicine, not unlike yoga, requires patience and resiliency.

It is 3 AM. I am an intern in psychiatry, 2 months out of medical school, and tonight I am on crash working the trauma bay. The attending is an uncompromising intellectual who graces the ER like Meryl Streep on the red carpet. She smiles at me with only a slight movement from the corner of her mouth, “You know you’re gonna have to do some sutures before you finish your rotation.”

4 AM. I am feeling gross, and I hate wearing scrubs. I scan the patient list, looking for more psychiatry cases. Three more hours. A nurse approaches me with a gravid look on her face. “Dr. Brown, we have a code blue coming in. I think he overdosed on something. We’re going to need all the hands we can get.” Less than 2 minutes later, I am running toward a man who had been rolled in. Clothes drenched in vomit, matted hair. And CPR starts. The attending runs the code like a ballad, her central nervous system bathed in adrenaline, crimson blood boiling in her veins. I’m observing in the corner of the room, praying that this guy does not die. I am so uncomfortable; this is not a comfortable feeling. “Dr. Brown, you’re up.”

Let me tell you, when you’re getting certified in Advanced Cardiac Life Support, you go to a class on a Saturday, there are snacks, and your instructor will probably be a paramedic who is earning side cash teaching CPR. You will watch funny videos—we even danced to the Bee Gees’ Stayin’ Alive. But this is not funny, nor is it fun. And my head is spinning so fast, the sound of the Bee Gees smears to silence.

I take off my white coat and trot to the center of the room. The lights are bright, I am hot, and people are moving really fast. I feel like I’m in a vignette. It seems like we’re in the fourth movement of a Shostakovich symphony, the attending is cueing, up and down, like Bernstein conducting the Philharmonic, her arms are flailing; this production is hers and everyone is in sync. The man’s skin is pale, almost gray, he smells like sweat and urine and vomit. His irises are blue, blue like the ocean. His beard is thick and opaque, speckled with premature dots of gray. He looks calm. Listless. Dead. He is looking at me, like the Mona Lisa, as if beckoning me to save him, to give him another chance. At life. I put my hands gently on his sternum and I start my round of chest compressions. His skin is rubbery. I feel like I’m breaking his ribs, am I? This is not like the class. The cardiac monitor flatlines. Was it like that before? I think so, I’m not really sure. The attending stops conducting and runs over. Someone taps me and says it’s time to switch. Shortly thereafter, time of death is pronounced. “Damn it,” I hear the attending exclaim quietly but deliberately. I am hot, and I have a headache. I take off my gloves. Where’s my cell phone? I’m going to check Facebook, maybe ESPN.com. I feel heavy. And then I’m sitting at the computer screen again, after the rain. The attending comes back to her seat. She has a green smoothie, she takes a sip, and is slow to return the oversized cup to the table.

This night 3 years ago remains vivid. I am looking at her now. The unabashed attending. We are all looking at her.

She pulls out a petite makeup case and opens an oval mirror. She applies 2 thin lines of lustrous lip gloss, smacks her lips, grounding herself, then places the mirror back in her bag. She takes one deep breath, pauses briefly, and, letting go, she sits up tall, her dignity restored, then looks at me and claps, “Come on, doctor, we’ve got more patients to see.”

That night in the ER, I experienced how troubling it is losing a life with the burden of responsibility, but also the beauty of Aparigraha, letting go, and moving forward. I learned this lesson, unspoken, from an admirable attending, and was reminded of it 3 years later as I pursued a deeper understanding of yoga.

Genetic variations in CYP450 enzymes determine enzymatic activity, which can have a large effect on drug levels, efficacy, and toxicity. However, there are many other important factors that clinicians should consider when trying to predict the effects of medications. While clinicians often focus on a patient’s genotype, this only provides information on a chromosomal level, and this information never changes. In contrast, a patient’s phenotype, or status of metabolism, is subject to change throughout the patient’s life.

Many circumstances influence phenotype, including the use of medications that induce or inhibit CYP450 enzymes, environmental factors, and comorbidities. Phenoconversion occurs when these factors result in a phenotype that is different from that predicted by genotype. Because of the possibility of phenoconversion, knowing a patient’s genotype may be of limited value in making clinical decisions. This article provides guidance on interpreting both the genotype and phenotype of CYP2D6 and CYP1A2. Case 1 and Case 2 illustrate these concepts.

CYP2D6

The enzyme activity of CYP2D6 varies among individuals and may include no activity, decreased activity, normal activity, or increased activity. After obtaining the genotype, the activity level of the CYP2D6 alleles may be determined. The frequency with which certain alleles occur varies with ancestry. More than 100 allelic variants and subvariants have been discovered, and new alleles are continuing to be discovered.¹Table 1² lists some of the most common CYP2D6 alleles.

Based on the CYP2D6 enzyme activity determined from the alleles, 4 “traditional” phenotypes can be predicted from the genotype (Table 2²). The 7-category phenotypes reported by some laboratory companies provide a more explicit method for reporting phenotypes.

Evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction.² Thus, genetics, rather than drug therapy, accounts for most ultra-rapid CYP2D6 metabolizers. CYP2D6 can be inhibited by the use of medications (Table 3^2-5) and/or substrates (Table 4^2,6). Similar to inhibitors, substrates may be saturating high affinity-low capacity enzymes such as CYP2D6, resulting in phenoconversion to poor metabolizers. However, this is unlikely to be the case for substrates of low affinity-high capacity enzymes such as CYP3A4.⁷ Ultimately, substrates and/or inhibitors of CYP2D6 may result in a phenotype that does not correspond to genotype.

Phenoconversion

Genotyping may not reflect the true prevalence of the CYP2D6 poor metabolizer phenotype when using multiple medications that are substrates and/or inhibitors of CYP2D6.⁸ In the presence of strong CYP2D6 inhibitors, up to 80% of individuals with a non-poor metabolizer genotype are converted to a poor metabolizer phenotype.⁸ While the phenotype provides a clearer representation of metabolism status than genotype, this information may not always be available.

Continue to: Determining CYP2D6 phenotype

Risperidone and venlafaxine levels are useful tools for predicting CYP2D6 phenotype.^3,8 When a risperidone level is ordered, the results include a risperidone level and a 9-hydroxyrisperidone level. The active metabolite of risperidone is 9-hydroxyrisperidone (paliperidone). The risperidone-to-9-hydroxyrisperidone (R-to-9-OHR) concentration ratio is an indicator of CYP2D6 phenotype.³ While considerable overlap may exist using R-to-9-OHR concentration ratios as a predictor of CYP2D6 phenotype, this provides a practical and economically viable option for guiding drug therapy and recommending CYP2D6 genetic testing. The median R-to-9-OHR concentration ratios with the 25th to 75th percentiles are listed below as indicators of CYP2D6 phenotypes⁹:

• Ultra-rapid metabolizer: 0.03 (0.02 to 0.06)
• Extensive metabolizer: 0.08 (0.04 to 0.17)
• Intermediate metabolizer: 0.56 (0.30 to 1.0)
• Poor metabolizer: 2.5 (1.8 to 4.1).

Although a R-to-9-OHR concentration ratio >1 generally indicates a poor metabolizer, it could also indicate the presence of a powerful CYP2D6 inhibitor.⁹

When a venlafaxine level is ordered, the results include a venlafaxine level and an O-desmethylvenlafaxine level. O-desmethylvenlafaxine (desvenlafaxine) is the active metabolite of venlafaxine. The O-desmethylvenlafaxine-to-venlafaxine concentration ratio is an indicator of CYP2D6 phenotype.⁸ In this instance, a ratio ≥1 indicates an extensive metabolizer, whereas <1 indicates a poor metabolizer.

CYP1A2

While the activity of CYP2D6 alleles is determined primarily by genetic factors and medications, the activity of CYP1A2 alleles is largely determined by environmental factors (diet, medications, disease) and genetic variability.² Consequently, CYP1A2 genotyping may be less clinically useful than CYP2D6 genotyping. The CYP1A2 genotype–phenotype relationship incorporates the degree of allele activity (Table 5²), and inducibility in the presence of environmental factors.

Continue to: CYP1A2 inhibiton

A variety of medications and environmental factors may inhibit CYP1A2.

Medications. Medications that may inhibit CYP1A2 include atazanavir, ciprofloxacin, ethinyl estradiol, and fluvoxamine.³

Caffeine. A significant increase in caffeine consumption can result in inhibition.³ Among non-tobacco smokers, an increase of 1 cup/d of coffee or 2 cans/d of caffeinated soda would be considered significant.³ However, tobacco smokers would require an increase of 3 cups/d of coffee or 6 cans/d of soda.

Diet. An increase in the daily dietary intake of certain vegetables for 6 days has been shown to result in inhibition.¹⁰ Apiaceous (Apiaceae or Umbelliferae) vegetables such as carrots (3/4 cup), celery (1/2 cup), dill (1 teaspoon), parsley (3 tablespoons), and parsnips (1¼ cup) can decrease CYP1A2 activity by approximately 13% to 25%. Allium (Liliaceae) vegetables, such as garlic, leeks, and onions, have no effect on CYP1A2 activity.

Infection. Pneumonia, upper respiratory infections with fever, pyelonephritis or appendicitis, or inflammation are suspected to decrease CYP1A2 activity.⁸

Continue to: CYP1A2 induction

A variety of medications and environmental factors may induce CYP1A2.

Medications. Certain medications may induce CYP1A2, including carbamazepine, phenytoin, rifampin, and primidone.

Cigarette smoking. A significant increase in smoking after 1 to 3 weeks may decrease drug levels, whereas a significant decrease in smoking after 1 to 3 weeks may result in elevated drug levels.³ Nicotine is not the causative agent of induction, but rather hydrocarbons found in cigarette smoke.¹¹

Diet. An increase in daily dietary intake of certain vegetables for 6 days has been shown to result in induction.³ Brassica (Cruciferae) vegetables such as broccoli (2 cups), cauliflower (1 cup), cabbage (1 cup), and radish sprouts (1/2 cup) have been found to increase CYP1A2 activity by 18% to 37%.¹⁰ Grilled meat also plays a role in induction.¹⁰

Related Resource

• Ellingrod VL, Ward KM. Using pharmacogenetics guidelines when prescribing: What's available. Current Psychiatry. 2018;17(1):43-46.

Drug Brand Names

Amiodarone • Cordarone, Pacerone
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz  
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban  
Carbamazepine • Carbatrol, Tegretol  
Chlorpromazine • Thorazine  
Chloroquine • Aralen
Cinacalcet • Sensipar
Ciprofloxacin • Cipro
Citalopram • Celexa
Clozapine • Clozaril
Desipramine • Norpramin  
Desvenlafaxine • Pristiq
Diphenhydramine • Benadryl
Doxepin • Silenor
Duloxetine • Cymbalta
Escitalopram • Lexapro
Ethinyl estradiol • Estinyl
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol  
Iloperidone • Fanapt
Imatinib • Gleevec
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenytoin • Dilantin
Pimavanserin • Nuplazid
Primidone • Mysoline
Quetiapine • Seroquel
Quinidine • Cardioquin
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Terbinafine • Lamisil
Thioridazine • Mellaril
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd  
Vortioxetine • Trintellix
Ziprasidone • Geodon

Genetic variations in CYP450 enzymes determine enzymatic activity, which can have a large effect on drug levels, efficacy, and toxicity. However, there are many other important factors that clinicians should consider when trying to predict the effects of medications. While clinicians often focus on a patient’s genotype, this only provides information on a chromosomal level, and this information never changes. In contrast, a patient’s phenotype, or status of metabolism, is subject to change throughout the patient’s life.

Many circumstances influence phenotype, including the use of medications that induce or inhibit CYP450 enzymes, environmental factors, and comorbidities. Phenoconversion occurs when these factors result in a phenotype that is different from that predicted by genotype. Because of the possibility of phenoconversion, knowing a patient’s genotype may be of limited value in making clinical decisions. This article provides guidance on interpreting both the genotype and phenotype of CYP2D6 and CYP1A2. Case 1 and Case 2 illustrate these concepts.

CYP2D6

The enzyme activity of CYP2D6 varies among individuals and may include no activity, decreased activity, normal activity, or increased activity. After obtaining the genotype, the activity level of the CYP2D6 alleles may be determined. The frequency with which certain alleles occur varies with ancestry. More than 100 allelic variants and subvariants have been discovered, and new alleles are continuing to be discovered.¹Table 1² lists some of the most common CYP2D6 alleles.

Based on the CYP2D6 enzyme activity determined from the alleles, 4 “traditional” phenotypes can be predicted from the genotype (Table 2²). The 7-category phenotypes reported by some laboratory companies provide a more explicit method for reporting phenotypes.

Evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction.² Thus, genetics, rather than drug therapy, accounts for most ultra-rapid CYP2D6 metabolizers. CYP2D6 can be inhibited by the use of medications (Table 3^2-5) and/or substrates (Table 4^2,6). Similar to inhibitors, substrates may be saturating high affinity-low capacity enzymes such as CYP2D6, resulting in phenoconversion to poor metabolizers. However, this is unlikely to be the case for substrates of low affinity-high capacity enzymes such as CYP3A4.⁷ Ultimately, substrates and/or inhibitors of CYP2D6 may result in a phenotype that does not correspond to genotype.

Phenoconversion

Genotyping may not reflect the true prevalence of the CYP2D6 poor metabolizer phenotype when using multiple medications that are substrates and/or inhibitors of CYP2D6.⁸ In the presence of strong CYP2D6 inhibitors, up to 80% of individuals with a non-poor metabolizer genotype are converted to a poor metabolizer phenotype.⁸ While the phenotype provides a clearer representation of metabolism status than genotype, this information may not always be available.

Continue to: Determining CYP2D6 phenotype

Risperidone and venlafaxine levels are useful tools for predicting CYP2D6 phenotype.^3,8 When a risperidone level is ordered, the results include a risperidone level and a 9-hydroxyrisperidone level. The active metabolite of risperidone is 9-hydroxyrisperidone (paliperidone). The risperidone-to-9-hydroxyrisperidone (R-to-9-OHR) concentration ratio is an indicator of CYP2D6 phenotype.³ While considerable overlap may exist using R-to-9-OHR concentration ratios as a predictor of CYP2D6 phenotype, this provides a practical and economically viable option for guiding drug therapy and recommending CYP2D6 genetic testing. The median R-to-9-OHR concentration ratios with the 25th to 75th percentiles are listed below as indicators of CYP2D6 phenotypes⁹:

• Ultra-rapid metabolizer: 0.03 (0.02 to 0.06)
• Extensive metabolizer: 0.08 (0.04 to 0.17)
• Intermediate metabolizer: 0.56 (0.30 to 1.0)
• Poor metabolizer: 2.5 (1.8 to 4.1).

Although a R-to-9-OHR concentration ratio >1 generally indicates a poor metabolizer, it could also indicate the presence of a powerful CYP2D6 inhibitor.⁹

When a venlafaxine level is ordered, the results include a venlafaxine level and an O-desmethylvenlafaxine level. O-desmethylvenlafaxine (desvenlafaxine) is the active metabolite of venlafaxine. The O-desmethylvenlafaxine-to-venlafaxine concentration ratio is an indicator of CYP2D6 phenotype.⁸ In this instance, a ratio ≥1 indicates an extensive metabolizer, whereas <1 indicates a poor metabolizer.

CYP1A2

While the activity of CYP2D6 alleles is determined primarily by genetic factors and medications, the activity of CYP1A2 alleles is largely determined by environmental factors (diet, medications, disease) and genetic variability.² Consequently, CYP1A2 genotyping may be less clinically useful than CYP2D6 genotyping. The CYP1A2 genotype–phenotype relationship incorporates the degree of allele activity (Table 5²), and inducibility in the presence of environmental factors.

Continue to: CYP1A2 inhibiton

A variety of medications and environmental factors may inhibit CYP1A2.

Medications. Medications that may inhibit CYP1A2 include atazanavir, ciprofloxacin, ethinyl estradiol, and fluvoxamine.³

Caffeine. A significant increase in caffeine consumption can result in inhibition.³ Among non-tobacco smokers, an increase of 1 cup/d of coffee or 2 cans/d of caffeinated soda would be considered significant.³ However, tobacco smokers would require an increase of 3 cups/d of coffee or 6 cans/d of soda.

Diet. An increase in the daily dietary intake of certain vegetables for 6 days has been shown to result in inhibition.¹⁰ Apiaceous (Apiaceae or Umbelliferae) vegetables such as carrots (3/4 cup), celery (1/2 cup), dill (1 teaspoon), parsley (3 tablespoons), and parsnips (1¼ cup) can decrease CYP1A2 activity by approximately 13% to 25%. Allium (Liliaceae) vegetables, such as garlic, leeks, and onions, have no effect on CYP1A2 activity.

Infection. Pneumonia, upper respiratory infections with fever, pyelonephritis or appendicitis, or inflammation are suspected to decrease CYP1A2 activity.⁸

Continue to: CYP1A2 induction

A variety of medications and environmental factors may induce CYP1A2.

Medications. Certain medications may induce CYP1A2, including carbamazepine, phenytoin, rifampin, and primidone.

Cigarette smoking. A significant increase in smoking after 1 to 3 weeks may decrease drug levels, whereas a significant decrease in smoking after 1 to 3 weeks may result in elevated drug levels.³ Nicotine is not the causative agent of induction, but rather hydrocarbons found in cigarette smoke.¹¹

Diet. An increase in daily dietary intake of certain vegetables for 6 days has been shown to result in induction.³ Brassica (Cruciferae) vegetables such as broccoli (2 cups), cauliflower (1 cup), cabbage (1 cup), and radish sprouts (1/2 cup) have been found to increase CYP1A2 activity by 18% to 37%.¹⁰ Grilled meat also plays a role in induction.¹⁰

Related Resource

• Ellingrod VL, Ward KM. Using pharmacogenetics guidelines when prescribing: What's available. Current Psychiatry. 2018;17(1):43-46.

Drug Brand Names

Amiodarone • Cordarone, Pacerone
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz  
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban  
Carbamazepine • Carbatrol, Tegretol  
Chlorpromazine • Thorazine  
Chloroquine • Aralen
Cinacalcet • Sensipar
Ciprofloxacin • Cipro
Citalopram • Celexa
Clozapine • Clozaril
Desipramine • Norpramin  
Desvenlafaxine • Pristiq
Diphenhydramine • Benadryl
Doxepin • Silenor
Duloxetine • Cymbalta
Escitalopram • Lexapro
Ethinyl estradiol • Estinyl
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol  
Iloperidone • Fanapt
Imatinib • Gleevec
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenytoin • Dilantin
Pimavanserin • Nuplazid
Primidone • Mysoline
Quetiapine • Seroquel
Quinidine • Cardioquin
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Terbinafine • Lamisil
Thioridazine • Mellaril
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd  
Vortioxetine • Trintellix
Ziprasidone • Geodon

Genetic variations in CYP450 enzymes determine enzymatic activity, which can have a large effect on drug levels, efficacy, and toxicity. However, there are many other important factors that clinicians should consider when trying to predict the effects of medications. While clinicians often focus on a patient’s genotype, this only provides information on a chromosomal level, and this information never changes. In contrast, a patient’s phenotype, or status of metabolism, is subject to change throughout the patient’s life.

Many circumstances influence phenotype, including the use of medications that induce or inhibit CYP450 enzymes, environmental factors, and comorbidities. Phenoconversion occurs when these factors result in a phenotype that is different from that predicted by genotype. Because of the possibility of phenoconversion, knowing a patient’s genotype may be of limited value in making clinical decisions. This article provides guidance on interpreting both the genotype and phenotype of CYP2D6 and CYP1A2. Case 1 and Case 2 illustrate these concepts.

CYP2D6

The enzyme activity of CYP2D6 varies among individuals and may include no activity, decreased activity, normal activity, or increased activity. After obtaining the genotype, the activity level of the CYP2D6 alleles may be determined. The frequency with which certain alleles occur varies with ancestry. More than 100 allelic variants and subvariants have been discovered, and new alleles are continuing to be discovered.¹Table 1² lists some of the most common CYP2D6 alleles.

Based on the CYP2D6 enzyme activity determined from the alleles, 4 “traditional” phenotypes can be predicted from the genotype (Table 2²). The 7-category phenotypes reported by some laboratory companies provide a more explicit method for reporting phenotypes.

Evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction.² Thus, genetics, rather than drug therapy, accounts for most ultra-rapid CYP2D6 metabolizers. CYP2D6 can be inhibited by the use of medications (Table 3^2-5) and/or substrates (Table 4^2,6). Similar to inhibitors, substrates may be saturating high affinity-low capacity enzymes such as CYP2D6, resulting in phenoconversion to poor metabolizers. However, this is unlikely to be the case for substrates of low affinity-high capacity enzymes such as CYP3A4.⁷ Ultimately, substrates and/or inhibitors of CYP2D6 may result in a phenotype that does not correspond to genotype.

Phenoconversion

Genotyping may not reflect the true prevalence of the CYP2D6 poor metabolizer phenotype when using multiple medications that are substrates and/or inhibitors of CYP2D6.⁸ In the presence of strong CYP2D6 inhibitors, up to 80% of individuals with a non-poor metabolizer genotype are converted to a poor metabolizer phenotype.⁸ While the phenotype provides a clearer representation of metabolism status than genotype, this information may not always be available.

Continue to: Determining CYP2D6 phenotype

Risperidone and venlafaxine levels are useful tools for predicting CYP2D6 phenotype.^3,8 When a risperidone level is ordered, the results include a risperidone level and a 9-hydroxyrisperidone level. The active metabolite of risperidone is 9-hydroxyrisperidone (paliperidone). The risperidone-to-9-hydroxyrisperidone (R-to-9-OHR) concentration ratio is an indicator of CYP2D6 phenotype.³ While considerable overlap may exist using R-to-9-OHR concentration ratios as a predictor of CYP2D6 phenotype, this provides a practical and economically viable option for guiding drug therapy and recommending CYP2D6 genetic testing. The median R-to-9-OHR concentration ratios with the 25th to 75th percentiles are listed below as indicators of CYP2D6 phenotypes⁹:

• Ultra-rapid metabolizer: 0.03 (0.02 to 0.06)
• Extensive metabolizer: 0.08 (0.04 to 0.17)
• Intermediate metabolizer: 0.56 (0.30 to 1.0)
• Poor metabolizer: 2.5 (1.8 to 4.1).

Although a R-to-9-OHR concentration ratio >1 generally indicates a poor metabolizer, it could also indicate the presence of a powerful CYP2D6 inhibitor.⁹

When a venlafaxine level is ordered, the results include a venlafaxine level and an O-desmethylvenlafaxine level. O-desmethylvenlafaxine (desvenlafaxine) is the active metabolite of venlafaxine. The O-desmethylvenlafaxine-to-venlafaxine concentration ratio is an indicator of CYP2D6 phenotype.⁸ In this instance, a ratio ≥1 indicates an extensive metabolizer, whereas <1 indicates a poor metabolizer.

CYP1A2

While the activity of CYP2D6 alleles is determined primarily by genetic factors and medications, the activity of CYP1A2 alleles is largely determined by environmental factors (diet, medications, disease) and genetic variability.² Consequently, CYP1A2 genotyping may be less clinically useful than CYP2D6 genotyping. The CYP1A2 genotype–phenotype relationship incorporates the degree of allele activity (Table 5²), and inducibility in the presence of environmental factors.

Continue to: CYP1A2 inhibiton

A variety of medications and environmental factors may inhibit CYP1A2.

Medications. Medications that may inhibit CYP1A2 include atazanavir, ciprofloxacin, ethinyl estradiol, and fluvoxamine.³

Caffeine. A significant increase in caffeine consumption can result in inhibition.³ Among non-tobacco smokers, an increase of 1 cup/d of coffee or 2 cans/d of caffeinated soda would be considered significant.³ However, tobacco smokers would require an increase of 3 cups/d of coffee or 6 cans/d of soda.

Diet. An increase in the daily dietary intake of certain vegetables for 6 days has been shown to result in inhibition.¹⁰ Apiaceous (Apiaceae or Umbelliferae) vegetables such as carrots (3/4 cup), celery (1/2 cup), dill (1 teaspoon), parsley (3 tablespoons), and parsnips (1¼ cup) can decrease CYP1A2 activity by approximately 13% to 25%. Allium (Liliaceae) vegetables, such as garlic, leeks, and onions, have no effect on CYP1A2 activity.

Infection. Pneumonia, upper respiratory infections with fever, pyelonephritis or appendicitis, or inflammation are suspected to decrease CYP1A2 activity.⁸

Continue to: CYP1A2 induction

A variety of medications and environmental factors may induce CYP1A2.

Medications. Certain medications may induce CYP1A2, including carbamazepine, phenytoin, rifampin, and primidone.

Cigarette smoking. A significant increase in smoking after 1 to 3 weeks may decrease drug levels, whereas a significant decrease in smoking after 1 to 3 weeks may result in elevated drug levels.³ Nicotine is not the causative agent of induction, but rather hydrocarbons found in cigarette smoke.¹¹

Diet. An increase in daily dietary intake of certain vegetables for 6 days has been shown to result in induction.³ Brassica (Cruciferae) vegetables such as broccoli (2 cups), cauliflower (1 cup), cabbage (1 cup), and radish sprouts (1/2 cup) have been found to increase CYP1A2 activity by 18% to 37%.¹⁰ Grilled meat also plays a role in induction.¹⁰

Related Resource

• Ellingrod VL, Ward KM. Using pharmacogenetics guidelines when prescribing: What's available. Current Psychiatry. 2018;17(1):43-46.

Drug Brand Names

Amiodarone • Cordarone, Pacerone
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz  
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban  
Carbamazepine • Carbatrol, Tegretol  
Chlorpromazine • Thorazine  
Chloroquine • Aralen
Cinacalcet • Sensipar
Ciprofloxacin • Cipro
Citalopram • Celexa
Clozapine • Clozaril
Desipramine • Norpramin  
Desvenlafaxine • Pristiq
Diphenhydramine • Benadryl
Doxepin • Silenor
Duloxetine • Cymbalta
Escitalopram • Lexapro
Ethinyl estradiol • Estinyl
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol  
Iloperidone • Fanapt
Imatinib • Gleevec
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenytoin • Dilantin
Pimavanserin • Nuplazid
Primidone • Mysoline
Quetiapine • Seroquel
Quinidine • Cardioquin
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Terbinafine • Lamisil
Thioridazine • Mellaril
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd  
Vortioxetine • Trintellix
Ziprasidone • Geodon