Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

CASE Anxious and jealous

Mrs. H, age 28, presents to the emergency department (ED) with pressured speech, emotional lability, loose associations, and echolalia. On physical examination, Mrs. H is noted to have hand tremors. Mrs. H says she has not slept for the past 5 days and is experiencing anxiety and heart palpitations.

She also says that for the past 2 years she has believed that her husband is having an affair with her best friend. However, her current presentation—which she attributes to the alleged affair—began a week before she came to the ED. According to her husband, Mrs. H was “perfectly fine until a week ago” and her symptoms “appeared out of nowhere.” He reports that this has never happened before.

Mrs. H is admitted to the psychiatry unit. The nursing team reports that on the first night, Mrs. H was “running and screaming on the unit, out of control,” and was “tearful, manicky, and dysphoric.”

Mrs. H has no significant medical or psychiatric history. Her family history is significant for hyperthyroidism in her mother and maternal grandmother. Mrs. H says she smokes cigarettes (1 pack/d) but denies alcohol or illicit drug use.

EVALUATION A telling thyroid panel

Mrs. H undergoes laboratory testing, including a complete blood count, comprehensive metabolic panel, and thyroid panel due to her family history of thyroid-related disorders. The thyroid panel shows the presence of the thyroid-stimulating hormone (TSH) receptor antibody; a low TSH level; elevated triiodothyronine (T3) and thyroxine (T4) levels, with T3 > T4; elevated thyroid peroxidase (TPO) antibody; and elevated thyroglobulin antibody (Table 1). A scan shows the thyroid gland to be normal/top-normal size and is read by radiology to be indicative of a resolving thyroiditis vs Graves’ disease. An electrocardiogram indicates a heart rate of 139 beats per minute.

[polldaddy:10352133]

The authors’ observations

Mrs. H fits the presentation of psychosis secondary to Graves’ disease. However, our differential consisted of thyroiditis, brief psychotic disorder, delusional disorder (jealous type), and bipolar mania.

Brief psychotic disorder, bipolar mania, and delusional disorder were better explained by Graves’ disease, and Mrs. H’s jealous delusion resulted in functional impairment, which eliminated delusional disorder. Her family history of hyper­thyroidism, as well as her sex and history of tobacco use, supported the diagnosis of Graves’ disease. Although Mrs. H did not experience goiter, ophthalmopathy, or dermopathy, which are common signs and symptoms of Graves’ disease (Table 2), she did present with irritability, insomnia, tachycardia, and a hand tremor. Her psychiatric symptoms included anxiety, emotional lability and, most importantly, psychosis. Her laboratory results included the presence of the TSH-receptor antibody, a low TSH level, and elevated T3 and T4 levels (T3>T4), confirming the diagnosis of early-onset Graves’ disease.

Continue to: Graves' disease

 

 

Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism, representing approximately 50% to 80% of cases.¹ Graves’ disease occurs most often in women, smokers, and those with a personal or family history of autoimmune disease; although patients of any age may be affected, the peak incidence occurs between age 40 and 60.¹

Graves’ disease results from the production of immunoglobulin G (IgG) antibodies that activate the TSH receptor on the surface of thyroid follicular cells.¹ The presence of the TSH-receptor antibody, in addition to a low TSH and elevated T3 and T4 levels (T3>T4), are common laboratory findings in patients with this disease. A thyroid scan will also show increased radiotracer accumulation.

Patients with Graves’ disease, as well as those with hyperthyroidism, tend to report weight loss, increased appetite, heat intolerance, irritability, insomnia, and palpitations. In addition to the above symptoms, the identifying signs and symptoms of Graves’ disease include a goiter, ophthalmopathy, and dermopathy (Table 2). Rarely, patients with Graves’ disease can present with psychosis, which is often complicated by thyrotoxicosis.²

[polldaddy:10352135]

TREATMENT Antipsychotic and a beta blocker

Based on her signs, symptoms, and laboratory findings, Mrs. H receives risperidone, 1 mg twice daily, for psychosis, and atenolol, 25 mg twice daily, for heart palpitations. Over 4 days, her symptoms decrease; she experiences more linear thought and decreased flight-of-ideas, and becomes unsure about the truth of her husband’s alleged affair. Her impulsive behaviors and severe mood lability cease. Her tachycardia remains controlled with atenolol.

The authors’ observations

Rapid initiation of treatment is important when managing patients with Graves’ disease, because untreated patients have a higher risk of psychiatric illness, cardiac disease, arrhythmia, and sudden cardiac death.¹ Patients with Graves’ disease typically are treated with thionamides, radioactive iodine, and/or surgery. When a patient presents with psychosis as a result of thyrotoxicosis, treatment focuses on improving the thyrotoxicosis through anti-thyroid medications and beta blockers (Table 3³). Psychotropic medications, such as antipsychotics, are not indicated for primary treatment, but are given to patients who have severe psychosis until symptoms have resolved.³ For Mrs. H, the severity of her psychosis necessitated risperidone in addition to atenolol.

OUTCOME Continuous medical management; no ablation

Mrs. H is discharged with immediate out­patient follow-up with an endocrinology team to discuss the best long-term management of her thyroiditis. Mrs. H opts for continuous medical management (as opposed to ablation) and is administered methimazole, 15 mg/d, to treat Graves’ disease.

The authors’ observations

This case provides useful information regarding recognizing psychosis as the initial sign of Graves’ disease. Although Graves’ disease represents 50% to 80% of cases of hyperthyroidism,¹ psychosis as the first clinical presentation of this disease is extremely rare. Several case reports, however, have described this phenomenon,^2,3 and further studies would be helpful to determine its true prevalence.

Continue to: Bottom Line

 

 

Bottom Line

Although extremely rare, psychosis as the initial clinical presentation of Graves’ disease can occur. The early diagnosis of Graves’ disease is critical to prevent cardiovascular implications and death.

Related Resources

• Abraham P, Acharya S. Current and emerging treatment options for Graves’ hyperthyroidism. Ther Clin Risk Manag. 2010;6:29-40.
• Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909.
• Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ. 2003;168(5):575-585.

Drug Brand Names

Atenolol • Tenormin
Methimazole • Tapazole
Risperidone • Risperdal

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Mr. S, age 55, comes to your clinic as a walk-in for management of major depressive disorder, insomnia, and migraines. He also has tobacco use disorder and hypertension. Several days ago, Mr. S had visited the clinic because he was continuing to experience depressive symptoms, so his sertraline was increased from 100 to 200 mg/d. His current medication regimen includes sertraline 200 mg/d, trazodone 100 mg/d, lisinopril 10 mg/d, and sumatriptan, 100 mg as needed for migraine. He says last week he used 4 or 5 doses of sumatriptan because he experienced several migraines. Mr. S also reports occasionally taking 2 tablets of trazodone instead of 1 on nights that he has trouble falling asleep.

Today, Mr. S presents with a low-grade fever, diarrhea, internal restlessness, and a racing heartbeat that started shortly after his last visit. During physical examination, he exhibits slow, continuous lateral eye movements. His vital signs are markedly elevated: blood pressure, 175/85 mm Hg; heart rate, 110 beats per minute; and temperature, 39°C (102.2°F). Based on his presentation, the treatment team decides to send Mr. S to urgent care for closer monitoring.

Serotonin syndrome is a drug-induced syndrome caused by overstimulation of serotonin receptors. The syndrome is characterized by a classic clinical triad consisting of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The clinical presentation is highly variable, and the severity ranges from mild to life-threatening.^1-3 The incidence and prevalence of serotonin syndrome has not been well defined.³ Serotonin syndrome may be underreported because mild cases are often overlooked due to nonspecific symptoms. In addition, lack of physician awareness of drug–drug interactions, signs and symptoms, and differential diagnoses may result in underdiagnosis or misdiagnosis.^1-3

What causes it?

Serotonin syndrome is usually a consequence of a drug–drug interaction between 2 or more serotonergic agents.⁴ Serotonin syndrome may result following medication misuse, overdose, initiation of a serotonergic agent, or increase in the dose of a currently prescribed serotonergic agent.^3,4 In addition to medication classes and specific agents, Table 1^2-5 lists the drug mechanisms associated with serotonin syndrome:

• inhibition of serotonin reuptake
• inhibition of serotonin metabolism
• increased serotonin synthesis
• agonism of the serotonin receptor.

The amount of serotonergic activity most likely to cause serotonin syndrome is unclear.⁴

Pathophysiology. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of the amino acid tryptophan. This neuro­transmitter is located in both the CNS and the periphery. Regulation of the serotonergic system begins in the presynaptic neurons with decarboxylation and hydroxylation of tryptophan resulting in serotonin synthesis. Once serotonin is produced, it is released into the synaptic cleft, where it binds to serotonin receptors.^1,4,5 After receptor binding, serotonin reuptake occurs in the presynaptic neurons, where it can be metabolized by the monoamine oxidase enzyme. Finally, the metabolites are excreted in the urine. Serotonin syndrome results when this regulatory system is disrupted due to hyperstimulation of the postsynaptic serotonin receptors, mainly via agonism of the 5-HT2A and 5-HT1A receptors.^1,4,5

Continue to: A nonspecific presentation

A nonspecific presentation

Unfortunately, many of the symptoms of serotonin syndrome are nonspecific, and the severity varies among patients.^2,3 The onset of symptoms usually occurs within 6 to 8 hours after ingestion of a serotonergic agent.⁵ It is important to immediately recognize the symptoms (Table 2^2-5) and formulate a differential diagnosis because sudden progression of symptoms is common and may lead to life-threatening circumstances.^1,3

In mild cases of serotonin syndrome, patients may have a low-grade fever or be afebrile. Hyperthermia tends to be present in moderate and severe cases, with temperatures >41°C (105.8°F) during life-threatening cases. Diaphoresis and tachycardia may be present regardless of severity. Additional autonomic irregularities include hypertension, tachypnea, nausea, vomiting, diarrhea, and hyperactive bowel sounds. In terms of neuromuscular abnormalities, hyperreflexia is a primary concern, as well as myoclonus. As the severity progresses to life-threatening, the clonus may convert from inducible to spontaneous and slow, continuous lateral eye movements may be present. Additional neuromuscular symptoms include tremor, akathisia, and muscle rigidity.^1,3-5

Common mental status changes during mild cases include restlessness and anxiety. Abnormal mentation during moderate cases may present as increased hypervigilance and agitation, and this may advance to delirium or coma in severe cases. As the severity intensifies, the risk of developing additional physiological complications also increases. Rhabdomyolysis may occur due to muscle damage and myoglobinuria secondary to hyperreflexia, myoclonus, hypertonicity, and muscle rigidity. Muscle breakdown may then progress to further complications, such as renal failure. In rare instances, serotonin syndrome can result in seizures or death.^1,3-5

Medication history tips off the diagnosis

The first step in diagnosing serotonin syndrome is to conduct a thorough review of the patient’s medication history, specifically taking into account any recent exposure to serotonergic agents.^3,5 It is important to ask about prescription medications as well as over-the-counter products, herbal supplements, and illicit substances.^1,4 When reviewing the medication history, investigate whether there may have been a recent change in therapy with serotonergic agents. Also, determine when the patient’s symptoms began in relation to exposure to serotonergic agents.⁴

After the medication review, conduct a thorough physical and neurologic examination to identify current symptoms and severity.^1,3 No specific laboratory test is available to definitively confirm the diagnosis of serotonin syndrome.^1,4 Monitoring of serum serotonin is not recommended because the levels do not correlate with symptom severity.³ The recommended diagnostic tool is the Hunter Serotonin Toxicity Criteria (Figure^1,3).^3,4 Historically, the Sternbach’s Diagnostic Criteria for serotonin syndrome were used for diagnosis; however, the Hunter Serotonin Toxicity Criteria are more sensitive (96% vs 75%) and more specific (97% vs 84%) than the Sternbach’s Diagnostic Criteria for serotonin syndrome.^1,3-5

Continue to: In addition to using the proper diagnostic tool...

In addition to using the proper diagnostic tool, conduct a differential diagnosis to rule out other drug-induced syndromes, such as anticholinergic toxidrome, neuroleptic malignant syndrome, or malignant hyperthermia.^1,3,5 Autonomic instability, including hypertension, tachycardia, tachypnea, and hyperthermia, may be present in all of the aforementioned drug-induced syndromes.¹ As a result, the clinician must monitor for other symptoms that may differentiate the disease states to establish a clear diagnosis.

Discontinue agents, offer supportive care

There are no official published guidelines for managing serotonin syndrome.⁵ Regardless of the severity of a patient’s presentation, all serotonergic agents should be discontinued immediately. In addition, supportive care should be initiated for symptom management. Intravenous fluid replacement is recommended for hydration and to treat hyperthermia. External cooling may also be warranted to reduce body temperatures. Vital signs should be stabilized with appropriate pharmacotherapy.^1,3-5

Benzodiazepines are considered a mainstay for relief of agitation during serotonin syndrome of any severity. In life-threatening cases—which are characterized by hyperthermia >41°C (105.8°F)—sedation, paralysis, and intubation may be necessary to maintain the airway, breathing, and circulation.^1,3-5 Because treatment of hyperthermia requires elimination of hyperreflexia, paralysis is recommended.¹ Nondepolarizing neuromuscular blocking agents, such as vecuronium, are preferred over depolarizing agents due to their decreased potential for rhabdomyolysis.^1,3

Cyproheptadine, a histamine-1 receptor antagonist and a 5-HT2A receptor antagonist, is recommended for off-label treatment of serotonin syndrome to help decrease the intensity of symptoms. This should be initiated as a single dose of 12 mg followed by 2 mg every 2 hours until symptoms improve.^1,3,5 After stabilization, a maintenance dose of 8 mg every 6 hours is recommended. Doses should not exceed the maximum recommended dose of 0.5 mg/kg/d.^1,3,6 The most common adverse reactions associated with cyproheptadine are sedation and anticholinergic adverse effects.^1,4,6

Antipsychotics, such as olanzapine and chlorpromazine, have been considered treatment alternatives due to their associated 5-HT2A receptor antagonism. However, there is limited data supporting such use.^1,4 Antipsychotics should be used with caution because neuroleptic malignant syndrome may be mistaken for serotonin syndrome. Use of antipyretics is not recommended for treating fever and hyperthermia because the increase in body temperature is secondary to excessive muscle activity rather than dysfunction of the hypothalamic temperature set point.^1,3,5 Physical restraints are also not recommended because their use may provoke further hyperthermia and increase the risk of rhabdomyolysis.^3,5

Continue to: Ultimately, the duration of treatment...

Ultimately, the duration of treatment will be influenced by the pharmacokinetics of the serotonergic agents that induced the serotonin syndrome. Following resolution, retrial of the offending serotonergic agents should be carefully assessed. A retrial should only be considered after an adequate washout period has been observed, and clinicians should consider utilizing lower doses.^2,5

Take steps for prevention

Patients at highest risk of developing serotonin syndrome are those who have multiple comorbidities that result in treatment with multiple serotonergic agents.³ Clinicians and patients alike need to be educated about the signs and symptoms of serotonin syndrome to promote early recognition. Also consider modifying your prescribing practices to minimize the use of multiple serotonergic agents. When switching between serotonergic agents, institute safe washout periods. Encourage patients to adhere to their prescribed medication regimens. Using electronic ordering systems can help detect drug–drug interactions.^1,3 Prophylaxis with cyproheptadine may be considered in high-risk patients; however, no clinical trials have been conducted to evaluate using cyproheptadine to prevent serotonin syndrome.⁷

CASE CONTINUED

Upon further assessment in urgent care, Mr. S is found to have muscle rigidity in addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms coincide with a recent increase of sertraline and increased use of both trazodone and sumatriptan, he meets Hunter Serotonin Toxicity Criteria. Therefore, his symptoms are likely related to excessive increase in serotonergic activity. Mr. S is admitted to the hospital for closer monitoring, and his sertraline, trazodone, and sumatriptan are held. He receives IV fluids for several days as well as cyproheptadine, 8 mg every 6 hours after stabilization, until his symptoms resolve. On Day 4, Mr. S no longer experiences diarrhea and internal restlessness. His vital signs return to normal, and as a result of symptom resolution, he is discharged from the hospital. The treatment team discusses changing his medication regimen to avoid multiple serotonergic agents. Mr. S is switched from sertraline to bupropion XL, 150 mg/d. Sumatriptan, 100 mg/d as needed, is continued for acute migraine treatment. Trazodone is discontinued and replaced with melatonin, 3 mg/d. The team also counsels Mr. S on the importance of proper adherence to his medication regimen. He is advised to return to the clinic in 2 weeks for reassessment of safety and efficacy.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Almotriptan • Axert
Buprenorphine • Subutex
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cyproheptadine • Periactin
Eletriptan • Relpax
Frovatriptan • Frova
Granisetron • Kytril
Lisinopril • Prinivil, Zestril
Meperidine • Demerol
Methadone • Dolophine, Methadose
Metoclopramide • Reglan
Mirtazapine • Remeron
Naratriptan • Amerge
Olanzapine • Zyprexa
Ondansetron • Zofran
Rizatriptan • Maxalt
Sertraline • Zoloft
Sumatriptan • Imitrex tablets
Tapentadol • Nucynta
Tramadol • Conzip
Trazodone • Desyrel, Oleptro
Valproic acid • Depakene, Depakote
Vecuronium • Norcuron
Zolmitriptan • Zomig

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

 

 

2. Girard TD, Exline MC, Carson SS, et al; MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

 

 

Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Ask a psychiatrist to name a psychotic disorder, and the answer will most likely be “schizophrenia.” But if you closely examine the symptom structure of DSM-5 psychiatric disorders, you will note the presence of psychosis in almost all of them.

Fixed false beliefs and impaired reality testing are core features of psychosis. Those are certainly prominent in severe psychoses such as schizophrenia, schizoaffective disorder, or delusional disorder. But psychosis is actually a continuum of varying severity across most psychiatric disorders, although they carry different diagnostic labels. Irrational false beliefs and impaired functioning due to poor reality testing are embedded among many DSM-5 disorders. Hallucinations are less common; they are perceptual aberrations, not thought abnormalities, although they can trigger delusional explanations as to their causation.

Consider the following:

• Bipolar disorder. A large proportion of patients with bipolar disorder manifest delusions, usually grandiose, but often paranoid or referential.
• Major depressive disorder (MDD). Although regarded as a “pure mood disorder,” the core symptoms of MDD—self-deprecation and sense of worthlessness—as well as the poor reality testing of suicidal thoughts (that death is a better option than living) are psychotic false beliefs.
• Anxiety and panic disorder. The central symptom in anxiety and panic attacks is a belief in impending doom and/or death. The fear in anxiety disorders is actually based on a false belief (eg, if I get on the plane, it will crash, and I will die). Thus, technically an irrational/psychotic thought process underpins the terror and fear of anxiety disorders.
• Borderline personality disorder. Frank psychotic symptoms, such as paranoid beliefs, are known to be a component of borderline personality disorder symptoms. Although these symptoms tend to be brief and episodic, they can have a deleterious effect on the person’s coping and relationships.
• Other personality disorders. While many individuals with narcissistic personality disorder are functional, their exaggerated sense of self-importance, entitlement, and self-aggrandizement certainly qualifies as a fixed false belief. Patients with other personality disorders, such as schizotypal and paranoid, are known to harbor false beliefs or magical thinking.
• Body dysmorphic disorder. False beliefs about one’s appearance (such as blemishes or asymmetry) are at the center of this disorder, and it meets the litmus test of a psychosis.
• Anorexia nervosa. This disorder is well known to be characterized by a fixed false belief that one is “fat,” even when the patient’s body borders on being cachectic in appearance according to objective observers.
• Autism. This spectrum of diseases includes false beliefs that drive the ritualistic or odd behaviors.
• Obsessive-compulsive disorder. Although obsessions are usually ego-dystonic, in severe cases, they become ego-syntonic, similar to delusions. On the other hand, compulsions are often driven by a false belief, such as believing that one’s hands are dirty and must be washed incessantly, or that the locks on the door must be rechecked repeatedly because an intruder may break into the house and harm the inhabitants.
• Neurodegenerative syndromes. Neurodegenerative syndromes are neuropsychiatric disorders that very frequently include psychotic symptoms, such as paranoid delusions, delusions of marital infidelity, Capgras syndrome, or folie à deux. These disorders include Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, frontal temporal dementia, metachromatic leukodystrophy, Huntington’s chorea, temporal lobe epilepsy, stroke, xenomelia, reduplicative phenomena, etc. This reflects the common emergence of faulty thinking with disintegration of neural tissue, both gray and white matter.

Continue to: So it should not be...

So it should not be surprising that antipsychotic medications, especially second-generation agents, have been shown to be helpful as monotherapy or adjunctive therapy in practically all the above psychiatric disorders, whether on-label or off-label.

Finally, it should also be noted that a case has been made for the existence of one dimension in all mental disorders manifesting in multiple psychopathologies.¹ It is possible that a continuum of delusional thinking is a common thread across many psychiatric disorders due to this putative shared dimension. The milder form of this dimension may also explain the presence of pre-psychotic thinking in a significant proportion of the general population who do not seek psychiatric help.² Just think of how many people you befriend, socialize with, and regard as perfectly “normal” endorse wild superstitions and astrological predictions, or believe in various conspiracy theories that have no basis in reality.

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Ask a psychiatrist to name a psychotic disorder, and the answer will most likely be “schizophrenia.” But if you closely examine the symptom structure of DSM-5 psychiatric disorders, you will note the presence of psychosis in almost all of them.

Fixed false beliefs and impaired reality testing are core features of psychosis. Those are certainly prominent in severe psychoses such as schizophrenia, schizoaffective disorder, or delusional disorder. But psychosis is actually a continuum of varying severity across most psychiatric disorders, although they carry different diagnostic labels. Irrational false beliefs and impaired functioning due to poor reality testing are embedded among many DSM-5 disorders. Hallucinations are less common; they are perceptual aberrations, not thought abnormalities, although they can trigger delusional explanations as to their causation.

Consider the following:

• Bipolar disorder. A large proportion of patients with bipolar disorder manifest delusions, usually grandiose, but often paranoid or referential.
• Major depressive disorder (MDD). Although regarded as a “pure mood disorder,” the core symptoms of MDD—self-deprecation and sense of worthlessness—as well as the poor reality testing of suicidal thoughts (that death is a better option than living) are psychotic false beliefs.
• Anxiety and panic disorder. The central symptom in anxiety and panic attacks is a belief in impending doom and/or death. The fear in anxiety disorders is actually based on a false belief (eg, if I get on the plane, it will crash, and I will die). Thus, technically an irrational/psychotic thought process underpins the terror and fear of anxiety disorders.
• Borderline personality disorder. Frank psychotic symptoms, such as paranoid beliefs, are known to be a component of borderline personality disorder symptoms. Although these symptoms tend to be brief and episodic, they can have a deleterious effect on the person’s coping and relationships.
• Other personality disorders. While many individuals with narcissistic personality disorder are functional, their exaggerated sense of self-importance, entitlement, and self-aggrandizement certainly qualifies as a fixed false belief. Patients with other personality disorders, such as schizotypal and paranoid, are known to harbor false beliefs or magical thinking.
• Body dysmorphic disorder. False beliefs about one’s appearance (such as blemishes or asymmetry) are at the center of this disorder, and it meets the litmus test of a psychosis.
• Anorexia nervosa. This disorder is well known to be characterized by a fixed false belief that one is “fat,” even when the patient’s body borders on being cachectic in appearance according to objective observers.
• Autism. This spectrum of diseases includes false beliefs that drive the ritualistic or odd behaviors.
• Obsessive-compulsive disorder. Although obsessions are usually ego-dystonic, in severe cases, they become ego-syntonic, similar to delusions. On the other hand, compulsions are often driven by a false belief, such as believing that one’s hands are dirty and must be washed incessantly, or that the locks on the door must be rechecked repeatedly because an intruder may break into the house and harm the inhabitants.
• Neurodegenerative syndromes. Neurodegenerative syndromes are neuropsychiatric disorders that very frequently include psychotic symptoms, such as paranoid delusions, delusions of marital infidelity, Capgras syndrome, or folie à deux. These disorders include Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, frontal temporal dementia, metachromatic leukodystrophy, Huntington’s chorea, temporal lobe epilepsy, stroke, xenomelia, reduplicative phenomena, etc. This reflects the common emergence of faulty thinking with disintegration of neural tissue, both gray and white matter.

Continue to: So it should not be...

So it should not be surprising that antipsychotic medications, especially second-generation agents, have been shown to be helpful as monotherapy or adjunctive therapy in practically all the above psychiatric disorders, whether on-label or off-label.

Finally, it should also be noted that a case has been made for the existence of one dimension in all mental disorders manifesting in multiple psychopathologies.¹ It is possible that a continuum of delusional thinking is a common thread across many psychiatric disorders due to this putative shared dimension. The milder form of this dimension may also explain the presence of pre-psychotic thinking in a significant proportion of the general population who do not seek psychiatric help.² Just think of how many people you befriend, socialize with, and regard as perfectly “normal” endorse wild superstitions and astrological predictions, or believe in various conspiracy theories that have no basis in reality.

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Ask a psychiatrist to name a psychotic disorder, and the answer will most likely be “schizophrenia.” But if you closely examine the symptom structure of DSM-5 psychiatric disorders, you will note the presence of psychosis in almost all of them.

Fixed false beliefs and impaired reality testing are core features of psychosis. Those are certainly prominent in severe psychoses such as schizophrenia, schizoaffective disorder, or delusional disorder. But psychosis is actually a continuum of varying severity across most psychiatric disorders, although they carry different diagnostic labels. Irrational false beliefs and impaired functioning due to poor reality testing are embedded among many DSM-5 disorders. Hallucinations are less common; they are perceptual aberrations, not thought abnormalities, although they can trigger delusional explanations as to their causation.

Consider the following:

• Bipolar disorder. A large proportion of patients with bipolar disorder manifest delusions, usually grandiose, but often paranoid or referential.
• Major depressive disorder (MDD). Although regarded as a “pure mood disorder,” the core symptoms of MDD—self-deprecation and sense of worthlessness—as well as the poor reality testing of suicidal thoughts (that death is a better option than living) are psychotic false beliefs.
• Anxiety and panic disorder. The central symptom in anxiety and panic attacks is a belief in impending doom and/or death. The fear in anxiety disorders is actually based on a false belief (eg, if I get on the plane, it will crash, and I will die). Thus, technically an irrational/psychotic thought process underpins the terror and fear of anxiety disorders.
• Borderline personality disorder. Frank psychotic symptoms, such as paranoid beliefs, are known to be a component of borderline personality disorder symptoms. Although these symptoms tend to be brief and episodic, they can have a deleterious effect on the person’s coping and relationships.
• Other personality disorders. While many individuals with narcissistic personality disorder are functional, their exaggerated sense of self-importance, entitlement, and self-aggrandizement certainly qualifies as a fixed false belief. Patients with other personality disorders, such as schizotypal and paranoid, are known to harbor false beliefs or magical thinking.
• Body dysmorphic disorder. False beliefs about one’s appearance (such as blemishes or asymmetry) are at the center of this disorder, and it meets the litmus test of a psychosis.
• Anorexia nervosa. This disorder is well known to be characterized by a fixed false belief that one is “fat,” even when the patient’s body borders on being cachectic in appearance according to objective observers.
• Autism. This spectrum of diseases includes false beliefs that drive the ritualistic or odd behaviors.
• Obsessive-compulsive disorder. Although obsessions are usually ego-dystonic, in severe cases, they become ego-syntonic, similar to delusions. On the other hand, compulsions are often driven by a false belief, such as believing that one’s hands are dirty and must be washed incessantly, or that the locks on the door must be rechecked repeatedly because an intruder may break into the house and harm the inhabitants.
• Neurodegenerative syndromes. Neurodegenerative syndromes are neuropsychiatric disorders that very frequently include psychotic symptoms, such as paranoid delusions, delusions of marital infidelity, Capgras syndrome, or folie à deux. These disorders include Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, frontal temporal dementia, metachromatic leukodystrophy, Huntington’s chorea, temporal lobe epilepsy, stroke, xenomelia, reduplicative phenomena, etc. This reflects the common emergence of faulty thinking with disintegration of neural tissue, both gray and white matter.

Continue to: So it should not be...

So it should not be surprising that antipsychotic medications, especially second-generation agents, have been shown to be helpful as monotherapy or adjunctive therapy in practically all the above psychiatric disorders, whether on-label or off-label.

Finally, it should also be noted that a case has been made for the existence of one dimension in all mental disorders manifesting in multiple psychopathologies.¹ It is possible that a continuum of delusional thinking is a common thread across many psychiatric disorders due to this putative shared dimension. The milder form of this dimension may also explain the presence of pre-psychotic thinking in a significant proportion of the general population who do not seek psychiatric help.² Just think of how many people you befriend, socialize with, and regard as perfectly “normal” endorse wild superstitions and astrological predictions, or believe in various conspiracy theories that have no basis in reality.

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Editor’s note:  Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Chief Resident at Nassau University Medical Center, East Meadow, New York, talked with Donald W. Black, MD, Professor of Psychiatry, Department of Psychiatry, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. Dr. Black is also Editor-in-Chief of Annals of Clinical Psychiatry, and Secretary/Treasurer and former President of the American Academy of Clinical Psychiatrists. He is a clinical and translational researcher with more than 300 publications. His work has focused on the course and treatment of severe personality disorders, including researching the effectiveness of the Systems Training for Emotional Predictability and Problem Solving (STEPPS) program for borderline personality disorder. He also conducts family and follow-up studies of behavioral addictions, including gambling disorder.

Dr. Ahmed: What made you choose the academic track, and how did your training lead you towards this path?

Dr. Black: I had always been interested in the idea of working at a medical school, and enjoyed writing and speaking. I was exposed to clinical research as a resident, and that confirmed my interest in academia, because I could envision combining all my interests, along with patient care. I always thought that patients were a major source of ideas for research and writing.

Dr. Ahmed: What are some of the pros and cons of working in academia?

Dr. Black: The pros include being able to influence future physicians through my teaching and writing; being able to pursue important research; and not being isolated from peers. Other advantages are being largely protected from utilization review; having more free time than peers in the private sector, who have difficulty finding coverage; and having defined benefits and a steady salary. I also share call with many peers.

When it comes to the cons, salaries are lower than in the private sector. The cons also include not being my own boss, and sometimes having to bend to the whims of an institution or supervisor.

Continue to: Dr. Ahmed...

Dr. Ahmed: Are you required to conduct research?

Dr. Black: Yes. This is one of the best aspects of my job: being able to make clinical discoveries that I can disseminate through writing and speaking. Over time, this has become increasingly challenging due to the difficulty of obtaining research funding from foundations or the federal government. This has become highly problematic, particularly for clinical researchers, because the National Institutes of Health has clearly been favoring neuroscience.

Dr. Ahmed: What is your typical day like?

Dr. Black: Because of the many hats I wear (or have worn), each day is different from the other. I combine patient care with research, writing, speaking, teaching, and administration. As a tenure-track faculty member, I am expected to write grants, conduct research, and publish. My clinical-track peers primarily provide patient care and teach students and residents.

Dr. Ahmed: What is unique about working in a training institute vs private practice?

Continue to: Dr. Black...

Dr. Black: As an academic psychiatrist, I feel I have the best of both worlds: patient care combined with opportunities my private practice colleagues do not have. Because I have published widely, and have developed a reputation, I am frequently invited to speak at meetings throughout the United States, and sometimes internationally. Travel is a perk of academia, and as someone who loves travel, that is important.

Dr. Ahmed: Where do you see psychiatry going?

Dr. Black: Psychiatry will always be an important specialty because no one else truly cares about patients with psychiatric illnesses. Mental illness will not go away, and society needs highly trained individuals to provide care. There are many “me too” clinicians who now share in caring for patients with psychiatric illnesses, but psychiatrists will always have the most training, and are in a position to provide supervision to others and to direct mental health care teams.

Dr. Ahmed: What advice do you have for residents contemplating a career in academic psychiatry?

Dr. Black: Because most medical schools now have both tenure and clinical tracks, no one needs to feel left out. Those who are interested in scholarly activities will gravitate to the tenure tract, and all that requires in terms of grants and papers, while those who are primarily interested in patient care and teaching will choose the clinical track.

Editor’s note:  Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Chief Resident at Nassau University Medical Center, East Meadow, New York, talked with Donald W. Black, MD, Professor of Psychiatry, Department of Psychiatry, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. Dr. Black is also Editor-in-Chief of Annals of Clinical Psychiatry, and Secretary/Treasurer and former President of the American Academy of Clinical Psychiatrists. He is a clinical and translational researcher with more than 300 publications. His work has focused on the course and treatment of severe personality disorders, including researching the effectiveness of the Systems Training for Emotional Predictability and Problem Solving (STEPPS) program for borderline personality disorder. He also conducts family and follow-up studies of behavioral addictions, including gambling disorder.

Dr. Ahmed: What made you choose the academic track, and how did your training lead you towards this path?

Dr. Black: I had always been interested in the idea of working at a medical school, and enjoyed writing and speaking. I was exposed to clinical research as a resident, and that confirmed my interest in academia, because I could envision combining all my interests, along with patient care. I always thought that patients were a major source of ideas for research and writing.

Dr. Ahmed: What are some of the pros and cons of working in academia?

Dr. Black: The pros include being able to influence future physicians through my teaching and writing; being able to pursue important research; and not being isolated from peers. Other advantages are being largely protected from utilization review; having more free time than peers in the private sector, who have difficulty finding coverage; and having defined benefits and a steady salary. I also share call with many peers.

When it comes to the cons, salaries are lower than in the private sector. The cons also include not being my own boss, and sometimes having to bend to the whims of an institution or supervisor.

Continue to: Dr. Ahmed...

Dr. Ahmed: Are you required to conduct research?

Dr. Black: Yes. This is one of the best aspects of my job: being able to make clinical discoveries that I can disseminate through writing and speaking. Over time, this has become increasingly challenging due to the difficulty of obtaining research funding from foundations or the federal government. This has become highly problematic, particularly for clinical researchers, because the National Institutes of Health has clearly been favoring neuroscience.

Dr. Ahmed: What is your typical day like?

Dr. Black: Because of the many hats I wear (or have worn), each day is different from the other. I combine patient care with research, writing, speaking, teaching, and administration. As a tenure-track faculty member, I am expected to write grants, conduct research, and publish. My clinical-track peers primarily provide patient care and teach students and residents.

Dr. Ahmed: What is unique about working in a training institute vs private practice?

Continue to: Dr. Black...

Dr. Black: As an academic psychiatrist, I feel I have the best of both worlds: patient care combined with opportunities my private practice colleagues do not have. Because I have published widely, and have developed a reputation, I am frequently invited to speak at meetings throughout the United States, and sometimes internationally. Travel is a perk of academia, and as someone who loves travel, that is important.

Dr. Ahmed: Where do you see psychiatry going?

Dr. Black: Psychiatry will always be an important specialty because no one else truly cares about patients with psychiatric illnesses. Mental illness will not go away, and society needs highly trained individuals to provide care. There are many “me too” clinicians who now share in caring for patients with psychiatric illnesses, but psychiatrists will always have the most training, and are in a position to provide supervision to others and to direct mental health care teams.

Dr. Ahmed: What advice do you have for residents contemplating a career in academic psychiatry?

Dr. Black: Because most medical schools now have both tenure and clinical tracks, no one needs to feel left out. Those who are interested in scholarly activities will gravitate to the tenure tract, and all that requires in terms of grants and papers, while those who are primarily interested in patient care and teaching will choose the clinical track.

Editor’s note:  Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Chief Resident at Nassau University Medical Center, East Meadow, New York, talked with Donald W. Black, MD, Professor of Psychiatry, Department of Psychiatry, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. Dr. Black is also Editor-in-Chief of Annals of Clinical Psychiatry, and Secretary/Treasurer and former President of the American Academy of Clinical Psychiatrists. He is a clinical and translational researcher with more than 300 publications. His work has focused on the course and treatment of severe personality disorders, including researching the effectiveness of the Systems Training for Emotional Predictability and Problem Solving (STEPPS) program for borderline personality disorder. He also conducts family and follow-up studies of behavioral addictions, including gambling disorder.

Dr. Ahmed: What made you choose the academic track, and how did your training lead you towards this path?

Dr. Black: I had always been interested in the idea of working at a medical school, and enjoyed writing and speaking. I was exposed to clinical research as a resident, and that confirmed my interest in academia, because I could envision combining all my interests, along with patient care. I always thought that patients were a major source of ideas for research and writing.

Dr. Ahmed: What are some of the pros and cons of working in academia?

Dr. Black: The pros include being able to influence future physicians through my teaching and writing; being able to pursue important research; and not being isolated from peers. Other advantages are being largely protected from utilization review; having more free time than peers in the private sector, who have difficulty finding coverage; and having defined benefits and a steady salary. I also share call with many peers.

When it comes to the cons, salaries are lower than in the private sector. The cons also include not being my own boss, and sometimes having to bend to the whims of an institution or supervisor.

Continue to: Dr. Ahmed...

Dr. Ahmed: Are you required to conduct research?

Dr. Black: Yes. This is one of the best aspects of my job: being able to make clinical discoveries that I can disseminate through writing and speaking. Over time, this has become increasingly challenging due to the difficulty of obtaining research funding from foundations or the federal government. This has become highly problematic, particularly for clinical researchers, because the National Institutes of Health has clearly been favoring neuroscience.

Dr. Ahmed: What is your typical day like?

Dr. Black: Because of the many hats I wear (or have worn), each day is different from the other. I combine patient care with research, writing, speaking, teaching, and administration. As a tenure-track faculty member, I am expected to write grants, conduct research, and publish. My clinical-track peers primarily provide patient care and teach students and residents.

Dr. Ahmed: What is unique about working in a training institute vs private practice?

Continue to: Dr. Black...

Dr. Black: As an academic psychiatrist, I feel I have the best of both worlds: patient care combined with opportunities my private practice colleagues do not have. Because I have published widely, and have developed a reputation, I am frequently invited to speak at meetings throughout the United States, and sometimes internationally. Travel is a perk of academia, and as someone who loves travel, that is important.

Dr. Ahmed: Where do you see psychiatry going?

Dr. Black: Psychiatry will always be an important specialty because no one else truly cares about patients with psychiatric illnesses. Mental illness will not go away, and society needs highly trained individuals to provide care. There are many “me too” clinicians who now share in caring for patients with psychiatric illnesses, but psychiatrists will always have the most training, and are in a position to provide supervision to others and to direct mental health care teams.

Dr. Ahmed: What advice do you have for residents contemplating a career in academic psychiatry?

Dr. Black: Because most medical schools now have both tenure and clinical tracks, no one needs to feel left out. Those who are interested in scholarly activities will gravitate to the tenure tract, and all that requires in terms of grants and papers, while those who are primarily interested in patient care and teaching will choose the clinical track.

Factors that change our brains

I greatly enjoyed Dr. Nasrallah’s editorial, “Your patient’s brain is different at every visit” (From the Editor, Current Psychiatry, May 2019, p. 6,8,10). This is my first time writing to Current Psychiatry, and the journal’s focus and articles have been informative and impactful throughout my training and in my current practice.

In reading this editorial, it is clear that a myriad of factors we consider and address with our patients during each visit underly intricate neurobiologic mechanisms and processes that ever deepen our understanding of the brain. In discussing the changes taking place in our patients, I can’t help but wonder what changes are also occurring in our brains (as Dr. Nasrallah noted). What would be the resulting impact of these changes in our next patient interaction and/or subsequent interaction(s) with the same patient? Looking through the editorial’s bullet points, many (if not all) of the factors contributing to brain changes apply equally and naturally to clinicians as well as patients. In this light, the editorial serves not only as a broad guideline for patient psychoeducation but also as a reminder of wellness and well-being for clinicians.

As a “fresh-out-of-training” psychiatrist, I can definitely work on several of the factors, such as diet and exercise. Trainees and residents can be more susceptible to overlook and befall some of these factors and changes, and may already be basing the clinical advice they give to their patients on these same factors and changes. As a child psychiatrist, I value the importance of modeling healthy behaviors for my patients, and their families and with coworkers or colleagues. In accordance with the impact these factors have on our brains, it’s important to emphasize what we can do to further strengthen rapport and therapeutic value through modeling. I strive to model the desired behaviors, attitudes, and dynamics that are the external, observable manifestation or symptomology of what takes place in my brain. To do so, I understand I need to be mindful in proactively managing the contributing factors, such as those listed in Dr. Nasrallah’s editorial. I imagine patients and their families would easily notice if we are in suboptimal physical and/or mental health that results in us not being prompt, fully engaged, or receptive. I believe that attending to these facets during training falls under the umbrella of professionalism. Being a professional in our field often entails practicing what we preach. So, I’m grateful that what we preach is informed by our field’s exciting research, continued advancements, and expertise that benefits our patients and us professionally and personally.

Philip Yen-Tsun Liu, MD
Child and adolescent psychiatrist
innovaTel Telepsychiatry
San Antonio, Texas

Dr. Nasrallah responds

I would like to thank Dr. Liu for his thoughtful response to my editorial. He seems to be very cognizant of the fact that experiential neuroplasticity and brain tissue remodeling occurs in both the patient and physician. I admire his focus on psychoeducation, wellness, and professionalism. He is right that we as psychiatrists (and nurse practitioners) must be role models for our patients in multiple ways, because it may help enhance clinical outcomes and have a positive impact on their brains.

I would also like to point Dr. Liu to the editorial “The most powerful placebo is not a pill” (From the Editor, Current Psychiatry, August 2011, p. 18-19), which I wrote 8 years ago (before he started his residency), about the importance of what we do and say as physicians.

Henry A. Nasrallah, MD
Editor-in-Chief
Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

 

 

The APA’s stance on neuroimaging

Can anyone in the modern world argue that the brain is irrelevant to psychiatry? Yet surprisingly, in September 2018, the American Psychiatric Association (APA) officially declared that neuroimaging of the brain has no clinical value in psychiatry.¹

Unfortunately, the APA focused almost exclusively on functional magnetic resonance imaging (fMRI) and neglected an extensive library of studies of single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The APA’s position on neuroimaging is as follows^1,2:

1. A neuroimaging finding must have a sensitivity and specificity (S/sp) of no less than 80%.
2. The psychiatric imaging literature does not support using neuroimaging in psychiatric diagnostics or treatment.
3. Neuroimaging has not had a significant impact on the diagnosis and treatment of psychiatric disorders.

The APA set unrealistic standards for biomarkers in a field that lacks pathologic markers of specific disease entities.³ Moreover, numerous widely used tests fall below the APA’s unrealistic S/sp cutoff, including the Hamilton Depression Rating Scale,⁴ Zung Depression Scale,⁵ the clock drawing test,⁶ and even the chest X-ray.³ Curiously, numerous replicated SPECT and PET studies were not included in the APA’s analysis.^1-3 For example, in a study of 196 veterans, posttraumatic stress disorder was distinguished from traumatic brain injury with an S/sp of 0.92/0.85.^7,8 Also, fluorodeoxyglucose (FDG)-PET has an S/sp of 0.84/0.74 in differentiating patients with Alzheimer’s disease from controls, while perfusion SPECT, using multi-detector cameras, has an S/sp of 0.93/0.84.^3,9 Moreover, both FDG-PET and SPECT can differentiate other forms of dementia from Alzheimer’s disease, yielding an additional benefit compared to amyloid imaging alone.^2,9 As President of the International Society of Applied Neuroimaging, I suggest neuroimaging should not be feared. Neuroimaging does not replace the diagnostician; rather, it aids him/her in a complex case.

Theodore A. Henderson, MD, PhD
President
Neuro-Luminance Brain Health Centers, Inc.
Denver, Colorado
Director
The Synaptic Space
Vice President
The Neuro-Laser Foundation
President
International Society of Applied Neuroimaging
Centennial, Colorado

Disclosure
The author has no ownership in, and receives no remuneration from, any neuroimaging company.

References
1. First MB, Drevets WC, Carter C, et al. Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018:175:915-916.
2. First MB, Drevets WC, Carter C, et al. Data supplement for Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018;175(suppl).
3. Henderson TA. Brain SPECT imaging in neuropsychiatric diagnosis and monitoring. EPatient. http://nmpangea.com/2018/10/09/738/. Published 2018. Accessed May 31, 2019.
4. Bagby RM, Ryder AG, Schuller DR, et al. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry. 2004;161(12):2163-2177.
5. Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung Self-rating Depression Scale. Br J Psychiatry. 1978;132:381-385.
6. Seigerschmidt E, Mösch E, Siemen M, et al. The clock drawing test and questionable dementia: reliability and validity. Int J Geriatr Psychiatry. 2002;17(11):1048-1054.
7. Raji CA, Willeumier K, Taylor D, et al. Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population. Brain Imaging Behav. 2015;9(3):527-534.
8. Amen DG, Raji CA, Willeumier K, et al. Functional neuroimaging distinguishes posttraumatic stress disorder from traumatic brain injury in focused and large community datasets. PLoS One. 2015;10(7):e0129659. doi: 10.1371/journal.pone.0129659.
9. Henderson TA. The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging. CNS Spectr. 2012;17(4):176-206.

Factors that change our brains

I greatly enjoyed Dr. Nasrallah’s editorial, “Your patient’s brain is different at every visit” (From the Editor, Current Psychiatry, May 2019, p. 6,8,10). This is my first time writing to Current Psychiatry, and the journal’s focus and articles have been informative and impactful throughout my training and in my current practice.

In reading this editorial, it is clear that a myriad of factors we consider and address with our patients during each visit underly intricate neurobiologic mechanisms and processes that ever deepen our understanding of the brain. In discussing the changes taking place in our patients, I can’t help but wonder what changes are also occurring in our brains (as Dr. Nasrallah noted). What would be the resulting impact of these changes in our next patient interaction and/or subsequent interaction(s) with the same patient? Looking through the editorial’s bullet points, many (if not all) of the factors contributing to brain changes apply equally and naturally to clinicians as well as patients. In this light, the editorial serves not only as a broad guideline for patient psychoeducation but also as a reminder of wellness and well-being for clinicians.

As a “fresh-out-of-training” psychiatrist, I can definitely work on several of the factors, such as diet and exercise. Trainees and residents can be more susceptible to overlook and befall some of these factors and changes, and may already be basing the clinical advice they give to their patients on these same factors and changes. As a child psychiatrist, I value the importance of modeling healthy behaviors for my patients, and their families and with coworkers or colleagues. In accordance with the impact these factors have on our brains, it’s important to emphasize what we can do to further strengthen rapport and therapeutic value through modeling. I strive to model the desired behaviors, attitudes, and dynamics that are the external, observable manifestation or symptomology of what takes place in my brain. To do so, I understand I need to be mindful in proactively managing the contributing factors, such as those listed in Dr. Nasrallah’s editorial. I imagine patients and their families would easily notice if we are in suboptimal physical and/or mental health that results in us not being prompt, fully engaged, or receptive. I believe that attending to these facets during training falls under the umbrella of professionalism. Being a professional in our field often entails practicing what we preach. So, I’m grateful that what we preach is informed by our field’s exciting research, continued advancements, and expertise that benefits our patients and us professionally and personally.

Philip Yen-Tsun Liu, MD
Child and adolescent psychiatrist
innovaTel Telepsychiatry
San Antonio, Texas

Dr. Nasrallah responds

I would like to thank Dr. Liu for his thoughtful response to my editorial. He seems to be very cognizant of the fact that experiential neuroplasticity and brain tissue remodeling occurs in both the patient and physician. I admire his focus on psychoeducation, wellness, and professionalism. He is right that we as psychiatrists (and nurse practitioners) must be role models for our patients in multiple ways, because it may help enhance clinical outcomes and have a positive impact on their brains.

I would also like to point Dr. Liu to the editorial “The most powerful placebo is not a pill” (From the Editor, Current Psychiatry, August 2011, p. 18-19), which I wrote 8 years ago (before he started his residency), about the importance of what we do and say as physicians.

Henry A. Nasrallah, MD
Editor-in-Chief
Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

 

 

The APA’s stance on neuroimaging

Can anyone in the modern world argue that the brain is irrelevant to psychiatry? Yet surprisingly, in September 2018, the American Psychiatric Association (APA) officially declared that neuroimaging of the brain has no clinical value in psychiatry.¹

Unfortunately, the APA focused almost exclusively on functional magnetic resonance imaging (fMRI) and neglected an extensive library of studies of single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The APA’s position on neuroimaging is as follows^1,2:

1. A neuroimaging finding must have a sensitivity and specificity (S/sp) of no less than 80%.
2. The psychiatric imaging literature does not support using neuroimaging in psychiatric diagnostics or treatment.
3. Neuroimaging has not had a significant impact on the diagnosis and treatment of psychiatric disorders.

The APA set unrealistic standards for biomarkers in a field that lacks pathologic markers of specific disease entities.³ Moreover, numerous widely used tests fall below the APA’s unrealistic S/sp cutoff, including the Hamilton Depression Rating Scale,⁴ Zung Depression Scale,⁵ the clock drawing test,⁶ and even the chest X-ray.³ Curiously, numerous replicated SPECT and PET studies were not included in the APA’s analysis.^1-3 For example, in a study of 196 veterans, posttraumatic stress disorder was distinguished from traumatic brain injury with an S/sp of 0.92/0.85.^7,8 Also, fluorodeoxyglucose (FDG)-PET has an S/sp of 0.84/0.74 in differentiating patients with Alzheimer’s disease from controls, while perfusion SPECT, using multi-detector cameras, has an S/sp of 0.93/0.84.^3,9 Moreover, both FDG-PET and SPECT can differentiate other forms of dementia from Alzheimer’s disease, yielding an additional benefit compared to amyloid imaging alone.^2,9 As President of the International Society of Applied Neuroimaging, I suggest neuroimaging should not be feared. Neuroimaging does not replace the diagnostician; rather, it aids him/her in a complex case.

Theodore A. Henderson, MD, PhD
President
Neuro-Luminance Brain Health Centers, Inc.
Denver, Colorado
Director
The Synaptic Space
Vice President
The Neuro-Laser Foundation
President
International Society of Applied Neuroimaging
Centennial, Colorado

Disclosure
The author has no ownership in, and receives no remuneration from, any neuroimaging company.

References
1. First MB, Drevets WC, Carter C, et al. Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018:175:915-916.
2. First MB, Drevets WC, Carter C, et al. Data supplement for Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018;175(suppl).
3. Henderson TA. Brain SPECT imaging in neuropsychiatric diagnosis and monitoring. EPatient. http://nmpangea.com/2018/10/09/738/. Published 2018. Accessed May 31, 2019.
4. Bagby RM, Ryder AG, Schuller DR, et al. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry. 2004;161(12):2163-2177.
5. Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung Self-rating Depression Scale. Br J Psychiatry. 1978;132:381-385.
6. Seigerschmidt E, Mösch E, Siemen M, et al. The clock drawing test and questionable dementia: reliability and validity. Int J Geriatr Psychiatry. 2002;17(11):1048-1054.
7. Raji CA, Willeumier K, Taylor D, et al. Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population. Brain Imaging Behav. 2015;9(3):527-534.
8. Amen DG, Raji CA, Willeumier K, et al. Functional neuroimaging distinguishes posttraumatic stress disorder from traumatic brain injury in focused and large community datasets. PLoS One. 2015;10(7):e0129659. doi: 10.1371/journal.pone.0129659.
9. Henderson TA. The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging. CNS Spectr. 2012;17(4):176-206.

Factors that change our brains

I greatly enjoyed Dr. Nasrallah’s editorial, “Your patient’s brain is different at every visit” (From the Editor, Current Psychiatry, May 2019, p. 6,8,10). This is my first time writing to Current Psychiatry, and the journal’s focus and articles have been informative and impactful throughout my training and in my current practice.

In reading this editorial, it is clear that a myriad of factors we consider and address with our patients during each visit underly intricate neurobiologic mechanisms and processes that ever deepen our understanding of the brain. In discussing the changes taking place in our patients, I can’t help but wonder what changes are also occurring in our brains (as Dr. Nasrallah noted). What would be the resulting impact of these changes in our next patient interaction and/or subsequent interaction(s) with the same patient? Looking through the editorial’s bullet points, many (if not all) of the factors contributing to brain changes apply equally and naturally to clinicians as well as patients. In this light, the editorial serves not only as a broad guideline for patient psychoeducation but also as a reminder of wellness and well-being for clinicians.

As a “fresh-out-of-training” psychiatrist, I can definitely work on several of the factors, such as diet and exercise. Trainees and residents can be more susceptible to overlook and befall some of these factors and changes, and may already be basing the clinical advice they give to their patients on these same factors and changes. As a child psychiatrist, I value the importance of modeling healthy behaviors for my patients, and their families and with coworkers or colleagues. In accordance with the impact these factors have on our brains, it’s important to emphasize what we can do to further strengthen rapport and therapeutic value through modeling. I strive to model the desired behaviors, attitudes, and dynamics that are the external, observable manifestation or symptomology of what takes place in my brain. To do so, I understand I need to be mindful in proactively managing the contributing factors, such as those listed in Dr. Nasrallah’s editorial. I imagine patients and their families would easily notice if we are in suboptimal physical and/or mental health that results in us not being prompt, fully engaged, or receptive. I believe that attending to these facets during training falls under the umbrella of professionalism. Being a professional in our field often entails practicing what we preach. So, I’m grateful that what we preach is informed by our field’s exciting research, continued advancements, and expertise that benefits our patients and us professionally and personally.

Philip Yen-Tsun Liu, MD
Child and adolescent psychiatrist
innovaTel Telepsychiatry
San Antonio, Texas

Dr. Nasrallah responds

I would like to thank Dr. Liu for his thoughtful response to my editorial. He seems to be very cognizant of the fact that experiential neuroplasticity and brain tissue remodeling occurs in both the patient and physician. I admire his focus on psychoeducation, wellness, and professionalism. He is right that we as psychiatrists (and nurse practitioners) must be role models for our patients in multiple ways, because it may help enhance clinical outcomes and have a positive impact on their brains.

I would also like to point Dr. Liu to the editorial “The most powerful placebo is not a pill” (From the Editor, Current Psychiatry, August 2011, p. 18-19), which I wrote 8 years ago (before he started his residency), about the importance of what we do and say as physicians.

Henry A. Nasrallah, MD
Editor-in-Chief
Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

 

 

The APA’s stance on neuroimaging

Can anyone in the modern world argue that the brain is irrelevant to psychiatry? Yet surprisingly, in September 2018, the American Psychiatric Association (APA) officially declared that neuroimaging of the brain has no clinical value in psychiatry.¹

Unfortunately, the APA focused almost exclusively on functional magnetic resonance imaging (fMRI) and neglected an extensive library of studies of single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The APA’s position on neuroimaging is as follows^1,2:

1. A neuroimaging finding must have a sensitivity and specificity (S/sp) of no less than 80%.
2. The psychiatric imaging literature does not support using neuroimaging in psychiatric diagnostics or treatment.
3. Neuroimaging has not had a significant impact on the diagnosis and treatment of psychiatric disorders.

The APA set unrealistic standards for biomarkers in a field that lacks pathologic markers of specific disease entities.³ Moreover, numerous widely used tests fall below the APA’s unrealistic S/sp cutoff, including the Hamilton Depression Rating Scale,⁴ Zung Depression Scale,⁵ the clock drawing test,⁶ and even the chest X-ray.³ Curiously, numerous replicated SPECT and PET studies were not included in the APA’s analysis.^1-3 For example, in a study of 196 veterans, posttraumatic stress disorder was distinguished from traumatic brain injury with an S/sp of 0.92/0.85.^7,8 Also, fluorodeoxyglucose (FDG)-PET has an S/sp of 0.84/0.74 in differentiating patients with Alzheimer’s disease from controls, while perfusion SPECT, using multi-detector cameras, has an S/sp of 0.93/0.84.^3,9 Moreover, both FDG-PET and SPECT can differentiate other forms of dementia from Alzheimer’s disease, yielding an additional benefit compared to amyloid imaging alone.^2,9 As President of the International Society of Applied Neuroimaging, I suggest neuroimaging should not be feared. Neuroimaging does not replace the diagnostician; rather, it aids him/her in a complex case.

Theodore A. Henderson, MD, PhD
President
Neuro-Luminance Brain Health Centers, Inc.
Denver, Colorado
Director
The Synaptic Space
Vice President
The Neuro-Laser Foundation
President
International Society of Applied Neuroimaging
Centennial, Colorado

Disclosure
The author has no ownership in, and receives no remuneration from, any neuroimaging company.

References
1. First MB, Drevets WC, Carter C, et al. Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018:175:915-916.
2. First MB, Drevets WC, Carter C, et al. Data supplement for Clinical applications of neuroimaging in psychiatric disorders. Am J Psychiatry. 2018;175(suppl).
3. Henderson TA. Brain SPECT imaging in neuropsychiatric diagnosis and monitoring. EPatient. http://nmpangea.com/2018/10/09/738/. Published 2018. Accessed May 31, 2019.
4. Bagby RM, Ryder AG, Schuller DR, et al. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry. 2004;161(12):2163-2177.
5. Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung Self-rating Depression Scale. Br J Psychiatry. 1978;132:381-385.
6. Seigerschmidt E, Mösch E, Siemen M, et al. The clock drawing test and questionable dementia: reliability and validity. Int J Geriatr Psychiatry. 2002;17(11):1048-1054.
7. Raji CA, Willeumier K, Taylor D, et al. Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population. Brain Imaging Behav. 2015;9(3):527-534.
8. Amen DG, Raji CA, Willeumier K, et al. Functional neuroimaging distinguishes posttraumatic stress disorder from traumatic brain injury in focused and large community datasets. PLoS One. 2015;10(7):e0129659. doi: 10.1371/journal.pone.0129659.
9. Henderson TA. The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging. CNS Spectr. 2012;17(4):176-206.