Evidence-Based Reviews

The no-show rate is high in ambulatory psychiatric clinics, especially those associated with academic medical institutions, which usually accept all public insurance providers and do not maintain a strict rule by which patients are charged a penalty when they fail to keep a scheduled appointment—a policy that, to the contrary, is customary in private practice. The University of Texas (UT) Health Sciences Center at Houston is primarily an academic medical center with resident-managed, faculty-supervised clinics that provide care to a large volume of patients.

At the UT clinics, we have struggled with a high no-show rate, and were challenged to reduce that rate. Our study of the problem, formulation and application of strat­egies to reduce that rate, and a discussion of our results are provided here for the benefit of psychiatric clinicians who struggle with this problem, to the detriment of their patients’ health and the financial well-being of the practice.

For patients who have a severe psychiatric illness, such as schizophrenia or bipolar disorder, 60% to 70% of the direct cost of their care is attributable to inpatient services.^1,2 Poor medication adherence is a critical factor: It results in exacerbation of symptoms, relapse, and hospitalization. The matter is compounded by patients’ failure to show up for scheduled follow-up appointments.

Studies show that failure to attend routinely scheduled outpatient appointments increases the risk of hospitaliza­tion. Recent research has shown that, among all causes of hospitalization, length of stay and relapse hospitalization are increased in patients with low adherence to their treatment regimen.³ Patients who miss an appoint­ment also are more unwell and more func­tionally impaired—also contributing to a higher risk and rate of rehospitalization.^4,5

To begin to address the problem at UT, we acknowledged that an elevated no-show rate is linked to medication nonadherence, increased risk of re-hospitalization, and increased costs associated with poor care.

Impact of nonadherence
Significant evidence supports the efficacy of antipsychotic medications for treating schizophrenia, of course,⁶ but that success story is undermined by the mean rate of medication nonadherence among schizo­phrenia patients, which can be as high as 49% in studies.⁷ (The actual rate might be higher because those studies do not account for persons who refuse treatment or drop out.)

Nonadherence increases the risk of relapse 3.7-fold, compared with what is seen in patients who adhere to treatment.⁸ Nonadherence to a medication regimen also can increase patients’ risk of engaging in assault and other dangerous behaviors, especially during periods of psychosis.⁸ Variables consistently associated with nonadherence include poor insight, nega­tive attitude or subjective response toward medication, previous nonadherence, sub­stance abuse, shorter duration of illness, inadequate discharge planning or after-care environment, and poorer therapeutic alliance.^7,8

Investigation of medication adher­ence in bipolar disorder suggests that 1 in 3 patients fail to take at least 30% of their medication.⁹ In such patients, medi­cation nonadherence can lead to mania, depression, hospital readmission, sui­cide, increased substance abuse, and nonresponse to treatment.^10,11

Depression also is associated with an increased rate of health care utilization and severe limitation in daily functioning.¹² Compared with non-depressed patients, depressed patients are 3 times more likely to be nonadherent with medical treatment recommendations.¹³ Estimates of medi­cation nonadherence for unipolar and bipolar disorders range from 10% to 60% (median, 40%). This prevalence has not changed significantly with the introduc­tion of new medications._¹⁴

Our literature review of research devoted to reducing no-shows found that few stud­ies have explored this critical treatment con­cern. The no-show rate was higher among younger patients and slightly higher among women, but varied by diagno­sis.¹⁵ The most common reason psychiatric patients gave for missing an appointment  was “forgetting”—a response heard twice as often among no-show patients in psy­chiatry than in other specialties.⁴

Little has been tried to solve the prob­lem. Often, community mental health centers and private practices double-book appointments. Double-booking is intended to reduce the financial burden on the prac­tice when a patient misses an appointment. This approach fails to address nonadher­ence or the poor care that usually results when a patient misses regular outpatient appointments.

Several methods have been employed to improve adherence, such as electronic pill dispensing.¹⁶ Increasing medication adher­ence appears to be a key factor in improv­ing quality-of-life measures in patients with schizophrenia.⁶

The UT project
Methods. This project was completed at the ambulatory psychiatry clinic at the UT Medical School at Houston. The clinic staff comprises residents and faculty members who provide outpatient care. During the study period, the clinic was scheduling as many as 800 office visits a month, includ­ing a mix of new and follow-up appoint­ments. Two weeks’ retrospective data revealed a no-show rate of 31%.

 

For the project, we defined no-show rate as the total number of patients who missed an appointment or canceled fewer than 24 hours before the scheduled time, divided by the total number of patients scheduled that day.

Table 1 demonstrates the no-show rate calculations for 1 of the weeks preceding the start of the project. Given approxi­mately 800 patient appointments a month, a 31% no-show rate meant that, first, 248 patients failed to receive recommended care and, second, 248 appointment slots were wasted.

Besides undermining such components of quality care as patient safety and medi­cation compliance, the high no-show rate also harms employee morale and produc­tivity; impairs medical education; and, possibly, increases the use of emergency and after-hour services.

We agreed that our current no-show rate of 31% was too high.

We then formed a team of residents, fac­ulty members, therapists, front office staff, an office manager, and an office nurse. We explored and hypothesized what could be contributing to the high no-show rate (Table 2).

Several interventions were then devised and implemented:
   • Patients. We increased patient educa­tion about 1) the need for regular follow-up and 2) risks associated with medication nonadherence.
   • Environment. We explored environ­mental limitations to access and agreed that certain static factors could not be mod­ified—eg, location of the clinic and lack of access to public transportation. We were able to make some changes to the environ­ment (explained later) to reduce wait time.
    • Staff. Some patients had complained of long wait times, which could hinder active participation in treatment. We agreed that the clinic nurse would make rounds through the waiting room every hour and talk to patients. The nurse would identify patients who had been waiting for longer than 30 minutes after their scheduled appointment time and notify the doctor accordingly. We also agreed to revise patient appointment reminder practices: instead of using an automated answering service, one of the staff members called patients personally to remind them about their appointments. (This also allowed us to update telephone numbers for many patients; numbers on record often were outdated.) We initially recruited summer interns and provided a written script to follow during calls to patients, which allowed patients to con­firm, cancel, or reschedule their appoint­ment. Once we demonstrated positive results from the change to personal calls, the department agreed to absorb the cost, and front desk personnel began making reminder calls.
   • Policies and procedures. Although some practices are able to charge a small fine for missed appointments, this was not allowed at our institution. Instead, we had several departmental policies on the books, such as discharging patients from our clinics if they missed 3 consecu­tive appointments and limiting prescrip­tion refills to a maximum of 6 months. These policies were neither communi­cated to patients and staff, nor were they implemented. We decided to educate patients and staff and implement the policies.
    • Transparency. We posted the no-show rate in common areas so that the team could review and follow the progression of that rate as we implemented the changes. This allowed team members to take own­ership of the project and facilitated active participation.

By implementing these changes, we aimed to reduce the no-show rate to 20%.

Results. We were able to reduce the no-show rate from a documented average of 31% to an average of 12% during the study period after implementing all the pro­posed changes in the outpatient clinics.

We calculated the no-show rate (as shown in Table 1 for May 2013), then collected the daily no-show rate from June to September 2013 (Figure). With these calculations, we demonstrated a reduction in the no-show rate to 12%. Because of the time and effort required, we reduced data collection from daily to weekly, beginning in September.

Applying the changes required con­sistent effort and substantial input from various stakeholders—front desk staff, residents, the nurse, therapists, and fac­ulty. Gradually, we were able to implement all the changes.

Keeping the no-show rate low required consistent effort and monitoring of the newly implemented procedures because even a slight change, such as failure to make reminder calls, resulted in a sudden increase in the no-show rate (that was the case in October of the study period, when we were short-staffed and could not call every patient). Patients told us that it was difficult to ignore a personal call; if they were not planning to keep the appoint­ment, the call allowed them to reschedule on the spot.

We also made sure that current no-show rates were posted in common areas, visible to team members every day.

 

Discussion
We attempted a literature review of research exploring approaches to reduc­ing the no-show rate but found few studies that explored this critical concern in patient treatment.¹⁵ Some data suggested that, in the setting studied, the no-show rate:
   • was higher among younger patients (age 20 to 39) than older ones (age 60 to 79)
   • was slightly higher in women than in men
   • varied by diagnosis.

We found a paucity of data regarding interventions that can reduce the no-show rate.

Among the changes we made, the one that had the greatest impact was person­alized appointment reminder calls, as evi­denced by our patients’ reports and the increase in the no-show rate when per­sonal calls were not made.

We also realized that, although we had several departmental policies in place regarding appointments, they were not being followed. Raising awareness among team members and their patients also was an effective deterrent to a no-show for an appointment. For example, patients were informed that 3 consecutive no-shows could lead to termination of care. Often, they reacted with surprise to this caution but also voiced a desire to improve their attendance to avoid such an outcome.

We found that establishing common operational definitions is important. It also was important to have a cohesive team, with every member agreeing on goals and changes to operational policies that needed to be implemented. Support from the department chair and the administra­tion, we learned, is vital to the success of such an intervention.

A note about limitations. The goal of the project was limited to reducing the no-show rate. We demonstrated that this is possible among patients who have a severe mental ill­ness, and that reducing the associated waste of time and resources can improve finances in an academic department of psychiatry. We would need additional measures, however, to quantify medication adherence and hos­pitalization; a larger, more inclusive project is needed to demonstrate that reducing the no-show rate reduces the symptomatic bur­den of psychiatric illness.

Comments in conclusion
This project was designed and conducted as a required part of a Clinical Safety and Effectiveness Program at Memorial Hermann Texas Medical Center and the UT Medical School at Houston.¹⁷ Although there was initial hesitancy about attempt­ing to reduce the no-show rate in a chroni­cally mentally ill population, the success of this project—indeed, it surpassed its proposed goals—demonstrates that opera­tional changes in any clinic can reduce the no-show rate. It also is important to main­tain operational changes, however; with­out consistent effort, desired results cannot be sustained.

Last, it is possible to replicate the meth­odology of this project and thereby attempt to reduce the no-show rate in other divi­sions of medicine that offer care to chroni­cally ill patients, such as pediatrics and family medicine.

Bottom Line
Failure to attend routinely scheduled outpatient appointments increases a patient’s functional impairment and risk of hospitalization. Patient education, appointment reminder phone calls, revised policies and procedures, and transparency regarding the no-show rate can reduce the number of missed appointments and improve patient outcomes.

Related Resources
• Mitchell AJ, Selmes T. Why don’t patients attend their ap­pointments? Maintaining engagement with psychiatric ser­vices. Advances in Psychiatric Treatment. 2007;13:423-434.
• Molfenter T. Reducing appointment no-shows: going from theory to practice. Subst Use Misuse. 2013;48(9):743-749.
• Williston MA, Block-Lerner J, Wolanin A, et al. Brief acceptance-based intervention for increasing intake attendance at a com­munity mental health center. Psychol Serv. 2014;11(3):324-332.

Disclosure
Dr. Gajwani receives grant or research support from the National Institute on Mental Health, the National Institute of Drug Abuse, The Stanley Foundation, and Forest Laboratories, Inc. He is a member of the speakers’ bureau of AstraZeneca, Merck, Otsuka America Pharmaceutical, and Sunovion Pharmaceuticals.

The no-show rate is high in ambulatory psychiatric clinics, especially those associated with academic medical institutions, which usually accept all public insurance providers and do not maintain a strict rule by which patients are charged a penalty when they fail to keep a scheduled appointment—a policy that, to the contrary, is customary in private practice. The University of Texas (UT) Health Sciences Center at Houston is primarily an academic medical center with resident-managed, faculty-supervised clinics that provide care to a large volume of patients.

At the UT clinics, we have struggled with a high no-show rate, and were challenged to reduce that rate. Our study of the problem, formulation and application of strat­egies to reduce that rate, and a discussion of our results are provided here for the benefit of psychiatric clinicians who struggle with this problem, to the detriment of their patients’ health and the financial well-being of the practice.

For patients who have a severe psychiatric illness, such as schizophrenia or bipolar disorder, 60% to 70% of the direct cost of their care is attributable to inpatient services.^1,2 Poor medication adherence is a critical factor: It results in exacerbation of symptoms, relapse, and hospitalization. The matter is compounded by patients’ failure to show up for scheduled follow-up appointments.

Studies show that failure to attend routinely scheduled outpatient appointments increases the risk of hospitaliza­tion. Recent research has shown that, among all causes of hospitalization, length of stay and relapse hospitalization are increased in patients with low adherence to their treatment regimen.³ Patients who miss an appoint­ment also are more unwell and more func­tionally impaired—also contributing to a higher risk and rate of rehospitalization.^4,5

To begin to address the problem at UT, we acknowledged that an elevated no-show rate is linked to medication nonadherence, increased risk of re-hospitalization, and increased costs associated with poor care.

Impact of nonadherence
Significant evidence supports the efficacy of antipsychotic medications for treating schizophrenia, of course,⁶ but that success story is undermined by the mean rate of medication nonadherence among schizo­phrenia patients, which can be as high as 49% in studies.⁷ (The actual rate might be higher because those studies do not account for persons who refuse treatment or drop out.)

Nonadherence increases the risk of relapse 3.7-fold, compared with what is seen in patients who adhere to treatment.⁸ Nonadherence to a medication regimen also can increase patients’ risk of engaging in assault and other dangerous behaviors, especially during periods of psychosis.⁸ Variables consistently associated with nonadherence include poor insight, nega­tive attitude or subjective response toward medication, previous nonadherence, sub­stance abuse, shorter duration of illness, inadequate discharge planning or after-care environment, and poorer therapeutic alliance.^7,8

Investigation of medication adher­ence in bipolar disorder suggests that 1 in 3 patients fail to take at least 30% of their medication.⁹ In such patients, medi­cation nonadherence can lead to mania, depression, hospital readmission, sui­cide, increased substance abuse, and nonresponse to treatment.^10,11

Depression also is associated with an increased rate of health care utilization and severe limitation in daily functioning.¹² Compared with non-depressed patients, depressed patients are 3 times more likely to be nonadherent with medical treatment recommendations.¹³ Estimates of medi­cation nonadherence for unipolar and bipolar disorders range from 10% to 60% (median, 40%). This prevalence has not changed significantly with the introduc­tion of new medications._¹⁴

Our literature review of research devoted to reducing no-shows found that few stud­ies have explored this critical treatment con­cern. The no-show rate was higher among younger patients and slightly higher among women, but varied by diagno­sis.¹⁵ The most common reason psychiatric patients gave for missing an appointment  was “forgetting”—a response heard twice as often among no-show patients in psy­chiatry than in other specialties.⁴

Little has been tried to solve the prob­lem. Often, community mental health centers and private practices double-book appointments. Double-booking is intended to reduce the financial burden on the prac­tice when a patient misses an appointment. This approach fails to address nonadher­ence or the poor care that usually results when a patient misses regular outpatient appointments.

Several methods have been employed to improve adherence, such as electronic pill dispensing.¹⁶ Increasing medication adher­ence appears to be a key factor in improv­ing quality-of-life measures in patients with schizophrenia.⁶

The UT project
Methods. This project was completed at the ambulatory psychiatry clinic at the UT Medical School at Houston. The clinic staff comprises residents and faculty members who provide outpatient care. During the study period, the clinic was scheduling as many as 800 office visits a month, includ­ing a mix of new and follow-up appoint­ments. Two weeks’ retrospective data revealed a no-show rate of 31%.

 

For the project, we defined no-show rate as the total number of patients who missed an appointment or canceled fewer than 24 hours before the scheduled time, divided by the total number of patients scheduled that day.

Table 1 demonstrates the no-show rate calculations for 1 of the weeks preceding the start of the project. Given approxi­mately 800 patient appointments a month, a 31% no-show rate meant that, first, 248 patients failed to receive recommended care and, second, 248 appointment slots were wasted.

Besides undermining such components of quality care as patient safety and medi­cation compliance, the high no-show rate also harms employee morale and produc­tivity; impairs medical education; and, possibly, increases the use of emergency and after-hour services.

We agreed that our current no-show rate of 31% was too high.

We then formed a team of residents, fac­ulty members, therapists, front office staff, an office manager, and an office nurse. We explored and hypothesized what could be contributing to the high no-show rate (Table 2).

Several interventions were then devised and implemented:
   • Patients. We increased patient educa­tion about 1) the need for regular follow-up and 2) risks associated with medication nonadherence.
   • Environment. We explored environ­mental limitations to access and agreed that certain static factors could not be mod­ified—eg, location of the clinic and lack of access to public transportation. We were able to make some changes to the environ­ment (explained later) to reduce wait time.
    • Staff. Some patients had complained of long wait times, which could hinder active participation in treatment. We agreed that the clinic nurse would make rounds through the waiting room every hour and talk to patients. The nurse would identify patients who had been waiting for longer than 30 minutes after their scheduled appointment time and notify the doctor accordingly. We also agreed to revise patient appointment reminder practices: instead of using an automated answering service, one of the staff members called patients personally to remind them about their appointments. (This also allowed us to update telephone numbers for many patients; numbers on record often were outdated.) We initially recruited summer interns and provided a written script to follow during calls to patients, which allowed patients to con­firm, cancel, or reschedule their appoint­ment. Once we demonstrated positive results from the change to personal calls, the department agreed to absorb the cost, and front desk personnel began making reminder calls.
   • Policies and procedures. Although some practices are able to charge a small fine for missed appointments, this was not allowed at our institution. Instead, we had several departmental policies on the books, such as discharging patients from our clinics if they missed 3 consecu­tive appointments and limiting prescrip­tion refills to a maximum of 6 months. These policies were neither communi­cated to patients and staff, nor were they implemented. We decided to educate patients and staff and implement the policies.
    • Transparency. We posted the no-show rate in common areas so that the team could review and follow the progression of that rate as we implemented the changes. This allowed team members to take own­ership of the project and facilitated active participation.

By implementing these changes, we aimed to reduce the no-show rate to 20%.

Results. We were able to reduce the no-show rate from a documented average of 31% to an average of 12% during the study period after implementing all the pro­posed changes in the outpatient clinics.

We calculated the no-show rate (as shown in Table 1 for May 2013), then collected the daily no-show rate from June to September 2013 (Figure). With these calculations, we demonstrated a reduction in the no-show rate to 12%. Because of the time and effort required, we reduced data collection from daily to weekly, beginning in September.

Applying the changes required con­sistent effort and substantial input from various stakeholders—front desk staff, residents, the nurse, therapists, and fac­ulty. Gradually, we were able to implement all the changes.

Keeping the no-show rate low required consistent effort and monitoring of the newly implemented procedures because even a slight change, such as failure to make reminder calls, resulted in a sudden increase in the no-show rate (that was the case in October of the study period, when we were short-staffed and could not call every patient). Patients told us that it was difficult to ignore a personal call; if they were not planning to keep the appoint­ment, the call allowed them to reschedule on the spot.

We also made sure that current no-show rates were posted in common areas, visible to team members every day.

 

Discussion
We attempted a literature review of research exploring approaches to reduc­ing the no-show rate but found few studies that explored this critical concern in patient treatment.¹⁵ Some data suggested that, in the setting studied, the no-show rate:
   • was higher among younger patients (age 20 to 39) than older ones (age 60 to 79)
   • was slightly higher in women than in men
   • varied by diagnosis.

We found a paucity of data regarding interventions that can reduce the no-show rate.

Among the changes we made, the one that had the greatest impact was person­alized appointment reminder calls, as evi­denced by our patients’ reports and the increase in the no-show rate when per­sonal calls were not made.

We also realized that, although we had several departmental policies in place regarding appointments, they were not being followed. Raising awareness among team members and their patients also was an effective deterrent to a no-show for an appointment. For example, patients were informed that 3 consecutive no-shows could lead to termination of care. Often, they reacted with surprise to this caution but also voiced a desire to improve their attendance to avoid such an outcome.

We found that establishing common operational definitions is important. It also was important to have a cohesive team, with every member agreeing on goals and changes to operational policies that needed to be implemented. Support from the department chair and the administra­tion, we learned, is vital to the success of such an intervention.

A note about limitations. The goal of the project was limited to reducing the no-show rate. We demonstrated that this is possible among patients who have a severe mental ill­ness, and that reducing the associated waste of time and resources can improve finances in an academic department of psychiatry. We would need additional measures, however, to quantify medication adherence and hos­pitalization; a larger, more inclusive project is needed to demonstrate that reducing the no-show rate reduces the symptomatic bur­den of psychiatric illness.

Comments in conclusion
This project was designed and conducted as a required part of a Clinical Safety and Effectiveness Program at Memorial Hermann Texas Medical Center and the UT Medical School at Houston.¹⁷ Although there was initial hesitancy about attempt­ing to reduce the no-show rate in a chroni­cally mentally ill population, the success of this project—indeed, it surpassed its proposed goals—demonstrates that opera­tional changes in any clinic can reduce the no-show rate. It also is important to main­tain operational changes, however; with­out consistent effort, desired results cannot be sustained.

Last, it is possible to replicate the meth­odology of this project and thereby attempt to reduce the no-show rate in other divi­sions of medicine that offer care to chroni­cally ill patients, such as pediatrics and family medicine.

Bottom Line
Failure to attend routinely scheduled outpatient appointments increases a patient’s functional impairment and risk of hospitalization. Patient education, appointment reminder phone calls, revised policies and procedures, and transparency regarding the no-show rate can reduce the number of missed appointments and improve patient outcomes.

Related Resources
• Mitchell AJ, Selmes T. Why don’t patients attend their ap­pointments? Maintaining engagement with psychiatric ser­vices. Advances in Psychiatric Treatment. 2007;13:423-434.
• Molfenter T. Reducing appointment no-shows: going from theory to practice. Subst Use Misuse. 2013;48(9):743-749.
• Williston MA, Block-Lerner J, Wolanin A, et al. Brief acceptance-based intervention for increasing intake attendance at a com­munity mental health center. Psychol Serv. 2014;11(3):324-332.

Disclosure
Dr. Gajwani receives grant or research support from the National Institute on Mental Health, the National Institute of Drug Abuse, The Stanley Foundation, and Forest Laboratories, Inc. He is a member of the speakers’ bureau of AstraZeneca, Merck, Otsuka America Pharmaceutical, and Sunovion Pharmaceuticals.

The no-show rate is high in ambulatory psychiatric clinics, especially those associated with academic medical institutions, which usually accept all public insurance providers and do not maintain a strict rule by which patients are charged a penalty when they fail to keep a scheduled appointment—a policy that, to the contrary, is customary in private practice. The University of Texas (UT) Health Sciences Center at Houston is primarily an academic medical center with resident-managed, faculty-supervised clinics that provide care to a large volume of patients.

At the UT clinics, we have struggled with a high no-show rate, and were challenged to reduce that rate. Our study of the problem, formulation and application of strat­egies to reduce that rate, and a discussion of our results are provided here for the benefit of psychiatric clinicians who struggle with this problem, to the detriment of their patients’ health and the financial well-being of the practice.

For patients who have a severe psychiatric illness, such as schizophrenia or bipolar disorder, 60% to 70% of the direct cost of their care is attributable to inpatient services.^1,2 Poor medication adherence is a critical factor: It results in exacerbation of symptoms, relapse, and hospitalization. The matter is compounded by patients’ failure to show up for scheduled follow-up appointments.

Studies show that failure to attend routinely scheduled outpatient appointments increases the risk of hospitaliza­tion. Recent research has shown that, among all causes of hospitalization, length of stay and relapse hospitalization are increased in patients with low adherence to their treatment regimen.³ Patients who miss an appoint­ment also are more unwell and more func­tionally impaired—also contributing to a higher risk and rate of rehospitalization.^4,5

To begin to address the problem at UT, we acknowledged that an elevated no-show rate is linked to medication nonadherence, increased risk of re-hospitalization, and increased costs associated with poor care.

Impact of nonadherence
Significant evidence supports the efficacy of antipsychotic medications for treating schizophrenia, of course,⁶ but that success story is undermined by the mean rate of medication nonadherence among schizo­phrenia patients, which can be as high as 49% in studies.⁷ (The actual rate might be higher because those studies do not account for persons who refuse treatment or drop out.)

Nonadherence increases the risk of relapse 3.7-fold, compared with what is seen in patients who adhere to treatment.⁸ Nonadherence to a medication regimen also can increase patients’ risk of engaging in assault and other dangerous behaviors, especially during periods of psychosis.⁸ Variables consistently associated with nonadherence include poor insight, nega­tive attitude or subjective response toward medication, previous nonadherence, sub­stance abuse, shorter duration of illness, inadequate discharge planning or after-care environment, and poorer therapeutic alliance.^7,8

Investigation of medication adher­ence in bipolar disorder suggests that 1 in 3 patients fail to take at least 30% of their medication.⁹ In such patients, medi­cation nonadherence can lead to mania, depression, hospital readmission, sui­cide, increased substance abuse, and nonresponse to treatment.^10,11

Depression also is associated with an increased rate of health care utilization and severe limitation in daily functioning.¹² Compared with non-depressed patients, depressed patients are 3 times more likely to be nonadherent with medical treatment recommendations.¹³ Estimates of medi­cation nonadherence for unipolar and bipolar disorders range from 10% to 60% (median, 40%). This prevalence has not changed significantly with the introduc­tion of new medications._¹⁴

Our literature review of research devoted to reducing no-shows found that few stud­ies have explored this critical treatment con­cern. The no-show rate was higher among younger patients and slightly higher among women, but varied by diagno­sis.¹⁵ The most common reason psychiatric patients gave for missing an appointment  was “forgetting”—a response heard twice as often among no-show patients in psy­chiatry than in other specialties.⁴

Little has been tried to solve the prob­lem. Often, community mental health centers and private practices double-book appointments. Double-booking is intended to reduce the financial burden on the prac­tice when a patient misses an appointment. This approach fails to address nonadher­ence or the poor care that usually results when a patient misses regular outpatient appointments.

Several methods have been employed to improve adherence, such as electronic pill dispensing.¹⁶ Increasing medication adher­ence appears to be a key factor in improv­ing quality-of-life measures in patients with schizophrenia.⁶

The UT project
Methods. This project was completed at the ambulatory psychiatry clinic at the UT Medical School at Houston. The clinic staff comprises residents and faculty members who provide outpatient care. During the study period, the clinic was scheduling as many as 800 office visits a month, includ­ing a mix of new and follow-up appoint­ments. Two weeks’ retrospective data revealed a no-show rate of 31%.

 

For the project, we defined no-show rate as the total number of patients who missed an appointment or canceled fewer than 24 hours before the scheduled time, divided by the total number of patients scheduled that day.

Table 1 demonstrates the no-show rate calculations for 1 of the weeks preceding the start of the project. Given approxi­mately 800 patient appointments a month, a 31% no-show rate meant that, first, 248 patients failed to receive recommended care and, second, 248 appointment slots were wasted.

Besides undermining such components of quality care as patient safety and medi­cation compliance, the high no-show rate also harms employee morale and produc­tivity; impairs medical education; and, possibly, increases the use of emergency and after-hour services.

We agreed that our current no-show rate of 31% was too high.

We then formed a team of residents, fac­ulty members, therapists, front office staff, an office manager, and an office nurse. We explored and hypothesized what could be contributing to the high no-show rate (Table 2).

Several interventions were then devised and implemented:
   • Patients. We increased patient educa­tion about 1) the need for regular follow-up and 2) risks associated with medication nonadherence.
   • Environment. We explored environ­mental limitations to access and agreed that certain static factors could not be mod­ified—eg, location of the clinic and lack of access to public transportation. We were able to make some changes to the environ­ment (explained later) to reduce wait time.
    • Staff. Some patients had complained of long wait times, which could hinder active participation in treatment. We agreed that the clinic nurse would make rounds through the waiting room every hour and talk to patients. The nurse would identify patients who had been waiting for longer than 30 minutes after their scheduled appointment time and notify the doctor accordingly. We also agreed to revise patient appointment reminder practices: instead of using an automated answering service, one of the staff members called patients personally to remind them about their appointments. (This also allowed us to update telephone numbers for many patients; numbers on record often were outdated.) We initially recruited summer interns and provided a written script to follow during calls to patients, which allowed patients to con­firm, cancel, or reschedule their appoint­ment. Once we demonstrated positive results from the change to personal calls, the department agreed to absorb the cost, and front desk personnel began making reminder calls.
   • Policies and procedures. Although some practices are able to charge a small fine for missed appointments, this was not allowed at our institution. Instead, we had several departmental policies on the books, such as discharging patients from our clinics if they missed 3 consecu­tive appointments and limiting prescrip­tion refills to a maximum of 6 months. These policies were neither communi­cated to patients and staff, nor were they implemented. We decided to educate patients and staff and implement the policies.
    • Transparency. We posted the no-show rate in common areas so that the team could review and follow the progression of that rate as we implemented the changes. This allowed team members to take own­ership of the project and facilitated active participation.

By implementing these changes, we aimed to reduce the no-show rate to 20%.

Results. We were able to reduce the no-show rate from a documented average of 31% to an average of 12% during the study period after implementing all the pro­posed changes in the outpatient clinics.

We calculated the no-show rate (as shown in Table 1 for May 2013), then collected the daily no-show rate from June to September 2013 (Figure). With these calculations, we demonstrated a reduction in the no-show rate to 12%. Because of the time and effort required, we reduced data collection from daily to weekly, beginning in September.

Applying the changes required con­sistent effort and substantial input from various stakeholders—front desk staff, residents, the nurse, therapists, and fac­ulty. Gradually, we were able to implement all the changes.

Keeping the no-show rate low required consistent effort and monitoring of the newly implemented procedures because even a slight change, such as failure to make reminder calls, resulted in a sudden increase in the no-show rate (that was the case in October of the study period, when we were short-staffed and could not call every patient). Patients told us that it was difficult to ignore a personal call; if they were not planning to keep the appoint­ment, the call allowed them to reschedule on the spot.

We also made sure that current no-show rates were posted in common areas, visible to team members every day.

 

Discussion
We attempted a literature review of research exploring approaches to reduc­ing the no-show rate but found few studies that explored this critical concern in patient treatment.¹⁵ Some data suggested that, in the setting studied, the no-show rate:
   • was higher among younger patients (age 20 to 39) than older ones (age 60 to 79)
   • was slightly higher in women than in men
   • varied by diagnosis.

We found a paucity of data regarding interventions that can reduce the no-show rate.

Among the changes we made, the one that had the greatest impact was person­alized appointment reminder calls, as evi­denced by our patients’ reports and the increase in the no-show rate when per­sonal calls were not made.

We also realized that, although we had several departmental policies in place regarding appointments, they were not being followed. Raising awareness among team members and their patients also was an effective deterrent to a no-show for an appointment. For example, patients were informed that 3 consecutive no-shows could lead to termination of care. Often, they reacted with surprise to this caution but also voiced a desire to improve their attendance to avoid such an outcome.

We found that establishing common operational definitions is important. It also was important to have a cohesive team, with every member agreeing on goals and changes to operational policies that needed to be implemented. Support from the department chair and the administra­tion, we learned, is vital to the success of such an intervention.

A note about limitations. The goal of the project was limited to reducing the no-show rate. We demonstrated that this is possible among patients who have a severe mental ill­ness, and that reducing the associated waste of time and resources can improve finances in an academic department of psychiatry. We would need additional measures, however, to quantify medication adherence and hos­pitalization; a larger, more inclusive project is needed to demonstrate that reducing the no-show rate reduces the symptomatic bur­den of psychiatric illness.

Comments in conclusion
This project was designed and conducted as a required part of a Clinical Safety and Effectiveness Program at Memorial Hermann Texas Medical Center and the UT Medical School at Houston.¹⁷ Although there was initial hesitancy about attempt­ing to reduce the no-show rate in a chroni­cally mentally ill population, the success of this project—indeed, it surpassed its proposed goals—demonstrates that opera­tional changes in any clinic can reduce the no-show rate. It also is important to main­tain operational changes, however; with­out consistent effort, desired results cannot be sustained.

Last, it is possible to replicate the meth­odology of this project and thereby attempt to reduce the no-show rate in other divi­sions of medicine that offer care to chroni­cally ill patients, such as pediatrics and family medicine.

Bottom Line
Failure to attend routinely scheduled outpatient appointments increases a patient’s functional impairment and risk of hospitalization. Patient education, appointment reminder phone calls, revised policies and procedures, and transparency regarding the no-show rate can reduce the number of missed appointments and improve patient outcomes.

Related Resources
• Mitchell AJ, Selmes T. Why don’t patients attend their ap­pointments? Maintaining engagement with psychiatric ser­vices. Advances in Psychiatric Treatment. 2007;13:423-434.
• Molfenter T. Reducing appointment no-shows: going from theory to practice. Subst Use Misuse. 2013;48(9):743-749.
• Williston MA, Block-Lerner J, Wolanin A, et al. Brief acceptance-based intervention for increasing intake attendance at a com­munity mental health center. Psychol Serv. 2014;11(3):324-332.

Disclosure
Dr. Gajwani receives grant or research support from the National Institute on Mental Health, the National Institute of Drug Abuse, The Stanley Foundation, and Forest Laboratories, Inc. He is a member of the speakers’ bureau of AstraZeneca, Merck, Otsuka America Pharmaceutical, and Sunovion Pharmaceuticals.

Many mental health practitioners have had training in cogni­tive-behavioral therapy (CBT)—short-term, evidence-based psychotherapy for treating a variety of psychiatric conditions (eg, posttraumatic stress disorder) and medical comorbidities (eg, insom­nia)—but only some are knowledgeable about how to best use CBT with a suicidal patient. This article provides a clinician-friendly summary of a 10-session evidence-based outpatient^1-3 and an adapted 6 to 8 session inpatient^4,5 cognitive-behavioral protocol (known as Post-Admission Cognitive Therapy [PACT]) that is designed to help patients who have suicide-related thoughts and/or behaviors.

3 phases of CBT for suicide prevention
An average of 9 hours of individual CBT for the prevention of suicide has been reported to reduce the likelihood of repeat suicide attempts in approximately 50% of patients.¹ Here, we introduce you to 3 phases of CBT for preventing suicide—phases that are the same for outpatients or inpatients. Our aim is to help you become familiar with CBT strategies that can be adapted for your treatment setting and used to intervene with vulnerable patients who are at risk for suicidal self-directed violence. A thorough assessment of the patient’s psychiatric diagnosis and history, presenting problems, and risk and protective factors for suicide must be completed before treatment begins.

Phase I. The patient is asked to tell a story associated with his (her) most recent episode of suicidal thoughts or behavior, or both. This narrative serves as 1) a foundation for planning treatment and 2) a model for understanding how best to deactivate the wish to die through the process of psychotherapy.

Phase II. The patient is assisted with modify­ing underdeveloped or overdeveloped skills that are most closely associated with the risk of triggering a suicidal crisis. For example, a patient with underdeveloped skills in regu­lating anger and hatred toward himself is taught to modulate these problematic emo­tions more effectively. In addition, effective problem-solving strategies are reviewed and practiced.

Phase III. The patient is guided through a relapse prevention task. The purpose of this exercise is to 1) highlight skills learned dur­ing therapy and 2) allow the patient to prac­tice effective problem-solving strategies that are aimed at minimizing the recurrence of suicidal self-directed violence.

Theorectical basis for preventing suicide with CBT
Aaron Beck, in 1979,⁶ proposed that a per­son’s biopsychosocial vulnerabilities can interact with suicidal thoughts and behaviors to produce a state that Beck labeled the “sui­cide mode.” Once produced, a suicide mode can become activated by cognitive, affective, motivational, and behavioral systems.

The frequency and severity of suicide mode activation can increase over time, especially for persons who do not have protective factors and those who have a his­tory of self-directed violence—in particular, attempted suicide. Moreover, some persons might experience a chronic state of suicide mode activation and, therefore, remain at elevated risk of suicide. Once a suicide-specific mode is activated, the person con­siders suicide the only option for solving his life problems. Suicide might be considered a rational decision at this point.⁶

The hypothesized mechanism of action associated with CBT for preventing suicide can be described as:  
   • deactivation of the suicide mode  
   • modification of the structure and con­tent of the suicide mode  
   • construction and practice of more adaptive structural modes to promote a desire to live.

The underlying philosophy of this inter­vention is that the suicide mode occurs inde­pendently of psychiatric diagnoses and must be targeted directly; treatment therefore is transdiagnostic.⁷ In other words, instead of addressing a symptom of a psychiatric disor­der, treatment directly targets suicide-related ideation and behaviors (Table 1).

Using that framework, psychiatric diag­noses are conceptualized in terms of how the associated symptoms contribute to the acti­vation, maintenance, and exacerbation of the suicide mode.

Protocol for preventing suicide
The outpatient protocol^1-3 comprises 10, 45- to 50-minute weekly individual psy­chotherapy sessions, with an allowance for booster sessions (as needed), until the patient is able to complete the relapse pre­vention task in Phase III. The inpatient protocol^4,5 comprises 6, 90-minute individ­ual psychotherapy sessions, with an allow­ance for 2 booster sessions (as needed) during the inpatient stay and as many as 4 telephone booster sessions after discharge.

Phase I: Tell the suicide story
Engage the patient in treatment. To increase adherence to treatment and mini­mize the risk of drop-out, practitioners are encouraged to establish a strong, early therapeutic alliance with the patient. Showing genuine empathy and provid­ing a safe, supportive, and nonjudgmental environment are instrumental for engag­ing patients in treatment. The practitioner listens carefully to the patient’s narrative, provides periodic summaries to check on accurate understanding, and keeps inter­ruptions to a minimum.

Collaboratively generate a safety plan. A crisis response plan or safety plan—an individualized, hierarchically arranged, written list of coping strategies to be implemented during a suicide crisis—is developed as soon as possible. Guidance on how to develop a structured safety plan has been provided by Stanley and Brown.^8,9

 

Practitioners must ensure that the safety plan contains contact information that the patient can use to reach the practitioner, the clinic, the on-call provider (if available), the local 24-hour emergency department, and the 24/7 National Suicide Prevention Lifeline (800-273-TALK [8255]). Discussion of how to limit access to lethal means also is important.

Because safety planning is a collaborative process, it is imperative that practitioners check on the patient’s willingness to follow the safety plan and help him overcome per­ceived obstacles in implementation. Copies of the plan can be kept at different locations and shared with family members, friends, or both with the patient’s permission.

Develop a cognitive-behavioral concep­tualization. The cognitive-behavioral con­ceptualization is an individualized map of a patient’s automatic thoughts (eg, “I am going to get fired today”), conditional assumptions (“If I get fired, then my life is over”), and core beliefs (“I am an utter failure”) that are activated before, during, and after suicidal self-directed violence. To develop that conceptualization, the patient is asked to tell a story about his (her) most recent suicidal crisis (the Box, offers a sample script) and to describe reactions to having survived a suicide attempt. (Note: Patients who report regret after an attempt are at greatest risk for dying by suicide.¹⁰)

This activity gives the patient an opportu­nity to disclose details surrounding his sui­cidal thoughts and actions, and might allow for a cathartic experience through storytell­ing. As practitioners listen to the suicide narrative, they collect data on the patient’s early childhood experiences (typically, suicide-activating events), associated auto­matic thoughts and images, emotional responses, and subsequent behaviors.

Based on this information, a cognitive-behavioral case conceptualization diagram (Figure 1, and Table 2) is generated collaboratively with the patient^a and used to personalize treatment planning.

^a Judith Beck offers sample case conceptualization diagrams in Cognitive behavior therapy: Basics and beyond, 2nd ed. New York, New York: Guilford Press; 2011.

Phase II: Build skills
Build skills to prevent episodes of sui­cidal self-directed violence. Information obtained from the conceptualization is used to generate an individualized cognitive-behavioral plan of intervention. The over­all goal is to determine skill-based problem areas that are associated with the most recent episode of suicidal self-directed violence.

Practitioner and patient collaboratively identify skills that are underdeveloped and ones that are overdeveloped so that they can be addressed systematically. In gen­eral, based on our clinical experience with suicidal patients, we recommend focusing on skills captured within ≥1 of the deficit domains in Table 3. Explanation of the vari­ous cognitive-behavioral strategies used in this phase of treatment is beyond the scope of this article, but 2 activities that highlight the clinical work conducted in this phase are described in the following sections. We selected those activities because they are easy to implement and, we have found, receive overall patient acceptability.

For a detailed understanding of strate­gies used in Phase II of CBT for preventing suicide, see Related Resources. In addition, the book Choosing to live: How to defeat suicide through cognitive therapy¹¹ can serve as a self-help guide for patients to follow through with CBT skill-building strategies.

Sample activity #1: Construct a ‘hope box.’ One activity that you can use to help a patient cope with suicide-activating core beliefs (eg, “My life is worthless”) involves construction of a so-called hope box. The box helps the patient directly challenge his extreme distress, by being reminded of pre­vious successes, positive experiences, and reasons for living. The process of construct­ing a hope box allows the patient to work on modifying his problematic core beliefs (eg, worthlessness, helplessness, incapable of being loved).

It can be helpful to have the patient con­struct his hope box during a session, to ensure that everything that is put in the box is truly helpful and personalized. Items included vary from patient to patient, and might con­sist of pictures of loved ones, a favorite poem, a prayer, coping cards (see next section), or all of these. For example, one of our patients chose to include a picture of herself in her early 20s as a reminder of a positive, fulfill­ing time in her life; this gave her hope that it is possible to experience those feelings again.

Bush et al^b at the National Center for Telehealth and Technology have developed a Virtual Hope Box, a free mobile applica­tion for tablets and smartphones (compatible with Android and iOS operating systems) that patients can use under the guidance of their practitioner.

^bwww.t2.health.mil/apps/virtual-hope-box

Sample activity #2: Generate coping cards. Effective problem-solving skills can be promoted by having the patient construct coping cards —wallet-size cards generated collaboratively in session. Coping cards are note cards that a patient keeps nearby to cope better during a difficult situation. They provide an easily accessible way to jump-start adaptive thinking during a suicidal crisis. The patient is encouraged to use cop­ing cards to practice adaptive thinking even when not in a crisis.

 

There are 3 kinds of coping cards:  
   • place a suicide-relevant automatic thought or core belief on one side of the card; on the other side, place an alternative, more adaptive response  
   • write a list of coping strategies  
   • write instructions to motivate or “acti­vate” the patient toward completing a spe­cific goal (Figure 2).

 

Phase III: Prevent relapse
Complete relapse prevention task. Relapse prevention is a common CBT strat­egy that aims to strengthen self-management to minimize likelihood of returning to a pre­viously stopped behavior. For patients who present only with suicidal thoughts, relapse prevention is directed at identifying trig­gers and minimizing the occurrence and/ or intensity of such thoughts in the future. For patients who present with suicidal self-directed violence, relapse prevention is directed at identifying triggers for suicidal actions and reducing the likelihood of acting on suicidal urges. The brief guidance pro­vided below will familiarize you with each of the relapse prevention steps, which may be completed in multiple sessions.

Step 1: Provide psychoeducation
Explain the difference between a lapse and a relapse. In general, you want the patient to understand that, although suicidal thoughts might persist and recur over time, suicidal self-directed violence must be prevented. Describe the purpose of the relapse preven­tion task (ie, to minimize the chance that suicidal thinking and actions will recur); address questions and concerns; and obtain permission to begin the procedure. Assure the patient that this is a collaborative activity and you will be in the room to ensure com­fort and safety.

STEP 2: Retell the suicide story
Ask the patient to imagine the chain of events, thoughts, and feelings that led to the most recent episode of suicide ideation or suicidal self-directed violence. Tell the patient that you want him to construct a movie script to describe the chain of events that resulted in the suicide crisis —but to do so slowly, taking enough time to describe the details of each scene of the movie.

Step 3: Apply CBT skills
Ask the patient again to take you through the sequence of events leading to the most recent episode of suicide ideation or suicidal self-directed violence. This time, however, direct him to use the skills learned in ther­apy to appropriately respond cognitively, affectively, and behaviorally to move further away from the suicide outcome.

If the patient is moving too fast or neglect­ing important points, stop and ask about alternative ways of thinking, feeling, and behaving. Use as much time as needed until the patient is able to demonstrate solid learn­ing of at least several learned CBT strategies to prevent suicidal self-directed violence.

Step 4: Generalize learning to prepare for future suicidal crises
In this stage —given your knowledge of the patient’s psychosocial history, cognitive- behavioral conceptualization, and suicide mode triggers —you collaboratively create a future scenario that is likely to activate suicidal self-directed violence. Question the patient about possible coping strategies, pro­vide helpful feedback, guide him through each link in the chain of events, and pro­pose additional alternative strategies if he is clearly neglecting important points of the intervention.

Step 5: Debrief and summarize lessons learned
Debrief the patient by providing a sum­mary of the skills he has learned in therapy, congratulate him for complet­ing this final therapeutic task, and assess overall emotional reaction to this activity. Remind him that mood fluctuations and future setbacks, in the form of lapses, are expected. Give him the option to request booster sessions and make plans for next steps in accomplishing general goals of therapy.

Treatment can be terminated when the patient is able to complete the relapse preven­tion task. If he is not ready or able to complete this exercise successfully, you can extend treatment. The duration of the extension is left to the practitioner’s judgment, based on the overall treatment plan. Brown and colleagues2 have reported a maximum num­ber of 24 outpatient sessions (for patients who need additional booster sessions); based on clinical experience, it is reasonable to assume that it would be highly unlikely for a patient not to meet treatment objectives after a methodical course of outpatient CBT.

In cases in which goals of treatment have not been met, consultation with colleagues, review of adherence problems, and consid­eration of obstacles for treatment efficacy would be recommended.

A checklist can be used to determine whether a patient is ready to end treatment. Variables that can be considered in assessing readiness for termination include:  
   • reduced scores on self-report measures for a number of weeks  
   • evidence of enhanced problem-solving  
   • engagement in adjunctive health care services  
   • development of a social support system.

 

Post-Admission Cognitive Therapy (PACT)
An inpatient cognitive-behavioral pro­tocol for the prevention of suicide, adapted from the efficacious outpatient model, is being evaluated at the Walter Reed National Military Medical Center, Bethesda, Maryland, and Fort Belvoir Community Hospital, Fort Belvoir, Virginia. The inpatient intervention is called PACT; components are summarized in Table 4.

Bottom Line
Cognitive-behavioral therapy for preventing suicide is an efficacious protocol for reducing the recurrence of suicidal self-directed violence. Post-Admission Cognitive Therapy is the adapted inpatient treatment package. You are encouraged to gain additional training and supervision on the delivery of these interventions to your high-risk suicidal patients.

Related Resources
• Academy of Cognitive Therapy. www.academyofct.org.
• National Suicide Prevention Lifeline. www.suicide preventionlifeline.org.
• Wenzel A, Brown GK, Beck AT. Cognitive therapy for suicidal patients: scientific and clinical applications. Washington, DC: American Psychological Association; 2009.

Disclosures
Support for research on inpatient cognitive-behavioral therapy for the prevention of suicide provided to Principal Investigator, Dr. Ghahramanlou-Holloway by the Department of Defense, Congressionally Directed Medical Research Program (W81XWH-08-2-0172), Military Operational Medicine Research Program (W81XWH-11-2-0106), and the National Alliance for Research on Schizophrenia and Depression (15219).

Many mental health practitioners have had training in cogni­tive-behavioral therapy (CBT)—short-term, evidence-based psychotherapy for treating a variety of psychiatric conditions (eg, posttraumatic stress disorder) and medical comorbidities (eg, insom­nia)—but only some are knowledgeable about how to best use CBT with a suicidal patient. This article provides a clinician-friendly summary of a 10-session evidence-based outpatient^1-3 and an adapted 6 to 8 session inpatient^4,5 cognitive-behavioral protocol (known as Post-Admission Cognitive Therapy [PACT]) that is designed to help patients who have suicide-related thoughts and/or behaviors.

3 phases of CBT for suicide prevention
An average of 9 hours of individual CBT for the prevention of suicide has been reported to reduce the likelihood of repeat suicide attempts in approximately 50% of patients.¹ Here, we introduce you to 3 phases of CBT for preventing suicide—phases that are the same for outpatients or inpatients. Our aim is to help you become familiar with CBT strategies that can be adapted for your treatment setting and used to intervene with vulnerable patients who are at risk for suicidal self-directed violence. A thorough assessment of the patient’s psychiatric diagnosis and history, presenting problems, and risk and protective factors for suicide must be completed before treatment begins.

Phase I. The patient is asked to tell a story associated with his (her) most recent episode of suicidal thoughts or behavior, or both. This narrative serves as 1) a foundation for planning treatment and 2) a model for understanding how best to deactivate the wish to die through the process of psychotherapy.

Phase II. The patient is assisted with modify­ing underdeveloped or overdeveloped skills that are most closely associated with the risk of triggering a suicidal crisis. For example, a patient with underdeveloped skills in regu­lating anger and hatred toward himself is taught to modulate these problematic emo­tions more effectively. In addition, effective problem-solving strategies are reviewed and practiced.

Phase III. The patient is guided through a relapse prevention task. The purpose of this exercise is to 1) highlight skills learned dur­ing therapy and 2) allow the patient to prac­tice effective problem-solving strategies that are aimed at minimizing the recurrence of suicidal self-directed violence.

Theorectical basis for preventing suicide with CBT
Aaron Beck, in 1979,⁶ proposed that a per­son’s biopsychosocial vulnerabilities can interact with suicidal thoughts and behaviors to produce a state that Beck labeled the “sui­cide mode.” Once produced, a suicide mode can become activated by cognitive, affective, motivational, and behavioral systems.

The frequency and severity of suicide mode activation can increase over time, especially for persons who do not have protective factors and those who have a his­tory of self-directed violence—in particular, attempted suicide. Moreover, some persons might experience a chronic state of suicide mode activation and, therefore, remain at elevated risk of suicide. Once a suicide-specific mode is activated, the person con­siders suicide the only option for solving his life problems. Suicide might be considered a rational decision at this point.⁶

The hypothesized mechanism of action associated with CBT for preventing suicide can be described as:  
   • deactivation of the suicide mode  
   • modification of the structure and con­tent of the suicide mode  
   • construction and practice of more adaptive structural modes to promote a desire to live.

The underlying philosophy of this inter­vention is that the suicide mode occurs inde­pendently of psychiatric diagnoses and must be targeted directly; treatment therefore is transdiagnostic.⁷ In other words, instead of addressing a symptom of a psychiatric disor­der, treatment directly targets suicide-related ideation and behaviors (Table 1).

Using that framework, psychiatric diag­noses are conceptualized in terms of how the associated symptoms contribute to the acti­vation, maintenance, and exacerbation of the suicide mode.

Protocol for preventing suicide
The outpatient protocol^1-3 comprises 10, 45- to 50-minute weekly individual psy­chotherapy sessions, with an allowance for booster sessions (as needed), until the patient is able to complete the relapse pre­vention task in Phase III. The inpatient protocol^4,5 comprises 6, 90-minute individ­ual psychotherapy sessions, with an allow­ance for 2 booster sessions (as needed) during the inpatient stay and as many as 4 telephone booster sessions after discharge.

Phase I: Tell the suicide story
Engage the patient in treatment. To increase adherence to treatment and mini­mize the risk of drop-out, practitioners are encouraged to establish a strong, early therapeutic alliance with the patient. Showing genuine empathy and provid­ing a safe, supportive, and nonjudgmental environment are instrumental for engag­ing patients in treatment. The practitioner listens carefully to the patient’s narrative, provides periodic summaries to check on accurate understanding, and keeps inter­ruptions to a minimum.

Collaboratively generate a safety plan. A crisis response plan or safety plan—an individualized, hierarchically arranged, written list of coping strategies to be implemented during a suicide crisis—is developed as soon as possible. Guidance on how to develop a structured safety plan has been provided by Stanley and Brown.^8,9

 

Practitioners must ensure that the safety plan contains contact information that the patient can use to reach the practitioner, the clinic, the on-call provider (if available), the local 24-hour emergency department, and the 24/7 National Suicide Prevention Lifeline (800-273-TALK [8255]). Discussion of how to limit access to lethal means also is important.

Because safety planning is a collaborative process, it is imperative that practitioners check on the patient’s willingness to follow the safety plan and help him overcome per­ceived obstacles in implementation. Copies of the plan can be kept at different locations and shared with family members, friends, or both with the patient’s permission.

Develop a cognitive-behavioral concep­tualization. The cognitive-behavioral con­ceptualization is an individualized map of a patient’s automatic thoughts (eg, “I am going to get fired today”), conditional assumptions (“If I get fired, then my life is over”), and core beliefs (“I am an utter failure”) that are activated before, during, and after suicidal self-directed violence. To develop that conceptualization, the patient is asked to tell a story about his (her) most recent suicidal crisis (the Box, offers a sample script) and to describe reactions to having survived a suicide attempt. (Note: Patients who report regret after an attempt are at greatest risk for dying by suicide.¹⁰)

This activity gives the patient an opportu­nity to disclose details surrounding his sui­cidal thoughts and actions, and might allow for a cathartic experience through storytell­ing. As practitioners listen to the suicide narrative, they collect data on the patient’s early childhood experiences (typically, suicide-activating events), associated auto­matic thoughts and images, emotional responses, and subsequent behaviors.

Based on this information, a cognitive-behavioral case conceptualization diagram (Figure 1, and Table 2) is generated collaboratively with the patient^a and used to personalize treatment planning.

^a Judith Beck offers sample case conceptualization diagrams in Cognitive behavior therapy: Basics and beyond, 2nd ed. New York, New York: Guilford Press; 2011.

Phase II: Build skills
Build skills to prevent episodes of sui­cidal self-directed violence. Information obtained from the conceptualization is used to generate an individualized cognitive-behavioral plan of intervention. The over­all goal is to determine skill-based problem areas that are associated with the most recent episode of suicidal self-directed violence.

Practitioner and patient collaboratively identify skills that are underdeveloped and ones that are overdeveloped so that they can be addressed systematically. In gen­eral, based on our clinical experience with suicidal patients, we recommend focusing on skills captured within ≥1 of the deficit domains in Table 3. Explanation of the vari­ous cognitive-behavioral strategies used in this phase of treatment is beyond the scope of this article, but 2 activities that highlight the clinical work conducted in this phase are described in the following sections. We selected those activities because they are easy to implement and, we have found, receive overall patient acceptability.

For a detailed understanding of strate­gies used in Phase II of CBT for preventing suicide, see Related Resources. In addition, the book Choosing to live: How to defeat suicide through cognitive therapy¹¹ can serve as a self-help guide for patients to follow through with CBT skill-building strategies.

Sample activity #1: Construct a ‘hope box.’ One activity that you can use to help a patient cope with suicide-activating core beliefs (eg, “My life is worthless”) involves construction of a so-called hope box. The box helps the patient directly challenge his extreme distress, by being reminded of pre­vious successes, positive experiences, and reasons for living. The process of construct­ing a hope box allows the patient to work on modifying his problematic core beliefs (eg, worthlessness, helplessness, incapable of being loved).

It can be helpful to have the patient con­struct his hope box during a session, to ensure that everything that is put in the box is truly helpful and personalized. Items included vary from patient to patient, and might con­sist of pictures of loved ones, a favorite poem, a prayer, coping cards (see next section), or all of these. For example, one of our patients chose to include a picture of herself in her early 20s as a reminder of a positive, fulfill­ing time in her life; this gave her hope that it is possible to experience those feelings again.

Bush et al^b at the National Center for Telehealth and Technology have developed a Virtual Hope Box, a free mobile applica­tion for tablets and smartphones (compatible with Android and iOS operating systems) that patients can use under the guidance of their practitioner.

^bwww.t2.health.mil/apps/virtual-hope-box

Sample activity #2: Generate coping cards. Effective problem-solving skills can be promoted by having the patient construct coping cards —wallet-size cards generated collaboratively in session. Coping cards are note cards that a patient keeps nearby to cope better during a difficult situation. They provide an easily accessible way to jump-start adaptive thinking during a suicidal crisis. The patient is encouraged to use cop­ing cards to practice adaptive thinking even when not in a crisis.

 

There are 3 kinds of coping cards:  
   • place a suicide-relevant automatic thought or core belief on one side of the card; on the other side, place an alternative, more adaptive response  
   • write a list of coping strategies  
   • write instructions to motivate or “acti­vate” the patient toward completing a spe­cific goal (Figure 2).

 

Phase III: Prevent relapse
Complete relapse prevention task. Relapse prevention is a common CBT strat­egy that aims to strengthen self-management to minimize likelihood of returning to a pre­viously stopped behavior. For patients who present only with suicidal thoughts, relapse prevention is directed at identifying trig­gers and minimizing the occurrence and/ or intensity of such thoughts in the future. For patients who present with suicidal self-directed violence, relapse prevention is directed at identifying triggers for suicidal actions and reducing the likelihood of acting on suicidal urges. The brief guidance pro­vided below will familiarize you with each of the relapse prevention steps, which may be completed in multiple sessions.

Step 1: Provide psychoeducation
Explain the difference between a lapse and a relapse. In general, you want the patient to understand that, although suicidal thoughts might persist and recur over time, suicidal self-directed violence must be prevented. Describe the purpose of the relapse preven­tion task (ie, to minimize the chance that suicidal thinking and actions will recur); address questions and concerns; and obtain permission to begin the procedure. Assure the patient that this is a collaborative activity and you will be in the room to ensure com­fort and safety.

STEP 2: Retell the suicide story
Ask the patient to imagine the chain of events, thoughts, and feelings that led to the most recent episode of suicide ideation or suicidal self-directed violence. Tell the patient that you want him to construct a movie script to describe the chain of events that resulted in the suicide crisis —but to do so slowly, taking enough time to describe the details of each scene of the movie.

Step 3: Apply CBT skills
Ask the patient again to take you through the sequence of events leading to the most recent episode of suicide ideation or suicidal self-directed violence. This time, however, direct him to use the skills learned in ther­apy to appropriately respond cognitively, affectively, and behaviorally to move further away from the suicide outcome.

If the patient is moving too fast or neglect­ing important points, stop and ask about alternative ways of thinking, feeling, and behaving. Use as much time as needed until the patient is able to demonstrate solid learn­ing of at least several learned CBT strategies to prevent suicidal self-directed violence.

Step 4: Generalize learning to prepare for future suicidal crises
In this stage —given your knowledge of the patient’s psychosocial history, cognitive- behavioral conceptualization, and suicide mode triggers —you collaboratively create a future scenario that is likely to activate suicidal self-directed violence. Question the patient about possible coping strategies, pro­vide helpful feedback, guide him through each link in the chain of events, and pro­pose additional alternative strategies if he is clearly neglecting important points of the intervention.

Step 5: Debrief and summarize lessons learned
Debrief the patient by providing a sum­mary of the skills he has learned in therapy, congratulate him for complet­ing this final therapeutic task, and assess overall emotional reaction to this activity. Remind him that mood fluctuations and future setbacks, in the form of lapses, are expected. Give him the option to request booster sessions and make plans for next steps in accomplishing general goals of therapy.

Treatment can be terminated when the patient is able to complete the relapse preven­tion task. If he is not ready or able to complete this exercise successfully, you can extend treatment. The duration of the extension is left to the practitioner’s judgment, based on the overall treatment plan. Brown and colleagues2 have reported a maximum num­ber of 24 outpatient sessions (for patients who need additional booster sessions); based on clinical experience, it is reasonable to assume that it would be highly unlikely for a patient not to meet treatment objectives after a methodical course of outpatient CBT.

In cases in which goals of treatment have not been met, consultation with colleagues, review of adherence problems, and consid­eration of obstacles for treatment efficacy would be recommended.

A checklist can be used to determine whether a patient is ready to end treatment. Variables that can be considered in assessing readiness for termination include:  
   • reduced scores on self-report measures for a number of weeks  
   • evidence of enhanced problem-solving  
   • engagement in adjunctive health care services  
   • development of a social support system.

 

Post-Admission Cognitive Therapy (PACT)
An inpatient cognitive-behavioral pro­tocol for the prevention of suicide, adapted from the efficacious outpatient model, is being evaluated at the Walter Reed National Military Medical Center, Bethesda, Maryland, and Fort Belvoir Community Hospital, Fort Belvoir, Virginia. The inpatient intervention is called PACT; components are summarized in Table 4.

Bottom Line
Cognitive-behavioral therapy for preventing suicide is an efficacious protocol for reducing the recurrence of suicidal self-directed violence. Post-Admission Cognitive Therapy is the adapted inpatient treatment package. You are encouraged to gain additional training and supervision on the delivery of these interventions to your high-risk suicidal patients.

Related Resources
• Academy of Cognitive Therapy. www.academyofct.org.
• National Suicide Prevention Lifeline. www.suicide preventionlifeline.org.
• Wenzel A, Brown GK, Beck AT. Cognitive therapy for suicidal patients: scientific and clinical applications. Washington, DC: American Psychological Association; 2009.

Disclosures
Support for research on inpatient cognitive-behavioral therapy for the prevention of suicide provided to Principal Investigator, Dr. Ghahramanlou-Holloway by the Department of Defense, Congressionally Directed Medical Research Program (W81XWH-08-2-0172), Military Operational Medicine Research Program (W81XWH-11-2-0106), and the National Alliance for Research on Schizophrenia and Depression (15219).

Many mental health practitioners have had training in cogni­tive-behavioral therapy (CBT)—short-term, evidence-based psychotherapy for treating a variety of psychiatric conditions (eg, posttraumatic stress disorder) and medical comorbidities (eg, insom­nia)—but only some are knowledgeable about how to best use CBT with a suicidal patient. This article provides a clinician-friendly summary of a 10-session evidence-based outpatient^1-3 and an adapted 6 to 8 session inpatient^4,5 cognitive-behavioral protocol (known as Post-Admission Cognitive Therapy [PACT]) that is designed to help patients who have suicide-related thoughts and/or behaviors.

3 phases of CBT for suicide prevention
An average of 9 hours of individual CBT for the prevention of suicide has been reported to reduce the likelihood of repeat suicide attempts in approximately 50% of patients.¹ Here, we introduce you to 3 phases of CBT for preventing suicide—phases that are the same for outpatients or inpatients. Our aim is to help you become familiar with CBT strategies that can be adapted for your treatment setting and used to intervene with vulnerable patients who are at risk for suicidal self-directed violence. A thorough assessment of the patient’s psychiatric diagnosis and history, presenting problems, and risk and protective factors for suicide must be completed before treatment begins.

Phase I. The patient is asked to tell a story associated with his (her) most recent episode of suicidal thoughts or behavior, or both. This narrative serves as 1) a foundation for planning treatment and 2) a model for understanding how best to deactivate the wish to die through the process of psychotherapy.

Phase II. The patient is assisted with modify­ing underdeveloped or overdeveloped skills that are most closely associated with the risk of triggering a suicidal crisis. For example, a patient with underdeveloped skills in regu­lating anger and hatred toward himself is taught to modulate these problematic emo­tions more effectively. In addition, effective problem-solving strategies are reviewed and practiced.

Phase III. The patient is guided through a relapse prevention task. The purpose of this exercise is to 1) highlight skills learned dur­ing therapy and 2) allow the patient to prac­tice effective problem-solving strategies that are aimed at minimizing the recurrence of suicidal self-directed violence.

Theorectical basis for preventing suicide with CBT
Aaron Beck, in 1979,⁶ proposed that a per­son’s biopsychosocial vulnerabilities can interact with suicidal thoughts and behaviors to produce a state that Beck labeled the “sui­cide mode.” Once produced, a suicide mode can become activated by cognitive, affective, motivational, and behavioral systems.

The frequency and severity of suicide mode activation can increase over time, especially for persons who do not have protective factors and those who have a his­tory of self-directed violence—in particular, attempted suicide. Moreover, some persons might experience a chronic state of suicide mode activation and, therefore, remain at elevated risk of suicide. Once a suicide-specific mode is activated, the person con­siders suicide the only option for solving his life problems. Suicide might be considered a rational decision at this point.⁶

The hypothesized mechanism of action associated with CBT for preventing suicide can be described as:  
   • deactivation of the suicide mode  
   • modification of the structure and con­tent of the suicide mode  
   • construction and practice of more adaptive structural modes to promote a desire to live.

The underlying philosophy of this inter­vention is that the suicide mode occurs inde­pendently of psychiatric diagnoses and must be targeted directly; treatment therefore is transdiagnostic.⁷ In other words, instead of addressing a symptom of a psychiatric disor­der, treatment directly targets suicide-related ideation and behaviors (Table 1).

Using that framework, psychiatric diag­noses are conceptualized in terms of how the associated symptoms contribute to the acti­vation, maintenance, and exacerbation of the suicide mode.

Protocol for preventing suicide
The outpatient protocol^1-3 comprises 10, 45- to 50-minute weekly individual psy­chotherapy sessions, with an allowance for booster sessions (as needed), until the patient is able to complete the relapse pre­vention task in Phase III. The inpatient protocol^4,5 comprises 6, 90-minute individ­ual psychotherapy sessions, with an allow­ance for 2 booster sessions (as needed) during the inpatient stay and as many as 4 telephone booster sessions after discharge.

Phase I: Tell the suicide story
Engage the patient in treatment. To increase adherence to treatment and mini­mize the risk of drop-out, practitioners are encouraged to establish a strong, early therapeutic alliance with the patient. Showing genuine empathy and provid­ing a safe, supportive, and nonjudgmental environment are instrumental for engag­ing patients in treatment. The practitioner listens carefully to the patient’s narrative, provides periodic summaries to check on accurate understanding, and keeps inter­ruptions to a minimum.

Collaboratively generate a safety plan. A crisis response plan or safety plan—an individualized, hierarchically arranged, written list of coping strategies to be implemented during a suicide crisis—is developed as soon as possible. Guidance on how to develop a structured safety plan has been provided by Stanley and Brown.^8,9

 

Practitioners must ensure that the safety plan contains contact information that the patient can use to reach the practitioner, the clinic, the on-call provider (if available), the local 24-hour emergency department, and the 24/7 National Suicide Prevention Lifeline (800-273-TALK [8255]). Discussion of how to limit access to lethal means also is important.

Because safety planning is a collaborative process, it is imperative that practitioners check on the patient’s willingness to follow the safety plan and help him overcome per­ceived obstacles in implementation. Copies of the plan can be kept at different locations and shared with family members, friends, or both with the patient’s permission.

Develop a cognitive-behavioral concep­tualization. The cognitive-behavioral con­ceptualization is an individualized map of a patient’s automatic thoughts (eg, “I am going to get fired today”), conditional assumptions (“If I get fired, then my life is over”), and core beliefs (“I am an utter failure”) that are activated before, during, and after suicidal self-directed violence. To develop that conceptualization, the patient is asked to tell a story about his (her) most recent suicidal crisis (the Box, offers a sample script) and to describe reactions to having survived a suicide attempt. (Note: Patients who report regret after an attempt are at greatest risk for dying by suicide.¹⁰)

This activity gives the patient an opportu­nity to disclose details surrounding his sui­cidal thoughts and actions, and might allow for a cathartic experience through storytell­ing. As practitioners listen to the suicide narrative, they collect data on the patient’s early childhood experiences (typically, suicide-activating events), associated auto­matic thoughts and images, emotional responses, and subsequent behaviors.

Based on this information, a cognitive-behavioral case conceptualization diagram (Figure 1, and Table 2) is generated collaboratively with the patient^a and used to personalize treatment planning.

^a Judith Beck offers sample case conceptualization diagrams in Cognitive behavior therapy: Basics and beyond, 2nd ed. New York, New York: Guilford Press; 2011.

Phase II: Build skills
Build skills to prevent episodes of sui­cidal self-directed violence. Information obtained from the conceptualization is used to generate an individualized cognitive-behavioral plan of intervention. The over­all goal is to determine skill-based problem areas that are associated with the most recent episode of suicidal self-directed violence.

Practitioner and patient collaboratively identify skills that are underdeveloped and ones that are overdeveloped so that they can be addressed systematically. In gen­eral, based on our clinical experience with suicidal patients, we recommend focusing on skills captured within ≥1 of the deficit domains in Table 3. Explanation of the vari­ous cognitive-behavioral strategies used in this phase of treatment is beyond the scope of this article, but 2 activities that highlight the clinical work conducted in this phase are described in the following sections. We selected those activities because they are easy to implement and, we have found, receive overall patient acceptability.

For a detailed understanding of strate­gies used in Phase II of CBT for preventing suicide, see Related Resources. In addition, the book Choosing to live: How to defeat suicide through cognitive therapy¹¹ can serve as a self-help guide for patients to follow through with CBT skill-building strategies.

Sample activity #1: Construct a ‘hope box.’ One activity that you can use to help a patient cope with suicide-activating core beliefs (eg, “My life is worthless”) involves construction of a so-called hope box. The box helps the patient directly challenge his extreme distress, by being reminded of pre­vious successes, positive experiences, and reasons for living. The process of construct­ing a hope box allows the patient to work on modifying his problematic core beliefs (eg, worthlessness, helplessness, incapable of being loved).

It can be helpful to have the patient con­struct his hope box during a session, to ensure that everything that is put in the box is truly helpful and personalized. Items included vary from patient to patient, and might con­sist of pictures of loved ones, a favorite poem, a prayer, coping cards (see next section), or all of these. For example, one of our patients chose to include a picture of herself in her early 20s as a reminder of a positive, fulfill­ing time in her life; this gave her hope that it is possible to experience those feelings again.

Bush et al^b at the National Center for Telehealth and Technology have developed a Virtual Hope Box, a free mobile applica­tion for tablets and smartphones (compatible with Android and iOS operating systems) that patients can use under the guidance of their practitioner.

^bwww.t2.health.mil/apps/virtual-hope-box

Sample activity #2: Generate coping cards. Effective problem-solving skills can be promoted by having the patient construct coping cards —wallet-size cards generated collaboratively in session. Coping cards are note cards that a patient keeps nearby to cope better during a difficult situation. They provide an easily accessible way to jump-start adaptive thinking during a suicidal crisis. The patient is encouraged to use cop­ing cards to practice adaptive thinking even when not in a crisis.

 

There are 3 kinds of coping cards:  
   • place a suicide-relevant automatic thought or core belief on one side of the card; on the other side, place an alternative, more adaptive response  
   • write a list of coping strategies  
   • write instructions to motivate or “acti­vate” the patient toward completing a spe­cific goal (Figure 2).

 

Phase III: Prevent relapse
Complete relapse prevention task. Relapse prevention is a common CBT strat­egy that aims to strengthen self-management to minimize likelihood of returning to a pre­viously stopped behavior. For patients who present only with suicidal thoughts, relapse prevention is directed at identifying trig­gers and minimizing the occurrence and/ or intensity of such thoughts in the future. For patients who present with suicidal self-directed violence, relapse prevention is directed at identifying triggers for suicidal actions and reducing the likelihood of acting on suicidal urges. The brief guidance pro­vided below will familiarize you with each of the relapse prevention steps, which may be completed in multiple sessions.

Step 1: Provide psychoeducation
Explain the difference between a lapse and a relapse. In general, you want the patient to understand that, although suicidal thoughts might persist and recur over time, suicidal self-directed violence must be prevented. Describe the purpose of the relapse preven­tion task (ie, to minimize the chance that suicidal thinking and actions will recur); address questions and concerns; and obtain permission to begin the procedure. Assure the patient that this is a collaborative activity and you will be in the room to ensure com­fort and safety.

STEP 2: Retell the suicide story
Ask the patient to imagine the chain of events, thoughts, and feelings that led to the most recent episode of suicide ideation or suicidal self-directed violence. Tell the patient that you want him to construct a movie script to describe the chain of events that resulted in the suicide crisis —but to do so slowly, taking enough time to describe the details of each scene of the movie.

Step 3: Apply CBT skills
Ask the patient again to take you through the sequence of events leading to the most recent episode of suicide ideation or suicidal self-directed violence. This time, however, direct him to use the skills learned in ther­apy to appropriately respond cognitively, affectively, and behaviorally to move further away from the suicide outcome.

If the patient is moving too fast or neglect­ing important points, stop and ask about alternative ways of thinking, feeling, and behaving. Use as much time as needed until the patient is able to demonstrate solid learn­ing of at least several learned CBT strategies to prevent suicidal self-directed violence.

Step 4: Generalize learning to prepare for future suicidal crises
In this stage —given your knowledge of the patient’s psychosocial history, cognitive- behavioral conceptualization, and suicide mode triggers —you collaboratively create a future scenario that is likely to activate suicidal self-directed violence. Question the patient about possible coping strategies, pro­vide helpful feedback, guide him through each link in the chain of events, and pro­pose additional alternative strategies if he is clearly neglecting important points of the intervention.

Step 5: Debrief and summarize lessons learned
Debrief the patient by providing a sum­mary of the skills he has learned in therapy, congratulate him for complet­ing this final therapeutic task, and assess overall emotional reaction to this activity. Remind him that mood fluctuations and future setbacks, in the form of lapses, are expected. Give him the option to request booster sessions and make plans for next steps in accomplishing general goals of therapy.

Treatment can be terminated when the patient is able to complete the relapse preven­tion task. If he is not ready or able to complete this exercise successfully, you can extend treatment. The duration of the extension is left to the practitioner’s judgment, based on the overall treatment plan. Brown and colleagues2 have reported a maximum num­ber of 24 outpatient sessions (for patients who need additional booster sessions); based on clinical experience, it is reasonable to assume that it would be highly unlikely for a patient not to meet treatment objectives after a methodical course of outpatient CBT.

In cases in which goals of treatment have not been met, consultation with colleagues, review of adherence problems, and consid­eration of obstacles for treatment efficacy would be recommended.

A checklist can be used to determine whether a patient is ready to end treatment. Variables that can be considered in assessing readiness for termination include:  
   • reduced scores on self-report measures for a number of weeks  
   • evidence of enhanced problem-solving  
   • engagement in adjunctive health care services  
   • development of a social support system.

 

Post-Admission Cognitive Therapy (PACT)
An inpatient cognitive-behavioral pro­tocol for the prevention of suicide, adapted from the efficacious outpatient model, is being evaluated at the Walter Reed National Military Medical Center, Bethesda, Maryland, and Fort Belvoir Community Hospital, Fort Belvoir, Virginia. The inpatient intervention is called PACT; components are summarized in Table 4.

Bottom Line
Cognitive-behavioral therapy for preventing suicide is an efficacious protocol for reducing the recurrence of suicidal self-directed violence. Post-Admission Cognitive Therapy is the adapted inpatient treatment package. You are encouraged to gain additional training and supervision on the delivery of these interventions to your high-risk suicidal patients.

Related Resources
• Academy of Cognitive Therapy. www.academyofct.org.
• National Suicide Prevention Lifeline. www.suicide preventionlifeline.org.
• Wenzel A, Brown GK, Beck AT. Cognitive therapy for suicidal patients: scientific and clinical applications. Washington, DC: American Psychological Association; 2009.

Disclosures
Support for research on inpatient cognitive-behavioral therapy for the prevention of suicide provided to Principal Investigator, Dr. Ghahramanlou-Holloway by the Department of Defense, Congressionally Directed Medical Research Program (W81XWH-08-2-0172), Military Operational Medicine Research Program (W81XWH-11-2-0106), and the National Alliance for Research on Schizophrenia and Depression (15219).

In this article, we highlight key steps that were needed to integrate clinical pharmacy specialists at an academic ambulatory psychiatric and addiction treatment center that serves pediatric and adult populations. Academic stakeholders identified addition of pharmacy services as a strategic goal in an effort to maximize services offered by the center and increase patient access to care while aligning with the standards set out by the patient-centered medical home (PCMH) model.

We outline the role of clinical pharmacists in the care of adult patients in ambulatory psychiatry, illustrate opportu­nities to enhance patient care, point out possible challenges with implementation, and propose future initiatives to optimize the practitioner-pharmacist partnership.

Background: Role of ambulatory pharmacists in psychiatry
Clinical pharmacists’ role in the psychiatric ambulatory care setting generally is associated with positive outcomes. One study looking at a collaborative care model that uti­lized clinical pharmacist follow-up in managing major depressive disorder found that patients who received phar­macist intervention in the collaborative care model had, on average, a significantly higher adherence rate and patient satisfaction score than the “usual care” group.¹ Within this study, patients in both groups experienced global clini­cal improvement with no significant difference; however, pharmacist interventions had a posi­tive impact on several aspects of the care model, suggesting that pharmacists can be used effectively in ambulatory psychiatry.

Furthermore, a systematic study evalu­ating pharmacists’ impact on clinical and functional mental health outcomes iden­tified 8 relevant studies conducted in the outpatient setting.² Although interven­tions varied widely, most studies focused on pharmacists’ providing a combination of drug monitoring, treatment recommen­dations, and patient education. Outcomes were largely positive, including an overall reduction in number and dosage of psy­chiatric drugs, inferred cost savings, and significant improvements in the safe and efficacious use of antidepressant and anti­psychotic medications.

These preliminary positive results require replication in larger, random­ized cohorts. Additionally, the role of the pharmacist as medication manager in the collaborative care model requires further study. Results so far, however, indicate that pharmacists can have a positive impact on the care of ambulatory psychiatry patients. Nevertheless, there is still considerable need for ongoing exploration in this field.

Pre-implementation
The need for pharmacy services. Various initiatives and existing practices within our health care system have underscored the need for a psychiatric pharmacist in the outpatient setting (Table 1).

A board-certified psychiatric pharma­cist (BCPP) possesses specialized knowl­edge about treating patients affected by psychiatric illnesses. BCPPs work with prescribers and members of other disci­plines, such as nurses and social workers, to optimize drug treatment by making pharmacotherapeutic recommendations and providing appropriate monitoring to enhance patient satisfaction and quality of life.^3,4

Existing relationship with pharmacy. Along with evidence to support the posi­tive impact clinical pharmacists can have in caring for patients with mental illness in the outpatient setting, a strong existing relationship between the Department of Psychiatry and our adult inpatient psychi­atric pharmacist helped make it possible to develop an ambulatory psychiatric phar­macist position.

Each day, the inpatient psychiatric pharmacist works closely with the attend­ing psychiatrists and psychiatry residents to provide treatment recommendations and counseling services for patients on the unit. The psychiatry residents highly valued their experiences with the pharmacist in the inpatient setting and expressed disappointment that this col­laborative relationship was no longer available after they transitioned into the ambulatory setting.

Further, by being involved in initia­tives that were relevant to both inpa­tient and outpatient psychiatry, such as metabolic monitoring for patients taking atypical antipsychotics, the clini­cal pharmacist in inpatient psychiatry had the opportunity to interact with key stakeholders in both settings. As a result of these pre-existing collabora­tive relationships, many clinicians were eager to have pharmacists available as a resource for patient care in the outpatient setting.

Pharmacist perspective: Outreach to psychiatry leadershipRecognizing the incentives and oppor­tunities inherent in our emerging health care system, pharmacists became integral members of the patient care team in the PCMH model. Thanks to this effort, we now have PCMH pharmacists at every primary care health center in our health system (14 sites), providing disease man­agement programs and polypharmacy services.

PCMH pharmacists’ role in the primary care setting fueled interest from specialty services and created opportunities to extend our existing partnership in inpa­tient psychiatry. One such opportunity to demonstrate the expertise of a psychi­atric pharmacist was fueled by the FDA’s citalopram dosing alert⁵ at a system-wide level. This warning emerged as a chance to showcase the skill set of psychiatric phar­macists and the pharmacists’ successes in our PCMH model. The partnership was extended to include the buy-in of ambula­tory pharmacy leadership and key stake­holders in ambulatory psychiatry.

 

Initial meetings included ambula­tory care site leadership in psychiatry to increase awareness and understanding of pharmacists’ potential role in direct patient care. Achieving site leadership support was critical to successful implementation of pharmacist services in psychiatry. We also obtained approval from the Chair of the Department of Psychiatry to elicit sup­port from faculty group practice.

Psychiatry leadership perspective
As fiscal pressures intensify at academic health centers, it becomes increasingly important for resources to be used as efficiently and effectively as possible. As a greater percentage of mental health patients with more “straightforward,” less complex conditions are being managed by their primary care providers or non­prescribing psychotherapists, or both, the acuity and complexity of cases in patients who present to psychiatric clinics have intensified. This intensification of patient needs and clinical acuity is in heightened conflict with the ongoing demand for clini­cian productivity and efficiency.

Additionally, the need to provide care to a seemingly ever-growing number of moderately or severely ill patients dur­ing shorter, less frequent visits presents a daunting task for clinicians and clinical leaders. Collaborative care models appear to offer the best hope for managing the seemingly overwhelming demand for services.

In this model, the patient, who is the critical member of the team, is expected to become an “expert” on his or her ill­ness and to partner with members of the multidisciplinary team; with this support, patients are encouraged to develop a broad range of self-management skills and strat­egies to manage their illness. We believe that clinical pharmacists can and should play a critical role, not only in deliver­ing direct clinical services to patients but also in developing and devising the care models that will most effectively apply each team member’s unique set of knowl­edge, skills, and experience. Given the large percentage of our patients who have multiple medical comorbidities and who require complex medical and psychiat­ric medication regimens, the role of the pharmacist in reviewing, educating, and advising patients and other team members on these crucial pharmacy concerns will be paramount.

In light of these complex medication issues, pharmacists are uniquely posi­tioned to serve as a liaison among the patient, the primary care provider, and other members of their treatment team. We anticipate that our ambulatory psychiatry pharmacists will greatly enhance the com­fort and confidence of patients and their primary care providers during periods of care transition.

Potential roles for pharmacists in ambulatory psychiatry
One potential role for pharmacists in ambulatory psychiatry is to perform polypharmacy assessments of patients receiving complex medication regimens, prompted by physician referral. The poly­ pharmacy intake interview, performed to obtain an accurate medication list and to identify patients’ concerns about their medications, can be conducted in per­son or by telephone. Patients’ knowledge about medications and medication adher­ence are discussed, as are their perceptions of effectiveness and adverse effects.

After initial data gathering, pharma­cists complete a review of the medications, identifying any problems associated with medication indication, efficacy, tolerance, or adverse effects, drug-drug interactions, drug-nutrient interactions, and nonadher­ence. Pharmacists work to reduce medica­tion costs if that is a concern of the patient, because nonadherence can result. A medi­cation care plan is then developed in con­sultation with the primary care provider; here, the medication list is reconciled, the electronic medical record is updated, and actions to address any medication-related problems are prioritized.

Other services that might be offered include:• group education classes, based on patient motivational interviewing strate­gies, to address therapeutic nonadherence and to improve understanding of their dis­ease and treatment regimens• medication safety and monitoring• treatment intensification, as needed, following established protocols.

These are a few of the ways in which pharmacists can be relied on to expand and improve access to patient care ser­vices within ambulatory psychiatry. Key stakeholders anticipate development of newer ideas as the pharmacist’s role in ambulatory psychiatry is increasingly clarified.

Reimbursement model
In creating a role for pharmacy in ambu­latory psychiatry, it was essential that the model be financially viable and appeal­ing. Alongside its clinical model, our insti­tution has developed a financial model to support the pharmacist’s role. The lump-sum payment to the health centers from Blue Cross Blue Shield of Michigan afforded the ambulatory care clinics an opportunity to invest in PCMH pharma­cists. This funding, and the reimbursement based on T-code billing (face-to-face visits and phone consultation) for depression and other conditions requiring chronic care, provides ongoing support. From our experience, understanding physician reimbursement models and identifying relevant changes in health care reform are necessary to integrate new providers, including pharmacists, into a team-based care model.

Implementation
Promoting pharmacy services. To fos­ter anticipated collaboration with clini­cal pharmacists, the medical director of outpatient psychiatry disseminated an announcement to all providers regard­ing the investiture of clinical pharmacists to support patient care activities, educa­tion, and research. Clinicians were edu­cated about the pharmacists’ potential roles and about guidelines and methods for referral. Use of our electronic health record system enabled us to establish a relatively simple referral process involv­ing sharing electronic messages with our pharmacists.

Further, as part of the planned integra­tion of clinical pharmacists in the ambula­tory psychiatry setting, pharmacists met strategically with members of various disciplines, clinical programs, specialty clinic programs, and teams throughout the center. In addition to answering questions about the referral process, they empha­sized the role of pharmacy and opportuni­ties for collaboration.

 

Collaborating with others. Because the involvement of clinical pharmacists is unfamiliar to some practitioners in outpa­tient psychiatry, it is important to develop services without infringing on the roles other disciplines play. Indeed, a survey by Wheeler et al6 identified many concerns and potential boundaries among pharmacists, other providers, and patients. Concerns included confusion of practitioner roles and boundaries, a too-traditional percep­tion of the pharmacist, and demonstration of competence.⁶

Early on, we developed a structured forum to discuss ongoing challenges and address issues related to the rapidly changing clinical landscape. During these discussions we conveyed that adding pharmacists to psychiatric services would be collaborative in nature and intended to augment existing services. This commu­nication was pivotal to maintain the psy­chiatrist’s role as the ultimate prescriber and authority in the care of their patients; however, the pharmacist’s expertise, when sought, would help spur clinical and aca­demic discussion that will benefit the patient. These discussions are paramount to achieving a productive, team-based approach, to overcome challenges, and to identify opportunities of value to our pro­viders and patients (Box).

Work in progress
Implementing change in any clinical set­ting invariably creates challenges, and our endeavors to integrate clinical phar­macists into ambulatory psychiatry are no exception. We have identified several factors that we believe will optimize suc­cessful collaboration between pharmacy and ambulatory psychiatry (Table 2). Our primary challenge has been changing cli­nician behavior. Clinical practitioners can become too comfortable, wedded to their routines, and often are understandably resistant to change. Additionally, clinical systems often are inadvertently designed to obstruct change in ways that are not readily apparent. Efforts must be focused on behaviors and practices the clinical cul­ture should encourage.

Regarding specific initiatives, clinical pharmacists have successfully identified patients on higher than recommended dosages of citalopram; they are work­ing alongside prescribers to recom­mend ways to minimize the risk of heart rhythm abnormalities in these patients. Numerous prescribers have sought clini­cal pharmacists’ input to manage phar­macotherapy in their patients and to respond to patients’ questions on drug information.

The prospect of access to clinical phar­macist expertise in the outpatient setting was heralded with excitement, but the flow of referrals and consultations has been uneven. However simple the path for referral is, clinicians’ use of the system has been inconsistent—perhaps because of referrals’ passive, clinician-dependent nature. Educational outreach efforts often prompt a brief spike in referrals, only to be followed over time by a slow, steady drop-off. More active strategies will be needed, such as embedding the pharma­cists as regular, active, visible members of the various clinical teams, and imple­menting a system in which patient record reviews are assigned to the pharmacists according to agreed-upon clusters of clin­ical criteria.

One of these tactics has, in the short term, showed success. Embedded in one of our newer clinics, which were designed to bridge primary and psychiatric care, clinical pharmacists are helping manage medically complicated patients. They assist with medication selection in light of drug interactions and medical comor­bidities, conduct detailed medication his­tories, schedule follow-up visits to assess medication adherence and tolerability, and counsel patients experiencing insur­ance changes that make their medications less affordable. Integrating pharmacists in the new clinics has resulted in a steady flow of patient referrals and collaborative care work.

Clinical pharmacists are brainstorming with outpatient psychiatry leadership to build on these early successes. Ongoing communication and enhanced collabora­tion are essential, and can only improve the lives of our psychiatric patients.

For the future
Our partnership in ambulatory psychiatry was timed to occur during implementa­tion of our health system’s new electronic health record initiative. Clinical pharma­cists can play a key role in demonstrating use of the system to provide consistently accurate drug information to patients and to monitor patients receiving specific medications.

Development of ambulatory patient medication education groups, which has proved useful on the inpatient side, is another endeavor in the works. Integrating the clinical pharmacist with psychiatrists, psychologists, nurse prac­titioners, social workers, and trainees on specific teams devoted to depression, bipolar disorder, anxiety, perinatal men­tal health, and personality disorders also might prove to be a wide-ranging and promising strategy.

Enhancing the education and training experiences of residents, fellows, medical students, pharmacy students, and allied health professional learners present in our clinics is another exciting prospect. This cross-disciplinary training will yield a new generation of providers who will be more comfortable collaborating with colleagues from other disciplines, all intent on pro­viding high-quality, efficient care. We hope that, as these initiatives take root, we will recognize many opportunities to dissemi­nate our collaborative efforts in scholarly venues, documenting and sharing the pos­itive impact of our partnership.

 

Bottom Line
Because psychiatric outpatients present with challenging medical comorbidities and increasingly complex medication regimens, specialized clinical pharmacists can enrich the management team by offering essential monitoring and polypharmacy services, patient education and counseling, and cross-discipline training. At one academic treatment center, psychiatric and non-psychiatric practitioners are gradually buying in to these promising collaborative efforts.


Related Resources
• Board of Pharmacy Specialties. www.bpsweb.org/specialties/psychiatric.cfm.
• Abramowitz P. Ambulatory care pharmacy practice: The future is now. www.connect.ashp.org/blogs/paul-abramowitz/2014/05/14/ambulatory-care-pharmacy-practice-the-future-is-now.

Drug Brand Name
Citalopram • Celexa

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

In this article, we highlight key steps that were needed to integrate clinical pharmacy specialists at an academic ambulatory psychiatric and addiction treatment center that serves pediatric and adult populations. Academic stakeholders identified addition of pharmacy services as a strategic goal in an effort to maximize services offered by the center and increase patient access to care while aligning with the standards set out by the patient-centered medical home (PCMH) model.

We outline the role of clinical pharmacists in the care of adult patients in ambulatory psychiatry, illustrate opportu­nities to enhance patient care, point out possible challenges with implementation, and propose future initiatives to optimize the practitioner-pharmacist partnership.

Background: Role of ambulatory pharmacists in psychiatry
Clinical pharmacists’ role in the psychiatric ambulatory care setting generally is associated with positive outcomes. One study looking at a collaborative care model that uti­lized clinical pharmacist follow-up in managing major depressive disorder found that patients who received phar­macist intervention in the collaborative care model had, on average, a significantly higher adherence rate and patient satisfaction score than the “usual care” group.¹ Within this study, patients in both groups experienced global clini­cal improvement with no significant difference; however, pharmacist interventions had a posi­tive impact on several aspects of the care model, suggesting that pharmacists can be used effectively in ambulatory psychiatry.

Furthermore, a systematic study evalu­ating pharmacists’ impact on clinical and functional mental health outcomes iden­tified 8 relevant studies conducted in the outpatient setting.² Although interven­tions varied widely, most studies focused on pharmacists’ providing a combination of drug monitoring, treatment recommen­dations, and patient education. Outcomes were largely positive, including an overall reduction in number and dosage of psy­chiatric drugs, inferred cost savings, and significant improvements in the safe and efficacious use of antidepressant and anti­psychotic medications.

These preliminary positive results require replication in larger, random­ized cohorts. Additionally, the role of the pharmacist as medication manager in the collaborative care model requires further study. Results so far, however, indicate that pharmacists can have a positive impact on the care of ambulatory psychiatry patients. Nevertheless, there is still considerable need for ongoing exploration in this field.

Pre-implementation
The need for pharmacy services. Various initiatives and existing practices within our health care system have underscored the need for a psychiatric pharmacist in the outpatient setting (Table 1).

A board-certified psychiatric pharma­cist (BCPP) possesses specialized knowl­edge about treating patients affected by psychiatric illnesses. BCPPs work with prescribers and members of other disci­plines, such as nurses and social workers, to optimize drug treatment by making pharmacotherapeutic recommendations and providing appropriate monitoring to enhance patient satisfaction and quality of life.^3,4

Existing relationship with pharmacy. Along with evidence to support the posi­tive impact clinical pharmacists can have in caring for patients with mental illness in the outpatient setting, a strong existing relationship between the Department of Psychiatry and our adult inpatient psychi­atric pharmacist helped make it possible to develop an ambulatory psychiatric phar­macist position.

Each day, the inpatient psychiatric pharmacist works closely with the attend­ing psychiatrists and psychiatry residents to provide treatment recommendations and counseling services for patients on the unit. The psychiatry residents highly valued their experiences with the pharmacist in the inpatient setting and expressed disappointment that this col­laborative relationship was no longer available after they transitioned into the ambulatory setting.

Further, by being involved in initia­tives that were relevant to both inpa­tient and outpatient psychiatry, such as metabolic monitoring for patients taking atypical antipsychotics, the clini­cal pharmacist in inpatient psychiatry had the opportunity to interact with key stakeholders in both settings. As a result of these pre-existing collabora­tive relationships, many clinicians were eager to have pharmacists available as a resource for patient care in the outpatient setting.

Pharmacist perspective: Outreach to psychiatry leadershipRecognizing the incentives and oppor­tunities inherent in our emerging health care system, pharmacists became integral members of the patient care team in the PCMH model. Thanks to this effort, we now have PCMH pharmacists at every primary care health center in our health system (14 sites), providing disease man­agement programs and polypharmacy services.

PCMH pharmacists’ role in the primary care setting fueled interest from specialty services and created opportunities to extend our existing partnership in inpa­tient psychiatry. One such opportunity to demonstrate the expertise of a psychi­atric pharmacist was fueled by the FDA’s citalopram dosing alert⁵ at a system-wide level. This warning emerged as a chance to showcase the skill set of psychiatric phar­macists and the pharmacists’ successes in our PCMH model. The partnership was extended to include the buy-in of ambula­tory pharmacy leadership and key stake­holders in ambulatory psychiatry.

 

Initial meetings included ambula­tory care site leadership in psychiatry to increase awareness and understanding of pharmacists’ potential role in direct patient care. Achieving site leadership support was critical to successful implementation of pharmacist services in psychiatry. We also obtained approval from the Chair of the Department of Psychiatry to elicit sup­port from faculty group practice.

Psychiatry leadership perspective
As fiscal pressures intensify at academic health centers, it becomes increasingly important for resources to be used as efficiently and effectively as possible. As a greater percentage of mental health patients with more “straightforward,” less complex conditions are being managed by their primary care providers or non­prescribing psychotherapists, or both, the acuity and complexity of cases in patients who present to psychiatric clinics have intensified. This intensification of patient needs and clinical acuity is in heightened conflict with the ongoing demand for clini­cian productivity and efficiency.

Additionally, the need to provide care to a seemingly ever-growing number of moderately or severely ill patients dur­ing shorter, less frequent visits presents a daunting task for clinicians and clinical leaders. Collaborative care models appear to offer the best hope for managing the seemingly overwhelming demand for services.

In this model, the patient, who is the critical member of the team, is expected to become an “expert” on his or her ill­ness and to partner with members of the multidisciplinary team; with this support, patients are encouraged to develop a broad range of self-management skills and strat­egies to manage their illness. We believe that clinical pharmacists can and should play a critical role, not only in deliver­ing direct clinical services to patients but also in developing and devising the care models that will most effectively apply each team member’s unique set of knowl­edge, skills, and experience. Given the large percentage of our patients who have multiple medical comorbidities and who require complex medical and psychiat­ric medication regimens, the role of the pharmacist in reviewing, educating, and advising patients and other team members on these crucial pharmacy concerns will be paramount.

In light of these complex medication issues, pharmacists are uniquely posi­tioned to serve as a liaison among the patient, the primary care provider, and other members of their treatment team. We anticipate that our ambulatory psychiatry pharmacists will greatly enhance the com­fort and confidence of patients and their primary care providers during periods of care transition.

Potential roles for pharmacists in ambulatory psychiatry
One potential role for pharmacists in ambulatory psychiatry is to perform polypharmacy assessments of patients receiving complex medication regimens, prompted by physician referral. The poly­ pharmacy intake interview, performed to obtain an accurate medication list and to identify patients’ concerns about their medications, can be conducted in per­son or by telephone. Patients’ knowledge about medications and medication adher­ence are discussed, as are their perceptions of effectiveness and adverse effects.

After initial data gathering, pharma­cists complete a review of the medications, identifying any problems associated with medication indication, efficacy, tolerance, or adverse effects, drug-drug interactions, drug-nutrient interactions, and nonadher­ence. Pharmacists work to reduce medica­tion costs if that is a concern of the patient, because nonadherence can result. A medi­cation care plan is then developed in con­sultation with the primary care provider; here, the medication list is reconciled, the electronic medical record is updated, and actions to address any medication-related problems are prioritized.

Other services that might be offered include:• group education classes, based on patient motivational interviewing strate­gies, to address therapeutic nonadherence and to improve understanding of their dis­ease and treatment regimens• medication safety and monitoring• treatment intensification, as needed, following established protocols.

These are a few of the ways in which pharmacists can be relied on to expand and improve access to patient care ser­vices within ambulatory psychiatry. Key stakeholders anticipate development of newer ideas as the pharmacist’s role in ambulatory psychiatry is increasingly clarified.

Reimbursement model
In creating a role for pharmacy in ambu­latory psychiatry, it was essential that the model be financially viable and appeal­ing. Alongside its clinical model, our insti­tution has developed a financial model to support the pharmacist’s role. The lump-sum payment to the health centers from Blue Cross Blue Shield of Michigan afforded the ambulatory care clinics an opportunity to invest in PCMH pharma­cists. This funding, and the reimbursement based on T-code billing (face-to-face visits and phone consultation) for depression and other conditions requiring chronic care, provides ongoing support. From our experience, understanding physician reimbursement models and identifying relevant changes in health care reform are necessary to integrate new providers, including pharmacists, into a team-based care model.

Implementation
Promoting pharmacy services. To fos­ter anticipated collaboration with clini­cal pharmacists, the medical director of outpatient psychiatry disseminated an announcement to all providers regard­ing the investiture of clinical pharmacists to support patient care activities, educa­tion, and research. Clinicians were edu­cated about the pharmacists’ potential roles and about guidelines and methods for referral. Use of our electronic health record system enabled us to establish a relatively simple referral process involv­ing sharing electronic messages with our pharmacists.

Further, as part of the planned integra­tion of clinical pharmacists in the ambula­tory psychiatry setting, pharmacists met strategically with members of various disciplines, clinical programs, specialty clinic programs, and teams throughout the center. In addition to answering questions about the referral process, they empha­sized the role of pharmacy and opportuni­ties for collaboration.

 

Collaborating with others. Because the involvement of clinical pharmacists is unfamiliar to some practitioners in outpa­tient psychiatry, it is important to develop services without infringing on the roles other disciplines play. Indeed, a survey by Wheeler et al6 identified many concerns and potential boundaries among pharmacists, other providers, and patients. Concerns included confusion of practitioner roles and boundaries, a too-traditional percep­tion of the pharmacist, and demonstration of competence.⁶

Early on, we developed a structured forum to discuss ongoing challenges and address issues related to the rapidly changing clinical landscape. During these discussions we conveyed that adding pharmacists to psychiatric services would be collaborative in nature and intended to augment existing services. This commu­nication was pivotal to maintain the psy­chiatrist’s role as the ultimate prescriber and authority in the care of their patients; however, the pharmacist’s expertise, when sought, would help spur clinical and aca­demic discussion that will benefit the patient. These discussions are paramount to achieving a productive, team-based approach, to overcome challenges, and to identify opportunities of value to our pro­viders and patients (Box).

Work in progress
Implementing change in any clinical set­ting invariably creates challenges, and our endeavors to integrate clinical phar­macists into ambulatory psychiatry are no exception. We have identified several factors that we believe will optimize suc­cessful collaboration between pharmacy and ambulatory psychiatry (Table 2). Our primary challenge has been changing cli­nician behavior. Clinical practitioners can become too comfortable, wedded to their routines, and often are understandably resistant to change. Additionally, clinical systems often are inadvertently designed to obstruct change in ways that are not readily apparent. Efforts must be focused on behaviors and practices the clinical cul­ture should encourage.

Regarding specific initiatives, clinical pharmacists have successfully identified patients on higher than recommended dosages of citalopram; they are work­ing alongside prescribers to recom­mend ways to minimize the risk of heart rhythm abnormalities in these patients. Numerous prescribers have sought clini­cal pharmacists’ input to manage phar­macotherapy in their patients and to respond to patients’ questions on drug information.

The prospect of access to clinical phar­macist expertise in the outpatient setting was heralded with excitement, but the flow of referrals and consultations has been uneven. However simple the path for referral is, clinicians’ use of the system has been inconsistent—perhaps because of referrals’ passive, clinician-dependent nature. Educational outreach efforts often prompt a brief spike in referrals, only to be followed over time by a slow, steady drop-off. More active strategies will be needed, such as embedding the pharma­cists as regular, active, visible members of the various clinical teams, and imple­menting a system in which patient record reviews are assigned to the pharmacists according to agreed-upon clusters of clin­ical criteria.

One of these tactics has, in the short term, showed success. Embedded in one of our newer clinics, which were designed to bridge primary and psychiatric care, clinical pharmacists are helping manage medically complicated patients. They assist with medication selection in light of drug interactions and medical comor­bidities, conduct detailed medication his­tories, schedule follow-up visits to assess medication adherence and tolerability, and counsel patients experiencing insur­ance changes that make their medications less affordable. Integrating pharmacists in the new clinics has resulted in a steady flow of patient referrals and collaborative care work.

Clinical pharmacists are brainstorming with outpatient psychiatry leadership to build on these early successes. Ongoing communication and enhanced collabora­tion are essential, and can only improve the lives of our psychiatric patients.

For the future
Our partnership in ambulatory psychiatry was timed to occur during implementa­tion of our health system’s new electronic health record initiative. Clinical pharma­cists can play a key role in demonstrating use of the system to provide consistently accurate drug information to patients and to monitor patients receiving specific medications.

Development of ambulatory patient medication education groups, which has proved useful on the inpatient side, is another endeavor in the works. Integrating the clinical pharmacist with psychiatrists, psychologists, nurse prac­titioners, social workers, and trainees on specific teams devoted to depression, bipolar disorder, anxiety, perinatal men­tal health, and personality disorders also might prove to be a wide-ranging and promising strategy.

Enhancing the education and training experiences of residents, fellows, medical students, pharmacy students, and allied health professional learners present in our clinics is another exciting prospect. This cross-disciplinary training will yield a new generation of providers who will be more comfortable collaborating with colleagues from other disciplines, all intent on pro­viding high-quality, efficient care. We hope that, as these initiatives take root, we will recognize many opportunities to dissemi­nate our collaborative efforts in scholarly venues, documenting and sharing the pos­itive impact of our partnership.

 

Bottom Line
Because psychiatric outpatients present with challenging medical comorbidities and increasingly complex medication regimens, specialized clinical pharmacists can enrich the management team by offering essential monitoring and polypharmacy services, patient education and counseling, and cross-discipline training. At one academic treatment center, psychiatric and non-psychiatric practitioners are gradually buying in to these promising collaborative efforts.


Related Resources
• Board of Pharmacy Specialties. www.bpsweb.org/specialties/psychiatric.cfm.
• Abramowitz P. Ambulatory care pharmacy practice: The future is now. www.connect.ashp.org/blogs/paul-abramowitz/2014/05/14/ambulatory-care-pharmacy-practice-the-future-is-now.

Drug Brand Name
Citalopram • Celexa

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

In this article, we highlight key steps that were needed to integrate clinical pharmacy specialists at an academic ambulatory psychiatric and addiction treatment center that serves pediatric and adult populations. Academic stakeholders identified addition of pharmacy services as a strategic goal in an effort to maximize services offered by the center and increase patient access to care while aligning with the standards set out by the patient-centered medical home (PCMH) model.

We outline the role of clinical pharmacists in the care of adult patients in ambulatory psychiatry, illustrate opportu­nities to enhance patient care, point out possible challenges with implementation, and propose future initiatives to optimize the practitioner-pharmacist partnership.

Background: Role of ambulatory pharmacists in psychiatry
Clinical pharmacists’ role in the psychiatric ambulatory care setting generally is associated with positive outcomes. One study looking at a collaborative care model that uti­lized clinical pharmacist follow-up in managing major depressive disorder found that patients who received phar­macist intervention in the collaborative care model had, on average, a significantly higher adherence rate and patient satisfaction score than the “usual care” group.¹ Within this study, patients in both groups experienced global clini­cal improvement with no significant difference; however, pharmacist interventions had a posi­tive impact on several aspects of the care model, suggesting that pharmacists can be used effectively in ambulatory psychiatry.

Furthermore, a systematic study evalu­ating pharmacists’ impact on clinical and functional mental health outcomes iden­tified 8 relevant studies conducted in the outpatient setting.² Although interven­tions varied widely, most studies focused on pharmacists’ providing a combination of drug monitoring, treatment recommen­dations, and patient education. Outcomes were largely positive, including an overall reduction in number and dosage of psy­chiatric drugs, inferred cost savings, and significant improvements in the safe and efficacious use of antidepressant and anti­psychotic medications.

These preliminary positive results require replication in larger, random­ized cohorts. Additionally, the role of the pharmacist as medication manager in the collaborative care model requires further study. Results so far, however, indicate that pharmacists can have a positive impact on the care of ambulatory psychiatry patients. Nevertheless, there is still considerable need for ongoing exploration in this field.

Pre-implementation
The need for pharmacy services. Various initiatives and existing practices within our health care system have underscored the need for a psychiatric pharmacist in the outpatient setting (Table 1).

A board-certified psychiatric pharma­cist (BCPP) possesses specialized knowl­edge about treating patients affected by psychiatric illnesses. BCPPs work with prescribers and members of other disci­plines, such as nurses and social workers, to optimize drug treatment by making pharmacotherapeutic recommendations and providing appropriate monitoring to enhance patient satisfaction and quality of life.^3,4

Existing relationship with pharmacy. Along with evidence to support the posi­tive impact clinical pharmacists can have in caring for patients with mental illness in the outpatient setting, a strong existing relationship between the Department of Psychiatry and our adult inpatient psychi­atric pharmacist helped make it possible to develop an ambulatory psychiatric phar­macist position.

Each day, the inpatient psychiatric pharmacist works closely with the attend­ing psychiatrists and psychiatry residents to provide treatment recommendations and counseling services for patients on the unit. The psychiatry residents highly valued their experiences with the pharmacist in the inpatient setting and expressed disappointment that this col­laborative relationship was no longer available after they transitioned into the ambulatory setting.

Further, by being involved in initia­tives that were relevant to both inpa­tient and outpatient psychiatry, such as metabolic monitoring for patients taking atypical antipsychotics, the clini­cal pharmacist in inpatient psychiatry had the opportunity to interact with key stakeholders in both settings. As a result of these pre-existing collabora­tive relationships, many clinicians were eager to have pharmacists available as a resource for patient care in the outpatient setting.

Pharmacist perspective: Outreach to psychiatry leadershipRecognizing the incentives and oppor­tunities inherent in our emerging health care system, pharmacists became integral members of the patient care team in the PCMH model. Thanks to this effort, we now have PCMH pharmacists at every primary care health center in our health system (14 sites), providing disease man­agement programs and polypharmacy services.

PCMH pharmacists’ role in the primary care setting fueled interest from specialty services and created opportunities to extend our existing partnership in inpa­tient psychiatry. One such opportunity to demonstrate the expertise of a psychi­atric pharmacist was fueled by the FDA’s citalopram dosing alert⁵ at a system-wide level. This warning emerged as a chance to showcase the skill set of psychiatric phar­macists and the pharmacists’ successes in our PCMH model. The partnership was extended to include the buy-in of ambula­tory pharmacy leadership and key stake­holders in ambulatory psychiatry.

 

Initial meetings included ambula­tory care site leadership in psychiatry to increase awareness and understanding of pharmacists’ potential role in direct patient care. Achieving site leadership support was critical to successful implementation of pharmacist services in psychiatry. We also obtained approval from the Chair of the Department of Psychiatry to elicit sup­port from faculty group practice.

Psychiatry leadership perspective
As fiscal pressures intensify at academic health centers, it becomes increasingly important for resources to be used as efficiently and effectively as possible. As a greater percentage of mental health patients with more “straightforward,” less complex conditions are being managed by their primary care providers or non­prescribing psychotherapists, or both, the acuity and complexity of cases in patients who present to psychiatric clinics have intensified. This intensification of patient needs and clinical acuity is in heightened conflict with the ongoing demand for clini­cian productivity and efficiency.

Additionally, the need to provide care to a seemingly ever-growing number of moderately or severely ill patients dur­ing shorter, less frequent visits presents a daunting task for clinicians and clinical leaders. Collaborative care models appear to offer the best hope for managing the seemingly overwhelming demand for services.

In this model, the patient, who is the critical member of the team, is expected to become an “expert” on his or her ill­ness and to partner with members of the multidisciplinary team; with this support, patients are encouraged to develop a broad range of self-management skills and strat­egies to manage their illness. We believe that clinical pharmacists can and should play a critical role, not only in deliver­ing direct clinical services to patients but also in developing and devising the care models that will most effectively apply each team member’s unique set of knowl­edge, skills, and experience. Given the large percentage of our patients who have multiple medical comorbidities and who require complex medical and psychiat­ric medication regimens, the role of the pharmacist in reviewing, educating, and advising patients and other team members on these crucial pharmacy concerns will be paramount.

In light of these complex medication issues, pharmacists are uniquely posi­tioned to serve as a liaison among the patient, the primary care provider, and other members of their treatment team. We anticipate that our ambulatory psychiatry pharmacists will greatly enhance the com­fort and confidence of patients and their primary care providers during periods of care transition.

Potential roles for pharmacists in ambulatory psychiatry
One potential role for pharmacists in ambulatory psychiatry is to perform polypharmacy assessments of patients receiving complex medication regimens, prompted by physician referral. The poly­ pharmacy intake interview, performed to obtain an accurate medication list and to identify patients’ concerns about their medications, can be conducted in per­son or by telephone. Patients’ knowledge about medications and medication adher­ence are discussed, as are their perceptions of effectiveness and adverse effects.

After initial data gathering, pharma­cists complete a review of the medications, identifying any problems associated with medication indication, efficacy, tolerance, or adverse effects, drug-drug interactions, drug-nutrient interactions, and nonadher­ence. Pharmacists work to reduce medica­tion costs if that is a concern of the patient, because nonadherence can result. A medi­cation care plan is then developed in con­sultation with the primary care provider; here, the medication list is reconciled, the electronic medical record is updated, and actions to address any medication-related problems are prioritized.

Other services that might be offered include:• group education classes, based on patient motivational interviewing strate­gies, to address therapeutic nonadherence and to improve understanding of their dis­ease and treatment regimens• medication safety and monitoring• treatment intensification, as needed, following established protocols.

These are a few of the ways in which pharmacists can be relied on to expand and improve access to patient care ser­vices within ambulatory psychiatry. Key stakeholders anticipate development of newer ideas as the pharmacist’s role in ambulatory psychiatry is increasingly clarified.

Reimbursement model
In creating a role for pharmacy in ambu­latory psychiatry, it was essential that the model be financially viable and appeal­ing. Alongside its clinical model, our insti­tution has developed a financial model to support the pharmacist’s role. The lump-sum payment to the health centers from Blue Cross Blue Shield of Michigan afforded the ambulatory care clinics an opportunity to invest in PCMH pharma­cists. This funding, and the reimbursement based on T-code billing (face-to-face visits and phone consultation) for depression and other conditions requiring chronic care, provides ongoing support. From our experience, understanding physician reimbursement models and identifying relevant changes in health care reform are necessary to integrate new providers, including pharmacists, into a team-based care model.

Implementation
Promoting pharmacy services. To fos­ter anticipated collaboration with clini­cal pharmacists, the medical director of outpatient psychiatry disseminated an announcement to all providers regard­ing the investiture of clinical pharmacists to support patient care activities, educa­tion, and research. Clinicians were edu­cated about the pharmacists’ potential roles and about guidelines and methods for referral. Use of our electronic health record system enabled us to establish a relatively simple referral process involv­ing sharing electronic messages with our pharmacists.

Further, as part of the planned integra­tion of clinical pharmacists in the ambula­tory psychiatry setting, pharmacists met strategically with members of various disciplines, clinical programs, specialty clinic programs, and teams throughout the center. In addition to answering questions about the referral process, they empha­sized the role of pharmacy and opportuni­ties for collaboration.

 

Collaborating with others. Because the involvement of clinical pharmacists is unfamiliar to some practitioners in outpa­tient psychiatry, it is important to develop services without infringing on the roles other disciplines play. Indeed, a survey by Wheeler et al6 identified many concerns and potential boundaries among pharmacists, other providers, and patients. Concerns included confusion of practitioner roles and boundaries, a too-traditional percep­tion of the pharmacist, and demonstration of competence.⁶

Early on, we developed a structured forum to discuss ongoing challenges and address issues related to the rapidly changing clinical landscape. During these discussions we conveyed that adding pharmacists to psychiatric services would be collaborative in nature and intended to augment existing services. This commu­nication was pivotal to maintain the psy­chiatrist’s role as the ultimate prescriber and authority in the care of their patients; however, the pharmacist’s expertise, when sought, would help spur clinical and aca­demic discussion that will benefit the patient. These discussions are paramount to achieving a productive, team-based approach, to overcome challenges, and to identify opportunities of value to our pro­viders and patients (Box).

Work in progress
Implementing change in any clinical set­ting invariably creates challenges, and our endeavors to integrate clinical phar­macists into ambulatory psychiatry are no exception. We have identified several factors that we believe will optimize suc­cessful collaboration between pharmacy and ambulatory psychiatry (Table 2). Our primary challenge has been changing cli­nician behavior. Clinical practitioners can become too comfortable, wedded to their routines, and often are understandably resistant to change. Additionally, clinical systems often are inadvertently designed to obstruct change in ways that are not readily apparent. Efforts must be focused on behaviors and practices the clinical cul­ture should encourage.

Regarding specific initiatives, clinical pharmacists have successfully identified patients on higher than recommended dosages of citalopram; they are work­ing alongside prescribers to recom­mend ways to minimize the risk of heart rhythm abnormalities in these patients. Numerous prescribers have sought clini­cal pharmacists’ input to manage phar­macotherapy in their patients and to respond to patients’ questions on drug information.

The prospect of access to clinical phar­macist expertise in the outpatient setting was heralded with excitement, but the flow of referrals and consultations has been uneven. However simple the path for referral is, clinicians’ use of the system has been inconsistent—perhaps because of referrals’ passive, clinician-dependent nature. Educational outreach efforts often prompt a brief spike in referrals, only to be followed over time by a slow, steady drop-off. More active strategies will be needed, such as embedding the pharma­cists as regular, active, visible members of the various clinical teams, and imple­menting a system in which patient record reviews are assigned to the pharmacists according to agreed-upon clusters of clin­ical criteria.

One of these tactics has, in the short term, showed success. Embedded in one of our newer clinics, which were designed to bridge primary and psychiatric care, clinical pharmacists are helping manage medically complicated patients. They assist with medication selection in light of drug interactions and medical comor­bidities, conduct detailed medication his­tories, schedule follow-up visits to assess medication adherence and tolerability, and counsel patients experiencing insur­ance changes that make their medications less affordable. Integrating pharmacists in the new clinics has resulted in a steady flow of patient referrals and collaborative care work.

Clinical pharmacists are brainstorming with outpatient psychiatry leadership to build on these early successes. Ongoing communication and enhanced collabora­tion are essential, and can only improve the lives of our psychiatric patients.

For the future
Our partnership in ambulatory psychiatry was timed to occur during implementa­tion of our health system’s new electronic health record initiative. Clinical pharma­cists can play a key role in demonstrating use of the system to provide consistently accurate drug information to patients and to monitor patients receiving specific medications.

Development of ambulatory patient medication education groups, which has proved useful on the inpatient side, is another endeavor in the works. Integrating the clinical pharmacist with psychiatrists, psychologists, nurse prac­titioners, social workers, and trainees on specific teams devoted to depression, bipolar disorder, anxiety, perinatal men­tal health, and personality disorders also might prove to be a wide-ranging and promising strategy.

Enhancing the education and training experiences of residents, fellows, medical students, pharmacy students, and allied health professional learners present in our clinics is another exciting prospect. This cross-disciplinary training will yield a new generation of providers who will be more comfortable collaborating with colleagues from other disciplines, all intent on pro­viding high-quality, efficient care. We hope that, as these initiatives take root, we will recognize many opportunities to dissemi­nate our collaborative efforts in scholarly venues, documenting and sharing the pos­itive impact of our partnership.

 

Bottom Line
Because psychiatric outpatients present with challenging medical comorbidities and increasingly complex medication regimens, specialized clinical pharmacists can enrich the management team by offering essential monitoring and polypharmacy services, patient education and counseling, and cross-discipline training. At one academic treatment center, psychiatric and non-psychiatric practitioners are gradually buying in to these promising collaborative efforts.


Related Resources
• Board of Pharmacy Specialties. www.bpsweb.org/specialties/psychiatric.cfm.
• Abramowitz P. Ambulatory care pharmacy practice: The future is now. www.connect.ashp.org/blogs/paul-abramowitz/2014/05/14/ambulatory-care-pharmacy-practice-the-future-is-now.

Drug Brand Name
Citalopram • Celexa

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

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

 

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

 

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

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

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

 

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

 

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

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

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

 

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

 

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

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

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

 

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

 

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

 

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

 

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

 

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

 

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

Electroconvulsive therapy and vagus nerve stimulation¹⁴ are effective interven­tions in treatment-resistant depression. The efficacy of transcranial magnetic stimula­tion remains to be clarified.

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

 

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

 

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

 

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


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

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

Electroconvulsive therapy and vagus nerve stimulation¹⁴ are effective interven­tions in treatment-resistant depression. The efficacy of transcranial magnetic stimula­tion remains to be clarified.

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

 

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

 

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

 

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


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

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

Electroconvulsive therapy and vagus nerve stimulation¹⁴ are effective interven­tions in treatment-resistant depression. The efficacy of transcranial magnetic stimula­tion remains to be clarified.

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

 

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

 

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

 

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


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