Poor dental hygiene is a serious and prevalent problem among people with mental illness or cognitive impairment: Dental caries and periodontal disease are 3.4 times more common among the mentally ill than among the general population.¹ Little has been published on the causes and prevention of these diseases among the mentally ill, however. Interprofessional education provides the opportunity to reinforce the connection between oral health and systemic health.

Untreated dental disease can result in edentulism (partial or complete tooth loss). Often, this condition leads to embarrassment, poor self-image, and social isolation—all of which can exacerbate the psychotic state and its symptoms. Working with your patient to improve oral health can, in turn, lead to better mental and physical health.

CASE REPORT
Edentulism in a man with schizophrenia
A 34-year-old man, given a diagnosis of schizophrenia at age 17, is admitted to the inpatient psychiatry unit for bizarre behavior. The next day, 4 maxillary and incisor teeth fall out suddenly while he is brushing his teeth. The patient is brought to emergency dental services.

Factors contributing to his tooth loss include:

• schizophrenia
• neglected oral hygiene
• adverse effects of antipsychotic medication
• lack of advice on the importance of oral hygiene
• failure to recognize signs of a dental problem.

What else can lead to edentulism?
Breakdown of the periodontal attachment² also can be caused by disinterest in oral hygiene practices; craving of, and preference for, carbohydrates because of reduced central serotonin activity^3,4; and xerostomia.

Xerostomia, or dry mouth, caused by psychotropic agents and an altered immune response, facilitates growth of pathogenic bacteria and can lead to several dental diseases (Table). These conditions are exacerbated by consumption of chewing gum, sweets, and sugary drinks in response to constantly feeling thirsty from xerostomia. Advise patients to take frequent sips of fluid or let ice cubes melt in their mouth.

Bruxism. Patients taking a selective serotonin reuptake inhibitor or an atypical antipsychotic can develop a movement disorder (eg, extrapyramidal symptoms or tardive dyskinesia) that includes clenching, grinding of the teeth (bruxism), or both, which can worsen their periodontal condition.

Lack of skills, physical dexterity, and motivation to maintain good oral hygiene are common among people with mental illness. Most patients visit a dentist only when they experience a serious oral problem or an emergency (ie, trauma). Many dentists treat psychiatric patients by extracting the tooth that is causing the pain, instead of pursuing complex tooth preservation or restoration techniques because of (1) the extent of the disease, (2) lack of knowledge related to psychiatric illnesses, and (3) frequent and timely follow-ups.⁵

Providing education about oral health to patients, implementing preventive steps, and educating other medical specialities about the link between oral health and systemic health can help to reduce the burden of dental problems among mentally ill patients.

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

Poor dental hygiene is a serious and prevalent problem among people with mental illness or cognitive impairment: Dental caries and periodontal disease are 3.4 times more common among the mentally ill than among the general population.¹ Little has been published on the causes and prevention of these diseases among the mentally ill, however. Interprofessional education provides the opportunity to reinforce the connection between oral health and systemic health.

Untreated dental disease can result in edentulism (partial or complete tooth loss). Often, this condition leads to embarrassment, poor self-image, and social isolation—all of which can exacerbate the psychotic state and its symptoms. Working with your patient to improve oral health can, in turn, lead to better mental and physical health.

CASE REPORT
Edentulism in a man with schizophrenia
A 34-year-old man, given a diagnosis of schizophrenia at age 17, is admitted to the inpatient psychiatry unit for bizarre behavior. The next day, 4 maxillary and incisor teeth fall out suddenly while he is brushing his teeth. The patient is brought to emergency dental services.

Factors contributing to his tooth loss include:

• schizophrenia
• neglected oral hygiene
• adverse effects of antipsychotic medication
• lack of advice on the importance of oral hygiene
• failure to recognize signs of a dental problem.

What else can lead to edentulism?
Breakdown of the periodontal attachment² also can be caused by disinterest in oral hygiene practices; craving of, and preference for, carbohydrates because of reduced central serotonin activity^3,4; and xerostomia.

Xerostomia, or dry mouth, caused by psychotropic agents and an altered immune response, facilitates growth of pathogenic bacteria and can lead to several dental diseases (Table). These conditions are exacerbated by consumption of chewing gum, sweets, and sugary drinks in response to constantly feeling thirsty from xerostomia. Advise patients to take frequent sips of fluid or let ice cubes melt in their mouth.

Bruxism. Patients taking a selective serotonin reuptake inhibitor or an atypical antipsychotic can develop a movement disorder (eg, extrapyramidal symptoms or tardive dyskinesia) that includes clenching, grinding of the teeth (bruxism), or both, which can worsen their periodontal condition.

Lack of skills, physical dexterity, and motivation to maintain good oral hygiene are common among people with mental illness. Most patients visit a dentist only when they experience a serious oral problem or an emergency (ie, trauma). Many dentists treat psychiatric patients by extracting the tooth that is causing the pain, instead of pursuing complex tooth preservation or restoration techniques because of (1) the extent of the disease, (2) lack of knowledge related to psychiatric illnesses, and (3) frequent and timely follow-ups.⁵

Providing education about oral health to patients, implementing preventive steps, and educating other medical specialities about the link between oral health and systemic health can help to reduce the burden of dental problems among mentally ill patients.

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

Poor dental hygiene is a serious and prevalent problem among people with mental illness or cognitive impairment: Dental caries and periodontal disease are 3.4 times more common among the mentally ill than among the general population.¹ Little has been published on the causes and prevention of these diseases among the mentally ill, however. Interprofessional education provides the opportunity to reinforce the connection between oral health and systemic health.

Untreated dental disease can result in edentulism (partial or complete tooth loss). Often, this condition leads to embarrassment, poor self-image, and social isolation—all of which can exacerbate the psychotic state and its symptoms. Working with your patient to improve oral health can, in turn, lead to better mental and physical health.

CASE REPORT
Edentulism in a man with schizophrenia
A 34-year-old man, given a diagnosis of schizophrenia at age 17, is admitted to the inpatient psychiatry unit for bizarre behavior. The next day, 4 maxillary and incisor teeth fall out suddenly while he is brushing his teeth. The patient is brought to emergency dental services.

Factors contributing to his tooth loss include:

• schizophrenia
• neglected oral hygiene
• adverse effects of antipsychotic medication
• lack of advice on the importance of oral hygiene
• failure to recognize signs of a dental problem.

What else can lead to edentulism?
Breakdown of the periodontal attachment² also can be caused by disinterest in oral hygiene practices; craving of, and preference for, carbohydrates because of reduced central serotonin activity^3,4; and xerostomia.

Xerostomia, or dry mouth, caused by psychotropic agents and an altered immune response, facilitates growth of pathogenic bacteria and can lead to several dental diseases (Table). These conditions are exacerbated by consumption of chewing gum, sweets, and sugary drinks in response to constantly feeling thirsty from xerostomia. Advise patients to take frequent sips of fluid or let ice cubes melt in their mouth.

Bruxism. Patients taking a selective serotonin reuptake inhibitor or an atypical antipsychotic can develop a movement disorder (eg, extrapyramidal symptoms or tardive dyskinesia) that includes clenching, grinding of the teeth (bruxism), or both, which can worsen their periodontal condition.

Lack of skills, physical dexterity, and motivation to maintain good oral hygiene are common among people with mental illness. Most patients visit a dentist only when they experience a serious oral problem or an emergency (ie, trauma). Many dentists treat psychiatric patients by extracting the tooth that is causing the pain, instead of pursuing complex tooth preservation or restoration techniques because of (1) the extent of the disease, (2) lack of knowledge related to psychiatric illnesses, and (3) frequent and timely follow-ups.⁵

Providing education about oral health to patients, implementing preventive steps, and educating other medical specialities about the link between oral health and systemic health can help to reduce the burden of dental problems among mentally ill patients.

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

Nonadherence to medical therapy is a widespread and complex problem that is a significant variable in the treatment of psychiatric illness and in patients’ prognosis. More than 50% of people who have a chronic illness struggle to comply with their medication regimen—for many reasons.¹

Many variables predict poor adherence, so it cannot be expected that a single solution will solve the problem entirely.² Novel adherence technologies are available, as we discuss in this article, and more are in development.

What is nonadherence to medical therapy?
Nonadherence can be defined primarily as not taking prescribed medication in the recommended dosage or frequency, or not taking prescribed medication at all.³ Nonadherence can result in an increased risk of relapse, hospitalization, poor therapeutic response, and delayed remission and recovery.

Secondarily, non-attendance or irregular attendance at appointments with providers is a form of nonadherence that can have a negative impact on treatment outcomes.⁴

Why is medical adherence important in psychiatry?
Medication nonadherence has major consequences for psychiatric patients⁵ and for the greater health care system; it is estimated that, in the United States, the cost of nonadherence is as high as $300 billion a year.⁶ In psychiatry, the rate of nonadherence to medical therapy has been reported to be 11% to 80% of patients with schizophrenia; 12% to 64% with bipolar disorders; and 30% to 60% with depression.^7-9 These surprising statistics make it imperative to design treatment strategies that include an effective patient-centric medication adherence plan, based on diagnosis, patient need, education, and support.

Why are patients nonadherent?
Many variables lead to patient nonadherence (Figure 1). The most common reason is that patients simply forget to take their medication.¹⁰ Among psychiatric patients, other reasons are:

• lack of insight
• negative emotional reaction to taking medication¹¹
• feeling better and no longer believing that the medication is needed^12,13
• distress associated with side effects^14,15
• high cost of medication¹⁵
• patient’s perception that medication won’t be effective^16,17
• concern about substance abuse¹⁸
• fear of dependency¹⁹
• complicated dosing regimen²⁰
• general lack of motivation.²¹

Emotional barriers to medication nonadherence are an underestimated area that can benefit greatly from the expertise and understanding of psychiatrists. These barriers include a sense of losing control, self-stigmatization, denial, poor insight, and beliefs about illness and medications.

Additional patient variables that contribute to nonadherence include:

• suboptimal health literacy
• stigma and shame about the need for psychiatric treatment
• lack of patient involvement in treatment decision-making.

Who is responsible for adherence?
Adherence to medical therapy is not the patient’s responsibility, exclusively. Rather, it is a collection of complex components that generally includes physicians and the health care system. Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifaceted.

Providers. Patients’ care often is managed by multiple physicians, which can lead to communication lapses about complicated drug regimens and potential adverse effects. To assist patients in adhering to their medication regimen, physicians should recognize, and acknowledge to the patient, that many psychiatric patients have difficulty taking their medications and provide advice and information in how to address this problem.

Families. Likewise, it is important to educate patients and their family about the need for medication—helping the patient see that it is his (her) choice and, indeed, his direct responsibility to take his medication and improve his health. The risk–benefit balance of treatment should be explained to the patient and his family, as well as the nature of the psychiatric diagnosis and how effective patient–physician collaboration can help him function and adhere to his medication regimen in a consistent, reliable manner.

The larger system. Health care systems can contribute to medication adherence by reducing time constraints on visits to providers, to allow time to discuss all aspects of medication adherence. Limited visits in the clinic means physicians are not able to (1) spend adequate time discussing the medication regimen to ensure full patient comprehension and (2) conduct an assessment of medication-taking behaviors. Team-based approaches could improve efficiency, patient understanding, adherence, and early detection of adherence issues.^22,23

Strategies such as additional clinic visits and reminder calls to discuss adherence carry a cost, but their long-term advantage is that, if patients understand how to better adhere to their medication regimens, their actions will have a positive impact on their health care costs and outcomes and on the wider health economy—as a result of reduced hospital admissions and reduced need to care for patients whose condition deteriorates because of nonadherence. It is imperative that we build strong relationships with other providers to show that we are committed to building supportive, effective adherence support programs that focus on the individual patient’s needs.

What is the available technology?
There is no standard way to measure non­adherence. The most common, and simplest, measure—asking the patient—is unreliable and severely overestimates adherence.

Direct measures of adherence include observing the patient taking his medications and testing for the concentration of those medications in blood or urine. Indirect adherence assessment methods, such as pill counts, a medication diary, self-report, clinician ratings, pharmacy chart review, and electronic devices that monitor the opening of a lid or tablet strip, have all been used; yet reviews of those methods have shown less than favorable results.⁶

Pre-packaged pill packs have helped some patients with a simple method for medication management.

Electronic monitoring, using a medication vial cap device (Figure 2) that electronically records the date and time of bottle opening, has become common in general medicine and among patients with schizophrenia.^6,13,24-26 Diaz et al²⁴ reported that electronic monitoring detected a greater nonadherence rate (57%) than what prescribers reported (7%) or patients self-reported (5%)—demonstrating that prescribers and patients grossly overestimate adherence. In another study that looked at electronic monitoring, researchers reported that adherence was much higher in depressed youth (87%)²⁷ than what had been seen in adults (67%) in a similar study.¹³

The downside to pill packs and electronic monitoring? There is no guarantee the patient has actually taken the medication despite the data reported by the system.

Event marker-signaling devices. Novel technologies have been developed to measure adherence:

Proteus Digital Health feedback system (www.proteus.com) requires that patients ingest a tablet containing a tiny, dietary mineral-based “ingestible event marker.” Upon contact with gastric fluid electrolytes, the event marker emits a unique signal that is transmitted through bodily tissue to a small receiver in a patch worn on the torso. The receiver then transmits a signal to a cellular phone, indicating the time and date when the medication was ingested (Figure 3).

A 4-week pilot study²⁸ found that the ingestible event marker is feasible and acceptable to patients: 27 of 28 participants (96%) completed the study, with a mean adherence rate of 74%. Although the system identifies ingestible sensors with high accuracy and is easily tolerated by patients, the pilot study was brief; a longer duration of adherence while wearing the patch needs to be studied.

Breath analysis, facial recognition. Even directly observing ingestion of a medication can be problematic: Some patients don’t swallow the medication and spit it out later. One way around that subterfuge is to consider using other advanced medication adherence solutions that are breath-based or use facial recognition technology and confirm ingestion.

Xhale SMART (www.xhale.com/smart) is a handheld device that generates a reminder to the patient to take his medication; afterward, he (she) must blow into the device so that ingestion of the medication is detected (Figure 4). The medication has breath-detectable adherence markers already incorporated. The adherence marker then is released into the stomach and small intestine, where the adherence marker metabolite is transported through the bloodstream into the lungs and exhaled. The patient must breathe into a breath analysis device, which measures medication ingestion compared with a baseline breath print.

Several articles in the literature have reported the accuracy of this device in detecting the ingested metabolite in every participant, without adverse effects.^29,30 Clinical data on the use of the breath-based detector is not available to the public at this time.

AiCure (www.aicure.com) is a facial recognition-based technology platform that can work through any smartphone. The device is powered by artificial intelligence software and motion-sensing technology that can detect, in real time, whether the patient is taking the medication as prescribed. Patients who take an incorrect dose, or who do not use the software, are automatically flagged for immediate follow-up. This technology enables real-time intervention by a provider with the nonadherent patient.

An important note: These innovative technological advances are tools that can help clinicians manage an important aspect of treatment, but they do not show the entire picture: The physician−patient relationship and the therapeutic alliance are key to optimal treatment adherence.

Engage and empower the patient
Novel adherence technologies are, as we’ve described, available, and more are being developed. Incorporating these technologies into clinical care requires continued input and support from clinicians and patients. Digital and mobile health applications are multi-beneficial: They can empower patients to self-manage medication regimens and appointments while they also receive social and psychological information and support as needed. Understanding one’s own illness can, ultimately, improve outcomes and significantly reduce health care costs.

Patient empowerment is key. The physician is an important influencer in this regard.

The role of the physician must not be undervalued in maintaining adherence to therapy; she (he) plays a vital role in continued patient engagement and behavioral training. Integrating physician-led oversight, patient education, and commitment, and novel digital mobile adherence technologies will help deliver better outcomes.

The push to engage. A “one size fits all” approach to maintaining adherence won’t be effective. We need to better understand the individual patient’s underlying cause(s) for nonadherence, then to tailor a solution to influence and change that behavior. One way to do this is by interacting and engaging more directly (and in a digital manner) with patients to monitor adherence.

A recent example of the move toward direct patient engagement is the agreement entered by Otsuka Pharmaceuticals and Proteus Digital Health to develop novel digital health products. The FDA has accepted for review the combination product of Otsuka’s brand of aripiprazole and Proteus’s ingestible sensor. If the product is approved by the FDA, physicians will be able to prescribe aripiprazole with the ingestible sensor embedded in the tablet and then measure medication adherence and other patient physiologic metrics (eg, activity, rest) through the wearable sensor patch and medical software application designed specifically for patient and physician use.

This technology could have huge potential in mental health care, where patients struggle with both adhering to their medication regimen and communicating with the health care team. Physicians could measure adherence when treating adults with schizophrenia, bipolar disorders, and major depressive disorder; flag those who are not adhering as having higher risk of disease progression and poorer outcome; and allow decisions to be made more quickly based on treatment need.

Developing and enhancing these collaborative and patient-centric approaches will increase self-monitoring and patient responsibility, and encourage behavior change.

‘All-in’ strategy. By continuing to use the latest technologies and connecting them to the range of stakeholders—physicians, nurses, pharmacists, payers—we will develop an all-inclusive adherence intervention strategy. All patients will be integrated, and all of them, and their family, will be provided with positive psychoeducational care and motivational counseling (Figure 5). In addition, such a support-based patient experience must be aligned with the work of clinical care providers. Compliance therapy and behavioral training, together with active patient engagement, can help improve insight, acceptance of treatment, and, over the long term, adherence.^31,32

Nonadherence to medical therapy is a widespread and complex problem that is a significant variable in the treatment of psychiatric illness and in patients’ prognosis. More than 50% of people who have a chronic illness struggle to comply with their medication regimen—for many reasons.¹

Many variables predict poor adherence, so it cannot be expected that a single solution will solve the problem entirely.² Novel adherence technologies are available, as we discuss in this article, and more are in development.

What is nonadherence to medical therapy?
Nonadherence can be defined primarily as not taking prescribed medication in the recommended dosage or frequency, or not taking prescribed medication at all.³ Nonadherence can result in an increased risk of relapse, hospitalization, poor therapeutic response, and delayed remission and recovery.

Secondarily, non-attendance or irregular attendance at appointments with providers is a form of nonadherence that can have a negative impact on treatment outcomes.⁴

Why is medical adherence important in psychiatry?
Medication nonadherence has major consequences for psychiatric patients⁵ and for the greater health care system; it is estimated that, in the United States, the cost of nonadherence is as high as $300 billion a year.⁶ In psychiatry, the rate of nonadherence to medical therapy has been reported to be 11% to 80% of patients with schizophrenia; 12% to 64% with bipolar disorders; and 30% to 60% with depression.^7-9 These surprising statistics make it imperative to design treatment strategies that include an effective patient-centric medication adherence plan, based on diagnosis, patient need, education, and support.

Why are patients nonadherent?
Many variables lead to patient nonadherence (Figure 1). The most common reason is that patients simply forget to take their medication.¹⁰ Among psychiatric patients, other reasons are:

• lack of insight
• negative emotional reaction to taking medication¹¹
• feeling better and no longer believing that the medication is needed^12,13
• distress associated with side effects^14,15
• high cost of medication¹⁵
• patient’s perception that medication won’t be effective^16,17
• concern about substance abuse¹⁸
• fear of dependency¹⁹
• complicated dosing regimen²⁰
• general lack of motivation.²¹

Emotional barriers to medication nonadherence are an underestimated area that can benefit greatly from the expertise and understanding of psychiatrists. These barriers include a sense of losing control, self-stigmatization, denial, poor insight, and beliefs about illness and medications.

Additional patient variables that contribute to nonadherence include:

• suboptimal health literacy
• stigma and shame about the need for psychiatric treatment
• lack of patient involvement in treatment decision-making.

Who is responsible for adherence?
Adherence to medical therapy is not the patient’s responsibility, exclusively. Rather, it is a collection of complex components that generally includes physicians and the health care system. Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifaceted.

Providers. Patients’ care often is managed by multiple physicians, which can lead to communication lapses about complicated drug regimens and potential adverse effects. To assist patients in adhering to their medication regimen, physicians should recognize, and acknowledge to the patient, that many psychiatric patients have difficulty taking their medications and provide advice and information in how to address this problem.

Families. Likewise, it is important to educate patients and their family about the need for medication—helping the patient see that it is his (her) choice and, indeed, his direct responsibility to take his medication and improve his health. The risk–benefit balance of treatment should be explained to the patient and his family, as well as the nature of the psychiatric diagnosis and how effective patient–physician collaboration can help him function and adhere to his medication regimen in a consistent, reliable manner.

The larger system. Health care systems can contribute to medication adherence by reducing time constraints on visits to providers, to allow time to discuss all aspects of medication adherence. Limited visits in the clinic means physicians are not able to (1) spend adequate time discussing the medication regimen to ensure full patient comprehension and (2) conduct an assessment of medication-taking behaviors. Team-based approaches could improve efficiency, patient understanding, adherence, and early detection of adherence issues.^22,23

Strategies such as additional clinic visits and reminder calls to discuss adherence carry a cost, but their long-term advantage is that, if patients understand how to better adhere to their medication regimens, their actions will have a positive impact on their health care costs and outcomes and on the wider health economy—as a result of reduced hospital admissions and reduced need to care for patients whose condition deteriorates because of nonadherence. It is imperative that we build strong relationships with other providers to show that we are committed to building supportive, effective adherence support programs that focus on the individual patient’s needs.

What is the available technology?
There is no standard way to measure non­adherence. The most common, and simplest, measure—asking the patient—is unreliable and severely overestimates adherence.

Direct measures of adherence include observing the patient taking his medications and testing for the concentration of those medications in blood or urine. Indirect adherence assessment methods, such as pill counts, a medication diary, self-report, clinician ratings, pharmacy chart review, and electronic devices that monitor the opening of a lid or tablet strip, have all been used; yet reviews of those methods have shown less than favorable results.⁶

Pre-packaged pill packs have helped some patients with a simple method for medication management.

Electronic monitoring, using a medication vial cap device (Figure 2) that electronically records the date and time of bottle opening, has become common in general medicine and among patients with schizophrenia.^6,13,24-26 Diaz et al²⁴ reported that electronic monitoring detected a greater nonadherence rate (57%) than what prescribers reported (7%) or patients self-reported (5%)—demonstrating that prescribers and patients grossly overestimate adherence. In another study that looked at electronic monitoring, researchers reported that adherence was much higher in depressed youth (87%)²⁷ than what had been seen in adults (67%) in a similar study.¹³

The downside to pill packs and electronic monitoring? There is no guarantee the patient has actually taken the medication despite the data reported by the system.

Event marker-signaling devices. Novel technologies have been developed to measure adherence:

Proteus Digital Health feedback system (www.proteus.com) requires that patients ingest a tablet containing a tiny, dietary mineral-based “ingestible event marker.” Upon contact with gastric fluid electrolytes, the event marker emits a unique signal that is transmitted through bodily tissue to a small receiver in a patch worn on the torso. The receiver then transmits a signal to a cellular phone, indicating the time and date when the medication was ingested (Figure 3).

A 4-week pilot study²⁸ found that the ingestible event marker is feasible and acceptable to patients: 27 of 28 participants (96%) completed the study, with a mean adherence rate of 74%. Although the system identifies ingestible sensors with high accuracy and is easily tolerated by patients, the pilot study was brief; a longer duration of adherence while wearing the patch needs to be studied.

Breath analysis, facial recognition. Even directly observing ingestion of a medication can be problematic: Some patients don’t swallow the medication and spit it out later. One way around that subterfuge is to consider using other advanced medication adherence solutions that are breath-based or use facial recognition technology and confirm ingestion.

Xhale SMART (www.xhale.com/smart) is a handheld device that generates a reminder to the patient to take his medication; afterward, he (she) must blow into the device so that ingestion of the medication is detected (Figure 4). The medication has breath-detectable adherence markers already incorporated. The adherence marker then is released into the stomach and small intestine, where the adherence marker metabolite is transported through the bloodstream into the lungs and exhaled. The patient must breathe into a breath analysis device, which measures medication ingestion compared with a baseline breath print.

Several articles in the literature have reported the accuracy of this device in detecting the ingested metabolite in every participant, without adverse effects.^29,30 Clinical data on the use of the breath-based detector is not available to the public at this time.

AiCure (www.aicure.com) is a facial recognition-based technology platform that can work through any smartphone. The device is powered by artificial intelligence software and motion-sensing technology that can detect, in real time, whether the patient is taking the medication as prescribed. Patients who take an incorrect dose, or who do not use the software, are automatically flagged for immediate follow-up. This technology enables real-time intervention by a provider with the nonadherent patient.

An important note: These innovative technological advances are tools that can help clinicians manage an important aspect of treatment, but they do not show the entire picture: The physician−patient relationship and the therapeutic alliance are key to optimal treatment adherence.

Engage and empower the patient
Novel adherence technologies are, as we’ve described, available, and more are being developed. Incorporating these technologies into clinical care requires continued input and support from clinicians and patients. Digital and mobile health applications are multi-beneficial: They can empower patients to self-manage medication regimens and appointments while they also receive social and psychological information and support as needed. Understanding one’s own illness can, ultimately, improve outcomes and significantly reduce health care costs.

Patient empowerment is key. The physician is an important influencer in this regard.

The role of the physician must not be undervalued in maintaining adherence to therapy; she (he) plays a vital role in continued patient engagement and behavioral training. Integrating physician-led oversight, patient education, and commitment, and novel digital mobile adherence technologies will help deliver better outcomes.

The push to engage. A “one size fits all” approach to maintaining adherence won’t be effective. We need to better understand the individual patient’s underlying cause(s) for nonadherence, then to tailor a solution to influence and change that behavior. One way to do this is by interacting and engaging more directly (and in a digital manner) with patients to monitor adherence.

A recent example of the move toward direct patient engagement is the agreement entered by Otsuka Pharmaceuticals and Proteus Digital Health to develop novel digital health products. The FDA has accepted for review the combination product of Otsuka’s brand of aripiprazole and Proteus’s ingestible sensor. If the product is approved by the FDA, physicians will be able to prescribe aripiprazole with the ingestible sensor embedded in the tablet and then measure medication adherence and other patient physiologic metrics (eg, activity, rest) through the wearable sensor patch and medical software application designed specifically for patient and physician use.

This technology could have huge potential in mental health care, where patients struggle with both adhering to their medication regimen and communicating with the health care team. Physicians could measure adherence when treating adults with schizophrenia, bipolar disorders, and major depressive disorder; flag those who are not adhering as having higher risk of disease progression and poorer outcome; and allow decisions to be made more quickly based on treatment need.

Developing and enhancing these collaborative and patient-centric approaches will increase self-monitoring and patient responsibility, and encourage behavior change.

‘All-in’ strategy. By continuing to use the latest technologies and connecting them to the range of stakeholders—physicians, nurses, pharmacists, payers—we will develop an all-inclusive adherence intervention strategy. All patients will be integrated, and all of them, and their family, will be provided with positive psychoeducational care and motivational counseling (Figure 5). In addition, such a support-based patient experience must be aligned with the work of clinical care providers. Compliance therapy and behavioral training, together with active patient engagement, can help improve insight, acceptance of treatment, and, over the long term, adherence.^31,32

Nonadherence to medical therapy is a widespread and complex problem that is a significant variable in the treatment of psychiatric illness and in patients’ prognosis. More than 50% of people who have a chronic illness struggle to comply with their medication regimen—for many reasons.¹

Many variables predict poor adherence, so it cannot be expected that a single solution will solve the problem entirely.² Novel adherence technologies are available, as we discuss in this article, and more are in development.

What is nonadherence to medical therapy?
Nonadherence can be defined primarily as not taking prescribed medication in the recommended dosage or frequency, or not taking prescribed medication at all.³ Nonadherence can result in an increased risk of relapse, hospitalization, poor therapeutic response, and delayed remission and recovery.

Secondarily, non-attendance or irregular attendance at appointments with providers is a form of nonadherence that can have a negative impact on treatment outcomes.⁴

Why is medical adherence important in psychiatry?
Medication nonadherence has major consequences for psychiatric patients⁵ and for the greater health care system; it is estimated that, in the United States, the cost of nonadherence is as high as $300 billion a year.⁶ In psychiatry, the rate of nonadherence to medical therapy has been reported to be 11% to 80% of patients with schizophrenia; 12% to 64% with bipolar disorders; and 30% to 60% with depression.^7-9 These surprising statistics make it imperative to design treatment strategies that include an effective patient-centric medication adherence plan, based on diagnosis, patient need, education, and support.

Why are patients nonadherent?
Many variables lead to patient nonadherence (Figure 1). The most common reason is that patients simply forget to take their medication.¹⁰ Among psychiatric patients, other reasons are:

• lack of insight
• negative emotional reaction to taking medication¹¹
• feeling better and no longer believing that the medication is needed^12,13
• distress associated with side effects^14,15
• high cost of medication¹⁵
• patient’s perception that medication won’t be effective^16,17
• concern about substance abuse¹⁸
• fear of dependency¹⁹
• complicated dosing regimen²⁰
• general lack of motivation.²¹

Emotional barriers to medication nonadherence are an underestimated area that can benefit greatly from the expertise and understanding of psychiatrists. These barriers include a sense of losing control, self-stigmatization, denial, poor insight, and beliefs about illness and medications.

Additional patient variables that contribute to nonadherence include:

• suboptimal health literacy
• stigma and shame about the need for psychiatric treatment
• lack of patient involvement in treatment decision-making.

Who is responsible for adherence?
Adherence to medical therapy is not the patient’s responsibility, exclusively. Rather, it is a collection of complex components that generally includes physicians and the health care system. Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifaceted.

Providers. Patients’ care often is managed by multiple physicians, which can lead to communication lapses about complicated drug regimens and potential adverse effects. To assist patients in adhering to their medication regimen, physicians should recognize, and acknowledge to the patient, that many psychiatric patients have difficulty taking their medications and provide advice and information in how to address this problem.

Families. Likewise, it is important to educate patients and their family about the need for medication—helping the patient see that it is his (her) choice and, indeed, his direct responsibility to take his medication and improve his health. The risk–benefit balance of treatment should be explained to the patient and his family, as well as the nature of the psychiatric diagnosis and how effective patient–physician collaboration can help him function and adhere to his medication regimen in a consistent, reliable manner.

The larger system. Health care systems can contribute to medication adherence by reducing time constraints on visits to providers, to allow time to discuss all aspects of medication adherence. Limited visits in the clinic means physicians are not able to (1) spend adequate time discussing the medication regimen to ensure full patient comprehension and (2) conduct an assessment of medication-taking behaviors. Team-based approaches could improve efficiency, patient understanding, adherence, and early detection of adherence issues.^22,23

Strategies such as additional clinic visits and reminder calls to discuss adherence carry a cost, but their long-term advantage is that, if patients understand how to better adhere to their medication regimens, their actions will have a positive impact on their health care costs and outcomes and on the wider health economy—as a result of reduced hospital admissions and reduced need to care for patients whose condition deteriorates because of nonadherence. It is imperative that we build strong relationships with other providers to show that we are committed to building supportive, effective adherence support programs that focus on the individual patient’s needs.

What is the available technology?
There is no standard way to measure non­adherence. The most common, and simplest, measure—asking the patient—is unreliable and severely overestimates adherence.

Direct measures of adherence include observing the patient taking his medications and testing for the concentration of those medications in blood or urine. Indirect adherence assessment methods, such as pill counts, a medication diary, self-report, clinician ratings, pharmacy chart review, and electronic devices that monitor the opening of a lid or tablet strip, have all been used; yet reviews of those methods have shown less than favorable results.⁶

Pre-packaged pill packs have helped some patients with a simple method for medication management.

Electronic monitoring, using a medication vial cap device (Figure 2) that electronically records the date and time of bottle opening, has become common in general medicine and among patients with schizophrenia.^6,13,24-26 Diaz et al²⁴ reported that electronic monitoring detected a greater nonadherence rate (57%) than what prescribers reported (7%) or patients self-reported (5%)—demonstrating that prescribers and patients grossly overestimate adherence. In another study that looked at electronic monitoring, researchers reported that adherence was much higher in depressed youth (87%)²⁷ than what had been seen in adults (67%) in a similar study.¹³

The downside to pill packs and electronic monitoring? There is no guarantee the patient has actually taken the medication despite the data reported by the system.

Event marker-signaling devices. Novel technologies have been developed to measure adherence:

Proteus Digital Health feedback system (www.proteus.com) requires that patients ingest a tablet containing a tiny, dietary mineral-based “ingestible event marker.” Upon contact with gastric fluid electrolytes, the event marker emits a unique signal that is transmitted through bodily tissue to a small receiver in a patch worn on the torso. The receiver then transmits a signal to a cellular phone, indicating the time and date when the medication was ingested (Figure 3).

A 4-week pilot study²⁸ found that the ingestible event marker is feasible and acceptable to patients: 27 of 28 participants (96%) completed the study, with a mean adherence rate of 74%. Although the system identifies ingestible sensors with high accuracy and is easily tolerated by patients, the pilot study was brief; a longer duration of adherence while wearing the patch needs to be studied.

Breath analysis, facial recognition. Even directly observing ingestion of a medication can be problematic: Some patients don’t swallow the medication and spit it out later. One way around that subterfuge is to consider using other advanced medication adherence solutions that are breath-based or use facial recognition technology and confirm ingestion.

Xhale SMART (www.xhale.com/smart) is a handheld device that generates a reminder to the patient to take his medication; afterward, he (she) must blow into the device so that ingestion of the medication is detected (Figure 4). The medication has breath-detectable adherence markers already incorporated. The adherence marker then is released into the stomach and small intestine, where the adherence marker metabolite is transported through the bloodstream into the lungs and exhaled. The patient must breathe into a breath analysis device, which measures medication ingestion compared with a baseline breath print.

Several articles in the literature have reported the accuracy of this device in detecting the ingested metabolite in every participant, without adverse effects.^29,30 Clinical data on the use of the breath-based detector is not available to the public at this time.

AiCure (www.aicure.com) is a facial recognition-based technology platform that can work through any smartphone. The device is powered by artificial intelligence software and motion-sensing technology that can detect, in real time, whether the patient is taking the medication as prescribed. Patients who take an incorrect dose, or who do not use the software, are automatically flagged for immediate follow-up. This technology enables real-time intervention by a provider with the nonadherent patient.

An important note: These innovative technological advances are tools that can help clinicians manage an important aspect of treatment, but they do not show the entire picture: The physician−patient relationship and the therapeutic alliance are key to optimal treatment adherence.

Engage and empower the patient
Novel adherence technologies are, as we’ve described, available, and more are being developed. Incorporating these technologies into clinical care requires continued input and support from clinicians and patients. Digital and mobile health applications are multi-beneficial: They can empower patients to self-manage medication regimens and appointments while they also receive social and psychological information and support as needed. Understanding one’s own illness can, ultimately, improve outcomes and significantly reduce health care costs.

Patient empowerment is key. The physician is an important influencer in this regard.

The role of the physician must not be undervalued in maintaining adherence to therapy; she (he) plays a vital role in continued patient engagement and behavioral training. Integrating physician-led oversight, patient education, and commitment, and novel digital mobile adherence technologies will help deliver better outcomes.

The push to engage. A “one size fits all” approach to maintaining adherence won’t be effective. We need to better understand the individual patient’s underlying cause(s) for nonadherence, then to tailor a solution to influence and change that behavior. One way to do this is by interacting and engaging more directly (and in a digital manner) with patients to monitor adherence.

A recent example of the move toward direct patient engagement is the agreement entered by Otsuka Pharmaceuticals and Proteus Digital Health to develop novel digital health products. The FDA has accepted for review the combination product of Otsuka’s brand of aripiprazole and Proteus’s ingestible sensor. If the product is approved by the FDA, physicians will be able to prescribe aripiprazole with the ingestible sensor embedded in the tablet and then measure medication adherence and other patient physiologic metrics (eg, activity, rest) through the wearable sensor patch and medical software application designed specifically for patient and physician use.

This technology could have huge potential in mental health care, where patients struggle with both adhering to their medication regimen and communicating with the health care team. Physicians could measure adherence when treating adults with schizophrenia, bipolar disorders, and major depressive disorder; flag those who are not adhering as having higher risk of disease progression and poorer outcome; and allow decisions to be made more quickly based on treatment need.

Developing and enhancing these collaborative and patient-centric approaches will increase self-monitoring and patient responsibility, and encourage behavior change.

‘All-in’ strategy. By continuing to use the latest technologies and connecting them to the range of stakeholders—physicians, nurses, pharmacists, payers—we will develop an all-inclusive adherence intervention strategy. All patients will be integrated, and all of them, and their family, will be provided with positive psychoeducational care and motivational counseling (Figure 5). In addition, such a support-based patient experience must be aligned with the work of clinical care providers. Compliance therapy and behavioral training, together with active patient engagement, can help improve insight, acceptance of treatment, and, over the long term, adherence.^31,32

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

Clinical question: Can cardiac catheterization prolong survival in patients with stable ischemic heart disease?

Background: Previous results from the COURAGE trial found no benefit of percutaneous intervention (PCI) as compared to medical therapy on a composite endpoint of death or nonfatal myocardial infarction or in total mortality at 4.6 years follow-up. The authors now report 15-year follow-up of the same patients.

Study design: Randomized, controlled trial.

Setting: The majority of the patients were from Veterans Affairs (VA) medical centers, although non-VA hospitals in the U.S. also were included.

Synopsis: Originally, 2,287 patients with stable ischemic heart disease and either an abnormal stress test or evidence of ischemia on ECG, as well at least 70% stenosis on angiography, were randomized to medical therapy or medical therapy plus PCI. Now, investigators have obtained extended follow-up information for 1,211 of the original patients (53%). They concluded that after 15 years of follow-up, there was no survival difference for the patients who initially received PCI in addition to medical management.

One limitation of the study was that it did not reflect important advances in both medical and interventional management of ischemic heart disease that have taken place since the study was conducted, which may affect patient mortality. It is also noteworthy that the investigators were unable to determine how many patients in the medical management group subsequently underwent revascularization after the study concluded and therefore may have crossed over between groups. Nevertheless, for now it appears that the major utility of PCI in stable ischemic heart disease is in symptomatic management.

Bottom Line: After 15 years of follow-up, there was still no mortality benefit to PCI as compared to optimal medical therapy for stable ischemic heart disease.

Citation: Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med. 2015;373(20):1937-1946

Short Take

Cauti Infections Are Rarely Clinically Relevant and Associated with Low Complication Rate

A single-center retrospective study in the ICU setting shows that the definition of catheter-associated urinary tract infections (CAUTIs) is nonspecific and they’re mostly diagnosed when urine cultures are sent for workup of fever. Most of the time, there are alternative explanations for the fever.

Citation: Tedja R, Wentink J, O’Horo J, Thompson R, Sampathkumar P et al. Catheter-associated urinary tract infections in intensive care unit patients. Infect Control Hosp Epidemiol. 2015;36(11):1330-1334.

Clinical question: Can cardiac catheterization prolong survival in patients with stable ischemic heart disease?

Background: Previous results from the COURAGE trial found no benefit of percutaneous intervention (PCI) as compared to medical therapy on a composite endpoint of death or nonfatal myocardial infarction or in total mortality at 4.6 years follow-up. The authors now report 15-year follow-up of the same patients.

Study design: Randomized, controlled trial.

Setting: The majority of the patients were from Veterans Affairs (VA) medical centers, although non-VA hospitals in the U.S. also were included.

Synopsis: Originally, 2,287 patients with stable ischemic heart disease and either an abnormal stress test or evidence of ischemia on ECG, as well at least 70% stenosis on angiography, were randomized to medical therapy or medical therapy plus PCI. Now, investigators have obtained extended follow-up information for 1,211 of the original patients (53%). They concluded that after 15 years of follow-up, there was no survival difference for the patients who initially received PCI in addition to medical management.

One limitation of the study was that it did not reflect important advances in both medical and interventional management of ischemic heart disease that have taken place since the study was conducted, which may affect patient mortality. It is also noteworthy that the investigators were unable to determine how many patients in the medical management group subsequently underwent revascularization after the study concluded and therefore may have crossed over between groups. Nevertheless, for now it appears that the major utility of PCI in stable ischemic heart disease is in symptomatic management.

Bottom Line: After 15 years of follow-up, there was still no mortality benefit to PCI as compared to optimal medical therapy for stable ischemic heart disease.

Citation: Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med. 2015;373(20):1937-1946

Short Take

Cauti Infections Are Rarely Clinically Relevant and Associated with Low Complication Rate

A single-center retrospective study in the ICU setting shows that the definition of catheter-associated urinary tract infections (CAUTIs) is nonspecific and they’re mostly diagnosed when urine cultures are sent for workup of fever. Most of the time, there are alternative explanations for the fever.

Citation: Tedja R, Wentink J, O’Horo J, Thompson R, Sampathkumar P et al. Catheter-associated urinary tract infections in intensive care unit patients. Infect Control Hosp Epidemiol. 2015;36(11):1330-1334.

Clinical question: Can cardiac catheterization prolong survival in patients with stable ischemic heart disease?

Background: Previous results from the COURAGE trial found no benefit of percutaneous intervention (PCI) as compared to medical therapy on a composite endpoint of death or nonfatal myocardial infarction or in total mortality at 4.6 years follow-up. The authors now report 15-year follow-up of the same patients.

Study design: Randomized, controlled trial.

Setting: The majority of the patients were from Veterans Affairs (VA) medical centers, although non-VA hospitals in the U.S. also were included.

Synopsis: Originally, 2,287 patients with stable ischemic heart disease and either an abnormal stress test or evidence of ischemia on ECG, as well at least 70% stenosis on angiography, were randomized to medical therapy or medical therapy plus PCI. Now, investigators have obtained extended follow-up information for 1,211 of the original patients (53%). They concluded that after 15 years of follow-up, there was no survival difference for the patients who initially received PCI in addition to medical management.

One limitation of the study was that it did not reflect important advances in both medical and interventional management of ischemic heart disease that have taken place since the study was conducted, which may affect patient mortality. It is also noteworthy that the investigators were unable to determine how many patients in the medical management group subsequently underwent revascularization after the study concluded and therefore may have crossed over between groups. Nevertheless, for now it appears that the major utility of PCI in stable ischemic heart disease is in symptomatic management.

Bottom Line: After 15 years of follow-up, there was still no mortality benefit to PCI as compared to optimal medical therapy for stable ischemic heart disease.

Citation: Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med. 2015;373(20):1937-1946

Short Take

Cauti Infections Are Rarely Clinically Relevant and Associated with Low Complication Rate

A single-center retrospective study in the ICU setting shows that the definition of catheter-associated urinary tract infections (CAUTIs) is nonspecific and they’re mostly diagnosed when urine cultures are sent for workup of fever. Most of the time, there are alternative explanations for the fever.

Citation: Tedja R, Wentink J, O’Horo J, Thompson R, Sampathkumar P et al. Catheter-associated urinary tract infections in intensive care unit patients. Infect Control Hosp Epidemiol. 2015;36(11):1330-1334.

Clinical question: Have healthcare-associated pneumonia (HCAP) guidelines improved treatment accuracy?

Background: Guidelines released in 2005 call for the use of broad-spectrum antibiotics for patients presenting with pneumonia who have had recent healthcare exposure. However, there is scant evidence to support the risk factors they identify, and the guidelines are likely to increase use of broad-spectrum antibiotics.

Study design: Observational, retrospective.

Setting: VA medical centers, 2006–2010.

Synopsis: In this study, VA medical center physicians evaluated 95,511 hospitalizations for pneumonia at 128 hospitals between 2006 and 2010, the years following the 2005 guidelines. Annual analyses were performed to assess antibiotics selection as well as evidence of resistant bacteria from blood and respiratory cultures. Researchers found that while the use of broad-spectrum antibiotics increased drastically during the study period (vancomycin from 16% to 31% and piperacillin-tazobactam from 16% to 27%, P<0.001 for both), the incidence of resistant organisms either decreased or remained stable.  

Additionally, physicians were no better at matching broad-spectrum antibiotics to patients infected with resistant organisms at the end of the study period than they were at the start. They conclude that more research is urgently needed to identify patients at risk for resistant organisms in order to more appropriately prescribe broad-spectrum antibiotics.

This study did not evaluate patients’ clinical outcomes, so it is unclear whether they may have benefitted clinically from the implementation of the guidelines. For now, the optimal approach to empiric therapy for HCAP remains undefined.

Bottom line: Despite a marked increase in the use of broad-spectrum antibiotics for HCAP in the years following a change in treatment guidelines, doctors showed no improvement at matching these antibiotics to patients infected with resistant organisms.

Citation: Jones BE, Jones MM, Huttner B, et al. Trends in antibiotic use and nosocomial pathogens in hospitalized veterans with pneumonia at 128 medical centers, 2006-2010. Clin Infect Dis. 2015;61(9):1403-1410.

Clinical question: Have healthcare-associated pneumonia (HCAP) guidelines improved treatment accuracy?

Background: Guidelines released in 2005 call for the use of broad-spectrum antibiotics for patients presenting with pneumonia who have had recent healthcare exposure. However, there is scant evidence to support the risk factors they identify, and the guidelines are likely to increase use of broad-spectrum antibiotics.

Study design: Observational, retrospective.

Setting: VA medical centers, 2006–2010.

Synopsis: In this study, VA medical center physicians evaluated 95,511 hospitalizations for pneumonia at 128 hospitals between 2006 and 2010, the years following the 2005 guidelines. Annual analyses were performed to assess antibiotics selection as well as evidence of resistant bacteria from blood and respiratory cultures. Researchers found that while the use of broad-spectrum antibiotics increased drastically during the study period (vancomycin from 16% to 31% and piperacillin-tazobactam from 16% to 27%, P<0.001 for both), the incidence of resistant organisms either decreased or remained stable.  

Additionally, physicians were no better at matching broad-spectrum antibiotics to patients infected with resistant organisms at the end of the study period than they were at the start. They conclude that more research is urgently needed to identify patients at risk for resistant organisms in order to more appropriately prescribe broad-spectrum antibiotics.

This study did not evaluate patients’ clinical outcomes, so it is unclear whether they may have benefitted clinically from the implementation of the guidelines. For now, the optimal approach to empiric therapy for HCAP remains undefined.

Bottom line: Despite a marked increase in the use of broad-spectrum antibiotics for HCAP in the years following a change in treatment guidelines, doctors showed no improvement at matching these antibiotics to patients infected with resistant organisms.

Citation: Jones BE, Jones MM, Huttner B, et al. Trends in antibiotic use and nosocomial pathogens in hospitalized veterans with pneumonia at 128 medical centers, 2006-2010. Clin Infect Dis. 2015;61(9):1403-1410.

Clinical question: Have healthcare-associated pneumonia (HCAP) guidelines improved treatment accuracy?

Background: Guidelines released in 2005 call for the use of broad-spectrum antibiotics for patients presenting with pneumonia who have had recent healthcare exposure. However, there is scant evidence to support the risk factors they identify, and the guidelines are likely to increase use of broad-spectrum antibiotics.

Study design: Observational, retrospective.

Setting: VA medical centers, 2006–2010.

Synopsis: In this study, VA medical center physicians evaluated 95,511 hospitalizations for pneumonia at 128 hospitals between 2006 and 2010, the years following the 2005 guidelines. Annual analyses were performed to assess antibiotics selection as well as evidence of resistant bacteria from blood and respiratory cultures. Researchers found that while the use of broad-spectrum antibiotics increased drastically during the study period (vancomycin from 16% to 31% and piperacillin-tazobactam from 16% to 27%, P<0.001 for both), the incidence of resistant organisms either decreased or remained stable.  

Additionally, physicians were no better at matching broad-spectrum antibiotics to patients infected with resistant organisms at the end of the study period than they were at the start. They conclude that more research is urgently needed to identify patients at risk for resistant organisms in order to more appropriately prescribe broad-spectrum antibiotics.

This study did not evaluate patients’ clinical outcomes, so it is unclear whether they may have benefitted clinically from the implementation of the guidelines. For now, the optimal approach to empiric therapy for HCAP remains undefined.

Bottom line: Despite a marked increase in the use of broad-spectrum antibiotics for HCAP in the years following a change in treatment guidelines, doctors showed no improvement at matching these antibiotics to patients infected with resistant organisms.

Citation: Jones BE, Jones MM, Huttner B, et al. Trends in antibiotic use and nosocomial pathogens in hospitalized veterans with pneumonia at 128 medical centers, 2006-2010. Clin Infect Dis. 2015;61(9):1403-1410.

NEW YORK (Reuters Health) - U.S. hospitals save money when they use the novel oral anticoagulant rivaroxaban instead of warfarin to treat patients with venous thromboembolism (VTE), a new analysis finds.

"These days it's important to consider the cost of new drugs to the health system," Dr. Steven Deitelzweig from Ochsner Health System in New Orleans, Louisiana, noted in an interview with Reuters Health.

"This retrospective observational analysis had an ample number of patients, they had very good clinical outcomes with rivaroxaban, and we also demonstrated that those clinical outcomes could be achieved with a notable reduction in the all-important utilization side of healthcare," he said.

It's estimated that VTE affects more than 900,000 Americans each year, at a cost to the healthcare system between $13 and $27 billion.

Dr. Deitelzweig and his colleagues did an economic analysis of rivaroxaban versus low-molecular-weight heparin (LMWH)/warfarin for VTE in the hospital setting.

Using Truven MarketScan Hospital Drug Database, they identified more than 2,400 older adults hospitalized for primary VTE between 2012 and 2013. They created two groups of 1,223 patients each. Each group included 751 pulmonary embolism (PE) patients and 472 deep vein thrombosis (DVT) patients.

According to the analysis, total hospitalization costs - including room rate, laboratory tests, inpatient procedures, pharmacy costs and all other inpatient services - were significantly lower and length of stay was significantly shorter for patients treated with rivaroxaban rather than LMWH/warfarin.

Patients receiving rivaroxaban spent an average of 1.5 fewer days in the hospital than their peers on LMWH/warfarin (3.7 versus 5.2 days, p<0.001).

"This finding is consistent with the length of stay reduction found in the EINSTEIN VTE clinical trials," the researchers note in their poster presented March 7 at the Society of Hospital Medicine annual meeting in San Diego, California.

"Length of stay is one metric that we track quite closely and care about. Even one day less in a hospital is a significant cost savings and allows hospitals that are very busy to take care of the next patient, as appropriate," Dr. Deitelzweig told Reuters Health.

The rivaroxaban group had an adjusted average cost savings of $1,888 per admission compared with the LMWH/warfarin group ($8,387 versus $10,275; p<0.001), the study found.

Limitations of the study include the fact that patient medical history was limited to the patient's current admission. Outpatient treatment prior to admission, particularly whether they had received either rivaroxaban or LMWH/warfarin prior to admission was unknown. And despite propensity score matching and further statistical modeling, there remains the potential for unmeasured confounders, they note.

The study was funded by Janssen Scientific Affairs, LLC. Janssen Pharmaceuticals markets rivaroxaban under the trade name Xarelto. Four authors are employees of Janssen Research and Development, LLC.

NEW YORK (Reuters Health) - U.S. hospitals save money when they use the novel oral anticoagulant rivaroxaban instead of warfarin to treat patients with venous thromboembolism (VTE), a new analysis finds.

"These days it's important to consider the cost of new drugs to the health system," Dr. Steven Deitelzweig from Ochsner Health System in New Orleans, Louisiana, noted in an interview with Reuters Health.

"This retrospective observational analysis had an ample number of patients, they had very good clinical outcomes with rivaroxaban, and we also demonstrated that those clinical outcomes could be achieved with a notable reduction in the all-important utilization side of healthcare," he said.

It's estimated that VTE affects more than 900,000 Americans each year, at a cost to the healthcare system between $13 and $27 billion.

Dr. Deitelzweig and his colleagues did an economic analysis of rivaroxaban versus low-molecular-weight heparin (LMWH)/warfarin for VTE in the hospital setting.

Using Truven MarketScan Hospital Drug Database, they identified more than 2,400 older adults hospitalized for primary VTE between 2012 and 2013. They created two groups of 1,223 patients each. Each group included 751 pulmonary embolism (PE) patients and 472 deep vein thrombosis (DVT) patients.

According to the analysis, total hospitalization costs - including room rate, laboratory tests, inpatient procedures, pharmacy costs and all other inpatient services - were significantly lower and length of stay was significantly shorter for patients treated with rivaroxaban rather than LMWH/warfarin.

Patients receiving rivaroxaban spent an average of 1.5 fewer days in the hospital than their peers on LMWH/warfarin (3.7 versus 5.2 days, p<0.001).

"This finding is consistent with the length of stay reduction found in the EINSTEIN VTE clinical trials," the researchers note in their poster presented March 7 at the Society of Hospital Medicine annual meeting in San Diego, California.

"Length of stay is one metric that we track quite closely and care about. Even one day less in a hospital is a significant cost savings and allows hospitals that are very busy to take care of the next patient, as appropriate," Dr. Deitelzweig told Reuters Health.

The rivaroxaban group had an adjusted average cost savings of $1,888 per admission compared with the LMWH/warfarin group ($8,387 versus $10,275; p<0.001), the study found.

Limitations of the study include the fact that patient medical history was limited to the patient's current admission. Outpatient treatment prior to admission, particularly whether they had received either rivaroxaban or LMWH/warfarin prior to admission was unknown. And despite propensity score matching and further statistical modeling, there remains the potential for unmeasured confounders, they note.

The study was funded by Janssen Scientific Affairs, LLC. Janssen Pharmaceuticals markets rivaroxaban under the trade name Xarelto. Four authors are employees of Janssen Research and Development, LLC.

NEW YORK (Reuters Health) - U.S. hospitals save money when they use the novel oral anticoagulant rivaroxaban instead of warfarin to treat patients with venous thromboembolism (VTE), a new analysis finds.

"These days it's important to consider the cost of new drugs to the health system," Dr. Steven Deitelzweig from Ochsner Health System in New Orleans, Louisiana, noted in an interview with Reuters Health.

"This retrospective observational analysis had an ample number of patients, they had very good clinical outcomes with rivaroxaban, and we also demonstrated that those clinical outcomes could be achieved with a notable reduction in the all-important utilization side of healthcare," he said.

It's estimated that VTE affects more than 900,000 Americans each year, at a cost to the healthcare system between $13 and $27 billion.

Dr. Deitelzweig and his colleagues did an economic analysis of rivaroxaban versus low-molecular-weight heparin (LMWH)/warfarin for VTE in the hospital setting.

Using Truven MarketScan Hospital Drug Database, they identified more than 2,400 older adults hospitalized for primary VTE between 2012 and 2013. They created two groups of 1,223 patients each. Each group included 751 pulmonary embolism (PE) patients and 472 deep vein thrombosis (DVT) patients.

According to the analysis, total hospitalization costs - including room rate, laboratory tests, inpatient procedures, pharmacy costs and all other inpatient services - were significantly lower and length of stay was significantly shorter for patients treated with rivaroxaban rather than LMWH/warfarin.

Patients receiving rivaroxaban spent an average of 1.5 fewer days in the hospital than their peers on LMWH/warfarin (3.7 versus 5.2 days, p<0.001).

"This finding is consistent with the length of stay reduction found in the EINSTEIN VTE clinical trials," the researchers note in their poster presented March 7 at the Society of Hospital Medicine annual meeting in San Diego, California.

"Length of stay is one metric that we track quite closely and care about. Even one day less in a hospital is a significant cost savings and allows hospitals that are very busy to take care of the next patient, as appropriate," Dr. Deitelzweig told Reuters Health.

The rivaroxaban group had an adjusted average cost savings of $1,888 per admission compared with the LMWH/warfarin group ($8,387 versus $10,275; p<0.001), the study found.

Limitations of the study include the fact that patient medical history was limited to the patient's current admission. Outpatient treatment prior to admission, particularly whether they had received either rivaroxaban or LMWH/warfarin prior to admission was unknown. And despite propensity score matching and further statistical modeling, there remains the potential for unmeasured confounders, they note.

The study was funded by Janssen Scientific Affairs, LLC. Janssen Pharmaceuticals markets rivaroxaban under the trade name Xarelto. Four authors are employees of Janssen Research and Development, LLC.

East African bat

Photo by Holly Lutz

A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.

Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.

It then spread to bats and on to other mammals.

“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.

“In learning about its past, we may be better able to understand the effects it has on us.”

Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.

When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.

In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.

“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”

In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.

“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”

The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future.

East African bat

Photo by Holly Lutz

A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.

Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.

It then spread to bats and on to other mammals.

“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.

“In learning about its past, we may be better able to understand the effects it has on us.”

Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.

When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.

In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.

“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”

In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.

“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”

The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future.

East African bat

Photo by Holly Lutz

A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.

Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.

It then spread to bats and on to other mammals.

“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.

“In learning about its past, we may be better able to understand the effects it has on us.”

Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.

When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.

In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.

“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”

In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.

“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”

The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future.