First-trimester exposure to pregabalin may increase the risk of major birth defects, according to a study published online ahead of print May 18 in Neurology.

Pregabalin is an FDA-approved treatment for seizures and neuropathic pain. It is also a common off-label treatment for restless legs syndrome, cyclic mood disorders, and generalized anxiety disorder.

Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues conducted a multicenter, observational cohort study in which they compared pregnancy outcomes of 164 women exposed to pregabalin with 656 controls who were not exposed to any known teratogenic medications or antiepileptic drugs. Data for this study were collected from 2004 to 2013 and included data from France, the United Kingdom, Italy, Finland, Switzerland, the Netherlands, and Turkey.

Of the women on the medication, 77% started taking pregabalin before they became pregnant and stopped taking the drug at a median of six weeks into their pregnancies. Of the women taking pregabalin, 13% were also taking another antiepileptic drug.

Pregnancies of the women who took pregabalin during the first trimester of pregnancy were three times more likely to result in major birth defects than those of women who did not take the drug—6.0% versus 2.1%, respectively. The major birth defects included heart defects and structural problems with the CNS or other organ systems. The study also revealed a lower rate of live births in the pregabalin group due to elective and medically indicated pregnancy terminations.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said Dr. Winterfeld.

She suggested that before a woman is prescribed pregabalin, it is important to make sure the benefits outweigh the risks and that she is carefully informed about the use of effective birth control.

—Adaeze Stephanie Onyechi

First-trimester exposure to pregabalin may increase the risk of major birth defects, according to a study published online ahead of print May 18 in Neurology.

Pregabalin is an FDA-approved treatment for seizures and neuropathic pain. It is also a common off-label treatment for restless legs syndrome, cyclic mood disorders, and generalized anxiety disorder.

Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues conducted a multicenter, observational cohort study in which they compared pregnancy outcomes of 164 women exposed to pregabalin with 656 controls who were not exposed to any known teratogenic medications or antiepileptic drugs. Data for this study were collected from 2004 to 2013 and included data from France, the United Kingdom, Italy, Finland, Switzerland, the Netherlands, and Turkey.

Of the women on the medication, 77% started taking pregabalin before they became pregnant and stopped taking the drug at a median of six weeks into their pregnancies. Of the women taking pregabalin, 13% were also taking another antiepileptic drug.

Pregnancies of the women who took pregabalin during the first trimester of pregnancy were three times more likely to result in major birth defects than those of women who did not take the drug—6.0% versus 2.1%, respectively. The major birth defects included heart defects and structural problems with the CNS or other organ systems. The study also revealed a lower rate of live births in the pregabalin group due to elective and medically indicated pregnancy terminations.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said Dr. Winterfeld.

She suggested that before a woman is prescribed pregabalin, it is important to make sure the benefits outweigh the risks and that she is carefully informed about the use of effective birth control.

—Adaeze Stephanie Onyechi

First-trimester exposure to pregabalin may increase the risk of major birth defects, according to a study published online ahead of print May 18 in Neurology.

Pregabalin is an FDA-approved treatment for seizures and neuropathic pain. It is also a common off-label treatment for restless legs syndrome, cyclic mood disorders, and generalized anxiety disorder.

Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues conducted a multicenter, observational cohort study in which they compared pregnancy outcomes of 164 women exposed to pregabalin with 656 controls who were not exposed to any known teratogenic medications or antiepileptic drugs. Data for this study were collected from 2004 to 2013 and included data from France, the United Kingdom, Italy, Finland, Switzerland, the Netherlands, and Turkey.

Of the women on the medication, 77% started taking pregabalin before they became pregnant and stopped taking the drug at a median of six weeks into their pregnancies. Of the women taking pregabalin, 13% were also taking another antiepileptic drug.

Pregnancies of the women who took pregabalin during the first trimester of pregnancy were three times more likely to result in major birth defects than those of women who did not take the drug—6.0% versus 2.1%, respectively. The major birth defects included heart defects and structural problems with the CNS or other organ systems. The study also revealed a lower rate of live births in the pregabalin group due to elective and medically indicated pregnancy terminations.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said Dr. Winterfeld.

She suggested that before a woman is prescribed pregabalin, it is important to make sure the benefits outweigh the risks and that she is carefully informed about the use of effective birth control.

—Adaeze Stephanie Onyechi

Patients who have survived sepsis or septic shock do not receive any significant benefit in the quality of their mental health by receiving primary care management intervention, according to a new study published by JAMA.

“Many survivors of sepsis have multiple medical comorbidities that are typically managed in primary care [but] interventions for managing sepsis sequelae in primary care have not been developed,” states the study, which was led by Jochen Gensichen, MD, of the Institute of General Practice & Family Medicine at Jena (Germany) University Hospital.

©invisioner/thinkstockphotos.com

“To our knowledge, this is the first large-scale, randomized controlled clinical trial of an intervention to improve outcomes in survivors of sepsis in primary care,” Dr. Gensichen and his coinvestigators added.

The study recruited sepsis and septic shock survivors from nine ICUs across Germany between February 2011 and December 2014, excluding any patients with cognitive impairment, defined as a Telephone Interview of Cognitive Status score no greater than 27. Ultimately, 291 patients aged 18 years or older (mean age of 61.6 years) were selected for inclusion and randomized into cohorts receiving either primary care–based intervention (n = 148) or usual care (n = 143) (JAMA. 2016;315:2703-11. doi: 10.1001/jama.2016.7207).

Those assigned to the usual care cohort received the standard care that their primary care providers would normally carry out, which included “periodic contacts, referrals to specialists, and prescription of medication and therapeutic aids at quantities comparable with those for other populations with multiple chronic conditions.” Those in the other cohort were given active monitoring of symptoms from providers who had been given evidence-based care training and clinical decision support from nurses who underwent training to become case managers. Case managers would take patients through an hour-long face-to-face training on sepsis sequelae within 2-20 days of ICU discharge, along with subsequent follow-up conversations over the phone.

“Case managers monitored patients’ symptoms using validated screening tools to assess critical illness polyneuropathy/myopathy, wasting, neurocognitive deficits, [posttraumatic stress disorder], depressive and pain symptoms, as well as patient self-management behaviors focusing on physical activity and individual self-management goals,” the authors said, noting that case managers would report their results to a consulting physician who “supervised the case managers and provided clinical decision support to the [primary care physicians].”

Baseline Mental Component Summary (MCS) scores were taken for subjects in both cohorts to determine mental health-based quality of life, which averaged 49.1 for the intervention cohort and 49.3 for the control. MCS scores at 6 months’ follow-up were 52.9 for the intervention group (95% confidence interval, 1.05-6.54) and 51.0 for the control group (95% CI, –1.22-4.51), for a mean change of 3.8 in the intervention cohort and 1.6 for the control group. The mean treatment effect was 2.15 (95% CI, –1.79-6.09; P = .28), indicating no significant difference between the two.

“There was no evidence for a differential treatment effect on the study’s primary outcome, postsepsis MCS scores,” the authors concluded. “This finding is similar to those from previous trials of care management interventions following critical illness.”

The authors added that “further research is needed to determine if modified approaches to primary care management may be more effective.”

The study was funded by the Center for Sepsis Control and Care, the German Federal Ministry of Education and Research, and the German Sepsis Society. Dr. Gensichen reported receiving personal fees from the Primary Health Care Foundation and receiving a grant from the German Federal Ministry of Education and Research.

[email protected]

Patients who have survived sepsis or septic shock do not receive any significant benefit in the quality of their mental health by receiving primary care management intervention, according to a new study published by JAMA.

“Many survivors of sepsis have multiple medical comorbidities that are typically managed in primary care [but] interventions for managing sepsis sequelae in primary care have not been developed,” states the study, which was led by Jochen Gensichen, MD, of the Institute of General Practice & Family Medicine at Jena (Germany) University Hospital.

©invisioner/thinkstockphotos.com

“To our knowledge, this is the first large-scale, randomized controlled clinical trial of an intervention to improve outcomes in survivors of sepsis in primary care,” Dr. Gensichen and his coinvestigators added.

The study recruited sepsis and septic shock survivors from nine ICUs across Germany between February 2011 and December 2014, excluding any patients with cognitive impairment, defined as a Telephone Interview of Cognitive Status score no greater than 27. Ultimately, 291 patients aged 18 years or older (mean age of 61.6 years) were selected for inclusion and randomized into cohorts receiving either primary care–based intervention (n = 148) or usual care (n = 143) (JAMA. 2016;315:2703-11. doi: 10.1001/jama.2016.7207).

Those assigned to the usual care cohort received the standard care that their primary care providers would normally carry out, which included “periodic contacts, referrals to specialists, and prescription of medication and therapeutic aids at quantities comparable with those for other populations with multiple chronic conditions.” Those in the other cohort were given active monitoring of symptoms from providers who had been given evidence-based care training and clinical decision support from nurses who underwent training to become case managers. Case managers would take patients through an hour-long face-to-face training on sepsis sequelae within 2-20 days of ICU discharge, along with subsequent follow-up conversations over the phone.

“Case managers monitored patients’ symptoms using validated screening tools to assess critical illness polyneuropathy/myopathy, wasting, neurocognitive deficits, [posttraumatic stress disorder], depressive and pain symptoms, as well as patient self-management behaviors focusing on physical activity and individual self-management goals,” the authors said, noting that case managers would report their results to a consulting physician who “supervised the case managers and provided clinical decision support to the [primary care physicians].”

Baseline Mental Component Summary (MCS) scores were taken for subjects in both cohorts to determine mental health-based quality of life, which averaged 49.1 for the intervention cohort and 49.3 for the control. MCS scores at 6 months’ follow-up were 52.9 for the intervention group (95% confidence interval, 1.05-6.54) and 51.0 for the control group (95% CI, –1.22-4.51), for a mean change of 3.8 in the intervention cohort and 1.6 for the control group. The mean treatment effect was 2.15 (95% CI, –1.79-6.09; P = .28), indicating no significant difference between the two.

“There was no evidence for a differential treatment effect on the study’s primary outcome, postsepsis MCS scores,” the authors concluded. “This finding is similar to those from previous trials of care management interventions following critical illness.”

The authors added that “further research is needed to determine if modified approaches to primary care management may be more effective.”

The study was funded by the Center for Sepsis Control and Care, the German Federal Ministry of Education and Research, and the German Sepsis Society. Dr. Gensichen reported receiving personal fees from the Primary Health Care Foundation and receiving a grant from the German Federal Ministry of Education and Research.

[email protected]

Patients who have survived sepsis or septic shock do not receive any significant benefit in the quality of their mental health by receiving primary care management intervention, according to a new study published by JAMA.

“Many survivors of sepsis have multiple medical comorbidities that are typically managed in primary care [but] interventions for managing sepsis sequelae in primary care have not been developed,” states the study, which was led by Jochen Gensichen, MD, of the Institute of General Practice & Family Medicine at Jena (Germany) University Hospital.

©invisioner/thinkstockphotos.com

“To our knowledge, this is the first large-scale, randomized controlled clinical trial of an intervention to improve outcomes in survivors of sepsis in primary care,” Dr. Gensichen and his coinvestigators added.

The study recruited sepsis and septic shock survivors from nine ICUs across Germany between February 2011 and December 2014, excluding any patients with cognitive impairment, defined as a Telephone Interview of Cognitive Status score no greater than 27. Ultimately, 291 patients aged 18 years or older (mean age of 61.6 years) were selected for inclusion and randomized into cohorts receiving either primary care–based intervention (n = 148) or usual care (n = 143) (JAMA. 2016;315:2703-11. doi: 10.1001/jama.2016.7207).

Those assigned to the usual care cohort received the standard care that their primary care providers would normally carry out, which included “periodic contacts, referrals to specialists, and prescription of medication and therapeutic aids at quantities comparable with those for other populations with multiple chronic conditions.” Those in the other cohort were given active monitoring of symptoms from providers who had been given evidence-based care training and clinical decision support from nurses who underwent training to become case managers. Case managers would take patients through an hour-long face-to-face training on sepsis sequelae within 2-20 days of ICU discharge, along with subsequent follow-up conversations over the phone.

“Case managers monitored patients’ symptoms using validated screening tools to assess critical illness polyneuropathy/myopathy, wasting, neurocognitive deficits, [posttraumatic stress disorder], depressive and pain symptoms, as well as patient self-management behaviors focusing on physical activity and individual self-management goals,” the authors said, noting that case managers would report their results to a consulting physician who “supervised the case managers and provided clinical decision support to the [primary care physicians].”

Baseline Mental Component Summary (MCS) scores were taken for subjects in both cohorts to determine mental health-based quality of life, which averaged 49.1 for the intervention cohort and 49.3 for the control. MCS scores at 6 months’ follow-up were 52.9 for the intervention group (95% confidence interval, 1.05-6.54) and 51.0 for the control group (95% CI, –1.22-4.51), for a mean change of 3.8 in the intervention cohort and 1.6 for the control group. The mean treatment effect was 2.15 (95% CI, –1.79-6.09; P = .28), indicating no significant difference between the two.

“There was no evidence for a differential treatment effect on the study’s primary outcome, postsepsis MCS scores,” the authors concluded. “This finding is similar to those from previous trials of care management interventions following critical illness.”

The authors added that “further research is needed to determine if modified approaches to primary care management may be more effective.”

The study was funded by the Center for Sepsis Control and Care, the German Federal Ministry of Education and Research, and the German Sepsis Society. Dr. Gensichen reported receiving personal fees from the Primary Health Care Foundation and receiving a grant from the German Federal Ministry of Education and Research.

[email protected]

Standardized rehabilitation therapy did not reduce hospital length of stay in patients with acute respiratory failure, based on data from a randomized trial of 300 adults published online in JAMA.

Hospital length of stay averaged 10 days for patients in the standardized rehabilitation therapy group (SRT) and 10 days in the control group that received usual ICU care, wrote Dr. Peter E. Morris of the division of pulmonary, critical care and sleep medicine at the University of Kentucky, Lexington, and his colleagues (JAMA. 2016 Jun;315:2694-702. doi: 10.1001/jama.2016.7201).

Hemera Technologies/Thinkstock

The patients were followed for 6 months; 84 patients in the SRT group and 81 in the usual group completed the study.

Patients in the SRT group received daily therapy including passive range of motion, physical therapy, and progressive-resistance exercises. The usual care group received weekday physical therapy as determined by the clinical team.

The researchers also assessed secondary outcomes related to physical function and quality of life, including ventilator days, Short Physical Performance Battery (SPPB) score, handgrip, Mini-Mental State Examination, and Functional Performance Inventory (FPI).

Overall, there was no difference in duration of ventilation or ICU care between the two groups, and score of handgrip strength and mental health also were similar at 6 months’ follow up. However, the SF-36 physical function scores were significantly higher in the SRT group (difference, 12.2; 95% confidence interval, 3.8-20.7; P = .001), and the FPI scores and SPPB scores were higher, compared with the usual care group at 6 months.

“These findings from the exploratory analysis may highlight the emerging role of placing long-term outcomes within critical care clinical trial design not only as a secondary outcome, but possibly as the primary outcome,” the researchers noted. “In view of the SPPB, SF-36 PFS, and FPI data at 6 months, the SRT group demonstrated a potential signal of improvement compared with the usual care group that was not evident at hospital discharge,” they wrote.

The study was supported by the National Institutes of Health, National Institute of Nursing Research, and National Heart, Lung, and Blood Institute. Lead author, Dr. Morris, had no financial conflicts to disclose.

Standardized rehabilitation therapy did not reduce hospital length of stay in patients with acute respiratory failure, based on data from a randomized trial of 300 adults published online in JAMA.

Hospital length of stay averaged 10 days for patients in the standardized rehabilitation therapy group (SRT) and 10 days in the control group that received usual ICU care, wrote Dr. Peter E. Morris of the division of pulmonary, critical care and sleep medicine at the University of Kentucky, Lexington, and his colleagues (JAMA. 2016 Jun;315:2694-702. doi: 10.1001/jama.2016.7201).

Hemera Technologies/Thinkstock

The patients were followed for 6 months; 84 patients in the SRT group and 81 in the usual group completed the study.

Patients in the SRT group received daily therapy including passive range of motion, physical therapy, and progressive-resistance exercises. The usual care group received weekday physical therapy as determined by the clinical team.

The researchers also assessed secondary outcomes related to physical function and quality of life, including ventilator days, Short Physical Performance Battery (SPPB) score, handgrip, Mini-Mental State Examination, and Functional Performance Inventory (FPI).

Overall, there was no difference in duration of ventilation or ICU care between the two groups, and score of handgrip strength and mental health also were similar at 6 months’ follow up. However, the SF-36 physical function scores were significantly higher in the SRT group (difference, 12.2; 95% confidence interval, 3.8-20.7; P = .001), and the FPI scores and SPPB scores were higher, compared with the usual care group at 6 months.

“These findings from the exploratory analysis may highlight the emerging role of placing long-term outcomes within critical care clinical trial design not only as a secondary outcome, but possibly as the primary outcome,” the researchers noted. “In view of the SPPB, SF-36 PFS, and FPI data at 6 months, the SRT group demonstrated a potential signal of improvement compared with the usual care group that was not evident at hospital discharge,” they wrote.

The study was supported by the National Institutes of Health, National Institute of Nursing Research, and National Heart, Lung, and Blood Institute. Lead author, Dr. Morris, had no financial conflicts to disclose.

Standardized rehabilitation therapy did not reduce hospital length of stay in patients with acute respiratory failure, based on data from a randomized trial of 300 adults published online in JAMA.

Hospital length of stay averaged 10 days for patients in the standardized rehabilitation therapy group (SRT) and 10 days in the control group that received usual ICU care, wrote Dr. Peter E. Morris of the division of pulmonary, critical care and sleep medicine at the University of Kentucky, Lexington, and his colleagues (JAMA. 2016 Jun;315:2694-702. doi: 10.1001/jama.2016.7201).

Hemera Technologies/Thinkstock

The patients were followed for 6 months; 84 patients in the SRT group and 81 in the usual group completed the study.

Patients in the SRT group received daily therapy including passive range of motion, physical therapy, and progressive-resistance exercises. The usual care group received weekday physical therapy as determined by the clinical team.

The researchers also assessed secondary outcomes related to physical function and quality of life, including ventilator days, Short Physical Performance Battery (SPPB) score, handgrip, Mini-Mental State Examination, and Functional Performance Inventory (FPI).

Overall, there was no difference in duration of ventilation or ICU care between the two groups, and score of handgrip strength and mental health also were similar at 6 months’ follow up. However, the SF-36 physical function scores were significantly higher in the SRT group (difference, 12.2; 95% confidence interval, 3.8-20.7; P = .001), and the FPI scores and SPPB scores were higher, compared with the usual care group at 6 months.

“These findings from the exploratory analysis may highlight the emerging role of placing long-term outcomes within critical care clinical trial design not only as a secondary outcome, but possibly as the primary outcome,” the researchers noted. “In view of the SPPB, SF-36 PFS, and FPI data at 6 months, the SRT group demonstrated a potential signal of improvement compared with the usual care group that was not evident at hospital discharge,” they wrote.

The study was supported by the National Institutes of Health, National Institute of Nursing Research, and National Heart, Lung, and Blood Institute. Lead author, Dr. Morris, had no financial conflicts to disclose.

Your patient who has schizophrenia, Mr. W, age 48, requests that you switch him from olanzapine, 10 mg/d, to another antipsychotic because he gained 25 lb over 1 month taking the drug. He now weighs 275 lb. Mr. W reports smoking at least 2 packs of cigarettes a day and takes lisinopril, 20 mg/d, for hypertension. You decide to start risperidone, 1 mg/d. First, however, your initial work-up includes:

• high-density lipoprotein (HDL), 24 mg/dL
• total cholesterol, 220 mg/dL
• blood pressure, 154/80 mm Hgwaist circumference, 39 in
• body mass index (BMI), 29
• hemoglobin A1c, of 5.6%.

A prolactin level is pending.

How do you interpret these values?

Metabolic syndrome is defined as the cluster of central obesity, insulin resistance, hypertension, and dyslipidemia. Metabolic syndrome increases a patient's risk of diabetes 5-fold and cardiovascular disease 3-fold.¹ Physical inactivity and eating high-fat foods typically precede weight gain and obesity that, in turn, develop into insulin resistance, hypertension, and dyslipidemia.¹

Patients with severe psychiatric illness have an increased rate of mortality from cardiovascular disease, compared with the general population.^2-4 The cause of this phenomenon is multifactorial: In general, patients with severe mental illness receive insufficient preventive health care, do not eat a balanced diet, and are more likely to smoke cigarettes than other people.^2-4

Also, compared with the general population, the diet of men with schizophrenia contains less vegetables and grains and women with schizophrenia consume less grains. An estimated 70% of patients with schizophrenia smoke.⁴ As measured by BMI, 86% of women with schizophrenia and 70% of men with schizophrenia are overweight or obese.⁴

Antipsychotics used to treat severe mental illness also have been implicated in metabolic syndrome, specifically second-generation antipsychotics (SGAs).⁵ Several theories aim to explain how antipsychotics lead to metabolic alterations.

Oxidative stress. One theory centers on the production of oxidative stress and the consequent reactive oxygen species that form after SGA treatment.⁶

Mitochondrial function. Another theory assesses the impact of antipsychotic treatment on mitochondrial function. Mitochondrial dysfunction causes decreased fatty acid oxidation, leading to lipid accumulation.⁷

The culminating affect of severe mental illness alone as well as treatment-emergent side effects of antipsychotics raises the question of how to best treat the dyslipidemia component of metabolic syndrome. This article will:

• review which antipsychotics impact lipids the most
• provide an overview of the most recent lipid guidelines
• describe how to best manage patients to prevent and treat dyslipidemia.

Impact of antipsychotics on lipids
Antipsychotic treatment can lead to metabolic syndrome; SGAs are implicated in most cases.⁸ A study by Liao et al⁹ investigated the risk of developing type 2 diabetes mellitus, hypertension, and hyperlipidemia in patients with schizophrenia who received treatment with a first-generation antipsychotic (FGA) compared with patients who received a SGA. The significance-adjusted hazard ratio for the development of hyperlipidemia in patients treated with a SGA was statistically significant compared with the general population (1.41; 95% CI, 1.09-1.83). The risk of hyperlipidemia in patients treated with a FGA was not significant.

Studies have aimed to describe which SGAs carry the greatest risk of hyperlipidemia.^10,11 To summarize findings, in 2004 the American Diabetes Association (ADA) and American Psychiatric Association released a consensus statement on the impact of antipsychotic medications on obesity and diabetes.¹² The statement listed the following antipsychotics in order of greatest to least impact on hyperlipidemia:

• clozapine
• olanzapine
• quetiapine
• risperidone
• ziprasidone
• aripiprazole.

To evaluate newer SGAs, a systematic review and meta-analysis by De Hert et al¹³ aimed to assess the metabolic risks associated with asenapine, iloperidone, lurasidone, and paliperidone. In general, the studies included in the meta-analysis showed little or no clinically meaningful differences among these newer agents in terms of total cholesterol in short-term trials, except for asenapine and iloperidone.

Asenapine was found to increase the total cholesterol level in long-term trials (>12 weeks) by an average of 6.53 mg/dL. These trials also demonstrated a decrease in HDL cholesterol (−0.13 mg/dL) and a decrease in low-density lipoprotein cholesterol (LDL-C) (−1.72 mg/dL to −0.86 mg/dL). The impact of asenapine on these lab results does not appear to be clinically significant.^13,14

Iloperidone. A study evaluating the impact iloperidone on lipid values showed a statistically significant increase in total cholesterol, HDL, and LDL-C levels after 12 weeks.^13,15

Overview: Latest lipid guidelines
Current literature lacks information regarding statin use for overall prevention of metabolic syndrome. However, the most recent update to the American Heart Association's guideline on treating blood cholesterol to reduce atherosclerotic cardiovascular risk in adults describes the role of statin therapy to address dyslipidemia, which is one component of metabolic syndrome.^16,17

Some of the greatest changes seen with the latest blood cholesterol guidelines include:

• focus on atherosclerotic cardiovascular disease (ASCVD) risk reduction to identify 4 statin benefit groups
• transition away from treating to a target LDL value
• use of the Pooled Cohort Equation to estimate 10-year ASCVD risk, rather than the Framingham Risk Score.

Placing patients in 1 of 4 statin benefit groups
Unlike the 2002 National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, the latest guidelines have identified 4 statin treatment benefit groups:

• patients with clinical ASCVD (including those who have had acute coronary syndrome, stroke, or myocardial infarction, or who have stable or unstable angina, transient ischemic attacks, or peripheral artery disease, or a combination of these findings)patients with LDL-C >190 mg/dL
• patients age 40 to 75 with type 1 or type 2 diabetes mellitus
• patients with an estimated 10-year ASCVD risk of ≥7.5% that was estimated using the Pooled Cohort Equation.^16,17

Table 1 represents each statin benefit group and recommended treatment options.

Selected statin therapy for each statin benefit group is further delineated into low-, moderate-, and high-intensity therapy. Intensity of statin therapy represents the expected LDL lowering capacity of selected statins. Low-intensity statin therapy, on average, is expected to lower LDL-C by <30%. Moderate-intensity statin therapy is expected to lower LDL-C by 30% to <50%. High-intensity statin therapy is expected to lower LDL-C by >50%.

When selecting treatment for patients, it is important to first determine the statin benefit group that the patient falls under, and then select the appropriate statin intensity. The categorization of the different statins based on LDL-C lowering capacity is described in Table 2.

Whenever a patient is started on statin therapy, order a liver function test and lipid profile at baseline. Repeat these tests 4 to 12 weeks after statin initiation, then every 3 to 12 months.

Transition away from treating to a target LDL-C goal
ATP III guidelines suggested that elevated LDL was the leading cause of coronary heart disease and recommended therapy with LDL-lowering medications.¹⁸ The panel that developed the 2013 lipid guideline concluded that there was no evidence that showed benefit in treating to a designated LDL-C goal.^16,17 Arguably, treating to a target may lead to overtreatment in some patients and under-treatment in others. Treatment is now recommended based on statin intensity.

Using the Pooled Cohort Equation
In moving away from the Framingham Risk Score, the latest lipid guidelines established a new calculation to assess cardiovascular disease. The Pooled Cohort Equation estimates the 10-year ASCVD risk for patients based on selected risk factors: age, sex, race, lipids, diabetes, smoking status, and blood pressure. Although other potential cardiovascular disease risk factors have been identified, the Pooled Cohort Equation focused on those risk factors that have been correlated with cardiovascular disease since the 1960s.^16,17,19 The Pooled Cohort Equation is intended to (1) more accurately identify higher-risk patients and (2) assess who would best benefit from statin therapy.

Recommended lab tests and subsequent treatment
With the new lipid guidelines in place to direct dyslipidemia treatment and a better understanding of how certain antipsychotics impact lipid values, the next step is monitoring parameters for patients. Before initiating antipsychotic treatment and in accordance with the 2014 National Institute for Health and Care Excellence (NICE) guidelines, baseline measurements should include weight, waist circumference, pulse, blood pressure, fasting blood glucose, hemoglobin A1c, blood lipid profile, and, if risperidone or paliperidone is initiated, prolactin level.²⁰ Additionally, patients should be assessed at baseline for any movement disorders as well as current nutritional status, diet, and level of physical activity.

Once treatment is selected on a patient-specific basis, weight should be measured weekly for the first 6 weeks, again at 12 weeks and 1 year, and then annually. Pulse and blood pressure should be obtained 12 weeks after treatment initiation and at 1 year. Fasting blood glucose, hemoglobin A1c, and blood lipid levels should be collected 12 weeks after treatment onset, then at the 1-year mark.²⁰ These laboratory parameters should be measured annually while the patient is receiving antipsychotic treatment.

Alternately, you can follow the monitoring parameters in the more dated 2004 ADA consensus statement:

• baseline assessment to include BMI, waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile, and personal and family history
• BMI measured again at 4 weeks, 8 weeks, 12 weeks, and then quarterly
• 12-week follow-up measurement of fasting plasma glucose, fasting lipids, and blood pressure
• annual measurement of fasting blood glucose, blood pressure, and waist circumference.¹²

In addition to the NICE guidelines and the ADA consensus statement, use of the current lipid guidelines and the Pooled Cohort Equation to assess 10-year ASCVD risk should be obtained at baseline and throughout antipsychotic treatment. If you identify an abnormality in the lipid profile, you have several options:

• Decrease the antipsychotic dosage
• Switch to an antipsychotic considered to be less risky
• Discontinue therapy
• Implement diet and exercise
• Refer the patient to a dietitian or other clinician skilled in managing overweight or obesity and hyperlipidemia.²¹

Furthermore, patients identified as being in 1 of the 4 statin benefit groups should be started on appropriate pharmacotherapy. Non-statin therapy as adjunct or in lieu of statin therapy is not considered to be first-line.¹⁶

CASE CONTINUED
After reviewing Mr. W's lab results, you calculate that he has a 24% ten-year ASCVD risk, using the Pooled Cohort Equation. Following the treatment algorithm for statin benefit groups, you see that Mr. W meets criteria for high-intensity statin therapy. You stop olanzapine, switch to risperidone, 1 mg/d, and initiate atorvastatin, 40 mg/d. You plan to assess Mr. W's weight weekly over the next 6 weeks and order a liver profile and lipid profile in 6 weeks.

Related Resource

• AHA/ACC 2013 Prevention Guidelines Tools CV Risk Calculator. https://professional.heart.org/professional/GuidelinesStatements/PreventionGuidelines/UCM_457698_Prevention-Guidelines.jsp.

Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Atorvastatin • Lipitor
Clozapine • Clozaril
Fluvastatin • Lescol
Iloperidone • Fanapt
Lovastatin • Mevacor
Lurasidone • Latuda
Olanzapine • Zyprexa
Paliperidone • Invega
Pitavastatin • Livalo
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Rosuvastatin • Crestor
Simvastatin • Zocor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio.

Your patient who has schizophrenia, Mr. W, age 48, requests that you switch him from olanzapine, 10 mg/d, to another antipsychotic because he gained 25 lb over 1 month taking the drug. He now weighs 275 lb. Mr. W reports smoking at least 2 packs of cigarettes a day and takes lisinopril, 20 mg/d, for hypertension. You decide to start risperidone, 1 mg/d. First, however, your initial work-up includes:

• high-density lipoprotein (HDL), 24 mg/dL
• total cholesterol, 220 mg/dL
• blood pressure, 154/80 mm Hgwaist circumference, 39 in
• body mass index (BMI), 29
• hemoglobin A1c, of 5.6%.

A prolactin level is pending.

How do you interpret these values?

Metabolic syndrome is defined as the cluster of central obesity, insulin resistance, hypertension, and dyslipidemia. Metabolic syndrome increases a patient's risk of diabetes 5-fold and cardiovascular disease 3-fold.¹ Physical inactivity and eating high-fat foods typically precede weight gain and obesity that, in turn, develop into insulin resistance, hypertension, and dyslipidemia.¹

Patients with severe psychiatric illness have an increased rate of mortality from cardiovascular disease, compared with the general population.^2-4 The cause of this phenomenon is multifactorial: In general, patients with severe mental illness receive insufficient preventive health care, do not eat a balanced diet, and are more likely to smoke cigarettes than other people.^2-4

Also, compared with the general population, the diet of men with schizophrenia contains less vegetables and grains and women with schizophrenia consume less grains. An estimated 70% of patients with schizophrenia smoke.⁴ As measured by BMI, 86% of women with schizophrenia and 70% of men with schizophrenia are overweight or obese.⁴

Antipsychotics used to treat severe mental illness also have been implicated in metabolic syndrome, specifically second-generation antipsychotics (SGAs).⁵ Several theories aim to explain how antipsychotics lead to metabolic alterations.

Oxidative stress. One theory centers on the production of oxidative stress and the consequent reactive oxygen species that form after SGA treatment.⁶

Mitochondrial function. Another theory assesses the impact of antipsychotic treatment on mitochondrial function. Mitochondrial dysfunction causes decreased fatty acid oxidation, leading to lipid accumulation.⁷

The culminating affect of severe mental illness alone as well as treatment-emergent side effects of antipsychotics raises the question of how to best treat the dyslipidemia component of metabolic syndrome. This article will:

• review which antipsychotics impact lipids the most
• provide an overview of the most recent lipid guidelines
• describe how to best manage patients to prevent and treat dyslipidemia.

Impact of antipsychotics on lipids
Antipsychotic treatment can lead to metabolic syndrome; SGAs are implicated in most cases.⁸ A study by Liao et al⁹ investigated the risk of developing type 2 diabetes mellitus, hypertension, and hyperlipidemia in patients with schizophrenia who received treatment with a first-generation antipsychotic (FGA) compared with patients who received a SGA. The significance-adjusted hazard ratio for the development of hyperlipidemia in patients treated with a SGA was statistically significant compared with the general population (1.41; 95% CI, 1.09-1.83). The risk of hyperlipidemia in patients treated with a FGA was not significant.

Studies have aimed to describe which SGAs carry the greatest risk of hyperlipidemia.^10,11 To summarize findings, in 2004 the American Diabetes Association (ADA) and American Psychiatric Association released a consensus statement on the impact of antipsychotic medications on obesity and diabetes.¹² The statement listed the following antipsychotics in order of greatest to least impact on hyperlipidemia:

• clozapine
• olanzapine
• quetiapine
• risperidone
• ziprasidone
• aripiprazole.

To evaluate newer SGAs, a systematic review and meta-analysis by De Hert et al¹³ aimed to assess the metabolic risks associated with asenapine, iloperidone, lurasidone, and paliperidone. In general, the studies included in the meta-analysis showed little or no clinically meaningful differences among these newer agents in terms of total cholesterol in short-term trials, except for asenapine and iloperidone.

Asenapine was found to increase the total cholesterol level in long-term trials (>12 weeks) by an average of 6.53 mg/dL. These trials also demonstrated a decrease in HDL cholesterol (−0.13 mg/dL) and a decrease in low-density lipoprotein cholesterol (LDL-C) (−1.72 mg/dL to −0.86 mg/dL). The impact of asenapine on these lab results does not appear to be clinically significant.^13,14

Iloperidone. A study evaluating the impact iloperidone on lipid values showed a statistically significant increase in total cholesterol, HDL, and LDL-C levels after 12 weeks.^13,15

Overview: Latest lipid guidelines
Current literature lacks information regarding statin use for overall prevention of metabolic syndrome. However, the most recent update to the American Heart Association's guideline on treating blood cholesterol to reduce atherosclerotic cardiovascular risk in adults describes the role of statin therapy to address dyslipidemia, which is one component of metabolic syndrome.^16,17

Some of the greatest changes seen with the latest blood cholesterol guidelines include:

• focus on atherosclerotic cardiovascular disease (ASCVD) risk reduction to identify 4 statin benefit groups
• transition away from treating to a target LDL value
• use of the Pooled Cohort Equation to estimate 10-year ASCVD risk, rather than the Framingham Risk Score.

Placing patients in 1 of 4 statin benefit groups
Unlike the 2002 National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, the latest guidelines have identified 4 statin treatment benefit groups:

• patients with clinical ASCVD (including those who have had acute coronary syndrome, stroke, or myocardial infarction, or who have stable or unstable angina, transient ischemic attacks, or peripheral artery disease, or a combination of these findings)patients with LDL-C >190 mg/dL
• patients age 40 to 75 with type 1 or type 2 diabetes mellitus
• patients with an estimated 10-year ASCVD risk of ≥7.5% that was estimated using the Pooled Cohort Equation.^16,17

Table 1 represents each statin benefit group and recommended treatment options.

Selected statin therapy for each statin benefit group is further delineated into low-, moderate-, and high-intensity therapy. Intensity of statin therapy represents the expected LDL lowering capacity of selected statins. Low-intensity statin therapy, on average, is expected to lower LDL-C by <30%. Moderate-intensity statin therapy is expected to lower LDL-C by 30% to <50%. High-intensity statin therapy is expected to lower LDL-C by >50%.

When selecting treatment for patients, it is important to first determine the statin benefit group that the patient falls under, and then select the appropriate statin intensity. The categorization of the different statins based on LDL-C lowering capacity is described in Table 2.

Whenever a patient is started on statin therapy, order a liver function test and lipid profile at baseline. Repeat these tests 4 to 12 weeks after statin initiation, then every 3 to 12 months.

Transition away from treating to a target LDL-C goal
ATP III guidelines suggested that elevated LDL was the leading cause of coronary heart disease and recommended therapy with LDL-lowering medications.¹⁸ The panel that developed the 2013 lipid guideline concluded that there was no evidence that showed benefit in treating to a designated LDL-C goal.^16,17 Arguably, treating to a target may lead to overtreatment in some patients and under-treatment in others. Treatment is now recommended based on statin intensity.

Using the Pooled Cohort Equation
In moving away from the Framingham Risk Score, the latest lipid guidelines established a new calculation to assess cardiovascular disease. The Pooled Cohort Equation estimates the 10-year ASCVD risk for patients based on selected risk factors: age, sex, race, lipids, diabetes, smoking status, and blood pressure. Although other potential cardiovascular disease risk factors have been identified, the Pooled Cohort Equation focused on those risk factors that have been correlated with cardiovascular disease since the 1960s.^16,17,19 The Pooled Cohort Equation is intended to (1) more accurately identify higher-risk patients and (2) assess who would best benefit from statin therapy.

Recommended lab tests and subsequent treatment
With the new lipid guidelines in place to direct dyslipidemia treatment and a better understanding of how certain antipsychotics impact lipid values, the next step is monitoring parameters for patients. Before initiating antipsychotic treatment and in accordance with the 2014 National Institute for Health and Care Excellence (NICE) guidelines, baseline measurements should include weight, waist circumference, pulse, blood pressure, fasting blood glucose, hemoglobin A1c, blood lipid profile, and, if risperidone or paliperidone is initiated, prolactin level.²⁰ Additionally, patients should be assessed at baseline for any movement disorders as well as current nutritional status, diet, and level of physical activity.

Once treatment is selected on a patient-specific basis, weight should be measured weekly for the first 6 weeks, again at 12 weeks and 1 year, and then annually. Pulse and blood pressure should be obtained 12 weeks after treatment initiation and at 1 year. Fasting blood glucose, hemoglobin A1c, and blood lipid levels should be collected 12 weeks after treatment onset, then at the 1-year mark.²⁰ These laboratory parameters should be measured annually while the patient is receiving antipsychotic treatment.

Alternately, you can follow the monitoring parameters in the more dated 2004 ADA consensus statement:

• baseline assessment to include BMI, waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile, and personal and family history
• BMI measured again at 4 weeks, 8 weeks, 12 weeks, and then quarterly
• 12-week follow-up measurement of fasting plasma glucose, fasting lipids, and blood pressure
• annual measurement of fasting blood glucose, blood pressure, and waist circumference.¹²

In addition to the NICE guidelines and the ADA consensus statement, use of the current lipid guidelines and the Pooled Cohort Equation to assess 10-year ASCVD risk should be obtained at baseline and throughout antipsychotic treatment. If you identify an abnormality in the lipid profile, you have several options:

• Decrease the antipsychotic dosage
• Switch to an antipsychotic considered to be less risky
• Discontinue therapy
• Implement diet and exercise
• Refer the patient to a dietitian or other clinician skilled in managing overweight or obesity and hyperlipidemia.²¹

Furthermore, patients identified as being in 1 of the 4 statin benefit groups should be started on appropriate pharmacotherapy. Non-statin therapy as adjunct or in lieu of statin therapy is not considered to be first-line.¹⁶

CASE CONTINUED
After reviewing Mr. W's lab results, you calculate that he has a 24% ten-year ASCVD risk, using the Pooled Cohort Equation. Following the treatment algorithm for statin benefit groups, you see that Mr. W meets criteria for high-intensity statin therapy. You stop olanzapine, switch to risperidone, 1 mg/d, and initiate atorvastatin, 40 mg/d. You plan to assess Mr. W's weight weekly over the next 6 weeks and order a liver profile and lipid profile in 6 weeks.

Related Resource

• AHA/ACC 2013 Prevention Guidelines Tools CV Risk Calculator. https://professional.heart.org/professional/GuidelinesStatements/PreventionGuidelines/UCM_457698_Prevention-Guidelines.jsp.

Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Atorvastatin • Lipitor
Clozapine • Clozaril
Fluvastatin • Lescol
Iloperidone • Fanapt
Lovastatin • Mevacor
Lurasidone • Latuda
Olanzapine • Zyprexa
Paliperidone • Invega
Pitavastatin • Livalo
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Rosuvastatin • Crestor
Simvastatin • Zocor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio.

Your patient who has schizophrenia, Mr. W, age 48, requests that you switch him from olanzapine, 10 mg/d, to another antipsychotic because he gained 25 lb over 1 month taking the drug. He now weighs 275 lb. Mr. W reports smoking at least 2 packs of cigarettes a day and takes lisinopril, 20 mg/d, for hypertension. You decide to start risperidone, 1 mg/d. First, however, your initial work-up includes:

• high-density lipoprotein (HDL), 24 mg/dL
• total cholesterol, 220 mg/dL
• blood pressure, 154/80 mm Hgwaist circumference, 39 in
• body mass index (BMI), 29
• hemoglobin A1c, of 5.6%.

A prolactin level is pending.

How do you interpret these values?

Metabolic syndrome is defined as the cluster of central obesity, insulin resistance, hypertension, and dyslipidemia. Metabolic syndrome increases a patient's risk of diabetes 5-fold and cardiovascular disease 3-fold.¹ Physical inactivity and eating high-fat foods typically precede weight gain and obesity that, in turn, develop into insulin resistance, hypertension, and dyslipidemia.¹

Patients with severe psychiatric illness have an increased rate of mortality from cardiovascular disease, compared with the general population.^2-4 The cause of this phenomenon is multifactorial: In general, patients with severe mental illness receive insufficient preventive health care, do not eat a balanced diet, and are more likely to smoke cigarettes than other people.^2-4

Also, compared with the general population, the diet of men with schizophrenia contains less vegetables and grains and women with schizophrenia consume less grains. An estimated 70% of patients with schizophrenia smoke.⁴ As measured by BMI, 86% of women with schizophrenia and 70% of men with schizophrenia are overweight or obese.⁴

Antipsychotics used to treat severe mental illness also have been implicated in metabolic syndrome, specifically second-generation antipsychotics (SGAs).⁵ Several theories aim to explain how antipsychotics lead to metabolic alterations.

Oxidative stress. One theory centers on the production of oxidative stress and the consequent reactive oxygen species that form after SGA treatment.⁶

Mitochondrial function. Another theory assesses the impact of antipsychotic treatment on mitochondrial function. Mitochondrial dysfunction causes decreased fatty acid oxidation, leading to lipid accumulation.⁷

The culminating affect of severe mental illness alone as well as treatment-emergent side effects of antipsychotics raises the question of how to best treat the dyslipidemia component of metabolic syndrome. This article will:

• review which antipsychotics impact lipids the most
• provide an overview of the most recent lipid guidelines
• describe how to best manage patients to prevent and treat dyslipidemia.

Impact of antipsychotics on lipids
Antipsychotic treatment can lead to metabolic syndrome; SGAs are implicated in most cases.⁸ A study by Liao et al⁹ investigated the risk of developing type 2 diabetes mellitus, hypertension, and hyperlipidemia in patients with schizophrenia who received treatment with a first-generation antipsychotic (FGA) compared with patients who received a SGA. The significance-adjusted hazard ratio for the development of hyperlipidemia in patients treated with a SGA was statistically significant compared with the general population (1.41; 95% CI, 1.09-1.83). The risk of hyperlipidemia in patients treated with a FGA was not significant.

Studies have aimed to describe which SGAs carry the greatest risk of hyperlipidemia.^10,11 To summarize findings, in 2004 the American Diabetes Association (ADA) and American Psychiatric Association released a consensus statement on the impact of antipsychotic medications on obesity and diabetes.¹² The statement listed the following antipsychotics in order of greatest to least impact on hyperlipidemia:

• clozapine
• olanzapine
• quetiapine
• risperidone
• ziprasidone
• aripiprazole.

To evaluate newer SGAs, a systematic review and meta-analysis by De Hert et al¹³ aimed to assess the metabolic risks associated with asenapine, iloperidone, lurasidone, and paliperidone. In general, the studies included in the meta-analysis showed little or no clinically meaningful differences among these newer agents in terms of total cholesterol in short-term trials, except for asenapine and iloperidone.

Asenapine was found to increase the total cholesterol level in long-term trials (>12 weeks) by an average of 6.53 mg/dL. These trials also demonstrated a decrease in HDL cholesterol (−0.13 mg/dL) and a decrease in low-density lipoprotein cholesterol (LDL-C) (−1.72 mg/dL to −0.86 mg/dL). The impact of asenapine on these lab results does not appear to be clinically significant.^13,14

Iloperidone. A study evaluating the impact iloperidone on lipid values showed a statistically significant increase in total cholesterol, HDL, and LDL-C levels after 12 weeks.^13,15

Overview: Latest lipid guidelines
Current literature lacks information regarding statin use for overall prevention of metabolic syndrome. However, the most recent update to the American Heart Association's guideline on treating blood cholesterol to reduce atherosclerotic cardiovascular risk in adults describes the role of statin therapy to address dyslipidemia, which is one component of metabolic syndrome.^16,17

Some of the greatest changes seen with the latest blood cholesterol guidelines include:

• focus on atherosclerotic cardiovascular disease (ASCVD) risk reduction to identify 4 statin benefit groups
• transition away from treating to a target LDL value
• use of the Pooled Cohort Equation to estimate 10-year ASCVD risk, rather than the Framingham Risk Score.

Placing patients in 1 of 4 statin benefit groups
Unlike the 2002 National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, the latest guidelines have identified 4 statin treatment benefit groups:

• patients with clinical ASCVD (including those who have had acute coronary syndrome, stroke, or myocardial infarction, or who have stable or unstable angina, transient ischemic attacks, or peripheral artery disease, or a combination of these findings)patients with LDL-C >190 mg/dL
• patients age 40 to 75 with type 1 or type 2 diabetes mellitus
• patients with an estimated 10-year ASCVD risk of ≥7.5% that was estimated using the Pooled Cohort Equation.^16,17

Table 1 represents each statin benefit group and recommended treatment options.

Selected statin therapy for each statin benefit group is further delineated into low-, moderate-, and high-intensity therapy. Intensity of statin therapy represents the expected LDL lowering capacity of selected statins. Low-intensity statin therapy, on average, is expected to lower LDL-C by <30%. Moderate-intensity statin therapy is expected to lower LDL-C by 30% to <50%. High-intensity statin therapy is expected to lower LDL-C by >50%.

When selecting treatment for patients, it is important to first determine the statin benefit group that the patient falls under, and then select the appropriate statin intensity. The categorization of the different statins based on LDL-C lowering capacity is described in Table 2.

Whenever a patient is started on statin therapy, order a liver function test and lipid profile at baseline. Repeat these tests 4 to 12 weeks after statin initiation, then every 3 to 12 months.

Transition away from treating to a target LDL-C goal
ATP III guidelines suggested that elevated LDL was the leading cause of coronary heart disease and recommended therapy with LDL-lowering medications.¹⁸ The panel that developed the 2013 lipid guideline concluded that there was no evidence that showed benefit in treating to a designated LDL-C goal.^16,17 Arguably, treating to a target may lead to overtreatment in some patients and under-treatment in others. Treatment is now recommended based on statin intensity.

Using the Pooled Cohort Equation
In moving away from the Framingham Risk Score, the latest lipid guidelines established a new calculation to assess cardiovascular disease. The Pooled Cohort Equation estimates the 10-year ASCVD risk for patients based on selected risk factors: age, sex, race, lipids, diabetes, smoking status, and blood pressure. Although other potential cardiovascular disease risk factors have been identified, the Pooled Cohort Equation focused on those risk factors that have been correlated with cardiovascular disease since the 1960s.^16,17,19 The Pooled Cohort Equation is intended to (1) more accurately identify higher-risk patients and (2) assess who would best benefit from statin therapy.

Recommended lab tests and subsequent treatment
With the new lipid guidelines in place to direct dyslipidemia treatment and a better understanding of how certain antipsychotics impact lipid values, the next step is monitoring parameters for patients. Before initiating antipsychotic treatment and in accordance with the 2014 National Institute for Health and Care Excellence (NICE) guidelines, baseline measurements should include weight, waist circumference, pulse, blood pressure, fasting blood glucose, hemoglobin A1c, blood lipid profile, and, if risperidone or paliperidone is initiated, prolactin level.²⁰ Additionally, patients should be assessed at baseline for any movement disorders as well as current nutritional status, diet, and level of physical activity.

Once treatment is selected on a patient-specific basis, weight should be measured weekly for the first 6 weeks, again at 12 weeks and 1 year, and then annually. Pulse and blood pressure should be obtained 12 weeks after treatment initiation and at 1 year. Fasting blood glucose, hemoglobin A1c, and blood lipid levels should be collected 12 weeks after treatment onset, then at the 1-year mark.²⁰ These laboratory parameters should be measured annually while the patient is receiving antipsychotic treatment.

Alternately, you can follow the monitoring parameters in the more dated 2004 ADA consensus statement:

• baseline assessment to include BMI, waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile, and personal and family history
• BMI measured again at 4 weeks, 8 weeks, 12 weeks, and then quarterly
• 12-week follow-up measurement of fasting plasma glucose, fasting lipids, and blood pressure
• annual measurement of fasting blood glucose, blood pressure, and waist circumference.¹²

In addition to the NICE guidelines and the ADA consensus statement, use of the current lipid guidelines and the Pooled Cohort Equation to assess 10-year ASCVD risk should be obtained at baseline and throughout antipsychotic treatment. If you identify an abnormality in the lipid profile, you have several options:

• Decrease the antipsychotic dosage
• Switch to an antipsychotic considered to be less risky
• Discontinue therapy
• Implement diet and exercise
• Refer the patient to a dietitian or other clinician skilled in managing overweight or obesity and hyperlipidemia.²¹

Furthermore, patients identified as being in 1 of the 4 statin benefit groups should be started on appropriate pharmacotherapy. Non-statin therapy as adjunct or in lieu of statin therapy is not considered to be first-line.¹⁶

CASE CONTINUED
After reviewing Mr. W's lab results, you calculate that he has a 24% ten-year ASCVD risk, using the Pooled Cohort Equation. Following the treatment algorithm for statin benefit groups, you see that Mr. W meets criteria for high-intensity statin therapy. You stop olanzapine, switch to risperidone, 1 mg/d, and initiate atorvastatin, 40 mg/d. You plan to assess Mr. W's weight weekly over the next 6 weeks and order a liver profile and lipid profile in 6 weeks.

Related Resource

• AHA/ACC 2013 Prevention Guidelines Tools CV Risk Calculator. https://professional.heart.org/professional/GuidelinesStatements/PreventionGuidelines/UCM_457698_Prevention-Guidelines.jsp.

Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Atorvastatin • Lipitor
Clozapine • Clozaril
Fluvastatin • Lescol
Iloperidone • Fanapt
Lovastatin • Mevacor
Lurasidone • Latuda
Olanzapine • Zyprexa
Paliperidone • Invega
Pitavastatin • Livalo
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Rosuvastatin • Crestor
Simvastatin • Zocor
Ziprasidone • Geodon

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio.

Brain stimulation often is used for treatment-resistant depression when medications and psychotherapy are not enough to elicit a meaningful response. It is both old and new again: electroconvulsive therapy (ECT) has been used for decades, while emerging technologies, such as transcranial magnetic stimulation (TMS), are gaining acceptance.

Patients and families often arrive at the office with fears and assumptions about these types of treatments, which should be discussed openly. There are also differences between these treatment approaches that can be discussed (Table).

Electroconvulsive therapy
Although ECT has been shown to be the most efficacious treatment for treatment-resistant depression,¹ the most common response from patients and families that I hear when discussing ECT use is, “Do you really still do that?” Many patients and family members associate this treatment with mass media portrayals over the past several decades, such as the motion picture One Flew Over the Cuckoo’s Nest, which paired inhumane and unnecessary use of ECT with a frontal lobotomy, thereby associating this treatment with something inherently unethical.

My approach to discussing ECT with patients and families is to convey these main points:

• Consensual. In most cases, ECT is performed with the explicit informed consent of the patient, and is not done against the patient’s will.
• Effective. ECT has a remission rate of 75% after the first 2 weeks of use in patients suffering from acute depressive illnesses.²
• Safe. ECT protocols have evolved to maximize efficacy while minimizing adverse effects. Advances in anesthesia use with paralytic agents and anti-inflammatory medications reduce convulsions and subsequent musculoskeletal discomfort.

In addition, I note that:

• Ultra-brief stimulation parameters often are used to minimize cognitive side effects.
• ECT is associated with some psychosocial limitations, including being unable to drive during acute treatment and requiring supervision for several hours after sessions.

Transcranial magnetic stimulation
The field of non-invasive brain stimulation—in particular, TMS—faces a different set of complex issues to navigate. Because TMS is relatively new (approved by the FDA in 2008 for treatment-resistant depression),³ patients and families might believe that TMS may be more effective than ECT, which has not been demonstrated.⁴ It is important to communicate that:

• Although TMS is a FDA-approved treatment that has helped many patients with treatment-resistant depression, ECT remains the clinical treatment of choice for severe depression.
• Among antidepressant non-responders who had stopped all other antidepressant treatment, 44% of those who received deep TMS responded to treatment after 16 weeks, compared with 26% who received sham treatment.⁵
• Most patients usually require TMS for 4 to 6 weeks, 5 days a week, before beginning a taper phase.
• TMS has few side effects (headache being the most common); serious adverse effects (seizures, mania) have been reported but are rare.³
• Patients usually are able to continue their daily life and other outpatient treatments without the restrictions often placed on patients receiving ECT.
• If the patient responded to ECT in the past but could not tolerate adverse cognitive effects, TMS might be a better choice than other treatments.

Brain stimulation often is used for treatment-resistant depression when medications and psychotherapy are not enough to elicit a meaningful response. It is both old and new again: electroconvulsive therapy (ECT) has been used for decades, while emerging technologies, such as transcranial magnetic stimulation (TMS), are gaining acceptance.

Patients and families often arrive at the office with fears and assumptions about these types of treatments, which should be discussed openly. There are also differences between these treatment approaches that can be discussed (Table).

Electroconvulsive therapy
Although ECT has been shown to be the most efficacious treatment for treatment-resistant depression,¹ the most common response from patients and families that I hear when discussing ECT use is, “Do you really still do that?” Many patients and family members associate this treatment with mass media portrayals over the past several decades, such as the motion picture One Flew Over the Cuckoo’s Nest, which paired inhumane and unnecessary use of ECT with a frontal lobotomy, thereby associating this treatment with something inherently unethical.

My approach to discussing ECT with patients and families is to convey these main points:

• Consensual. In most cases, ECT is performed with the explicit informed consent of the patient, and is not done against the patient’s will.
• Effective. ECT has a remission rate of 75% after the first 2 weeks of use in patients suffering from acute depressive illnesses.²
• Safe. ECT protocols have evolved to maximize efficacy while minimizing adverse effects. Advances in anesthesia use with paralytic agents and anti-inflammatory medications reduce convulsions and subsequent musculoskeletal discomfort.

In addition, I note that:

• Ultra-brief stimulation parameters often are used to minimize cognitive side effects.
• ECT is associated with some psychosocial limitations, including being unable to drive during acute treatment and requiring supervision for several hours after sessions.

Transcranial magnetic stimulation
The field of non-invasive brain stimulation—in particular, TMS—faces a different set of complex issues to navigate. Because TMS is relatively new (approved by the FDA in 2008 for treatment-resistant depression),³ patients and families might believe that TMS may be more effective than ECT, which has not been demonstrated.⁴ It is important to communicate that:

• Although TMS is a FDA-approved treatment that has helped many patients with treatment-resistant depression, ECT remains the clinical treatment of choice for severe depression.
• Among antidepressant non-responders who had stopped all other antidepressant treatment, 44% of those who received deep TMS responded to treatment after 16 weeks, compared with 26% who received sham treatment.⁵
• Most patients usually require TMS for 4 to 6 weeks, 5 days a week, before beginning a taper phase.
• TMS has few side effects (headache being the most common); serious adverse effects (seizures, mania) have been reported but are rare.³
• Patients usually are able to continue their daily life and other outpatient treatments without the restrictions often placed on patients receiving ECT.
• If the patient responded to ECT in the past but could not tolerate adverse cognitive effects, TMS might be a better choice than other treatments.

Brain stimulation often is used for treatment-resistant depression when medications and psychotherapy are not enough to elicit a meaningful response. It is both old and new again: electroconvulsive therapy (ECT) has been used for decades, while emerging technologies, such as transcranial magnetic stimulation (TMS), are gaining acceptance.

Patients and families often arrive at the office with fears and assumptions about these types of treatments, which should be discussed openly. There are also differences between these treatment approaches that can be discussed (Table).

Electroconvulsive therapy
Although ECT has been shown to be the most efficacious treatment for treatment-resistant depression,¹ the most common response from patients and families that I hear when discussing ECT use is, “Do you really still do that?” Many patients and family members associate this treatment with mass media portrayals over the past several decades, such as the motion picture One Flew Over the Cuckoo’s Nest, which paired inhumane and unnecessary use of ECT with a frontal lobotomy, thereby associating this treatment with something inherently unethical.

My approach to discussing ECT with patients and families is to convey these main points:

• Consensual. In most cases, ECT is performed with the explicit informed consent of the patient, and is not done against the patient’s will.
• Effective. ECT has a remission rate of 75% after the first 2 weeks of use in patients suffering from acute depressive illnesses.²
• Safe. ECT protocols have evolved to maximize efficacy while minimizing adverse effects. Advances in anesthesia use with paralytic agents and anti-inflammatory medications reduce convulsions and subsequent musculoskeletal discomfort.

In addition, I note that:

• Ultra-brief stimulation parameters often are used to minimize cognitive side effects.
• ECT is associated with some psychosocial limitations, including being unable to drive during acute treatment and requiring supervision for several hours after sessions.

Transcranial magnetic stimulation
The field of non-invasive brain stimulation—in particular, TMS—faces a different set of complex issues to navigate. Because TMS is relatively new (approved by the FDA in 2008 for treatment-resistant depression),³ patients and families might believe that TMS may be more effective than ECT, which has not been demonstrated.⁴ It is important to communicate that:

• Although TMS is a FDA-approved treatment that has helped many patients with treatment-resistant depression, ECT remains the clinical treatment of choice for severe depression.
• Among antidepressant non-responders who had stopped all other antidepressant treatment, 44% of those who received deep TMS responded to treatment after 16 weeks, compared with 26% who received sham treatment.⁵
• Most patients usually require TMS for 4 to 6 weeks, 5 days a week, before beginning a taper phase.
• TMS has few side effects (headache being the most common); serious adverse effects (seizures, mania) have been reported but are rare.³
• Patients usually are able to continue their daily life and other outpatient treatments without the restrictions often placed on patients receiving ECT.
• If the patient responded to ECT in the past but could not tolerate adverse cognitive effects, TMS might be a better choice than other treatments.

Although clozapine is the medication with the clearest benefits in treatment-resistant schizophrenia, many eligible patients never receive it. In the United States, 20% to 30% of patients with schizophrenia can be classified as treatment resistant, but clozapine accounts for <5% of antipsychotics prescribed.^1,2 Clinicians worldwide tend to under-prescribe clozapine³—a reluctance one author coined as “clozaphobia.”⁴

Admittedly, clozapine has had a turbulent history—both lauded as a near-miracle drug and condemned as a deadly agent. The FDA has overhauled its prescribing and monitoring guidelines, however, offering psychiatrists a perfect opportunity to reacquaint themselves with this potentially life-changing intervention.

We begin this article with clozapine’s story, then spotlight new terrain the FDA created in 2015 when the agency introduced the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Our goal in the 3 articles of this series is to deepen your appreciation for this tricyclic antipsychotic and provide practical clinical guidance for using it safely and effectively.

Setbacks, but the drug has an enduring presenceThe 1950s was an exciting era of exploration for new psychotropic medications. While searching for tricyclic antidepressants, Wander Laboratories discovered neuroleptic tricyclics, with clozapine identified in 1959 (Figure 1). Haloperidol’s development and release in the 1960s reinforced the prevailing dogma of the time that effective neuroleptics correlated with extrapyramidal symptoms, thus limiting interest in the newly discovered, but pharmacologically unique, clozapine. Throughout the 1960s, most research on clozapine was published in German, with less of an international presence.⁵

Agranulocytosis deaths. Clozapine earned its scarlet letter in 1975, when 8 patients in Finland died of agranulocytosis.⁶ Sandoz, its manufacturer, withdrew clozapine from the market and halted all clinical trials. The Finnish epidemic triggered detailed investigations into blood dyscrasias and early identification of agranulocytosis associated with clozapine and other antipsychotics.⁷

Clozapine endured only because of its unique efficacy. When psychiatrists witnessed relapses in patients who had to discontinue clozapine, some countries allowed its use with strict monitoring.⁵ The FDA kept clozapine minimally available in the United States by allowing so-called “compassionate need programs” to continue.⁷

New data, FDA approval. Two studies in 1987 and 1988 that compared clozapine with chlorpromazine for treatment-refractory schizophrenia demonstrated clozapine’s superior effect on both negative and positive symptoms.^8,9 The FDA approved clozapine for refractory schizophrenia in 1989, and clozapine became clinically available in 1990.

Initially, the high annual cost of clozapine’s required “bundle” ($8,900 per patient for medication and monitoring) led to political outcry. As patients and their family struggled to afford the newly released medication, multiple states filed antitrust lawsuits. A federal court found both the manufacturer and individual states at fault and required expanded access to clozapine and its necessary monitoring. National clozapine registries were formed, and bundling was eliminated.⁷

The clozapine REMS programSix clozapine registries operated independently, each managed by a different manufacturer,¹⁰ until the FDA introduced REMS in September 2015. The REMS program created a centralized registry to monitor all U.S. patients treated with clozapine and made important changes to prescribing and monitoring guidelines.^11,12 It also incorporated the National Non-Rechallenge Master File (NNRMF).

Initially, the REMS program was scheduled for rollout October 12, 2015, the closing date of the 6 registries. Since November 2015, pharmacies have been required to register with the program to dispense clozapine. A similar registration deadline for clozapine prescribers was extended indefinitely, however, because of technical problems. Once the deadline is finalized, all clozapine prescribers must complete 3 steps to be certified in the REMS program (Table 1).¹¹

New requirements. Certified clozapine prescribers will have new responsibilities: enrolling patients and submitting lab results. They can designate someone else to perform these tasks on their behalf, but designees must enroll in the REMS program and the prescriber must confirm the designee. Pharmacists can no longer enroll patients for clozapine therapy unless they are confirmed as a prescriber designee. For outpatients, the absolute neutrophil count (ANC) must be reported before the pharmacy can dispense clozapine. For inpatients, the ANC must be reported within 7 days of the patient’s most recent blood draw.

Once the system is fully operational, Social Security numbers will no longer be used as patient identification for dispensing clozapine. Instead, outpatient pharmacies will obtain a predispense authorization, or PDA, from the REMS program. A person initiated on clozapine as an inpatient must be re-enrolled after discharge by their outpatient prescriber.

The REMS program includes information about clozapine patients who were maintained through the 6 registries, and these patients have been allowed to continue clozapine treatment. Data pertaining to patients last prescribed clozapine before October 1, 2012, did not transfer into the new system unless their name was on the NNRMF.

CASE 
Is Mr. A a candidate for clozapine?Age 28, with schizophrenia, Mr. A is highly disorganized and psychotic when brought to the emergency room by police for inappropriate behavior. His family arrives and reports that similar events have occurred several times over the past few years. Mr. A’s outpatient psychiatrist has prescribed 3 different antipsychotic medications at adequate dosages, including 1 long-acting injectable, but Mr. A has remained consistently symptomatic.

Although disorganized and psychotic, Mr. A does not meet criteria for long-term involuntary hospitalization. His family wants to take him home, and the treatment team discusses clozapine as an anti­psychotic option. Mr. A and his family agree to a trial of clozapine during voluntary hospitalization, but they would like him home within a week to attend his sister’s birthday party.

The treatment team decides to initiate clozapine and monitor his response in a controlled setting for a few days before transitioning him to outpatient care.

Initiating clozapine therapyThe case of Mr. A exemplifies a situation in which initiating clozapine is a reasonable clinical consideration. As the first step, we recommend checking baseline lab values and vital signs (Table 2), keeping in mind that the REMS program requires a baseline ANC within 7 days of initiating clozapine. When working with a highly disorganized or agitated patient, balance benefits of testing against the risk of harm to staff and patient.

REMS guidelines recommend a baseline ANC ≥1,500/µL for a new patient starting clozapine, except when benign ethnic neutropenia (BEN) has been confirmed. (Initiation guidelines for BEN are discussed later in this article.)

Dosing alternatives. We recommend following the manufacturer’s dosing guidelines when initiating clozapine (Figure 2).^13,14 Three oral forms are available: tablet, disintegrating tablet, and suspension. All can be titrated using the schedule suggested with tablets. The disintegrating tablets or suspension might be beneficial for a patient with either:

• a history of “cheeking” or otherwise disposing of tablets
• a medical condition that affects swallowing or absorption.

The disintegrating tablet is available in 12.5-mg, 25-mg, 100-mg, 150-mg, and 200-mg doses. It dissolves without requiring additional liquids. Each mL of the suspension contains 50 mg of clozapine.

Rapid titration? One group, working in Romania, examined the safety and efficacy of rapid titration of clozapine in 111 inpatients with schizophrenia.¹⁵ In the absence of additional studies, we do not recommend routine rapid titration of clozapine.

Monitoring: Greater flexibilityUnder the REMS program, laboratory monitoring of clozapine treatment must continue indefinitely. If not, pharmacies cannot dispense clozapine. Fortunately, the ANC is the only lab value tracked by the registry, and the frequency of required blood draws decreases over time (Figure 3).

Other guideline changes provide clinicians with greater flexibility to make patient-specific treatment decisions; for example, the allowable ANC to continue clozapine therapy has decreased. Usually, clozapine therapy should be interrupted for an ANC <1,000/µL if the prescriber suspects clozapine-induced neutropenia. Even when the ANC drops below 1,000/µL, however, prescribers can now continue clozapine treatment if they consider the benefits to outweigh risks for a given patient.

Separate guidelines now exist for patients with BEN, most commonly observed in persons of certain ethnic groups. BEN typically is diagnosed based on repeated ANC values <1,500/µL over several months. Patients with BEN do not have an increased risk of oral or systemic infections, as occur with other congenital neutropenias.¹⁶ In patients with BEN, clozapine therapy:

• can be initiated only after at least 2 baseline ANC measurements ≥1,000/µL
• should be interrupted for an ANC <500/µL if the prescriber suspects clozapine-induced neutropenia.

Substantial drops in ANC no longer require action (repeat lab draws) unless the drop causes neutropenia. Prescribers will receive an automated notification any time a patient experiences neutropenia that is considered mild (ANC 1,000 to 1,499/µL), moderate (ANC 500 to 999/µL), or severe (ANC <500/µL).

The NNRMF list is no longer definitive. All patients are now eligible for rechallenge, assuming they meet the new clozapine initiation criteria.

Next, when rediscovering clozapine: Adverse effectsDespite an intimidating list of side effects and interactions, clozapine is associated with a significant reduction in patients’ risk of overall mortality. In Part 2 of this series in the August 2016 issue, we discuss early identification of clozapine’s adverse effects and provide guidance for management.

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

Although clozapine is the medication with the clearest benefits in treatment-resistant schizophrenia, many eligible patients never receive it. In the United States, 20% to 30% of patients with schizophrenia can be classified as treatment resistant, but clozapine accounts for <5% of antipsychotics prescribed.^1,2 Clinicians worldwide tend to under-prescribe clozapine³—a reluctance one author coined as “clozaphobia.”⁴

Admittedly, clozapine has had a turbulent history—both lauded as a near-miracle drug and condemned as a deadly agent. The FDA has overhauled its prescribing and monitoring guidelines, however, offering psychiatrists a perfect opportunity to reacquaint themselves with this potentially life-changing intervention.

We begin this article with clozapine’s story, then spotlight new terrain the FDA created in 2015 when the agency introduced the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Our goal in the 3 articles of this series is to deepen your appreciation for this tricyclic antipsychotic and provide practical clinical guidance for using it safely and effectively.

Setbacks, but the drug has an enduring presenceThe 1950s was an exciting era of exploration for new psychotropic medications. While searching for tricyclic antidepressants, Wander Laboratories discovered neuroleptic tricyclics, with clozapine identified in 1959 (Figure 1). Haloperidol’s development and release in the 1960s reinforced the prevailing dogma of the time that effective neuroleptics correlated with extrapyramidal symptoms, thus limiting interest in the newly discovered, but pharmacologically unique, clozapine. Throughout the 1960s, most research on clozapine was published in German, with less of an international presence.⁵

Agranulocytosis deaths. Clozapine earned its scarlet letter in 1975, when 8 patients in Finland died of agranulocytosis.⁶ Sandoz, its manufacturer, withdrew clozapine from the market and halted all clinical trials. The Finnish epidemic triggered detailed investigations into blood dyscrasias and early identification of agranulocytosis associated with clozapine and other antipsychotics.⁷

Clozapine endured only because of its unique efficacy. When psychiatrists witnessed relapses in patients who had to discontinue clozapine, some countries allowed its use with strict monitoring.⁵ The FDA kept clozapine minimally available in the United States by allowing so-called “compassionate need programs” to continue.⁷

New data, FDA approval. Two studies in 1987 and 1988 that compared clozapine with chlorpromazine for treatment-refractory schizophrenia demonstrated clozapine’s superior effect on both negative and positive symptoms.^8,9 The FDA approved clozapine for refractory schizophrenia in 1989, and clozapine became clinically available in 1990.

Initially, the high annual cost of clozapine’s required “bundle” ($8,900 per patient for medication and monitoring) led to political outcry. As patients and their family struggled to afford the newly released medication, multiple states filed antitrust lawsuits. A federal court found both the manufacturer and individual states at fault and required expanded access to clozapine and its necessary monitoring. National clozapine registries were formed, and bundling was eliminated.⁷

The clozapine REMS programSix clozapine registries operated independently, each managed by a different manufacturer,¹⁰ until the FDA introduced REMS in September 2015. The REMS program created a centralized registry to monitor all U.S. patients treated with clozapine and made important changes to prescribing and monitoring guidelines.^11,12 It also incorporated the National Non-Rechallenge Master File (NNRMF).

Initially, the REMS program was scheduled for rollout October 12, 2015, the closing date of the 6 registries. Since November 2015, pharmacies have been required to register with the program to dispense clozapine. A similar registration deadline for clozapine prescribers was extended indefinitely, however, because of technical problems. Once the deadline is finalized, all clozapine prescribers must complete 3 steps to be certified in the REMS program (Table 1).¹¹

New requirements. Certified clozapine prescribers will have new responsibilities: enrolling patients and submitting lab results. They can designate someone else to perform these tasks on their behalf, but designees must enroll in the REMS program and the prescriber must confirm the designee. Pharmacists can no longer enroll patients for clozapine therapy unless they are confirmed as a prescriber designee. For outpatients, the absolute neutrophil count (ANC) must be reported before the pharmacy can dispense clozapine. For inpatients, the ANC must be reported within 7 days of the patient’s most recent blood draw.

Once the system is fully operational, Social Security numbers will no longer be used as patient identification for dispensing clozapine. Instead, outpatient pharmacies will obtain a predispense authorization, or PDA, from the REMS program. A person initiated on clozapine as an inpatient must be re-enrolled after discharge by their outpatient prescriber.

The REMS program includes information about clozapine patients who were maintained through the 6 registries, and these patients have been allowed to continue clozapine treatment. Data pertaining to patients last prescribed clozapine before October 1, 2012, did not transfer into the new system unless their name was on the NNRMF.

CASE 
Is Mr. A a candidate for clozapine?Age 28, with schizophrenia, Mr. A is highly disorganized and psychotic when brought to the emergency room by police for inappropriate behavior. His family arrives and reports that similar events have occurred several times over the past few years. Mr. A’s outpatient psychiatrist has prescribed 3 different antipsychotic medications at adequate dosages, including 1 long-acting injectable, but Mr. A has remained consistently symptomatic.

Although disorganized and psychotic, Mr. A does not meet criteria for long-term involuntary hospitalization. His family wants to take him home, and the treatment team discusses clozapine as an anti­psychotic option. Mr. A and his family agree to a trial of clozapine during voluntary hospitalization, but they would like him home within a week to attend his sister’s birthday party.

The treatment team decides to initiate clozapine and monitor his response in a controlled setting for a few days before transitioning him to outpatient care.

Initiating clozapine therapyThe case of Mr. A exemplifies a situation in which initiating clozapine is a reasonable clinical consideration. As the first step, we recommend checking baseline lab values and vital signs (Table 2), keeping in mind that the REMS program requires a baseline ANC within 7 days of initiating clozapine. When working with a highly disorganized or agitated patient, balance benefits of testing against the risk of harm to staff and patient.

REMS guidelines recommend a baseline ANC ≥1,500/µL for a new patient starting clozapine, except when benign ethnic neutropenia (BEN) has been confirmed. (Initiation guidelines for BEN are discussed later in this article.)

Dosing alternatives. We recommend following the manufacturer’s dosing guidelines when initiating clozapine (Figure 2).^13,14 Three oral forms are available: tablet, disintegrating tablet, and suspension. All can be titrated using the schedule suggested with tablets. The disintegrating tablets or suspension might be beneficial for a patient with either:

• a history of “cheeking” or otherwise disposing of tablets
• a medical condition that affects swallowing or absorption.

The disintegrating tablet is available in 12.5-mg, 25-mg, 100-mg, 150-mg, and 200-mg doses. It dissolves without requiring additional liquids. Each mL of the suspension contains 50 mg of clozapine.

Rapid titration? One group, working in Romania, examined the safety and efficacy of rapid titration of clozapine in 111 inpatients with schizophrenia.¹⁵ In the absence of additional studies, we do not recommend routine rapid titration of clozapine.

Monitoring: Greater flexibilityUnder the REMS program, laboratory monitoring of clozapine treatment must continue indefinitely. If not, pharmacies cannot dispense clozapine. Fortunately, the ANC is the only lab value tracked by the registry, and the frequency of required blood draws decreases over time (Figure 3).

Other guideline changes provide clinicians with greater flexibility to make patient-specific treatment decisions; for example, the allowable ANC to continue clozapine therapy has decreased. Usually, clozapine therapy should be interrupted for an ANC <1,000/µL if the prescriber suspects clozapine-induced neutropenia. Even when the ANC drops below 1,000/µL, however, prescribers can now continue clozapine treatment if they consider the benefits to outweigh risks for a given patient.

Separate guidelines now exist for patients with BEN, most commonly observed in persons of certain ethnic groups. BEN typically is diagnosed based on repeated ANC values <1,500/µL over several months. Patients with BEN do not have an increased risk of oral or systemic infections, as occur with other congenital neutropenias.¹⁶ In patients with BEN, clozapine therapy:

• can be initiated only after at least 2 baseline ANC measurements ≥1,000/µL
• should be interrupted for an ANC <500/µL if the prescriber suspects clozapine-induced neutropenia.

Substantial drops in ANC no longer require action (repeat lab draws) unless the drop causes neutropenia. Prescribers will receive an automated notification any time a patient experiences neutropenia that is considered mild (ANC 1,000 to 1,499/µL), moderate (ANC 500 to 999/µL), or severe (ANC <500/µL).

The NNRMF list is no longer definitive. All patients are now eligible for rechallenge, assuming they meet the new clozapine initiation criteria.

Next, when rediscovering clozapine: Adverse effectsDespite an intimidating list of side effects and interactions, clozapine is associated with a significant reduction in patients’ risk of overall mortality. In Part 2 of this series in the August 2016 issue, we discuss early identification of clozapine’s adverse effects and provide guidance for management.

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

Although clozapine is the medication with the clearest benefits in treatment-resistant schizophrenia, many eligible patients never receive it. In the United States, 20% to 30% of patients with schizophrenia can be classified as treatment resistant, but clozapine accounts for <5% of antipsychotics prescribed.^1,2 Clinicians worldwide tend to under-prescribe clozapine³—a reluctance one author coined as “clozaphobia.”⁴

Admittedly, clozapine has had a turbulent history—both lauded as a near-miracle drug and condemned as a deadly agent. The FDA has overhauled its prescribing and monitoring guidelines, however, offering psychiatrists a perfect opportunity to reacquaint themselves with this potentially life-changing intervention.

We begin this article with clozapine’s story, then spotlight new terrain the FDA created in 2015 when the agency introduced the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Our goal in the 3 articles of this series is to deepen your appreciation for this tricyclic antipsychotic and provide practical clinical guidance for using it safely and effectively.

Setbacks, but the drug has an enduring presenceThe 1950s was an exciting era of exploration for new psychotropic medications. While searching for tricyclic antidepressants, Wander Laboratories discovered neuroleptic tricyclics, with clozapine identified in 1959 (Figure 1). Haloperidol’s development and release in the 1960s reinforced the prevailing dogma of the time that effective neuroleptics correlated with extrapyramidal symptoms, thus limiting interest in the newly discovered, but pharmacologically unique, clozapine. Throughout the 1960s, most research on clozapine was published in German, with less of an international presence.⁵

Agranulocytosis deaths. Clozapine earned its scarlet letter in 1975, when 8 patients in Finland died of agranulocytosis.⁶ Sandoz, its manufacturer, withdrew clozapine from the market and halted all clinical trials. The Finnish epidemic triggered detailed investigations into blood dyscrasias and early identification of agranulocytosis associated with clozapine and other antipsychotics.⁷

Clozapine endured only because of its unique efficacy. When psychiatrists witnessed relapses in patients who had to discontinue clozapine, some countries allowed its use with strict monitoring.⁵ The FDA kept clozapine minimally available in the United States by allowing so-called “compassionate need programs” to continue.⁷

New data, FDA approval. Two studies in 1987 and 1988 that compared clozapine with chlorpromazine for treatment-refractory schizophrenia demonstrated clozapine’s superior effect on both negative and positive symptoms.^8,9 The FDA approved clozapine for refractory schizophrenia in 1989, and clozapine became clinically available in 1990.

Initially, the high annual cost of clozapine’s required “bundle” ($8,900 per patient for medication and monitoring) led to political outcry. As patients and their family struggled to afford the newly released medication, multiple states filed antitrust lawsuits. A federal court found both the manufacturer and individual states at fault and required expanded access to clozapine and its necessary monitoring. National clozapine registries were formed, and bundling was eliminated.⁷

The clozapine REMS programSix clozapine registries operated independently, each managed by a different manufacturer,¹⁰ until the FDA introduced REMS in September 2015. The REMS program created a centralized registry to monitor all U.S. patients treated with clozapine and made important changes to prescribing and monitoring guidelines.^11,12 It also incorporated the National Non-Rechallenge Master File (NNRMF).

Initially, the REMS program was scheduled for rollout October 12, 2015, the closing date of the 6 registries. Since November 2015, pharmacies have been required to register with the program to dispense clozapine. A similar registration deadline for clozapine prescribers was extended indefinitely, however, because of technical problems. Once the deadline is finalized, all clozapine prescribers must complete 3 steps to be certified in the REMS program (Table 1).¹¹

New requirements. Certified clozapine prescribers will have new responsibilities: enrolling patients and submitting lab results. They can designate someone else to perform these tasks on their behalf, but designees must enroll in the REMS program and the prescriber must confirm the designee. Pharmacists can no longer enroll patients for clozapine therapy unless they are confirmed as a prescriber designee. For outpatients, the absolute neutrophil count (ANC) must be reported before the pharmacy can dispense clozapine. For inpatients, the ANC must be reported within 7 days of the patient’s most recent blood draw.

Once the system is fully operational, Social Security numbers will no longer be used as patient identification for dispensing clozapine. Instead, outpatient pharmacies will obtain a predispense authorization, or PDA, from the REMS program. A person initiated on clozapine as an inpatient must be re-enrolled after discharge by their outpatient prescriber.

The REMS program includes information about clozapine patients who were maintained through the 6 registries, and these patients have been allowed to continue clozapine treatment. Data pertaining to patients last prescribed clozapine before October 1, 2012, did not transfer into the new system unless their name was on the NNRMF.

CASE 
Is Mr. A a candidate for clozapine?Age 28, with schizophrenia, Mr. A is highly disorganized and psychotic when brought to the emergency room by police for inappropriate behavior. His family arrives and reports that similar events have occurred several times over the past few years. Mr. A’s outpatient psychiatrist has prescribed 3 different antipsychotic medications at adequate dosages, including 1 long-acting injectable, but Mr. A has remained consistently symptomatic.

Although disorganized and psychotic, Mr. A does not meet criteria for long-term involuntary hospitalization. His family wants to take him home, and the treatment team discusses clozapine as an anti­psychotic option. Mr. A and his family agree to a trial of clozapine during voluntary hospitalization, but they would like him home within a week to attend his sister’s birthday party.

The treatment team decides to initiate clozapine and monitor his response in a controlled setting for a few days before transitioning him to outpatient care.

Initiating clozapine therapyThe case of Mr. A exemplifies a situation in which initiating clozapine is a reasonable clinical consideration. As the first step, we recommend checking baseline lab values and vital signs (Table 2), keeping in mind that the REMS program requires a baseline ANC within 7 days of initiating clozapine. When working with a highly disorganized or agitated patient, balance benefits of testing against the risk of harm to staff and patient.

REMS guidelines recommend a baseline ANC ≥1,500/µL for a new patient starting clozapine, except when benign ethnic neutropenia (BEN) has been confirmed. (Initiation guidelines for BEN are discussed later in this article.)

Dosing alternatives. We recommend following the manufacturer’s dosing guidelines when initiating clozapine (Figure 2).^13,14 Three oral forms are available: tablet, disintegrating tablet, and suspension. All can be titrated using the schedule suggested with tablets. The disintegrating tablets or suspension might be beneficial for a patient with either:

• a history of “cheeking” or otherwise disposing of tablets
• a medical condition that affects swallowing or absorption.

The disintegrating tablet is available in 12.5-mg, 25-mg, 100-mg, 150-mg, and 200-mg doses. It dissolves without requiring additional liquids. Each mL of the suspension contains 50 mg of clozapine.

Rapid titration? One group, working in Romania, examined the safety and efficacy of rapid titration of clozapine in 111 inpatients with schizophrenia.¹⁵ In the absence of additional studies, we do not recommend routine rapid titration of clozapine.

Monitoring: Greater flexibilityUnder the REMS program, laboratory monitoring of clozapine treatment must continue indefinitely. If not, pharmacies cannot dispense clozapine. Fortunately, the ANC is the only lab value tracked by the registry, and the frequency of required blood draws decreases over time (Figure 3).

Other guideline changes provide clinicians with greater flexibility to make patient-specific treatment decisions; for example, the allowable ANC to continue clozapine therapy has decreased. Usually, clozapine therapy should be interrupted for an ANC <1,000/µL if the prescriber suspects clozapine-induced neutropenia. Even when the ANC drops below 1,000/µL, however, prescribers can now continue clozapine treatment if they consider the benefits to outweigh risks for a given patient.

Separate guidelines now exist for patients with BEN, most commonly observed in persons of certain ethnic groups. BEN typically is diagnosed based on repeated ANC values <1,500/µL over several months. Patients with BEN do not have an increased risk of oral or systemic infections, as occur with other congenital neutropenias.¹⁶ In patients with BEN, clozapine therapy:

• can be initiated only after at least 2 baseline ANC measurements ≥1,000/µL
• should be interrupted for an ANC <500/µL if the prescriber suspects clozapine-induced neutropenia.

Substantial drops in ANC no longer require action (repeat lab draws) unless the drop causes neutropenia. Prescribers will receive an automated notification any time a patient experiences neutropenia that is considered mild (ANC 1,000 to 1,499/µL), moderate (ANC 500 to 999/µL), or severe (ANC <500/µL).

The NNRMF list is no longer definitive. All patients are now eligible for rechallenge, assuming they meet the new clozapine initiation criteria.

Next, when rediscovering clozapine: Adverse effectsDespite an intimidating list of side effects and interactions, clozapine is associated with a significant reduction in patients’ risk of overall mortality. In Part 2 of this series in the August 2016 issue, we discuss early identification of clozapine’s adverse effects and provide guidance for management.

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

Approximately 80% of patients with schizophrenia relapse within 5 years¹ despite the availability and increased use of second-generation antipsychotics. Long-acting depot formulations are a proven, effective treatment option for patients with schizophrenia. In October 2015, another long-acting injectable antipsychotic, aripiprazole lauroxil, was FDA-approved for schizophrenia.² Aripiprazole lauroxil is administered IM every 4 to 6 weeks in the deltoid or gluteal region and is available in multiple dosages (Table 1).

Mechanism of action
Aripiprazole lauroxil is a prodrug of aripiprazole. Prodrugs are chemical compounds that exert their pharmacological effects after they undergo a biologic transformation and transform into a more active metabolite.³ The development of prodrugs is an established method used to improve physio-chemical or pharmacokinetic properties of the pharmacologically active compound.

After IM injection, aripiprazole lauroxil is most likely converted by an enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. Aripiprazole’s mechanism of action is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonistic activity at 5-HT2A receptors.^2,4

Dosing and administration
If your patient has never taken aripiprazole, ensure that she (he) will tolerate the drug by initiating a trial of oral aripiprazole before beginning treatment with aripiprazole lauroxil; establishing tolerability might take as long as 2 weeks because of the half-life of aripiprazole.

Aripiprazole lauroxil can be started at 441 mg, 662 mg, or 882 mg administered monthly; these dosages correspond to 300 mg, 450 mg, and 600 mg of aripiprazole, or 10 mg/d, 15 mg/d, ≥20 mg/d of oral aripiprazole, respectively (Table 2).² Aripiprazole lauroxil can be administered either in the deltoid muscle (441 mg only) or gluteal muscle (441 mg, 662 mg, or 882 mg).^2,4,5 Treatment with the 441-mg, 662-mg, or 882-mg dosages can be given every 4 weeks but the 882-mg dosage can be given every 6 weeks and only in the gluteal muscle, which provides greater dosing flexibility compared with extended-release injectable aripiprazole.^2,4,5

Supplementation with oral aripiprazole is required for 21 days before the first aripiprazole lauroxil injection.^2,4 The next injection should not be given earlier than 14 days after the previous dose. When a dose is missed, follow the guidelines outlined in Table 3.²

After a single injection, aripiprazole starts to appear in the systemic circulation at Day 5 or Day 6 and continues to be released for another 36 days.² Steady-state concentration will be reached after the fourth monthly injection. The termination half-life of aripiprazole lauroxil ranged from 29 to 35 days after each monthly injection.²

Packaging. Aripiprazole lauroxil is available as single-dose, pre-filled, color-coded syringes for IM injection at 441 mg (light blue), 662 mg (green), and 882 mg (burgundy); syringes do not require refrigeration (Table 2).² The syringe needs to be tapped at least 10 times to dislodge any material that might have settled. Shake the syringe vigorously for at least 30 seconds to ensure a uniform suspension. Shake it again for 30 seconds if the syringe is not used within 15 minutes.²

Efficacy
The efficacy of aripiprazole lauroxil for treating patients with schizophrenia has been established, in part, on the basis of efficacy data from clinical trials of oral aripiprazole. In addition, efficacy has been established in a 12-week, multicenter, randomized, placebo-controlled, double-blind, fixed-dose study of 622 individuals age 18 to 70 with schizophrenia.^4,5 All eligible patients were diagnosed with schizophrenia as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV Disorders, Clinical Trial Version and were experiencing an acute exacerbation of their illness at the time of the study. To be eligible for the study, participants had to have a Positive and Negative Syndrome Scale (PANSS) total score of 70 to 120 and score of ≥4 for ≥2 of the selected positive items (delusions, conceptual disorganization, hallucinatory behavior, and suspiciousness/persecution). Individuals also were required to have a Clinical Global Impression-Severity scale score of ≥4. Efficacy was assessed using the PANSS and Clinical Global Impression–Improvement scale (CGI-I).

Patients were randomized in a 1:1:1 ratio to receive IM aripiprazole lauroxil, 441 mg, aripiprazole lauroxil, 882 mg, or placebo once monthly in the gluteal region for 12 weeks. The gluteal muscle was selected as the injection site to maintain blinding to the study drug.^4,5 After establishing tolerability to oral aripiprazole, participants received oral aripiprazole or placebo daily for the first 3 weeks. The IM injections were administered on Days 1, 29, and 57.

Efficacy was measured primarily as change in total PANSS score from the baseline to day 85^4,5; secondary efficacy variable was the CGI-I score at day 85. Statistically significant separation in PANSS score was observed in each aripiprazole lauroxil dosage group (441 mg and 882 mg) compared with placebo. Significant improvement in both active treatment groups was observed as early as Day 8 and continued throughout the study (P ≤ .004). The number of patients who improved much or very much on the CGI-I was significantly greater in either aripiprazole lauroxil group, compared with placebo (P < .001).

Contraindications
Allergic reactions. Patients who are hypersensitive to oral aripiprazole should not receive aripiprazole lauroxil. Hypersensitivity reactions have ranged from pruritus and urticaria to anaphylaxis.²

Drug−drug interactions. Reduce aripiprazole lauroxil dosage to the next lower dosage when used in combination with strong cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, clarithromycin) or strong CYP2D6 inhibitors (eg, quinidine, fluoxetine, paroxetine) for more than 2 weeks or if the patient is known to be a poor metabolizer of CYP2D6, because concentration of aripiprazole lauroxil could increase. No dose adjustment is required if the patient is already taking 441 mg/month or if CYP450 modulators are added for less than 2 weeks.² Similarly, a dosage increase is recommended when aripiprazole lauroxil is used in combination with strong CYP3A4 inducers (eg, carbamazepine, rifampin).²

Overdose
No data are available on aripiprazole lauroxil overdose. However, there is one known case of oral aripiprazole overdose in a patient who ingested 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dosage) but recovered completely.² Common side effects reported in at least 5% of all overdose cases include vomiting, somnolence, and tremor. If an overdose occurs, call a poison control center immediately.

‘Black-box’ warning for patients with dementia
Aripiprazole lauroxil, similar to all other atypical antipsychotics, has a “black-box” warning stating that (1) it is not approved for treating dementia-related psychosis, and (2) it is associated with an increased risk of death with off-label use to treat behavioral problems in older adults with dementia-related psychosis.² Meta-analysis of 17 placebo-controlled trials in patients taking an atypical antipsychotic (olanzapine, aripiprazole, risperidone, or quetiapine) revealed a risk of death in drug-treated patients 1.6 to 1.7 times that of placebo-treated patients.⁶

Adverse reactions
The overall safety profile of aripiprazole lauroxil is similar to that of oral aripiprazole. Most commonly observed adverse reaction during clinical trials of aripiprazole lauroxil was akathisia (incidence ≥5% and at least twice rate seen with placebo).² Other common adverse reactions are shown in Table 4.² Recently, the FDA issued a warning that compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with all formulations of aripiprazole.⁷ According to reports, these urges stopped when the drug was discontinued or the dosage reduced. Although rare, these impulse-control problems could result in harm if they are not recognized. See the full prescribing information for a complete set of adverse reactions.

Related Resources

• Kennedy WK. When and how to use long-acting injectable antipsychotics. Current Psychiatry. 2012;11(8):40-43.
• Citrome L, Du Y, Risinger R, et al. Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia. Int Clin Psychopharmacol. 2016;31(2):69-75.

Drug Brand Names
Aripiprazole • Abilify
Aripiprazole extended-release • Abilify Maintena
Aripiprazole lauroxil • Aristada
Carbamazepine • Tegretol
Clarithromycin • Biaxin
Fluoxetine • Prozac
Itraconazole • Sporanox
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Quinidine • Quinidex
Rifampin • Rifadin
Risperidone • Risperdal

Acknowledgement
Maaz A. Khan, a student at the University of Oklahoma, Norman, Oklahoma, contributed to this article.

Approximately 80% of patients with schizophrenia relapse within 5 years¹ despite the availability and increased use of second-generation antipsychotics. Long-acting depot formulations are a proven, effective treatment option for patients with schizophrenia. In October 2015, another long-acting injectable antipsychotic, aripiprazole lauroxil, was FDA-approved for schizophrenia.² Aripiprazole lauroxil is administered IM every 4 to 6 weeks in the deltoid or gluteal region and is available in multiple dosages (Table 1).

Mechanism of action
Aripiprazole lauroxil is a prodrug of aripiprazole. Prodrugs are chemical compounds that exert their pharmacological effects after they undergo a biologic transformation and transform into a more active metabolite.³ The development of prodrugs is an established method used to improve physio-chemical or pharmacokinetic properties of the pharmacologically active compound.

After IM injection, aripiprazole lauroxil is most likely converted by an enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. Aripiprazole’s mechanism of action is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonistic activity at 5-HT2A receptors.^2,4

Dosing and administration
If your patient has never taken aripiprazole, ensure that she (he) will tolerate the drug by initiating a trial of oral aripiprazole before beginning treatment with aripiprazole lauroxil; establishing tolerability might take as long as 2 weeks because of the half-life of aripiprazole.

Aripiprazole lauroxil can be started at 441 mg, 662 mg, or 882 mg administered monthly; these dosages correspond to 300 mg, 450 mg, and 600 mg of aripiprazole, or 10 mg/d, 15 mg/d, ≥20 mg/d of oral aripiprazole, respectively (Table 2).² Aripiprazole lauroxil can be administered either in the deltoid muscle (441 mg only) or gluteal muscle (441 mg, 662 mg, or 882 mg).^2,4,5 Treatment with the 441-mg, 662-mg, or 882-mg dosages can be given every 4 weeks but the 882-mg dosage can be given every 6 weeks and only in the gluteal muscle, which provides greater dosing flexibility compared with extended-release injectable aripiprazole.^2,4,5

Supplementation with oral aripiprazole is required for 21 days before the first aripiprazole lauroxil injection.^2,4 The next injection should not be given earlier than 14 days after the previous dose. When a dose is missed, follow the guidelines outlined in Table 3.²

After a single injection, aripiprazole starts to appear in the systemic circulation at Day 5 or Day 6 and continues to be released for another 36 days.² Steady-state concentration will be reached after the fourth monthly injection. The termination half-life of aripiprazole lauroxil ranged from 29 to 35 days after each monthly injection.²

Packaging. Aripiprazole lauroxil is available as single-dose, pre-filled, color-coded syringes for IM injection at 441 mg (light blue), 662 mg (green), and 882 mg (burgundy); syringes do not require refrigeration (Table 2).² The syringe needs to be tapped at least 10 times to dislodge any material that might have settled. Shake the syringe vigorously for at least 30 seconds to ensure a uniform suspension. Shake it again for 30 seconds if the syringe is not used within 15 minutes.²

Efficacy
The efficacy of aripiprazole lauroxil for treating patients with schizophrenia has been established, in part, on the basis of efficacy data from clinical trials of oral aripiprazole. In addition, efficacy has been established in a 12-week, multicenter, randomized, placebo-controlled, double-blind, fixed-dose study of 622 individuals age 18 to 70 with schizophrenia.^4,5 All eligible patients were diagnosed with schizophrenia as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV Disorders, Clinical Trial Version and were experiencing an acute exacerbation of their illness at the time of the study. To be eligible for the study, participants had to have a Positive and Negative Syndrome Scale (PANSS) total score of 70 to 120 and score of ≥4 for ≥2 of the selected positive items (delusions, conceptual disorganization, hallucinatory behavior, and suspiciousness/persecution). Individuals also were required to have a Clinical Global Impression-Severity scale score of ≥4. Efficacy was assessed using the PANSS and Clinical Global Impression–Improvement scale (CGI-I).

Patients were randomized in a 1:1:1 ratio to receive IM aripiprazole lauroxil, 441 mg, aripiprazole lauroxil, 882 mg, or placebo once monthly in the gluteal region for 12 weeks. The gluteal muscle was selected as the injection site to maintain blinding to the study drug.^4,5 After establishing tolerability to oral aripiprazole, participants received oral aripiprazole or placebo daily for the first 3 weeks. The IM injections were administered on Days 1, 29, and 57.

Efficacy was measured primarily as change in total PANSS score from the baseline to day 85^4,5; secondary efficacy variable was the CGI-I score at day 85. Statistically significant separation in PANSS score was observed in each aripiprazole lauroxil dosage group (441 mg and 882 mg) compared with placebo. Significant improvement in both active treatment groups was observed as early as Day 8 and continued throughout the study (P ≤ .004). The number of patients who improved much or very much on the CGI-I was significantly greater in either aripiprazole lauroxil group, compared with placebo (P < .001).

Contraindications
Allergic reactions. Patients who are hypersensitive to oral aripiprazole should not receive aripiprazole lauroxil. Hypersensitivity reactions have ranged from pruritus and urticaria to anaphylaxis.²

Drug−drug interactions. Reduce aripiprazole lauroxil dosage to the next lower dosage when used in combination with strong cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, clarithromycin) or strong CYP2D6 inhibitors (eg, quinidine, fluoxetine, paroxetine) for more than 2 weeks or if the patient is known to be a poor metabolizer of CYP2D6, because concentration of aripiprazole lauroxil could increase. No dose adjustment is required if the patient is already taking 441 mg/month or if CYP450 modulators are added for less than 2 weeks.² Similarly, a dosage increase is recommended when aripiprazole lauroxil is used in combination with strong CYP3A4 inducers (eg, carbamazepine, rifampin).²

Overdose
No data are available on aripiprazole lauroxil overdose. However, there is one known case of oral aripiprazole overdose in a patient who ingested 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dosage) but recovered completely.² Common side effects reported in at least 5% of all overdose cases include vomiting, somnolence, and tremor. If an overdose occurs, call a poison control center immediately.

‘Black-box’ warning for patients with dementia
Aripiprazole lauroxil, similar to all other atypical antipsychotics, has a “black-box” warning stating that (1) it is not approved for treating dementia-related psychosis, and (2) it is associated with an increased risk of death with off-label use to treat behavioral problems in older adults with dementia-related psychosis.² Meta-analysis of 17 placebo-controlled trials in patients taking an atypical antipsychotic (olanzapine, aripiprazole, risperidone, or quetiapine) revealed a risk of death in drug-treated patients 1.6 to 1.7 times that of placebo-treated patients.⁶

Adverse reactions
The overall safety profile of aripiprazole lauroxil is similar to that of oral aripiprazole. Most commonly observed adverse reaction during clinical trials of aripiprazole lauroxil was akathisia (incidence ≥5% and at least twice rate seen with placebo).² Other common adverse reactions are shown in Table 4.² Recently, the FDA issued a warning that compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with all formulations of aripiprazole.⁷ According to reports, these urges stopped when the drug was discontinued or the dosage reduced. Although rare, these impulse-control problems could result in harm if they are not recognized. See the full prescribing information for a complete set of adverse reactions.

Related Resources

• Kennedy WK. When and how to use long-acting injectable antipsychotics. Current Psychiatry. 2012;11(8):40-43.
• Citrome L, Du Y, Risinger R, et al. Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia. Int Clin Psychopharmacol. 2016;31(2):69-75.

Drug Brand Names
Aripiprazole • Abilify
Aripiprazole extended-release • Abilify Maintena
Aripiprazole lauroxil • Aristada
Carbamazepine • Tegretol
Clarithromycin • Biaxin
Fluoxetine • Prozac
Itraconazole • Sporanox
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Quinidine • Quinidex
Rifampin • Rifadin
Risperidone • Risperdal

Acknowledgement
Maaz A. Khan, a student at the University of Oklahoma, Norman, Oklahoma, contributed to this article.

Approximately 80% of patients with schizophrenia relapse within 5 years¹ despite the availability and increased use of second-generation antipsychotics. Long-acting depot formulations are a proven, effective treatment option for patients with schizophrenia. In October 2015, another long-acting injectable antipsychotic, aripiprazole lauroxil, was FDA-approved for schizophrenia.² Aripiprazole lauroxil is administered IM every 4 to 6 weeks in the deltoid or gluteal region and is available in multiple dosages (Table 1).

Mechanism of action
Aripiprazole lauroxil is a prodrug of aripiprazole. Prodrugs are chemical compounds that exert their pharmacological effects after they undergo a biologic transformation and transform into a more active metabolite.³ The development of prodrugs is an established method used to improve physio-chemical or pharmacokinetic properties of the pharmacologically active compound.

After IM injection, aripiprazole lauroxil is most likely converted by an enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. Aripiprazole’s mechanism of action is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonistic activity at 5-HT2A receptors.^2,4

Dosing and administration
If your patient has never taken aripiprazole, ensure that she (he) will tolerate the drug by initiating a trial of oral aripiprazole before beginning treatment with aripiprazole lauroxil; establishing tolerability might take as long as 2 weeks because of the half-life of aripiprazole.

Aripiprazole lauroxil can be started at 441 mg, 662 mg, or 882 mg administered monthly; these dosages correspond to 300 mg, 450 mg, and 600 mg of aripiprazole, or 10 mg/d, 15 mg/d, ≥20 mg/d of oral aripiprazole, respectively (Table 2).² Aripiprazole lauroxil can be administered either in the deltoid muscle (441 mg only) or gluteal muscle (441 mg, 662 mg, or 882 mg).^2,4,5 Treatment with the 441-mg, 662-mg, or 882-mg dosages can be given every 4 weeks but the 882-mg dosage can be given every 6 weeks and only in the gluteal muscle, which provides greater dosing flexibility compared with extended-release injectable aripiprazole.^2,4,5

Supplementation with oral aripiprazole is required for 21 days before the first aripiprazole lauroxil injection.^2,4 The next injection should not be given earlier than 14 days after the previous dose. When a dose is missed, follow the guidelines outlined in Table 3.²

After a single injection, aripiprazole starts to appear in the systemic circulation at Day 5 or Day 6 and continues to be released for another 36 days.² Steady-state concentration will be reached after the fourth monthly injection. The termination half-life of aripiprazole lauroxil ranged from 29 to 35 days after each monthly injection.²

Packaging. Aripiprazole lauroxil is available as single-dose, pre-filled, color-coded syringes for IM injection at 441 mg (light blue), 662 mg (green), and 882 mg (burgundy); syringes do not require refrigeration (Table 2).² The syringe needs to be tapped at least 10 times to dislodge any material that might have settled. Shake the syringe vigorously for at least 30 seconds to ensure a uniform suspension. Shake it again for 30 seconds if the syringe is not used within 15 minutes.²

Efficacy
The efficacy of aripiprazole lauroxil for treating patients with schizophrenia has been established, in part, on the basis of efficacy data from clinical trials of oral aripiprazole. In addition, efficacy has been established in a 12-week, multicenter, randomized, placebo-controlled, double-blind, fixed-dose study of 622 individuals age 18 to 70 with schizophrenia.^4,5 All eligible patients were diagnosed with schizophrenia as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV Disorders, Clinical Trial Version and were experiencing an acute exacerbation of their illness at the time of the study. To be eligible for the study, participants had to have a Positive and Negative Syndrome Scale (PANSS) total score of 70 to 120 and score of ≥4 for ≥2 of the selected positive items (delusions, conceptual disorganization, hallucinatory behavior, and suspiciousness/persecution). Individuals also were required to have a Clinical Global Impression-Severity scale score of ≥4. Efficacy was assessed using the PANSS and Clinical Global Impression–Improvement scale (CGI-I).

Patients were randomized in a 1:1:1 ratio to receive IM aripiprazole lauroxil, 441 mg, aripiprazole lauroxil, 882 mg, or placebo once monthly in the gluteal region for 12 weeks. The gluteal muscle was selected as the injection site to maintain blinding to the study drug.^4,5 After establishing tolerability to oral aripiprazole, participants received oral aripiprazole or placebo daily for the first 3 weeks. The IM injections were administered on Days 1, 29, and 57.

Efficacy was measured primarily as change in total PANSS score from the baseline to day 85^4,5; secondary efficacy variable was the CGI-I score at day 85. Statistically significant separation in PANSS score was observed in each aripiprazole lauroxil dosage group (441 mg and 882 mg) compared with placebo. Significant improvement in both active treatment groups was observed as early as Day 8 and continued throughout the study (P ≤ .004). The number of patients who improved much or very much on the CGI-I was significantly greater in either aripiprazole lauroxil group, compared with placebo (P < .001).

Contraindications
Allergic reactions. Patients who are hypersensitive to oral aripiprazole should not receive aripiprazole lauroxil. Hypersensitivity reactions have ranged from pruritus and urticaria to anaphylaxis.²

Drug−drug interactions. Reduce aripiprazole lauroxil dosage to the next lower dosage when used in combination with strong cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, clarithromycin) or strong CYP2D6 inhibitors (eg, quinidine, fluoxetine, paroxetine) for more than 2 weeks or if the patient is known to be a poor metabolizer of CYP2D6, because concentration of aripiprazole lauroxil could increase. No dose adjustment is required if the patient is already taking 441 mg/month or if CYP450 modulators are added for less than 2 weeks.² Similarly, a dosage increase is recommended when aripiprazole lauroxil is used in combination with strong CYP3A4 inducers (eg, carbamazepine, rifampin).²

Overdose
No data are available on aripiprazole lauroxil overdose. However, there is one known case of oral aripiprazole overdose in a patient who ingested 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dosage) but recovered completely.² Common side effects reported in at least 5% of all overdose cases include vomiting, somnolence, and tremor. If an overdose occurs, call a poison control center immediately.

‘Black-box’ warning for patients with dementia
Aripiprazole lauroxil, similar to all other atypical antipsychotics, has a “black-box” warning stating that (1) it is not approved for treating dementia-related psychosis, and (2) it is associated with an increased risk of death with off-label use to treat behavioral problems in older adults with dementia-related psychosis.² Meta-analysis of 17 placebo-controlled trials in patients taking an atypical antipsychotic (olanzapine, aripiprazole, risperidone, or quetiapine) revealed a risk of death in drug-treated patients 1.6 to 1.7 times that of placebo-treated patients.⁶

Adverse reactions
The overall safety profile of aripiprazole lauroxil is similar to that of oral aripiprazole. Most commonly observed adverse reaction during clinical trials of aripiprazole lauroxil was akathisia (incidence ≥5% and at least twice rate seen with placebo).² Other common adverse reactions are shown in Table 4.² Recently, the FDA issued a warning that compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with all formulations of aripiprazole.⁷ According to reports, these urges stopped when the drug was discontinued or the dosage reduced. Although rare, these impulse-control problems could result in harm if they are not recognized. See the full prescribing information for a complete set of adverse reactions.

Related Resources

• Kennedy WK. When and how to use long-acting injectable antipsychotics. Current Psychiatry. 2012;11(8):40-43.
• Citrome L, Du Y, Risinger R, et al. Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia. Int Clin Psychopharmacol. 2016;31(2):69-75.

Drug Brand Names
Aripiprazole • Abilify
Aripiprazole extended-release • Abilify Maintena
Aripiprazole lauroxil • Aristada
Carbamazepine • Tegretol
Clarithromycin • Biaxin
Fluoxetine • Prozac
Itraconazole • Sporanox
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Quinidine • Quinidex
Rifampin • Rifadin
Risperidone • Risperdal

Acknowledgement
Maaz A. Khan, a student at the University of Oklahoma, Norman, Oklahoma, contributed to this article.

Baby Boomers represent a rapidly growing segment of digital device users.¹ As these people age, their continued, even increasing, use of the Internet can be expected.¹ At the same time, many older adults (age ≥65) are engaged in intimate relationships and regard sexuality as an important part of life.²

At this intersection, the Internet is likely to play a role in geriatric sexuality and “digital intimacy”—in that older adults can adopt patterns of using online dating sites similar to what their younger counterparts engage in. There is a need among clinicians to avoid stereotypical perceptions of “ageism” and the myth of “geriatric asexuality” as a result of older patients’ continued sexual interest and their adoption of social media technologies to facilitate the development of new intimate relationships. Acknowledgement of these realities by clinicians may assist in understanding and communication regarding these important areas of patients’ lives.

Why online dating?
Contemporary social and demographic changes (eg, higher divorce rates, increased longevity, aging of Baby Boomers) have influenced patterns of dating behaviors.³ Consistent with evolutionary theory, studies on courtship behaviors show that women remain the “choosers” of partners in relationships at all ages³; in contemporary society, however, there is an increasing ratio of women to men in later life, and the degree to which this demographic change might influence older men and women who are pursuing sexual relationships is unclear.³ Older adults might be aware of these demographic realities, and may use the Internet to increase their chances of finding a relationship.

For older homosexual men and women, demographic trends also are important because fewer available partners of similar sexual orientation might be available in their immediate communities, similarly incentivizing the use of online dating sites.

Hand in hand: Risk and vulnerability
Clinicians can discuss with geriatric patients who present with questions or concerns about sexuality and risks of online dating. Although risks associated with digital dating can involve anyone, those who are recently divorced, widowed, disabled, or elderly can be targeted by predators or fraudulent schemes, and thus become victims. Recognizing those risks and the vulnerability in the geriatric patient is crucial.

Chronic illness. Age-related physiological changes do not necessarily make one vulnerable; however, chronic diseases of aging, including major neurocognitive disorders, can impair daily function and increase disability and vulnerability. The majority of online dating sites do not discriminate among users, including those with disabilities such as incapacitating neuropsychiatric disorders. The clinician may need to assess cognitive status of patients specific to their capacity to fully understand the risks of use of social media. Inability to accomplish basic mastery of computer skills or inability to maintain appropriate boundaries and safeguards in relationships initiated and maintained using the Internet may assist in this determination. Patients with other problematic Internet use (eg, excessive devotion to online shopping or online gambling) may be prone to misusing social media and dating sites as well. Patients with clear impairment of memory or poor social judgment based on a neurocognitive disorder also might not maintain proper boundaries with social media use.

Feeling alone. Older persons might feel socially isolated, and therefore may be more willing to participate in online dating to increase their chances of establishing an intimate relationship or companionship. Research has shown that increased social ties, participation in groups, contact with friends and family, and perceived social support are associated with longer survival; on the other hand, social disengagement, low participation in leisure activities, and limited social networks are associated with higher risk of major neurocognitive disorders and increased disability.⁴

Little is known about social vulnerability in institutional settings, but institutional living could decrease social vulnerability in important ways (eg, access to social support, networks and activities, not living alone).⁴ Although the literature on older adults and “digital” or “virtual” dating is limited, there are essentially no such data from within institutional settings. It is important to separately address the issue of cognitively impaired patients’ capacity to consent to sexual activity both within institutional settings and elsewhere, as it raises numerous ethical dilemmas for clinicians.

Being sexually active. Early research into online dating focused particularly on the risks of sexually transmitted infections (STIs),⁵ which could be acquired through failure to use condoms with a new partner.⁶ Older women particularly are less likely to use condoms with new sexual partners.⁶ Screening at-risk adults should occur regardless of age. Effective interventions are needed to increase condom use in this age group. Research in the general population has started to investigate how the use of technology can minimize the risks associated with online dating.⁵ The Table^5,6 lists strategies that can be used to minimize some of the risks of online dating among geriatric patients, including STIs and victimization.

Clinicians working with sexually active geriatric patients need to perform sexual risk assessments, complete capacity assessments, and provide preventive measures.

Legal issues
Criminal and civil liability issues have arisen with online dating involving cases of murder, rape, fraud, identity theft, loans, theft, domestic violence, stalking, and burglary. Online dating also raises concerns around the right to fair use of the Internet in different contexts. Flirting in cyberspace can occur with e-mail, text, Twitter, Skype, and Instant Messenger. Practices likely will vary depending on whether older adults are institutionalized or living in the community, as well as their mental status (eg, having a major neurocognitive disorder).

Some questions with legal implications worth considering include:

• To what extent is there a duty to accommodate healthy sexual relationships in institutionalized settings?
• At what point does monitoring and supervision become overly intrusive?
• Are older adults fully aware of the potential ramifications of sharing sensitive information in cyberspace?
• What is the threshold for capacity to consent among older adults to understand the sexual nature of the act and consent to the act?

Nursing homes and health care providers may become concerned about potential liability if their organization provides digital devices or electronic platforms that are not closely monitored. Clinicians have a duty to protect patients under their care from risks associated with predators who target vulnerable and lonely people, whether financially, emotionally, or physically. Some patients in nursing home settings may benefit from discussing with their family members or attorney the possibility of completing a “sexual power of attorney”⁷ that could be completed in conjunction with an advance health care directive that addresses or authorizes an agent to make decisions about their sexual activities if cognitively impaired in the future.

One might also consider to what extent local regulatory oversight will protect your patient. Not all jurisdictions regulate online dating services similarly; many existing regulations focus on unfair contracts and pay less heed to safety concerns.

As a result, some dissatisfied clients have been known to sue an online dating service for breach of contract or misrepresentation. One of the most significant issues, however, is making sure there are appropriate background checks. Online dating services may need to change their policies to screen and verify for criminal background checks.⁸ Older adults interested in online dating should be made aware of these emerging issues.

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

Baby Boomers represent a rapidly growing segment of digital device users.¹ As these people age, their continued, even increasing, use of the Internet can be expected.¹ At the same time, many older adults (age ≥65) are engaged in intimate relationships and regard sexuality as an important part of life.²

At this intersection, the Internet is likely to play a role in geriatric sexuality and “digital intimacy”—in that older adults can adopt patterns of using online dating sites similar to what their younger counterparts engage in. There is a need among clinicians to avoid stereotypical perceptions of “ageism” and the myth of “geriatric asexuality” as a result of older patients’ continued sexual interest and their adoption of social media technologies to facilitate the development of new intimate relationships. Acknowledgement of these realities by clinicians may assist in understanding and communication regarding these important areas of patients’ lives.

Why online dating?
Contemporary social and demographic changes (eg, higher divorce rates, increased longevity, aging of Baby Boomers) have influenced patterns of dating behaviors.³ Consistent with evolutionary theory, studies on courtship behaviors show that women remain the “choosers” of partners in relationships at all ages³; in contemporary society, however, there is an increasing ratio of women to men in later life, and the degree to which this demographic change might influence older men and women who are pursuing sexual relationships is unclear.³ Older adults might be aware of these demographic realities, and may use the Internet to increase their chances of finding a relationship.

For older homosexual men and women, demographic trends also are important because fewer available partners of similar sexual orientation might be available in their immediate communities, similarly incentivizing the use of online dating sites.

Hand in hand: Risk and vulnerability
Clinicians can discuss with geriatric patients who present with questions or concerns about sexuality and risks of online dating. Although risks associated with digital dating can involve anyone, those who are recently divorced, widowed, disabled, or elderly can be targeted by predators or fraudulent schemes, and thus become victims. Recognizing those risks and the vulnerability in the geriatric patient is crucial.

Chronic illness. Age-related physiological changes do not necessarily make one vulnerable; however, chronic diseases of aging, including major neurocognitive disorders, can impair daily function and increase disability and vulnerability. The majority of online dating sites do not discriminate among users, including those with disabilities such as incapacitating neuropsychiatric disorders. The clinician may need to assess cognitive status of patients specific to their capacity to fully understand the risks of use of social media. Inability to accomplish basic mastery of computer skills or inability to maintain appropriate boundaries and safeguards in relationships initiated and maintained using the Internet may assist in this determination. Patients with other problematic Internet use (eg, excessive devotion to online shopping or online gambling) may be prone to misusing social media and dating sites as well. Patients with clear impairment of memory or poor social judgment based on a neurocognitive disorder also might not maintain proper boundaries with social media use.

Feeling alone. Older persons might feel socially isolated, and therefore may be more willing to participate in online dating to increase their chances of establishing an intimate relationship or companionship. Research has shown that increased social ties, participation in groups, contact with friends and family, and perceived social support are associated with longer survival; on the other hand, social disengagement, low participation in leisure activities, and limited social networks are associated with higher risk of major neurocognitive disorders and increased disability.⁴

Little is known about social vulnerability in institutional settings, but institutional living could decrease social vulnerability in important ways (eg, access to social support, networks and activities, not living alone).⁴ Although the literature on older adults and “digital” or “virtual” dating is limited, there are essentially no such data from within institutional settings. It is important to separately address the issue of cognitively impaired patients’ capacity to consent to sexual activity both within institutional settings and elsewhere, as it raises numerous ethical dilemmas for clinicians.

Being sexually active. Early research into online dating focused particularly on the risks of sexually transmitted infections (STIs),⁵ which could be acquired through failure to use condoms with a new partner.⁶ Older women particularly are less likely to use condoms with new sexual partners.⁶ Screening at-risk adults should occur regardless of age. Effective interventions are needed to increase condom use in this age group. Research in the general population has started to investigate how the use of technology can minimize the risks associated with online dating.⁵ The Table^5,6 lists strategies that can be used to minimize some of the risks of online dating among geriatric patients, including STIs and victimization.

Clinicians working with sexually active geriatric patients need to perform sexual risk assessments, complete capacity assessments, and provide preventive measures.

Legal issues
Criminal and civil liability issues have arisen with online dating involving cases of murder, rape, fraud, identity theft, loans, theft, domestic violence, stalking, and burglary. Online dating also raises concerns around the right to fair use of the Internet in different contexts. Flirting in cyberspace can occur with e-mail, text, Twitter, Skype, and Instant Messenger. Practices likely will vary depending on whether older adults are institutionalized or living in the community, as well as their mental status (eg, having a major neurocognitive disorder).

Some questions with legal implications worth considering include:

• To what extent is there a duty to accommodate healthy sexual relationships in institutionalized settings?
• At what point does monitoring and supervision become overly intrusive?
• Are older adults fully aware of the potential ramifications of sharing sensitive information in cyberspace?
• What is the threshold for capacity to consent among older adults to understand the sexual nature of the act and consent to the act?

Nursing homes and health care providers may become concerned about potential liability if their organization provides digital devices or electronic platforms that are not closely monitored. Clinicians have a duty to protect patients under their care from risks associated with predators who target vulnerable and lonely people, whether financially, emotionally, or physically. Some patients in nursing home settings may benefit from discussing with their family members or attorney the possibility of completing a “sexual power of attorney”⁷ that could be completed in conjunction with an advance health care directive that addresses or authorizes an agent to make decisions about their sexual activities if cognitively impaired in the future.

One might also consider to what extent local regulatory oversight will protect your patient. Not all jurisdictions regulate online dating services similarly; many existing regulations focus on unfair contracts and pay less heed to safety concerns.

As a result, some dissatisfied clients have been known to sue an online dating service for breach of contract or misrepresentation. One of the most significant issues, however, is making sure there are appropriate background checks. Online dating services may need to change their policies to screen and verify for criminal background checks.⁸ Older adults interested in online dating should be made aware of these emerging issues.

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

Baby Boomers represent a rapidly growing segment of digital device users.¹ As these people age, their continued, even increasing, use of the Internet can be expected.¹ At the same time, many older adults (age ≥65) are engaged in intimate relationships and regard sexuality as an important part of life.²

At this intersection, the Internet is likely to play a role in geriatric sexuality and “digital intimacy”—in that older adults can adopt patterns of using online dating sites similar to what their younger counterparts engage in. There is a need among clinicians to avoid stereotypical perceptions of “ageism” and the myth of “geriatric asexuality” as a result of older patients’ continued sexual interest and their adoption of social media technologies to facilitate the development of new intimate relationships. Acknowledgement of these realities by clinicians may assist in understanding and communication regarding these important areas of patients’ lives.

Why online dating?
Contemporary social and demographic changes (eg, higher divorce rates, increased longevity, aging of Baby Boomers) have influenced patterns of dating behaviors.³ Consistent with evolutionary theory, studies on courtship behaviors show that women remain the “choosers” of partners in relationships at all ages³; in contemporary society, however, there is an increasing ratio of women to men in later life, and the degree to which this demographic change might influence older men and women who are pursuing sexual relationships is unclear.³ Older adults might be aware of these demographic realities, and may use the Internet to increase their chances of finding a relationship.

For older homosexual men and women, demographic trends also are important because fewer available partners of similar sexual orientation might be available in their immediate communities, similarly incentivizing the use of online dating sites.

Hand in hand: Risk and vulnerability
Clinicians can discuss with geriatric patients who present with questions or concerns about sexuality and risks of online dating. Although risks associated with digital dating can involve anyone, those who are recently divorced, widowed, disabled, or elderly can be targeted by predators or fraudulent schemes, and thus become victims. Recognizing those risks and the vulnerability in the geriatric patient is crucial.

Chronic illness. Age-related physiological changes do not necessarily make one vulnerable; however, chronic diseases of aging, including major neurocognitive disorders, can impair daily function and increase disability and vulnerability. The majority of online dating sites do not discriminate among users, including those with disabilities such as incapacitating neuropsychiatric disorders. The clinician may need to assess cognitive status of patients specific to their capacity to fully understand the risks of use of social media. Inability to accomplish basic mastery of computer skills or inability to maintain appropriate boundaries and safeguards in relationships initiated and maintained using the Internet may assist in this determination. Patients with other problematic Internet use (eg, excessive devotion to online shopping or online gambling) may be prone to misusing social media and dating sites as well. Patients with clear impairment of memory or poor social judgment based on a neurocognitive disorder also might not maintain proper boundaries with social media use.

Feeling alone. Older persons might feel socially isolated, and therefore may be more willing to participate in online dating to increase their chances of establishing an intimate relationship or companionship. Research has shown that increased social ties, participation in groups, contact with friends and family, and perceived social support are associated with longer survival; on the other hand, social disengagement, low participation in leisure activities, and limited social networks are associated with higher risk of major neurocognitive disorders and increased disability.⁴

Little is known about social vulnerability in institutional settings, but institutional living could decrease social vulnerability in important ways (eg, access to social support, networks and activities, not living alone).⁴ Although the literature on older adults and “digital” or “virtual” dating is limited, there are essentially no such data from within institutional settings. It is important to separately address the issue of cognitively impaired patients’ capacity to consent to sexual activity both within institutional settings and elsewhere, as it raises numerous ethical dilemmas for clinicians.

Being sexually active. Early research into online dating focused particularly on the risks of sexually transmitted infections (STIs),⁵ which could be acquired through failure to use condoms with a new partner.⁶ Older women particularly are less likely to use condoms with new sexual partners.⁶ Screening at-risk adults should occur regardless of age. Effective interventions are needed to increase condom use in this age group. Research in the general population has started to investigate how the use of technology can minimize the risks associated with online dating.⁵ The Table^5,6 lists strategies that can be used to minimize some of the risks of online dating among geriatric patients, including STIs and victimization.

Clinicians working with sexually active geriatric patients need to perform sexual risk assessments, complete capacity assessments, and provide preventive measures.

Legal issues
Criminal and civil liability issues have arisen with online dating involving cases of murder, rape, fraud, identity theft, loans, theft, domestic violence, stalking, and burglary. Online dating also raises concerns around the right to fair use of the Internet in different contexts. Flirting in cyberspace can occur with e-mail, text, Twitter, Skype, and Instant Messenger. Practices likely will vary depending on whether older adults are institutionalized or living in the community, as well as their mental status (eg, having a major neurocognitive disorder).

Some questions with legal implications worth considering include:

• To what extent is there a duty to accommodate healthy sexual relationships in institutionalized settings?
• At what point does monitoring and supervision become overly intrusive?
• Are older adults fully aware of the potential ramifications of sharing sensitive information in cyberspace?
• What is the threshold for capacity to consent among older adults to understand the sexual nature of the act and consent to the act?

Nursing homes and health care providers may become concerned about potential liability if their organization provides digital devices or electronic platforms that are not closely monitored. Clinicians have a duty to protect patients under their care from risks associated with predators who target vulnerable and lonely people, whether financially, emotionally, or physically. Some patients in nursing home settings may benefit from discussing with their family members or attorney the possibility of completing a “sexual power of attorney”⁷ that could be completed in conjunction with an advance health care directive that addresses or authorizes an agent to make decisions about their sexual activities if cognitively impaired in the future.

One might also consider to what extent local regulatory oversight will protect your patient. Not all jurisdictions regulate online dating services similarly; many existing regulations focus on unfair contracts and pay less heed to safety concerns.

As a result, some dissatisfied clients have been known to sue an online dating service for breach of contract or misrepresentation. One of the most significant issues, however, is making sure there are appropriate background checks. Online dating services may need to change their policies to screen and verify for criminal background checks.⁸ Older adults interested in online dating should be made aware of these emerging issues.

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

Dr. Emjay Tan’s case study of a 36-year-old man who became “Manic after taking a vacation” (Cases That Test Your Skills, Current Psychiatry. April 2016, p. 45-50) is off the mark by attributing the manic episode to scopolamine—theoretically possible, but statistically improbable.

Dr. Tan may be unaware of a more frequent event: vacation hypomania. About one-third of my bipolar disorder patients had their first manic episode while on an overseas vacation or upon their return. It isn’t the fun, excitement, or novelty of a vacation that triggers the episode, but sleep deprivation, which is part and parcel of such events, particularly when they involve a holiday in a substantially different time zone. 

Few people get to sleep more than a few hours the night before departing on a vacation; there’s so much to do: packing, getting to the airport hours before the flight, etc. Not many people sleep soundly on the plane, and many experience the effects of jet lag both during the first few days of vacation and when the vacationer returns home. Many vacations come with substantial and protracted sleep deprivation, and sleep deprivation is an excellent way to trigger a hypomanic episode. I suspect that is why Dr. Tan’s patient, who did not have a history of psychiatric symptoms, but who might have been genetically predisposed, became manifestly symptomatic shortly following his return from an overseas holiday.

Of course, it isn’t just first episodes of hypomania that are triggered by sleep deprivation in patients with undiagnosed bipolar disorder; the event is common in the lives of people who already receive treatment. Accordingly, my patients know that I might increase their lithium dosage for at least a few days to give them added protection as they head overseas, coupled with advice to do their best to get proper sleep.

Despite such prophylaxis, many of my bipolar disorder patients have taken a long flight overseas and, then, after half a day in the air, continued “flying.” To the best of my knowledge, none ever took scopolamine.

Martin Blinder, MD
Past Assistant Clinical Professor of Psychiatry
University of California, San Francisco
Past Adjunct Professor of Law
University of California
Hastings College of Law
San Francisco, California

Dr. Emjay Tan’s case study of a 36-year-old man who became “Manic after taking a vacation” (Cases That Test Your Skills, Current Psychiatry. April 2016, p. 45-50) is off the mark by attributing the manic episode to scopolamine—theoretically possible, but statistically improbable.

Dr. Tan may be unaware of a more frequent event: vacation hypomania. About one-third of my bipolar disorder patients had their first manic episode while on an overseas vacation or upon their return. It isn’t the fun, excitement, or novelty of a vacation that triggers the episode, but sleep deprivation, which is part and parcel of such events, particularly when they involve a holiday in a substantially different time zone. 

Few people get to sleep more than a few hours the night before departing on a vacation; there’s so much to do: packing, getting to the airport hours before the flight, etc. Not many people sleep soundly on the plane, and many experience the effects of jet lag both during the first few days of vacation and when the vacationer returns home. Many vacations come with substantial and protracted sleep deprivation, and sleep deprivation is an excellent way to trigger a hypomanic episode. I suspect that is why Dr. Tan’s patient, who did not have a history of psychiatric symptoms, but who might have been genetically predisposed, became manifestly symptomatic shortly following his return from an overseas holiday.

Of course, it isn’t just first episodes of hypomania that are triggered by sleep deprivation in patients with undiagnosed bipolar disorder; the event is common in the lives of people who already receive treatment. Accordingly, my patients know that I might increase their lithium dosage for at least a few days to give them added protection as they head overseas, coupled with advice to do their best to get proper sleep.

Despite such prophylaxis, many of my bipolar disorder patients have taken a long flight overseas and, then, after half a day in the air, continued “flying.” To the best of my knowledge, none ever took scopolamine.

Martin Blinder, MD
Past Assistant Clinical Professor of Psychiatry
University of California, San Francisco
Past Adjunct Professor of Law
University of California
Hastings College of Law
San Francisco, California

Dr. Emjay Tan’s case study of a 36-year-old man who became “Manic after taking a vacation” (Cases That Test Your Skills, Current Psychiatry. April 2016, p. 45-50) is off the mark by attributing the manic episode to scopolamine—theoretically possible, but statistically improbable.

Dr. Tan may be unaware of a more frequent event: vacation hypomania. About one-third of my bipolar disorder patients had their first manic episode while on an overseas vacation or upon their return. It isn’t the fun, excitement, or novelty of a vacation that triggers the episode, but sleep deprivation, which is part and parcel of such events, particularly when they involve a holiday in a substantially different time zone. 

Few people get to sleep more than a few hours the night before departing on a vacation; there’s so much to do: packing, getting to the airport hours before the flight, etc. Not many people sleep soundly on the plane, and many experience the effects of jet lag both during the first few days of vacation and when the vacationer returns home. Many vacations come with substantial and protracted sleep deprivation, and sleep deprivation is an excellent way to trigger a hypomanic episode. I suspect that is why Dr. Tan’s patient, who did not have a history of psychiatric symptoms, but who might have been genetically predisposed, became manifestly symptomatic shortly following his return from an overseas holiday.

Of course, it isn’t just first episodes of hypomania that are triggered by sleep deprivation in patients with undiagnosed bipolar disorder; the event is common in the lives of people who already receive treatment. Accordingly, my patients know that I might increase their lithium dosage for at least a few days to give them added protection as they head overseas, coupled with advice to do their best to get proper sleep.

Despite such prophylaxis, many of my bipolar disorder patients have taken a long flight overseas and, then, after half a day in the air, continued “flying.” To the best of my knowledge, none ever took scopolamine.

Martin Blinder, MD
Past Assistant Clinical Professor of Psychiatry
University of California, San Francisco
Past Adjunct Professor of Law
University of California
Hastings College of Law
San Francisco, California

Here are 5 commonly held beliefs about stopping tobacco use, and about your role in helping these patients, that go up in smoke on close inspection.

Treating nicotine use disorder isn’t really a psychiatrist’s job. False! Smoking is the leading preventable cause of death, causing 1 in every 5 deaths in the United States and as many as 1 of every 2 deaths among patients with depression, bipolar disorder, or schizophrenia.^1,2 As psychiatrists, our experience with treating addiction positions us to address nicotine use disorder more effectively than deferring exclusively to primary care.

I can’t treat my patients’ nicotine dependence until they are ready to quit. Not so! Treatment with varenicline, bupropion, or nicotine replacement therapy is likely to decrease smoking even if the patient has not made a commitment to quit. A smoker treated with pharmacotherapy is more likely to try to quit than one who is not receiving medication.^3,4

Motivational interviewing is an excellent intervention to facilitate readiness to quit smoking. Many smokers want to quit—but if they don’t believe that effective treatments exist or that psychiatrists provide such care, they won’t initiate that conversation with you.

Smokeless tobacco isn’t so bad. Poppycock! Chewing and dipping tobacco contains many undesirable chemicals, including abrasives, salts, sweeteners, and carcinogens. Smokeless tobacco is a risk factor for cancer of the mouth and pancreas, as well as tooth decay, periodontal disease, hypertension, hyperlipidemia, myocardial infarction, and fatal stroke.⁵

Nicotine replacement products are as bad as smoking. Claptrap! You can reassure patients that nicotine is not a carcinogen. If your patients use the same amount of nicotine but replace tobacco in whole or in part with a patch, gum, or an inhaler, they will have better health even if they use nicotine replacement for the rest of their life. Nicotine replacement products are less addictive than cigarettes because they release nicotine more slowly. (Cigarettes bring peak levels of nicotine to the brain even faster than IV administration does.) Nicotine replacement is recommended for at least 3 months after quitting tobacco or for as long the patient needs it.³

Nicotine replacement products are dangerous for current smokers. Balderdash! Many patients are afraid of using nicotine from >1 source. A common myth is that using a nicotine patch while smoking increases the risk of heart attack, which discourages patients from trying a nicotine replacement product before they are sure they will stop smoking. Nicotine replacement is likely to reduce the frequency of their smoking and reduce harm, not add to it.³

Here are 5 commonly held beliefs about stopping tobacco use, and about your role in helping these patients, that go up in smoke on close inspection.

Treating nicotine use disorder isn’t really a psychiatrist’s job. False! Smoking is the leading preventable cause of death, causing 1 in every 5 deaths in the United States and as many as 1 of every 2 deaths among patients with depression, bipolar disorder, or schizophrenia.^1,2 As psychiatrists, our experience with treating addiction positions us to address nicotine use disorder more effectively than deferring exclusively to primary care.

I can’t treat my patients’ nicotine dependence until they are ready to quit. Not so! Treatment with varenicline, bupropion, or nicotine replacement therapy is likely to decrease smoking even if the patient has not made a commitment to quit. A smoker treated with pharmacotherapy is more likely to try to quit than one who is not receiving medication.^3,4

Motivational interviewing is an excellent intervention to facilitate readiness to quit smoking. Many smokers want to quit—but if they don’t believe that effective treatments exist or that psychiatrists provide such care, they won’t initiate that conversation with you.

Smokeless tobacco isn’t so bad. Poppycock! Chewing and dipping tobacco contains many undesirable chemicals, including abrasives, salts, sweeteners, and carcinogens. Smokeless tobacco is a risk factor for cancer of the mouth and pancreas, as well as tooth decay, periodontal disease, hypertension, hyperlipidemia, myocardial infarction, and fatal stroke.⁵

Nicotine replacement products are as bad as smoking. Claptrap! You can reassure patients that nicotine is not a carcinogen. If your patients use the same amount of nicotine but replace tobacco in whole or in part with a patch, gum, or an inhaler, they will have better health even if they use nicotine replacement for the rest of their life. Nicotine replacement products are less addictive than cigarettes because they release nicotine more slowly. (Cigarettes bring peak levels of nicotine to the brain even faster than IV administration does.) Nicotine replacement is recommended for at least 3 months after quitting tobacco or for as long the patient needs it.³

Nicotine replacement products are dangerous for current smokers. Balderdash! Many patients are afraid of using nicotine from >1 source. A common myth is that using a nicotine patch while smoking increases the risk of heart attack, which discourages patients from trying a nicotine replacement product before they are sure they will stop smoking. Nicotine replacement is likely to reduce the frequency of their smoking and reduce harm, not add to it.³

Here are 5 commonly held beliefs about stopping tobacco use, and about your role in helping these patients, that go up in smoke on close inspection.

Treating nicotine use disorder isn’t really a psychiatrist’s job. False! Smoking is the leading preventable cause of death, causing 1 in every 5 deaths in the United States and as many as 1 of every 2 deaths among patients with depression, bipolar disorder, or schizophrenia.^1,2 As psychiatrists, our experience with treating addiction positions us to address nicotine use disorder more effectively than deferring exclusively to primary care.

I can’t treat my patients’ nicotine dependence until they are ready to quit. Not so! Treatment with varenicline, bupropion, or nicotine replacement therapy is likely to decrease smoking even if the patient has not made a commitment to quit. A smoker treated with pharmacotherapy is more likely to try to quit than one who is not receiving medication.^3,4

Motivational interviewing is an excellent intervention to facilitate readiness to quit smoking. Many smokers want to quit—but if they don’t believe that effective treatments exist or that psychiatrists provide such care, they won’t initiate that conversation with you.

Smokeless tobacco isn’t so bad. Poppycock! Chewing and dipping tobacco contains many undesirable chemicals, including abrasives, salts, sweeteners, and carcinogens. Smokeless tobacco is a risk factor for cancer of the mouth and pancreas, as well as tooth decay, periodontal disease, hypertension, hyperlipidemia, myocardial infarction, and fatal stroke.⁵

Nicotine replacement products are as bad as smoking. Claptrap! You can reassure patients that nicotine is not a carcinogen. If your patients use the same amount of nicotine but replace tobacco in whole or in part with a patch, gum, or an inhaler, they will have better health even if they use nicotine replacement for the rest of their life. Nicotine replacement products are less addictive than cigarettes because they release nicotine more slowly. (Cigarettes bring peak levels of nicotine to the brain even faster than IV administration does.) Nicotine replacement is recommended for at least 3 months after quitting tobacco or for as long the patient needs it.³

Nicotine replacement products are dangerous for current smokers. Balderdash! Many patients are afraid of using nicotine from >1 source. A common myth is that using a nicotine patch while smoking increases the risk of heart attack, which discourages patients from trying a nicotine replacement product before they are sure they will stop smoking. Nicotine replacement is likely to reduce the frequency of their smoking and reduce harm, not add to it.³