Bipolar Disorder

WASHINGTON – In 2015, the Florida Agency for Health Care Administration published clinical guidelines for numerous psychiatric conditions, including bipolar disorder, demoting several first-line therapies, and promoting others.

Because the authors of the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults agreed that inflammation is a mechanism of action in bipolar disorder, they adopted an approach to care that seeks to avoid inflammation at all costs.

“Some medications create metabolic disturbances, which can be disruptive to the inflammatory milieu,” said Roger McIntyre, MD, a professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit at the University Health Network, Toronto. Dr. McIntyre, one of the coauthors of the guidelines, discussed why the combination of olanzapine and fluoxetine has been deferred in the algorithm, why other medications have moved further up, why antidepressants also are lower in the order of priority, and why psychoeducation, social rhythm therapy, and lifestyle changes have been emphasized more than ever before.

“There is no way our bipolar patients are going to achieve their goals with medication alone,” Dr. McIntyre said at the meeting, held by the Global Academy for Medical Education. In addition, Dr. McIntyre outlined why adding bipolar screening in the primary care setting is critical in 2016, and called the new recommendations “the most up-to-date guidelines for treating bipolar disorder, and the new nosology of major depression disorder with mixed features.”

To access the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults online, visit the Florida Medicaid Drug Therapy Management Program for Behavioral Health website.

Dr. McIntyre has numerous industry relationships, including research funding from Eli Lilly, Janssen-Ortho, Astra-Zeneca; Pfizer, and Lundbeck. Global Academy and this news organization are owned by the same company.

[email protected]

On Twitter @whitneymcknight

WASHINGTON – In 2015, the Florida Agency for Health Care Administration published clinical guidelines for numerous psychiatric conditions, including bipolar disorder, demoting several first-line therapies, and promoting others.

Because the authors of the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults agreed that inflammation is a mechanism of action in bipolar disorder, they adopted an approach to care that seeks to avoid inflammation at all costs.

“Some medications create metabolic disturbances, which can be disruptive to the inflammatory milieu,” said Roger McIntyre, MD, a professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit at the University Health Network, Toronto. Dr. McIntyre, one of the coauthors of the guidelines, discussed why the combination of olanzapine and fluoxetine has been deferred in the algorithm, why other medications have moved further up, why antidepressants also are lower in the order of priority, and why psychoeducation, social rhythm therapy, and lifestyle changes have been emphasized more than ever before.

“There is no way our bipolar patients are going to achieve their goals with medication alone,” Dr. McIntyre said at the meeting, held by the Global Academy for Medical Education. In addition, Dr. McIntyre outlined why adding bipolar screening in the primary care setting is critical in 2016, and called the new recommendations “the most up-to-date guidelines for treating bipolar disorder, and the new nosology of major depression disorder with mixed features.”

To access the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults online, visit the Florida Medicaid Drug Therapy Management Program for Behavioral Health website.

Dr. McIntyre has numerous industry relationships, including research funding from Eli Lilly, Janssen-Ortho, Astra-Zeneca; Pfizer, and Lundbeck. Global Academy and this news organization are owned by the same company.

[email protected]

On Twitter @whitneymcknight

WASHINGTON – In 2015, the Florida Agency for Health Care Administration published clinical guidelines for numerous psychiatric conditions, including bipolar disorder, demoting several first-line therapies, and promoting others.

Because the authors of the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults agreed that inflammation is a mechanism of action in bipolar disorder, they adopted an approach to care that seeks to avoid inflammation at all costs.

“Some medications create metabolic disturbances, which can be disruptive to the inflammatory milieu,” said Roger McIntyre, MD, a professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit at the University Health Network, Toronto. Dr. McIntyre, one of the coauthors of the guidelines, discussed why the combination of olanzapine and fluoxetine has been deferred in the algorithm, why other medications have moved further up, why antidepressants also are lower in the order of priority, and why psychoeducation, social rhythm therapy, and lifestyle changes have been emphasized more than ever before.

“There is no way our bipolar patients are going to achieve their goals with medication alone,” Dr. McIntyre said at the meeting, held by the Global Academy for Medical Education. In addition, Dr. McIntyre outlined why adding bipolar screening in the primary care setting is critical in 2016, and called the new recommendations “the most up-to-date guidelines for treating bipolar disorder, and the new nosology of major depression disorder with mixed features.”

To access the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults online, visit the Florida Medicaid Drug Therapy Management Program for Behavioral Health website.

Dr. McIntyre has numerous industry relationships, including research funding from Eli Lilly, Janssen-Ortho, Astra-Zeneca; Pfizer, and Lundbeck. Global Academy and this news organization are owned by the same company.

[email protected]

On Twitter @whitneymcknight

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.

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

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

ATLANTA – A new smartphone application aimed at providing psychoeducation to patients with bipolar disorder was well received and showed promise for improving outcomes in a feasibility study, according to Dr. Eduard Vieta.

Early results of the study showed that adherence was quite high, with retention at 76% among 49 patients with bipolar disorder who tested the SIMPle app (Self Monitoring and Psychoeducation in Bipolar Patients with a Smartphone Application), Dr. Vieta said at the annual meeting of the American Psychiatric Association.

The app, currently available for free for Android and iPhones, is an interactive educational program that includes weekly and daily tests, with alerts for patients to take medications or see their doctor.

The patients in the study were representative of generally stable bipolar disorder patients in a real-world setting, as the app ideally would be used by those who are “in near remission or at least not acutely ill,” said Dr. Vieta of the University of Barcelona.

“People like the app and did follow the daily and weekly tests, which is a good sign,” he said, noting that satisfaction was high, and good correlation between test scores and mood changes suggested that the app is reliable for monitoring mood changes.

There were 10 suicide alerts during the study that were quickly addressed because messages were received immediately, he said.

The latest version of the app includes simpler navigation, rewards for fulfilling the daily and weekly testing, and medication reminders.

Dr. Vieta and his colleagues at the University of Barcelona previously have demonstrated the value of psychoeducation among patients with bipolar disorder. They developed a successful psychoeducation program in the late 1990s, which led to a trial published in 2003 and development of a training manual in 2006 that has been translated into numerous languages.

The program and trial showed that adding psychoeducation to medication in patients with bipolar disorder improves outcomes in terms of relapse and hospitalizations: the rate of relapses in the study was reduced by nearly 80%, Dr. Vieta said.

Providing such education, however, which has become a standard of care, is limited by the need for personnel training and by staffing and financial resource constraints.

“We wanted something nonstigmatizing but also linked to the clinical care team. … Clearly, we would like to make this intervention more widely available without compromising quality,” Dr. Vieta said, describing the impetus for the SIMPle app.

A phase II, randomized controlled study of the app is now underway, he said, adding that “this is really quite exciting. … There is huge potential for things we can do with this app.”

Dr. Vieta is a consultant or adviser for several pharmaceutical companies. He also has received research grants, honoraria, or consulting fees from numerous entities.

[email protected]

ATLANTA – A new smartphone application aimed at providing psychoeducation to patients with bipolar disorder was well received and showed promise for improving outcomes in a feasibility study, according to Dr. Eduard Vieta.

Early results of the study showed that adherence was quite high, with retention at 76% among 49 patients with bipolar disorder who tested the SIMPle app (Self Monitoring and Psychoeducation in Bipolar Patients with a Smartphone Application), Dr. Vieta said at the annual meeting of the American Psychiatric Association.

The app, currently available for free for Android and iPhones, is an interactive educational program that includes weekly and daily tests, with alerts for patients to take medications or see their doctor.

The patients in the study were representative of generally stable bipolar disorder patients in a real-world setting, as the app ideally would be used by those who are “in near remission or at least not acutely ill,” said Dr. Vieta of the University of Barcelona.

“People like the app and did follow the daily and weekly tests, which is a good sign,” he said, noting that satisfaction was high, and good correlation between test scores and mood changes suggested that the app is reliable for monitoring mood changes.

There were 10 suicide alerts during the study that were quickly addressed because messages were received immediately, he said.

The latest version of the app includes simpler navigation, rewards for fulfilling the daily and weekly testing, and medication reminders.

Dr. Vieta and his colleagues at the University of Barcelona previously have demonstrated the value of psychoeducation among patients with bipolar disorder. They developed a successful psychoeducation program in the late 1990s, which led to a trial published in 2003 and development of a training manual in 2006 that has been translated into numerous languages.

The program and trial showed that adding psychoeducation to medication in patients with bipolar disorder improves outcomes in terms of relapse and hospitalizations: the rate of relapses in the study was reduced by nearly 80%, Dr. Vieta said.

Providing such education, however, which has become a standard of care, is limited by the need for personnel training and by staffing and financial resource constraints.

“We wanted something nonstigmatizing but also linked to the clinical care team. … Clearly, we would like to make this intervention more widely available without compromising quality,” Dr. Vieta said, describing the impetus for the SIMPle app.

A phase II, randomized controlled study of the app is now underway, he said, adding that “this is really quite exciting. … There is huge potential for things we can do with this app.”

Dr. Vieta is a consultant or adviser for several pharmaceutical companies. He also has received research grants, honoraria, or consulting fees from numerous entities.

[email protected]

ATLANTA – A new smartphone application aimed at providing psychoeducation to patients with bipolar disorder was well received and showed promise for improving outcomes in a feasibility study, according to Dr. Eduard Vieta.

Early results of the study showed that adherence was quite high, with retention at 76% among 49 patients with bipolar disorder who tested the SIMPle app (Self Monitoring and Psychoeducation in Bipolar Patients with a Smartphone Application), Dr. Vieta said at the annual meeting of the American Psychiatric Association.

The app, currently available for free for Android and iPhones, is an interactive educational program that includes weekly and daily tests, with alerts for patients to take medications or see their doctor.

The patients in the study were representative of generally stable bipolar disorder patients in a real-world setting, as the app ideally would be used by those who are “in near remission or at least not acutely ill,” said Dr. Vieta of the University of Barcelona.

“People like the app and did follow the daily and weekly tests, which is a good sign,” he said, noting that satisfaction was high, and good correlation between test scores and mood changes suggested that the app is reliable for monitoring mood changes.

There were 10 suicide alerts during the study that were quickly addressed because messages were received immediately, he said.

The latest version of the app includes simpler navigation, rewards for fulfilling the daily and weekly testing, and medication reminders.

Dr. Vieta and his colleagues at the University of Barcelona previously have demonstrated the value of psychoeducation among patients with bipolar disorder. They developed a successful psychoeducation program in the late 1990s, which led to a trial published in 2003 and development of a training manual in 2006 that has been translated into numerous languages.

The program and trial showed that adding psychoeducation to medication in patients with bipolar disorder improves outcomes in terms of relapse and hospitalizations: the rate of relapses in the study was reduced by nearly 80%, Dr. Vieta said.

Providing such education, however, which has become a standard of care, is limited by the need for personnel training and by staffing and financial resource constraints.

“We wanted something nonstigmatizing but also linked to the clinical care team. … Clearly, we would like to make this intervention more widely available without compromising quality,” Dr. Vieta said, describing the impetus for the SIMPle app.

A phase II, randomized controlled study of the app is now underway, he said, adding that “this is really quite exciting. … There is huge potential for things we can do with this app.”

Dr. Vieta is a consultant or adviser for several pharmaceutical companies. He also has received research grants, honoraria, or consulting fees from numerous entities.

[email protected]

Olanzapine can cause a rare but serious skin reaction that can affect other parts of the body, according to a Food and Drug Administration safety alert released May 10.

The condition linked to all products containing the second-generation antipsychotic is called Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS. Symptoms of DRESS include a rash that can spread to all parts of the body, fever, swollen lymph nodes, and swelling. In addition, DRESS can result in injury to the liver, kidneys, lungs, heart, or pancreas, and it also can lead to death. The mortality tied to DRESS can reach 10%, the FDA said.

The FDA Adverse Event Reporting System database has identified 23 cases worldwide of DRESS resulting from olanzapine since 1996, including one patient who died. Currently, the only way to treat DRESS is to withdraw the drug promptly. “Health care professionals should immediately stop treatment with olanzapine if DRESS is suspected,” the safety alert states. “The important ways to manage DRESS are early recognition of the syndrome, discontinuation of the offending agent as soon as possible, and supportive care.”

Olanzapine, used to treat schizophrenia and manic episodes of bipolar disorder, is available in generic versions. The medication also is available under the brand names Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax. The agency said it would add a warning describing DRESS to the labels of drugs containing olanzapine.

Read the full safety alert on the FDA website.

[email protected]

Olanzapine can cause a rare but serious skin reaction that can affect other parts of the body, according to a Food and Drug Administration safety alert released May 10.

The condition linked to all products containing the second-generation antipsychotic is called Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS. Symptoms of DRESS include a rash that can spread to all parts of the body, fever, swollen lymph nodes, and swelling. In addition, DRESS can result in injury to the liver, kidneys, lungs, heart, or pancreas, and it also can lead to death. The mortality tied to DRESS can reach 10%, the FDA said.

The FDA Adverse Event Reporting System database has identified 23 cases worldwide of DRESS resulting from olanzapine since 1996, including one patient who died. Currently, the only way to treat DRESS is to withdraw the drug promptly. “Health care professionals should immediately stop treatment with olanzapine if DRESS is suspected,” the safety alert states. “The important ways to manage DRESS are early recognition of the syndrome, discontinuation of the offending agent as soon as possible, and supportive care.”

Olanzapine, used to treat schizophrenia and manic episodes of bipolar disorder, is available in generic versions. The medication also is available under the brand names Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax. The agency said it would add a warning describing DRESS to the labels of drugs containing olanzapine.

Read the full safety alert on the FDA website.

[email protected]

Olanzapine can cause a rare but serious skin reaction that can affect other parts of the body, according to a Food and Drug Administration safety alert released May 10.

The condition linked to all products containing the second-generation antipsychotic is called Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS. Symptoms of DRESS include a rash that can spread to all parts of the body, fever, swollen lymph nodes, and swelling. In addition, DRESS can result in injury to the liver, kidneys, lungs, heart, or pancreas, and it also can lead to death. The mortality tied to DRESS can reach 10%, the FDA said.

The FDA Adverse Event Reporting System database has identified 23 cases worldwide of DRESS resulting from olanzapine since 1996, including one patient who died. Currently, the only way to treat DRESS is to withdraw the drug promptly. “Health care professionals should immediately stop treatment with olanzapine if DRESS is suspected,” the safety alert states. “The important ways to manage DRESS are early recognition of the syndrome, discontinuation of the offending agent as soon as possible, and supportive care.”

Olanzapine, used to treat schizophrenia and manic episodes of bipolar disorder, is available in generic versions. The medication also is available under the brand names Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax. The agency said it would add a warning describing DRESS to the labels of drugs containing olanzapine.

Read the full safety alert on the FDA website.

[email protected]

A description of two bipolar I disorder cases presents examples of the phenomenon of transient neutrophilia that occurred during admission into a state psychiatric hospital. A brief review of the mechanisms that may explain this hematologic response is included.

Background

In 1889, the U.S. territory of New Mexico established the New Mexico Insane Asylum, and it was known as such until 1955, when it became the State Hospital. In 1970, it became the Las Vegas Medical Center but changed its name in 2005 to the New Mexico Behavioral Health Institute (NMBHI), which services the entire state for inpatient and long-term care patients. On average, it accepts two admissions per day, of which two patients per month present with neutrophilia (white blood cell [WBC] count greater than 11,000), which resolves after 1-4 days in the hospital.

Case presentations

Case one. A 21-year-old Native American man presented with multiple psychiatric admissions for bipolar I disorder and major depression with suicidal ideation. He was brought into the local emergency department by police, who found him walking down the interstate highway trying to hitch a ride back to his native pueblo after a disagreement with a fellow resident at a local boarding home. He had discontinued his Seroquel and lithium 2 weeks earlier because he felt he no longer needed them and required medical clearance for admission.¹ His presenting hemogram in the ED was normal except for an elevated WBC count of 20,000. His vital signs were normal except for tachycardia of 110 beats per minute. On exam the patient demonstrated a flat affect and anxiety but other than mild ingrown toenails and tachycardia, there were no abnormal findings.

He received a chest x-ray and abdominal computed tomography scan that were both normal, and the patient was cleared for admission. He was cooperative with staff and restarted his lithium. A repeat WBC at day 5 was 9,700.

Case two. A 24-year-old white man with a history of bipolar I disorder and dependency on benzodiazepines and Ritalin was transferred from a distant county jail after 10 days of incarceration. He started screaming in his cell, praying, and perseverating that he “needed to kill himself,” which triggered his transfer to the NMBHI. His aggressive behavior upon arrival necessitated a transfer to the local ED for sedation and four-point restraints. He received Versed and Ativan IVP before allowing a blood collection, which revealed dehydration and a WBC count of 17,100. After 4 L of normal saline, his labs normalized with a WBC of 10,100, and he was admitted for a 7-day committal.

Discussion

Neutrophilia can result from granulocytes moving from pericapillary tissue margins into the circulating pool.² It may occur in association with vigorous exercise, seizures, paroxysmal tachycardia, and adrenergic stress.³ The duration is fewer than 30 minutes and usually results in WBC counts of 15,000-20,000.⁴ Beta receptors on endothelial cells may mediate neutrophil adherence and release from marginal sites. A left shift is absent, because there is no change of the inflow of cells from the marrow.

In these two cases, a transient neutrophilia and tachycardia were observed. Neither case was febrile, and the platelet count remained normal. Both patients voluntarily stopped taking their lithium about 2 weeks before decompensating from bipolar I disorders. Stress was evident in both cases, one from walking on a cold December night after a disagreement, while the other patient in case two was highly agitated and aggressive requiring four-point restraints and intravenous sedation in the ED before admission to NMBHI. Past histories of psychiatric admissions were noted in both cases, and neither subject smoked tobacco – which can increase WBC by 25%-50% with the use of one-two packs per day, respectively.⁵

These two cases show that clinicians should consider stress in its many permutations to the long list of causes to explain elevated WBC, particularly in the ED. They also illustrate the power of antianxiety medications for some patients with acute mania who present to the ED.

References

1. J Emerg Med. 2012;43(5):866-70.

2. “Wintrobe’s Clinical Hematology,” Philadelphia: Lea & Febiger, 1981, p.1292.

3. “Diagnostic Hematology,” London: Springer, 2009, p. 324.

4. Gen Hosp Psychiatry. 2005;27(6):454-56.

5. Euro Heart J. 2003 Jul;24(14)1365-72.

Dr. Taylor is a staff physician affiliated with the New Mexico Behavioral Health Institute, New Mexico Department of Health, Santa Fe. He reports no financial disclosures or conflicts of interest. The author wishes to thank Dr. Dan Collins from the NMBHI for recommending that he research and write about this topic. In addition, document access was greatly aided by Lisa Apodaca and Mary Bunker, CNP, from the NMBHI, and Karen Ebler and Dr. Irwin Hoffman from Christus St. Vincent Hospital in Santa Fe. Finally, the following colleagues helped by proofreading the manuscript: Dr. Wendy Dimmette, Dr. Richard Nail, and Dr. Matt Streicherz. Eva Romero and Dr. Troy Jones provided useful historical documentation.

A description of two bipolar I disorder cases presents examples of the phenomenon of transient neutrophilia that occurred during admission into a state psychiatric hospital. A brief review of the mechanisms that may explain this hematologic response is included.

Background

In 1889, the U.S. territory of New Mexico established the New Mexico Insane Asylum, and it was known as such until 1955, when it became the State Hospital. In 1970, it became the Las Vegas Medical Center but changed its name in 2005 to the New Mexico Behavioral Health Institute (NMBHI), which services the entire state for inpatient and long-term care patients. On average, it accepts two admissions per day, of which two patients per month present with neutrophilia (white blood cell [WBC] count greater than 11,000), which resolves after 1-4 days in the hospital.

Case presentations

Case one. A 21-year-old Native American man presented with multiple psychiatric admissions for bipolar I disorder and major depression with suicidal ideation. He was brought into the local emergency department by police, who found him walking down the interstate highway trying to hitch a ride back to his native pueblo after a disagreement with a fellow resident at a local boarding home. He had discontinued his Seroquel and lithium 2 weeks earlier because he felt he no longer needed them and required medical clearance for admission.¹ His presenting hemogram in the ED was normal except for an elevated WBC count of 20,000. His vital signs were normal except for tachycardia of 110 beats per minute. On exam the patient demonstrated a flat affect and anxiety but other than mild ingrown toenails and tachycardia, there were no abnormal findings.

He received a chest x-ray and abdominal computed tomography scan that were both normal, and the patient was cleared for admission. He was cooperative with staff and restarted his lithium. A repeat WBC at day 5 was 9,700.

Case two. A 24-year-old white man with a history of bipolar I disorder and dependency on benzodiazepines and Ritalin was transferred from a distant county jail after 10 days of incarceration. He started screaming in his cell, praying, and perseverating that he “needed to kill himself,” which triggered his transfer to the NMBHI. His aggressive behavior upon arrival necessitated a transfer to the local ED for sedation and four-point restraints. He received Versed and Ativan IVP before allowing a blood collection, which revealed dehydration and a WBC count of 17,100. After 4 L of normal saline, his labs normalized with a WBC of 10,100, and he was admitted for a 7-day committal.

Discussion

Neutrophilia can result from granulocytes moving from pericapillary tissue margins into the circulating pool.² It may occur in association with vigorous exercise, seizures, paroxysmal tachycardia, and adrenergic stress.³ The duration is fewer than 30 minutes and usually results in WBC counts of 15,000-20,000.⁴ Beta receptors on endothelial cells may mediate neutrophil adherence and release from marginal sites. A left shift is absent, because there is no change of the inflow of cells from the marrow.

In these two cases, a transient neutrophilia and tachycardia were observed. Neither case was febrile, and the platelet count remained normal. Both patients voluntarily stopped taking their lithium about 2 weeks before decompensating from bipolar I disorders. Stress was evident in both cases, one from walking on a cold December night after a disagreement, while the other patient in case two was highly agitated and aggressive requiring four-point restraints and intravenous sedation in the ED before admission to NMBHI. Past histories of psychiatric admissions were noted in both cases, and neither subject smoked tobacco – which can increase WBC by 25%-50% with the use of one-two packs per day, respectively.⁵

These two cases show that clinicians should consider stress in its many permutations to the long list of causes to explain elevated WBC, particularly in the ED. They also illustrate the power of antianxiety medications for some patients with acute mania who present to the ED.

References

1. J Emerg Med. 2012;43(5):866-70.

2. “Wintrobe’s Clinical Hematology,” Philadelphia: Lea & Febiger, 1981, p.1292.

3. “Diagnostic Hematology,” London: Springer, 2009, p. 324.

4. Gen Hosp Psychiatry. 2005;27(6):454-56.

5. Euro Heart J. 2003 Jul;24(14)1365-72.

Dr. Taylor is a staff physician affiliated with the New Mexico Behavioral Health Institute, New Mexico Department of Health, Santa Fe. He reports no financial disclosures or conflicts of interest. The author wishes to thank Dr. Dan Collins from the NMBHI for recommending that he research and write about this topic. In addition, document access was greatly aided by Lisa Apodaca and Mary Bunker, CNP, from the NMBHI, and Karen Ebler and Dr. Irwin Hoffman from Christus St. Vincent Hospital in Santa Fe. Finally, the following colleagues helped by proofreading the manuscript: Dr. Wendy Dimmette, Dr. Richard Nail, and Dr. Matt Streicherz. Eva Romero and Dr. Troy Jones provided useful historical documentation.

A description of two bipolar I disorder cases presents examples of the phenomenon of transient neutrophilia that occurred during admission into a state psychiatric hospital. A brief review of the mechanisms that may explain this hematologic response is included.

Background

In 1889, the U.S. territory of New Mexico established the New Mexico Insane Asylum, and it was known as such until 1955, when it became the State Hospital. In 1970, it became the Las Vegas Medical Center but changed its name in 2005 to the New Mexico Behavioral Health Institute (NMBHI), which services the entire state for inpatient and long-term care patients. On average, it accepts two admissions per day, of which two patients per month present with neutrophilia (white blood cell [WBC] count greater than 11,000), which resolves after 1-4 days in the hospital.

Case presentations

Case one. A 21-year-old Native American man presented with multiple psychiatric admissions for bipolar I disorder and major depression with suicidal ideation. He was brought into the local emergency department by police, who found him walking down the interstate highway trying to hitch a ride back to his native pueblo after a disagreement with a fellow resident at a local boarding home. He had discontinued his Seroquel and lithium 2 weeks earlier because he felt he no longer needed them and required medical clearance for admission.¹ His presenting hemogram in the ED was normal except for an elevated WBC count of 20,000. His vital signs were normal except for tachycardia of 110 beats per minute. On exam the patient demonstrated a flat affect and anxiety but other than mild ingrown toenails and tachycardia, there were no abnormal findings.

He received a chest x-ray and abdominal computed tomography scan that were both normal, and the patient was cleared for admission. He was cooperative with staff and restarted his lithium. A repeat WBC at day 5 was 9,700.

Case two. A 24-year-old white man with a history of bipolar I disorder and dependency on benzodiazepines and Ritalin was transferred from a distant county jail after 10 days of incarceration. He started screaming in his cell, praying, and perseverating that he “needed to kill himself,” which triggered his transfer to the NMBHI. His aggressive behavior upon arrival necessitated a transfer to the local ED for sedation and four-point restraints. He received Versed and Ativan IVP before allowing a blood collection, which revealed dehydration and a WBC count of 17,100. After 4 L of normal saline, his labs normalized with a WBC of 10,100, and he was admitted for a 7-day committal.

Discussion

Neutrophilia can result from granulocytes moving from pericapillary tissue margins into the circulating pool.² It may occur in association with vigorous exercise, seizures, paroxysmal tachycardia, and adrenergic stress.³ The duration is fewer than 30 minutes and usually results in WBC counts of 15,000-20,000.⁴ Beta receptors on endothelial cells may mediate neutrophil adherence and release from marginal sites. A left shift is absent, because there is no change of the inflow of cells from the marrow.

In these two cases, a transient neutrophilia and tachycardia were observed. Neither case was febrile, and the platelet count remained normal. Both patients voluntarily stopped taking their lithium about 2 weeks before decompensating from bipolar I disorders. Stress was evident in both cases, one from walking on a cold December night after a disagreement, while the other patient in case two was highly agitated and aggressive requiring four-point restraints and intravenous sedation in the ED before admission to NMBHI. Past histories of psychiatric admissions were noted in both cases, and neither subject smoked tobacco – which can increase WBC by 25%-50% with the use of one-two packs per day, respectively.⁵

These two cases show that clinicians should consider stress in its many permutations to the long list of causes to explain elevated WBC, particularly in the ED. They also illustrate the power of antianxiety medications for some patients with acute mania who present to the ED.

References

1. J Emerg Med. 2012;43(5):866-70.

2. “Wintrobe’s Clinical Hematology,” Philadelphia: Lea & Febiger, 1981, p.1292.

3. “Diagnostic Hematology,” London: Springer, 2009, p. 324.

4. Gen Hosp Psychiatry. 2005;27(6):454-56.

5. Euro Heart J. 2003 Jul;24(14)1365-72.

Dr. Taylor is a staff physician affiliated with the New Mexico Behavioral Health Institute, New Mexico Department of Health, Santa Fe. He reports no financial disclosures or conflicts of interest. The author wishes to thank Dr. Dan Collins from the NMBHI for recommending that he research and write about this topic. In addition, document access was greatly aided by Lisa Apodaca and Mary Bunker, CNP, from the NMBHI, and Karen Ebler and Dr. Irwin Hoffman from Christus St. Vincent Hospital in Santa Fe. Finally, the following colleagues helped by proofreading the manuscript: Dr. Wendy Dimmette, Dr. Richard Nail, and Dr. Matt Streicherz. Eva Romero and Dr. Troy Jones provided useful historical documentation.

A new analysis of registry data from European countries does not support a risk of orofacial cleft and clubfoot with exposure to lamotrigine monotherapy, in contrast to signals from previous studies of the antiepileptic drug.

First author Helen Dolk, Dr.P.H., professor of epidemiology and health services research and the head of the center for maternal, fetal, and infant research at the University of Ulster in Coleraine, Northern Ireland, and her colleagues analyzed data from 10.1 million births exposed to antiepileptic drugs including lamotrigine (Lamictal) as a monotherapy during the first trimester between 1995 and 2011. The births were recorded in 21 population-based registries from 16 European countries. The outcomes of interest were major congenital malformations in general, as well as orofacial clefts and clubfoot (Neurology. 2016 April 6. doi: 10.1212/WNL.0000000000002540).

©KatarzynaBialasiewicz/thinkstockphotos.com

Assessment of all antiepileptic drug-exposed congenital malformation registrations revealed that 12% of pregnant registrants were exposed to lamotrigine monotherapy, with an additional 7% exposed to lamotrigine as part of polytherapy. A total of 77.1% of pregnant women exposed to lamotrigine monotherapy had records indicative of a diagnosis of epilepsy. The proportion of lamotrigine monotherapy exposures was observed to have increased over the study period, likely based on a movement away from the traditional use of valproate because of teratogenic concerns.

A total of 147 lamotrigine monotherapy-exposed babies with congenital malformations not attributable to chromosomal irregularities were identified from the total sample. The odds ratio for having a child with orofacial clefts after exposure to lamotrigine monotherapy was 1.31 (95% confidence interval, 0.73-2.33). Based on these data, the authors said they estimated exposure to lamotrigine would result in orofacial clefts in fewer than 1 in every 550 exposed babies.

The odds ratio for having a child with clubfoot after exposure to lamotrigine monotherapy was 1.83 (95% CI, 1.01-3.31). Although the study results confirmed the statistically significant signal for an overall excess of clubfoot risk found in a previous study conducted by this research team that analyzed births during 1995-2005, the investigators could not reproduce this result in an independent study population of 6.3 million births during 2005-2011(odds ratio, 1.43; 95% CI, 0.66-3.08). There were no significant differences in the risk for developing any other congenital malformations associated with lamotrigine monotherapy, the investigators said.

The authors said their results were in accord with those from several previous studies that did not detect an increased risk of orofacial clefts. In addition, they said statistically significant independent evidence of a clubfoot excess was not detected in the current study, despite findings from their previous study suggesting an increased risk.

The EUROCAT Central Database was funded by the EU Public Health Programme. GlaxoSmithKline, which markets lamotrigine, provided a grant for additional funding of this study. Dr. Dolk and her coauthors reported that their institutions received funding from GlaxoSmithKline for data or staff time contributed to this study.

A new analysis of registry data from European countries does not support a risk of orofacial cleft and clubfoot with exposure to lamotrigine monotherapy, in contrast to signals from previous studies of the antiepileptic drug.

First author Helen Dolk, Dr.P.H., professor of epidemiology and health services research and the head of the center for maternal, fetal, and infant research at the University of Ulster in Coleraine, Northern Ireland, and her colleagues analyzed data from 10.1 million births exposed to antiepileptic drugs including lamotrigine (Lamictal) as a monotherapy during the first trimester between 1995 and 2011. The births were recorded in 21 population-based registries from 16 European countries. The outcomes of interest were major congenital malformations in general, as well as orofacial clefts and clubfoot (Neurology. 2016 April 6. doi: 10.1212/WNL.0000000000002540).

©KatarzynaBialasiewicz/thinkstockphotos.com

Assessment of all antiepileptic drug-exposed congenital malformation registrations revealed that 12% of pregnant registrants were exposed to lamotrigine monotherapy, with an additional 7% exposed to lamotrigine as part of polytherapy. A total of 77.1% of pregnant women exposed to lamotrigine monotherapy had records indicative of a diagnosis of epilepsy. The proportion of lamotrigine monotherapy exposures was observed to have increased over the study period, likely based on a movement away from the traditional use of valproate because of teratogenic concerns.

A total of 147 lamotrigine monotherapy-exposed babies with congenital malformations not attributable to chromosomal irregularities were identified from the total sample. The odds ratio for having a child with orofacial clefts after exposure to lamotrigine monotherapy was 1.31 (95% confidence interval, 0.73-2.33). Based on these data, the authors said they estimated exposure to lamotrigine would result in orofacial clefts in fewer than 1 in every 550 exposed babies.

The odds ratio for having a child with clubfoot after exposure to lamotrigine monotherapy was 1.83 (95% CI, 1.01-3.31). Although the study results confirmed the statistically significant signal for an overall excess of clubfoot risk found in a previous study conducted by this research team that analyzed births during 1995-2005, the investigators could not reproduce this result in an independent study population of 6.3 million births during 2005-2011(odds ratio, 1.43; 95% CI, 0.66-3.08). There were no significant differences in the risk for developing any other congenital malformations associated with lamotrigine monotherapy, the investigators said.

The authors said their results were in accord with those from several previous studies that did not detect an increased risk of orofacial clefts. In addition, they said statistically significant independent evidence of a clubfoot excess was not detected in the current study, despite findings from their previous study suggesting an increased risk.

The EUROCAT Central Database was funded by the EU Public Health Programme. GlaxoSmithKline, which markets lamotrigine, provided a grant for additional funding of this study. Dr. Dolk and her coauthors reported that their institutions received funding from GlaxoSmithKline for data or staff time contributed to this study.

A new analysis of registry data from European countries does not support a risk of orofacial cleft and clubfoot with exposure to lamotrigine monotherapy, in contrast to signals from previous studies of the antiepileptic drug.

First author Helen Dolk, Dr.P.H., professor of epidemiology and health services research and the head of the center for maternal, fetal, and infant research at the University of Ulster in Coleraine, Northern Ireland, and her colleagues analyzed data from 10.1 million births exposed to antiepileptic drugs including lamotrigine (Lamictal) as a monotherapy during the first trimester between 1995 and 2011. The births were recorded in 21 population-based registries from 16 European countries. The outcomes of interest were major congenital malformations in general, as well as orofacial clefts and clubfoot (Neurology. 2016 April 6. doi: 10.1212/WNL.0000000000002540).

©KatarzynaBialasiewicz/thinkstockphotos.com

Assessment of all antiepileptic drug-exposed congenital malformation registrations revealed that 12% of pregnant registrants were exposed to lamotrigine monotherapy, with an additional 7% exposed to lamotrigine as part of polytherapy. A total of 77.1% of pregnant women exposed to lamotrigine monotherapy had records indicative of a diagnosis of epilepsy. The proportion of lamotrigine monotherapy exposures was observed to have increased over the study period, likely based on a movement away from the traditional use of valproate because of teratogenic concerns.

A total of 147 lamotrigine monotherapy-exposed babies with congenital malformations not attributable to chromosomal irregularities were identified from the total sample. The odds ratio for having a child with orofacial clefts after exposure to lamotrigine monotherapy was 1.31 (95% confidence interval, 0.73-2.33). Based on these data, the authors said they estimated exposure to lamotrigine would result in orofacial clefts in fewer than 1 in every 550 exposed babies.

The odds ratio for having a child with clubfoot after exposure to lamotrigine monotherapy was 1.83 (95% CI, 1.01-3.31). Although the study results confirmed the statistically significant signal for an overall excess of clubfoot risk found in a previous study conducted by this research team that analyzed births during 1995-2005, the investigators could not reproduce this result in an independent study population of 6.3 million births during 2005-2011(odds ratio, 1.43; 95% CI, 0.66-3.08). There were no significant differences in the risk for developing any other congenital malformations associated with lamotrigine monotherapy, the investigators said.

The authors said their results were in accord with those from several previous studies that did not detect an increased risk of orofacial clefts. In addition, they said statistically significant independent evidence of a clubfoot excess was not detected in the current study, despite findings from their previous study suggesting an increased risk.

The EUROCAT Central Database was funded by the EU Public Health Programme. GlaxoSmithKline, which markets lamotrigine, provided a grant for additional funding of this study. Dr. Dolk and her coauthors reported that their institutions received funding from GlaxoSmithKline for data or staff time contributed to this study.

Ketamine was 80% effective at decreasing depression symptoms, in a study of 100 depression patients who received less frequent and lower total doses of ketamine than are typically administered to treat depression.

Each study participant received no more than one ketamine intravenous infusion per week, with 4.3 having been the average total number of ketamine infusions received by a patient during the study. The frequency with which an infusion was received and the total number of infusions received by a patient were tailored to each patient’s responses to the therapy, according to the study’s author, Dr. Theodore Henderson. This study used a schedule of treatments for patients that differed from the established protocol for ketamine usage as an antidepressant, which is 3 times per week.

Prior to receiving the intravenous ketamine infusions, study participant’s Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score was 17.87 plus or minus 2.8 points, which corresponds to being severely depressed. The QIDS-SR score for each of the 80 study participants who responded to the therapy decreased by 10.8 plus or minus 3.5 points. The QIDS-SR of each of the 20 non-responders to the therapy changed by 0.8 plus or minus 1.8 points.

This study showed “clinical improvement with much fewer infusions for most patients. From a mechanistic standpoint, this can only be possible if ketamine is inducing increased BDNF [brain-derived neurotrophic factor] which leads to lasting changes in synapses, dendrites, and neuronal circuits,” Dr. Henderson said.

The study participants comprised 80 patients with recurrent unipolar depression and 20 patients with recurrent bipolar depression from Neuro-Luminance Ketamine Infusion Centers. Side effects experienced by the patients included elevated blood pressure, nausea, and dizziness, which was very common.

“Further controlled studies of the best clinical methods for ketamine infusion therapy are encouraged.” Dr. Henderson said.

Read the study in Neural Regeneration Research (doi: 10.4103/1673-5374.177708).

[email protected]

Ketamine was 80% effective at decreasing depression symptoms, in a study of 100 depression patients who received less frequent and lower total doses of ketamine than are typically administered to treat depression.

Each study participant received no more than one ketamine intravenous infusion per week, with 4.3 having been the average total number of ketamine infusions received by a patient during the study. The frequency with which an infusion was received and the total number of infusions received by a patient were tailored to each patient’s responses to the therapy, according to the study’s author, Dr. Theodore Henderson. This study used a schedule of treatments for patients that differed from the established protocol for ketamine usage as an antidepressant, which is 3 times per week.

Prior to receiving the intravenous ketamine infusions, study participant’s Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score was 17.87 plus or minus 2.8 points, which corresponds to being severely depressed. The QIDS-SR score for each of the 80 study participants who responded to the therapy decreased by 10.8 plus or minus 3.5 points. The QIDS-SR of each of the 20 non-responders to the therapy changed by 0.8 plus or minus 1.8 points.

This study showed “clinical improvement with much fewer infusions for most patients. From a mechanistic standpoint, this can only be possible if ketamine is inducing increased BDNF [brain-derived neurotrophic factor] which leads to lasting changes in synapses, dendrites, and neuronal circuits,” Dr. Henderson said.

The study participants comprised 80 patients with recurrent unipolar depression and 20 patients with recurrent bipolar depression from Neuro-Luminance Ketamine Infusion Centers. Side effects experienced by the patients included elevated blood pressure, nausea, and dizziness, which was very common.

“Further controlled studies of the best clinical methods for ketamine infusion therapy are encouraged.” Dr. Henderson said.

Read the study in Neural Regeneration Research (doi: 10.4103/1673-5374.177708).

[email protected]

Ketamine was 80% effective at decreasing depression symptoms, in a study of 100 depression patients who received less frequent and lower total doses of ketamine than are typically administered to treat depression.

Each study participant received no more than one ketamine intravenous infusion per week, with 4.3 having been the average total number of ketamine infusions received by a patient during the study. The frequency with which an infusion was received and the total number of infusions received by a patient were tailored to each patient’s responses to the therapy, according to the study’s author, Dr. Theodore Henderson. This study used a schedule of treatments for patients that differed from the established protocol for ketamine usage as an antidepressant, which is 3 times per week.

Prior to receiving the intravenous ketamine infusions, study participant’s Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score was 17.87 plus or minus 2.8 points, which corresponds to being severely depressed. The QIDS-SR score for each of the 80 study participants who responded to the therapy decreased by 10.8 plus or minus 3.5 points. The QIDS-SR of each of the 20 non-responders to the therapy changed by 0.8 plus or minus 1.8 points.

This study showed “clinical improvement with much fewer infusions for most patients. From a mechanistic standpoint, this can only be possible if ketamine is inducing increased BDNF [brain-derived neurotrophic factor] which leads to lasting changes in synapses, dendrites, and neuronal circuits,” Dr. Henderson said.

The study participants comprised 80 patients with recurrent unipolar depression and 20 patients with recurrent bipolar depression from Neuro-Luminance Ketamine Infusion Centers. Side effects experienced by the patients included elevated blood pressure, nausea, and dizziness, which was very common.

“Further controlled studies of the best clinical methods for ketamine infusion therapy are encouraged.” Dr. Henderson said.

Read the study in Neural Regeneration Research (doi: 10.4103/1673-5374.177708).

[email protected]

Second-generation antipsychotic use is associated with a previous incidence of psychiatric hospitalization in patients with bipolar disorder I but not in those with bipolar II, a study by Dr. Dong Yeon Park and associates shows.

The researchers found that the use of the second-generation agents (SGAs) was twice as common in the bipolar disorder I study group. Forty-four percent of 243 bipolar I patients used at least one of the antipsychotics, compared with 21.2% of 260 patients with bipolar disorder II.

Most bipolar I patients had a history of psychiatric hospitalization; however, hospitalization was significantly more common among patients in an SGA subgroup. In that group, more than 80% of those patients had a history of psychiatric hospitalization, compared with 58.1% of patients with bipolar I who were not taking SGAs. Comparatively, 12.7% of bipolar II patients taking SGAs had a history of psychiatric hospitalization, compared with 9.3% of bipolar II patients who were not taking SGAs.

Patients with bipolar I who were on SGAs also were more likely to be currently depressed, have current complex pharmacotherapy, and have a higher Clinical Global Impression for Bipolar Version Overall Severity score. Meanwhile, bipolar disorder II patients taking SGAs were more likely to be currently using mood stabilizers than were bipolar II patients who were not taking SGAs, reported Dr. Park, of the department of psychiatry at Seoul National Hospital, South Korea.

“More research is needed to assess differential demographic and clinical correlates of current SGA use in patients with bipolar II disorder compared to bipolar I disorder. Challenges related to the variable expense and side effects of SGAs highlight the importance of increasing knowledge of the strengths and limitations of use of these agents in patients with different types of bipolar disorders,” the investigators concluded.

Find the study in the Journal of Psychiatric Research (doi: 10.1016/j.jpsychires.2016.01.016).

[email protected]

Second-generation antipsychotic use is associated with a previous incidence of psychiatric hospitalization in patients with bipolar disorder I but not in those with bipolar II, a study by Dr. Dong Yeon Park and associates shows.

The researchers found that the use of the second-generation agents (SGAs) was twice as common in the bipolar disorder I study group. Forty-four percent of 243 bipolar I patients used at least one of the antipsychotics, compared with 21.2% of 260 patients with bipolar disorder II.

Most bipolar I patients had a history of psychiatric hospitalization; however, hospitalization was significantly more common among patients in an SGA subgroup. In that group, more than 80% of those patients had a history of psychiatric hospitalization, compared with 58.1% of patients with bipolar I who were not taking SGAs. Comparatively, 12.7% of bipolar II patients taking SGAs had a history of psychiatric hospitalization, compared with 9.3% of bipolar II patients who were not taking SGAs.

Patients with bipolar I who were on SGAs also were more likely to be currently depressed, have current complex pharmacotherapy, and have a higher Clinical Global Impression for Bipolar Version Overall Severity score. Meanwhile, bipolar disorder II patients taking SGAs were more likely to be currently using mood stabilizers than were bipolar II patients who were not taking SGAs, reported Dr. Park, of the department of psychiatry at Seoul National Hospital, South Korea.

“More research is needed to assess differential demographic and clinical correlates of current SGA use in patients with bipolar II disorder compared to bipolar I disorder. Challenges related to the variable expense and side effects of SGAs highlight the importance of increasing knowledge of the strengths and limitations of use of these agents in patients with different types of bipolar disorders,” the investigators concluded.

Find the study in the Journal of Psychiatric Research (doi: 10.1016/j.jpsychires.2016.01.016).

[email protected]

Second-generation antipsychotic use is associated with a previous incidence of psychiatric hospitalization in patients with bipolar disorder I but not in those with bipolar II, a study by Dr. Dong Yeon Park and associates shows.

The researchers found that the use of the second-generation agents (SGAs) was twice as common in the bipolar disorder I study group. Forty-four percent of 243 bipolar I patients used at least one of the antipsychotics, compared with 21.2% of 260 patients with bipolar disorder II.

Most bipolar I patients had a history of psychiatric hospitalization; however, hospitalization was significantly more common among patients in an SGA subgroup. In that group, more than 80% of those patients had a history of psychiatric hospitalization, compared with 58.1% of patients with bipolar I who were not taking SGAs. Comparatively, 12.7% of bipolar II patients taking SGAs had a history of psychiatric hospitalization, compared with 9.3% of bipolar II patients who were not taking SGAs.

Patients with bipolar I who were on SGAs also were more likely to be currently depressed, have current complex pharmacotherapy, and have a higher Clinical Global Impression for Bipolar Version Overall Severity score. Meanwhile, bipolar disorder II patients taking SGAs were more likely to be currently using mood stabilizers than were bipolar II patients who were not taking SGAs, reported Dr. Park, of the department of psychiatry at Seoul National Hospital, South Korea.

“More research is needed to assess differential demographic and clinical correlates of current SGA use in patients with bipolar II disorder compared to bipolar I disorder. Challenges related to the variable expense and side effects of SGAs highlight the importance of increasing knowledge of the strengths and limitations of use of these agents in patients with different types of bipolar disorders,” the investigators concluded.

Find the study in the Journal of Psychiatric Research (doi: 10.1016/j.jpsychires.2016.01.016).

[email protected]