Current Psychiatry

Discuss this article at www.facebook.com/CurrentPsychiatry

Although diabetes and schizophrenia are common companions, it is unclear how this association should influence our practice. What do we need to know about diabetes, and what are the key intervention points for psychiatrists?

This article is informed by my experience monitoring >1,000 patients with schizophrenia in a large urban mental health facility using an electronic metabolic monitoring system and consulting on hundreds of individuals with comorbid schizophrenia and diabetes in a mental health metabolic clinic.

A significant link

The association between schizophrenia and diabetes has been recognized for more than a century.¹ The prevalence of diabetes is increased 2- to 3-fold in patients with schizophrenia.^2,3 This relationship is specific to type 2 diabetes mellitus (T2DM); type 1 diabetes mellitus, an autoimmune disease, is less common in patients with schizophrenia.⁴ Factors that contribute to comorbidity between schizophrenia and T2DM include:

• illness susceptibility: the mechanisms remain unclear but include the thrifty phenotype hypothesis,⁵ autonomic hyperactivity,⁶ and potential cellular and genetic links^7,8
  
• lifestyle: diet, physical inactivity, and cigarette smoking^9-12
  
• antipsychotic use¹³
  
• social health determinants, such as income, housing, and food insecurity.¹⁴
  

When evaluating a patient’s risk for a cardiac event, we consider having a diabetes diagnosis equivalent to having had a myocardial infarction.¹⁵ Likely, the high prevalence of T2DM among schizophrenia patients and challenges in managing diabetes and prediabetes underlies these patients’ reduced life expectancy.¹⁶ Self-care, a cornerstone of diabetes management, is challenging for patients with schizophrenia because of deficits in executive functioning, working memory, and motivation, coupled with negative symptoms and social and economic disadvantages that often accompany schizophrenia.

How diabetes impacts practice

What psychiatrists need to know. Insulin resistance—reduced biologic effectiveness of insulin—is the precursor of T2DM. Insulin is required to move glucose from the blood into cells. Weight gain, particularly abdominal adiposity, is the principal driver of insulin resistance. The body responds by producing more insulin (hyperinsulinemia) to maintain glucose homeostasis. Hyperinsulinemia underlies metabolic syndrome, an important risk marker for developing T2DM. Diabetes usually develops after many years when the pancreas fails to compensate for insulin resistance.

In most cases the development of diabetes in patients with schizophrenia follows this course. Weight gain, a consequence of lifestyle factors as well as antipsychotics and other psychotropics that promote obesity, leads to progressive insulin resistance. Consequently, metabolic syndrome is twice as prevalent among patients with schizophrenia compared with matched controls.^17,18

Occasionally patients develop T2DM within a few weeks or months of starting antipsychotic treatment—usually with clozapine or olanzapine—before they gain weight, which suggests a second mechanism may be involved. Animal studies have documented rapid development of insulin resistance after a single subcutaneous injection of antipsychotics that have high metabolic liability, possibly through a direct effect on insulin signaling.¹⁹ This phenomenon has been difficult to demonstrate in humans.²⁰

Managing diabetes is complex and ideally involves a range of health practitioners who work with patients to provide education, promote self-care behaviors, and direct complex health care. These services are outside the scope of psychiatric practice, but given the functional deficits in seriously mentally ill patients, it is important to have an overview of diabetes care (Table 3).

In addition to diagnosing diabetes, psychiatrists should be able to identify patients at risk for developing diabetes and initiate prevention strategies. Interventions are focused on lifestyle—weight reduction, increased physical activity, diet, and smoking cessation—as well as pharmacologic strategies such as metformin.

What patients need to know. Similar to schizophrenia, a diabetes diagnosis may be difficult for patients to accept. Initially, a patient may have no manifestations or symptoms. However, untreated diabetes has serious long-term health consequences—including blindness, amputations, kidney disease, and early death from heart attacks.

Patients should actively participate in treatment that involves learning about the illness, making lifestyle changes, working on self-care, and keeping regular medical appointments. Three components of lifestyle change must be addressed:

• Diet: counseling with a dietician or other health professional to reduce or stabilize body weight and make changes in diet quality, portion size, and meal frequency to improve glucose control and reduce long-term diabetes complications
  
• Physical activity: increasing physical activity, initially by walking daily, to benefit glucose control and weight maintenance
  
• Smoking: reducing or stopping cigarette smoking to improve glucose control and reduce diabetes complications.
  

American Diabetes Association diagnostic criteria for diabetes

Signs and symptoms of diabetes and diabetic ketoacidosis

Components of diabetes care

Managing patients at risk for diabetes

Metabolic monitoring

Metabolic monitoring is the key to keeping patients with schizophrenia well. Treating metabolic conditions falls outside of psychiatric practice; however, many argue that mental health clinicians should monitor basic metabolic parameters during antipsychotic treatment and advocate medical interventions when indicated because:

• most antipsychotics are associated with weight gain and metabolic side effects
  
• patients with schizophrenia have cognitive deficits that impact health maintenance
  
• mental health providers often are the primary health care contacts for patients with serious mental illness.
  

• identify treatable medical conditions such as diabetes, dyslipidemia, and hypertension when treatment delay or no treatment has consequences
  
• identify individuals with prediabetes and metabolic syndrome for targeted prevention
  
• determine the association between antipsychotic treatment and metabolic disturbance to evaluate the risk of treatment vs antipsychotic switching.
  

How to intervene

To switch or not to switch? For many psychiatrists, deciding whether or when to switch from a high or intermediate metabolic liability antipsychotic to one with low metabolic liability is difficult. Clinicians must balance potential metabolic benefits against the risk of psychotic decompensation and side effects. Ultimately, patients and their families make the decision, taking into account information provided to them. For medical-legal purposes, document the discussion of potential risks and benefits. These are difficult decisions and there are no clear guidelines. In my clinical experience, the following issues need to be considered:

• The antipsychotics that many clinicians consider to be the most effective—clozapine and olanzapine—also have the greatest metabolic liability and risk for emergent T2DM.
  
• Patients who are stable and in psychotic remission may risk a relapse of their illness if switched.
  
• The clearest indication for switching is when a patient who does not have diabetes develops the condition shortly after starting an antipsychotic. This scenario is rare, but evidence suggests that diabetes may resolve or reverse with an antipsychotic switch.³³
  
• In patients who gain weight while taking a high- or intermediate-liability antipsychotic and are able to tolerate a switch to a low-liability antipsychotic, the effect size of weight reduction can be large and may result in a patient returning to their pretreatment weight.
  
• To reduce relapse risk, patients switching antipsychotics should be closely monitored at least weekly for ≥1 month. A plateau cross-taper—building the new antipsychotic up to therapeutic levels before gradually reducing the first antipsychotic—may be safer than abrupt discontinuation or standard cross-titration.
  
• Switching from one high or intermediate liability antipsychotic to another (eg, olanzapine to quetiapine or risperidone) often provides little if any metabolic benefit on body weight or diabetes control.
  
• Established diabetes (type 1 or type 2) should not be a contraindication to antipsychotic treatment, including clozapine, if clinically warranted. Monitor metabolic parameters more closely for 6 to 12 months after the switch. In most cases, patients experience limited, if any, metabolic consequences. If so, diabetes medication can be adjusted.
  
• Patients who have experienced significant weight gain on an atypical antipsychotic often do not gain more weight when switched to clozapine. A patient may reach a “ceiling” in terms of weight gain and medication-related metabolic effects.
  

Contribute to diabetes chronic disease management. Mental health practitioners can complement diabetes care in patients with serious mental illness by:

• navigating the health system and negotiating for service on patients’ behalf
  
• promoting positive relationships among diabetes and mental health treatment teams
  
• evaluating and treating depression that may be comorbid with diabetes
  
• assessing treatment capacity, self-care deficits, cognitive functioning, psychotic symptoms, negative symptoms, etc., that impact diabetes self-care and collaborating with diabetes care providers to support patients.
  

Start with a low-liability agent

Patients who are early in the course of psychotic illness are most susceptible to the metabolic effects of antipsychotics.¹³ The average weight gain observed with olanzapine was 34 lbs at 2 years in first episode psychosis patients (mean age 24 ± 4.9).³⁴ Metabolic consequences with medium-liability second-generation antipsychotics—such as quetiapine and risperidone—are extreme, particularly in children, adolescents, and young adults (age 35,36 Although frank diabetes is uncommon in early psychosis because patients are, to a certain extent, protected by insulin compensation—increased insulin secretion maintains glucose levels within a therapeutic range—diabetes risk is increased, and hyperinsulinemia and hypertriglyceridemia are early markers of metabolic strain. Also, response to initial antipsychotic treatment—possibly independent of the agent selected—is robust in early psychosis.³⁷

Related Resources

• American Diabetes Association. www.diabetes.org.
  
• International Diabetes Federation. www.idf.org.
  
• Framingham Heart Study. Coronary heart disease (10-year risk). www.framinghamheartstudy.org/risk/coronary.html.
  
• National Cholesterol Education Program. Risk assessment tool for estimating your 10-year risk of having a heart attack. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
  

• Clozapine • Clozaril
  
• Metformin • Glucophage
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Dr. Cohn is a speaker for Pfizer Canada.

Discuss this article at www.facebook.com/CurrentPsychiatry

Although diabetes and schizophrenia are common companions, it is unclear how this association should influence our practice. What do we need to know about diabetes, and what are the key intervention points for psychiatrists?

This article is informed by my experience monitoring >1,000 patients with schizophrenia in a large urban mental health facility using an electronic metabolic monitoring system and consulting on hundreds of individuals with comorbid schizophrenia and diabetes in a mental health metabolic clinic.

A significant link

The association between schizophrenia and diabetes has been recognized for more than a century.¹ The prevalence of diabetes is increased 2- to 3-fold in patients with schizophrenia.^2,3 This relationship is specific to type 2 diabetes mellitus (T2DM); type 1 diabetes mellitus, an autoimmune disease, is less common in patients with schizophrenia.⁴ Factors that contribute to comorbidity between schizophrenia and T2DM include:

• illness susceptibility: the mechanisms remain unclear but include the thrifty phenotype hypothesis,⁵ autonomic hyperactivity,⁶ and potential cellular and genetic links^7,8
  
• lifestyle: diet, physical inactivity, and cigarette smoking^9-12
  
• antipsychotic use¹³
  
• social health determinants, such as income, housing, and food insecurity.¹⁴
  

When evaluating a patient’s risk for a cardiac event, we consider having a diabetes diagnosis equivalent to having had a myocardial infarction.¹⁵ Likely, the high prevalence of T2DM among schizophrenia patients and challenges in managing diabetes and prediabetes underlies these patients’ reduced life expectancy.¹⁶ Self-care, a cornerstone of diabetes management, is challenging for patients with schizophrenia because of deficits in executive functioning, working memory, and motivation, coupled with negative symptoms and social and economic disadvantages that often accompany schizophrenia.

How diabetes impacts practice

What psychiatrists need to know. Insulin resistance—reduced biologic effectiveness of insulin—is the precursor of T2DM. Insulin is required to move glucose from the blood into cells. Weight gain, particularly abdominal adiposity, is the principal driver of insulin resistance. The body responds by producing more insulin (hyperinsulinemia) to maintain glucose homeostasis. Hyperinsulinemia underlies metabolic syndrome, an important risk marker for developing T2DM. Diabetes usually develops after many years when the pancreas fails to compensate for insulin resistance.

In most cases the development of diabetes in patients with schizophrenia follows this course. Weight gain, a consequence of lifestyle factors as well as antipsychotics and other psychotropics that promote obesity, leads to progressive insulin resistance. Consequently, metabolic syndrome is twice as prevalent among patients with schizophrenia compared with matched controls.^17,18

Occasionally patients develop T2DM within a few weeks or months of starting antipsychotic treatment—usually with clozapine or olanzapine—before they gain weight, which suggests a second mechanism may be involved. Animal studies have documented rapid development of insulin resistance after a single subcutaneous injection of antipsychotics that have high metabolic liability, possibly through a direct effect on insulin signaling.¹⁹ This phenomenon has been difficult to demonstrate in humans.²⁰

Managing diabetes is complex and ideally involves a range of health practitioners who work with patients to provide education, promote self-care behaviors, and direct complex health care. These services are outside the scope of psychiatric practice, but given the functional deficits in seriously mentally ill patients, it is important to have an overview of diabetes care (Table 3).

In addition to diagnosing diabetes, psychiatrists should be able to identify patients at risk for developing diabetes and initiate prevention strategies. Interventions are focused on lifestyle—weight reduction, increased physical activity, diet, and smoking cessation—as well as pharmacologic strategies such as metformin.

What patients need to know. Similar to schizophrenia, a diabetes diagnosis may be difficult for patients to accept. Initially, a patient may have no manifestations or symptoms. However, untreated diabetes has serious long-term health consequences—including blindness, amputations, kidney disease, and early death from heart attacks.

Patients should actively participate in treatment that involves learning about the illness, making lifestyle changes, working on self-care, and keeping regular medical appointments. Three components of lifestyle change must be addressed:

• Diet: counseling with a dietician or other health professional to reduce or stabilize body weight and make changes in diet quality, portion size, and meal frequency to improve glucose control and reduce long-term diabetes complications
  
• Physical activity: increasing physical activity, initially by walking daily, to benefit glucose control and weight maintenance
  
• Smoking: reducing or stopping cigarette smoking to improve glucose control and reduce diabetes complications.
  

American Diabetes Association diagnostic criteria for diabetes

Signs and symptoms of diabetes and diabetic ketoacidosis

Components of diabetes care

Managing patients at risk for diabetes

Metabolic monitoring

Metabolic monitoring is the key to keeping patients with schizophrenia well. Treating metabolic conditions falls outside of psychiatric practice; however, many argue that mental health clinicians should monitor basic metabolic parameters during antipsychotic treatment and advocate medical interventions when indicated because:

• most antipsychotics are associated with weight gain and metabolic side effects
  
• patients with schizophrenia have cognitive deficits that impact health maintenance
  
• mental health providers often are the primary health care contacts for patients with serious mental illness.
  

• identify treatable medical conditions such as diabetes, dyslipidemia, and hypertension when treatment delay or no treatment has consequences
  
• identify individuals with prediabetes and metabolic syndrome for targeted prevention
  
• determine the association between antipsychotic treatment and metabolic disturbance to evaluate the risk of treatment vs antipsychotic switching.
  

How to intervene

To switch or not to switch? For many psychiatrists, deciding whether or when to switch from a high or intermediate metabolic liability antipsychotic to one with low metabolic liability is difficult. Clinicians must balance potential metabolic benefits against the risk of psychotic decompensation and side effects. Ultimately, patients and their families make the decision, taking into account information provided to them. For medical-legal purposes, document the discussion of potential risks and benefits. These are difficult decisions and there are no clear guidelines. In my clinical experience, the following issues need to be considered:

• The antipsychotics that many clinicians consider to be the most effective—clozapine and olanzapine—also have the greatest metabolic liability and risk for emergent T2DM.
  
• Patients who are stable and in psychotic remission may risk a relapse of their illness if switched.
  
• The clearest indication for switching is when a patient who does not have diabetes develops the condition shortly after starting an antipsychotic. This scenario is rare, but evidence suggests that diabetes may resolve or reverse with an antipsychotic switch.³³
  
• In patients who gain weight while taking a high- or intermediate-liability antipsychotic and are able to tolerate a switch to a low-liability antipsychotic, the effect size of weight reduction can be large and may result in a patient returning to their pretreatment weight.
  
• To reduce relapse risk, patients switching antipsychotics should be closely monitored at least weekly for ≥1 month. A plateau cross-taper—building the new antipsychotic up to therapeutic levels before gradually reducing the first antipsychotic—may be safer than abrupt discontinuation or standard cross-titration.
  
• Switching from one high or intermediate liability antipsychotic to another (eg, olanzapine to quetiapine or risperidone) often provides little if any metabolic benefit on body weight or diabetes control.
  
• Established diabetes (type 1 or type 2) should not be a contraindication to antipsychotic treatment, including clozapine, if clinically warranted. Monitor metabolic parameters more closely for 6 to 12 months after the switch. In most cases, patients experience limited, if any, metabolic consequences. If so, diabetes medication can be adjusted.
  
• Patients who have experienced significant weight gain on an atypical antipsychotic often do not gain more weight when switched to clozapine. A patient may reach a “ceiling” in terms of weight gain and medication-related metabolic effects.
  

Contribute to diabetes chronic disease management. Mental health practitioners can complement diabetes care in patients with serious mental illness by:

• navigating the health system and negotiating for service on patients’ behalf
  
• promoting positive relationships among diabetes and mental health treatment teams
  
• evaluating and treating depression that may be comorbid with diabetes
  
• assessing treatment capacity, self-care deficits, cognitive functioning, psychotic symptoms, negative symptoms, etc., that impact diabetes self-care and collaborating with diabetes care providers to support patients.
  

Start with a low-liability agent

Patients who are early in the course of psychotic illness are most susceptible to the metabolic effects of antipsychotics.¹³ The average weight gain observed with olanzapine was 34 lbs at 2 years in first episode psychosis patients (mean age 24 ± 4.9).³⁴ Metabolic consequences with medium-liability second-generation antipsychotics—such as quetiapine and risperidone—are extreme, particularly in children, adolescents, and young adults (age 35,36 Although frank diabetes is uncommon in early psychosis because patients are, to a certain extent, protected by insulin compensation—increased insulin secretion maintains glucose levels within a therapeutic range—diabetes risk is increased, and hyperinsulinemia and hypertriglyceridemia are early markers of metabolic strain. Also, response to initial antipsychotic treatment—possibly independent of the agent selected—is robust in early psychosis.³⁷

Related Resources

• American Diabetes Association. www.diabetes.org.
  
• International Diabetes Federation. www.idf.org.
  
• Framingham Heart Study. Coronary heart disease (10-year risk). www.framinghamheartstudy.org/risk/coronary.html.
  
• National Cholesterol Education Program. Risk assessment tool for estimating your 10-year risk of having a heart attack. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
  

• Clozapine • Clozaril
  
• Metformin • Glucophage
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Dr. Cohn is a speaker for Pfizer Canada.

Discuss this article at www.facebook.com/CurrentPsychiatry

Although diabetes and schizophrenia are common companions, it is unclear how this association should influence our practice. What do we need to know about diabetes, and what are the key intervention points for psychiatrists?

This article is informed by my experience monitoring >1,000 patients with schizophrenia in a large urban mental health facility using an electronic metabolic monitoring system and consulting on hundreds of individuals with comorbid schizophrenia and diabetes in a mental health metabolic clinic.

A significant link

The association between schizophrenia and diabetes has been recognized for more than a century.¹ The prevalence of diabetes is increased 2- to 3-fold in patients with schizophrenia.^2,3 This relationship is specific to type 2 diabetes mellitus (T2DM); type 1 diabetes mellitus, an autoimmune disease, is less common in patients with schizophrenia.⁴ Factors that contribute to comorbidity between schizophrenia and T2DM include:

• illness susceptibility: the mechanisms remain unclear but include the thrifty phenotype hypothesis,⁵ autonomic hyperactivity,⁶ and potential cellular and genetic links^7,8
  
• lifestyle: diet, physical inactivity, and cigarette smoking^9-12
  
• antipsychotic use¹³
  
• social health determinants, such as income, housing, and food insecurity.¹⁴
  

When evaluating a patient’s risk for a cardiac event, we consider having a diabetes diagnosis equivalent to having had a myocardial infarction.¹⁵ Likely, the high prevalence of T2DM among schizophrenia patients and challenges in managing diabetes and prediabetes underlies these patients’ reduced life expectancy.¹⁶ Self-care, a cornerstone of diabetes management, is challenging for patients with schizophrenia because of deficits in executive functioning, working memory, and motivation, coupled with negative symptoms and social and economic disadvantages that often accompany schizophrenia.

How diabetes impacts practice

What psychiatrists need to know. Insulin resistance—reduced biologic effectiveness of insulin—is the precursor of T2DM. Insulin is required to move glucose from the blood into cells. Weight gain, particularly abdominal adiposity, is the principal driver of insulin resistance. The body responds by producing more insulin (hyperinsulinemia) to maintain glucose homeostasis. Hyperinsulinemia underlies metabolic syndrome, an important risk marker for developing T2DM. Diabetes usually develops after many years when the pancreas fails to compensate for insulin resistance.

In most cases the development of diabetes in patients with schizophrenia follows this course. Weight gain, a consequence of lifestyle factors as well as antipsychotics and other psychotropics that promote obesity, leads to progressive insulin resistance. Consequently, metabolic syndrome is twice as prevalent among patients with schizophrenia compared with matched controls.^17,18

Occasionally patients develop T2DM within a few weeks or months of starting antipsychotic treatment—usually with clozapine or olanzapine—before they gain weight, which suggests a second mechanism may be involved. Animal studies have documented rapid development of insulin resistance after a single subcutaneous injection of antipsychotics that have high metabolic liability, possibly through a direct effect on insulin signaling.¹⁹ This phenomenon has been difficult to demonstrate in humans.²⁰

Managing diabetes is complex and ideally involves a range of health practitioners who work with patients to provide education, promote self-care behaviors, and direct complex health care. These services are outside the scope of psychiatric practice, but given the functional deficits in seriously mentally ill patients, it is important to have an overview of diabetes care (Table 3).

In addition to diagnosing diabetes, psychiatrists should be able to identify patients at risk for developing diabetes and initiate prevention strategies. Interventions are focused on lifestyle—weight reduction, increased physical activity, diet, and smoking cessation—as well as pharmacologic strategies such as metformin.

What patients need to know. Similar to schizophrenia, a diabetes diagnosis may be difficult for patients to accept. Initially, a patient may have no manifestations or symptoms. However, untreated diabetes has serious long-term health consequences—including blindness, amputations, kidney disease, and early death from heart attacks.

Patients should actively participate in treatment that involves learning about the illness, making lifestyle changes, working on self-care, and keeping regular medical appointments. Three components of lifestyle change must be addressed:

• Diet: counseling with a dietician or other health professional to reduce or stabilize body weight and make changes in diet quality, portion size, and meal frequency to improve glucose control and reduce long-term diabetes complications
  
• Physical activity: increasing physical activity, initially by walking daily, to benefit glucose control and weight maintenance
  
• Smoking: reducing or stopping cigarette smoking to improve glucose control and reduce diabetes complications.
  

American Diabetes Association diagnostic criteria for diabetes

Signs and symptoms of diabetes and diabetic ketoacidosis

Components of diabetes care

Managing patients at risk for diabetes

Metabolic monitoring

Metabolic monitoring is the key to keeping patients with schizophrenia well. Treating metabolic conditions falls outside of psychiatric practice; however, many argue that mental health clinicians should monitor basic metabolic parameters during antipsychotic treatment and advocate medical interventions when indicated because:

• most antipsychotics are associated with weight gain and metabolic side effects
  
• patients with schizophrenia have cognitive deficits that impact health maintenance
  
• mental health providers often are the primary health care contacts for patients with serious mental illness.
  

• identify treatable medical conditions such as diabetes, dyslipidemia, and hypertension when treatment delay or no treatment has consequences
  
• identify individuals with prediabetes and metabolic syndrome for targeted prevention
  
• determine the association between antipsychotic treatment and metabolic disturbance to evaluate the risk of treatment vs antipsychotic switching.
  

How to intervene

To switch or not to switch? For many psychiatrists, deciding whether or when to switch from a high or intermediate metabolic liability antipsychotic to one with low metabolic liability is difficult. Clinicians must balance potential metabolic benefits against the risk of psychotic decompensation and side effects. Ultimately, patients and their families make the decision, taking into account information provided to them. For medical-legal purposes, document the discussion of potential risks and benefits. These are difficult decisions and there are no clear guidelines. In my clinical experience, the following issues need to be considered:

• The antipsychotics that many clinicians consider to be the most effective—clozapine and olanzapine—also have the greatest metabolic liability and risk for emergent T2DM.
  
• Patients who are stable and in psychotic remission may risk a relapse of their illness if switched.
  
• The clearest indication for switching is when a patient who does not have diabetes develops the condition shortly after starting an antipsychotic. This scenario is rare, but evidence suggests that diabetes may resolve or reverse with an antipsychotic switch.³³
  
• In patients who gain weight while taking a high- or intermediate-liability antipsychotic and are able to tolerate a switch to a low-liability antipsychotic, the effect size of weight reduction can be large and may result in a patient returning to their pretreatment weight.
  
• To reduce relapse risk, patients switching antipsychotics should be closely monitored at least weekly for ≥1 month. A plateau cross-taper—building the new antipsychotic up to therapeutic levels before gradually reducing the first antipsychotic—may be safer than abrupt discontinuation or standard cross-titration.
  
• Switching from one high or intermediate liability antipsychotic to another (eg, olanzapine to quetiapine or risperidone) often provides little if any metabolic benefit on body weight or diabetes control.
  
• Established diabetes (type 1 or type 2) should not be a contraindication to antipsychotic treatment, including clozapine, if clinically warranted. Monitor metabolic parameters more closely for 6 to 12 months after the switch. In most cases, patients experience limited, if any, metabolic consequences. If so, diabetes medication can be adjusted.
  
• Patients who have experienced significant weight gain on an atypical antipsychotic often do not gain more weight when switched to clozapine. A patient may reach a “ceiling” in terms of weight gain and medication-related metabolic effects.
  

Contribute to diabetes chronic disease management. Mental health practitioners can complement diabetes care in patients with serious mental illness by:

• navigating the health system and negotiating for service on patients’ behalf
  
• promoting positive relationships among diabetes and mental health treatment teams
  
• evaluating and treating depression that may be comorbid with diabetes
  
• assessing treatment capacity, self-care deficits, cognitive functioning, psychotic symptoms, negative symptoms, etc., that impact diabetes self-care and collaborating with diabetes care providers to support patients.
  

Start with a low-liability agent

Patients who are early in the course of psychotic illness are most susceptible to the metabolic effects of antipsychotics.¹³ The average weight gain observed with olanzapine was 34 lbs at 2 years in first episode psychosis patients (mean age 24 ± 4.9).³⁴ Metabolic consequences with medium-liability second-generation antipsychotics—such as quetiapine and risperidone—are extreme, particularly in children, adolescents, and young adults (age 35,36 Although frank diabetes is uncommon in early psychosis because patients are, to a certain extent, protected by insulin compensation—increased insulin secretion maintains glucose levels within a therapeutic range—diabetes risk is increased, and hyperinsulinemia and hypertriglyceridemia are early markers of metabolic strain. Also, response to initial antipsychotic treatment—possibly independent of the agent selected—is robust in early psychosis.³⁷

Related Resources

• American Diabetes Association. www.diabetes.org.
  
• International Diabetes Federation. www.idf.org.
  
• Framingham Heart Study. Coronary heart disease (10-year risk). www.framinghamheartstudy.org/risk/coronary.html.
  
• National Cholesterol Education Program. Risk assessment tool for estimating your 10-year risk of having a heart attack. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
  

• Clozapine • Clozaril
  
• Metformin • Glucophage
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Dr. Cohn is a speaker for Pfizer Canada.

Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV) and the authors’ response to a letter on treating resistant depression (Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR) remind us of depression’s complexity and the wide range of treatments available. I question whether in our zeal to help our patients we have forgotten the bedrock principle of medicine: Primum non nocere (First, do no harm).

Do we as psychiatrists make this principle a staple of our daily practice? Do we ask, “Which treatment modality offers the greatest likelihood of restoring wellness with the least risk of harm?” or do we restrict such inquiry to the confines of pharmacotherapy, considering only which medicine is least harmful? Is it not common practice to prescribe atypical antipsychotics to patients who have failed antidepressants? Do we offer modalities such as transcranial magnetic stimulation (TMS) before introducing atypical antipsychotics? If we keep our oath to abstain from doing harm, should we offer TMS before atypicals?

Some have argued that the high cost of TMS is reason not to offer it. But what is the cost of developing type 2 diabetes mellitus? Should we put patients at risk for such a disorder without giving them the option to choose a modality that doesn’t confer such risk?

The language used in Drs. Desseilles, Fava, Mischoulon, and Freeman’s “Comments & Controversies” response suggesting TMS was in the “same vein” as vagus nerve stimulation and deep brain stimulation concerned me. Such a comment—hopefully inadvertently—suggests a failure to recognize our oath to first, do no harm. Do the authors really believe that such invasive procedures confer no greater risk of harm than TMS? Are such modalities in the same vein as TMS, or do they take us to a new level of treatment risk and complexity?

Although no evidence suggests TMS is a panacea that successfully treats all patients with treatment-resistant depression, we can say with great confidence it is the safest of all somatic treatments and confers the least risk of harm. Because no evidence demonstrates that any other somatic treatment provides greater efficacy, do our ethics not require us to offer TMS as part of informed consent, before starting atypical antipsychotics, which carry a risk of metabolic syndrome, type 2 diabetes mellitus, sexual dysfunction, parkinsonism, and a host of other potentially life-altering problems and complications?

Timothy R. Jennings, MD, FAPA
President, TMS Chattanooga
Adjunct Faculty
University of Tennessee College of Medicine
Chattanooga, TN

Dr. Nasrallah responds

Dr. Jennings is correct in reminding us that above all, physicians must do no harm. However, there are certain other principles in medicine: 1) the lack of treatment for severe illness can result in serious harm, and 2) there always is a side-effect burden with any treatment. The risk-benefit considerations are complicated when dealing with chronically suffering, disabled, or suicidal patients with refractory depression.

Bold new interventions must be developed for such desperate cases at the cost of side effects, which must not be unacceptably severe. That’s why controlled studies to prove the usefulness of a new therapy are conducted in a few hundred patients so that millions of others can benefit from a new treatment mechanism. That’s how medical science advances, always balancing risks and benefits. It’s up to the clinician to determine which intervention is the best and least harmful for each patient. However, what may be considered an effective treatment may quickly be discarded when better and less harmful treatments are found, such as abandoning prefrontal lobotomy for aggressive psychotic patients shortly after chlorpromazine was discovered.

The authors respond

We thank Dr. Jennings for his comments and appreciate his concern to offer patients pharmacologic or nonpharmacologic treatments with the least amount of side effects. We also recognize the diversity of clinical situations, which, according to factors such as the degree of depression severity, the therapeutic choice of the patient, and the availability of treatments, lead the clinician to suggest an antidepressant treatment that is the most efficient and least harmful as possible.

By proposing that the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire consider the diversity of antidepressant treatments that various clinical situations have necessitated, we by no means encourage the use of antidepressant treatments that are inefficient and harmful to the patient. We look to provide clinicians with tools that take into consideration the therapeutic interventions available for treatment-resistant depression. In the same manner, we have not established a hierarchy of pharmacologic options, because we hope clinicians will identify the multiple treatments that the patient needs. If it is essential to “abstain from doing harm,” we must not forget that if healing is an ideal objective, we often only “treat” our patients with the best available methods.

As Dr. Jennings suggests, the least harmful treatments often are those that target depression’s physiopathology with the highest degree of specificity. In the same vein, neuromodulation treatments target the different neurobiologic mechanisms underlying depression. However, response predictors of TMS include age, degrees of treatment resistance, and the absence of comorbid anxiety or psychotic symptoms.^{Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/FTE612). This so-called side effect may be the central antidepressant effect, because short-term memory loss may be a central effect in any seizure therapy for depression.}

John S. Kafka, MD
Private Practice
Emeritus Professor of Psychiatry and Behavioral Sciences
George Washington University School of Medicine and Health Sciences
Washington, DC

Dr. Nasrallah responds

Memory loss with regular and heavy ketamine use or with a course of bilateral electroconvulsive therapy (ECT) is widely regarded as an undesirable side effect, not a therapeutic effect or mechanism. The side effects of short-term ketamine use in refractory depression studies included dissociation and unusual beliefs—such as conspiracy theories—as well as full-fledged delusions.

Both ketamine and ECT increase brain-derived neurotrophic factor (BDNF), which has been found to significantly decline in depression. The BDNF deficit is emerging as the leading mechanism of antidepressant therapy, both pharmacologic and non-pharmacologic, in both animal models and clinical populations.

Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV) and the authors’ response to a letter on treating resistant depression (Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR) remind us of depression’s complexity and the wide range of treatments available. I question whether in our zeal to help our patients we have forgotten the bedrock principle of medicine: Primum non nocere (First, do no harm).

Do we as psychiatrists make this principle a staple of our daily practice? Do we ask, “Which treatment modality offers the greatest likelihood of restoring wellness with the least risk of harm?” or do we restrict such inquiry to the confines of pharmacotherapy, considering only which medicine is least harmful? Is it not common practice to prescribe atypical antipsychotics to patients who have failed antidepressants? Do we offer modalities such as transcranial magnetic stimulation (TMS) before introducing atypical antipsychotics? If we keep our oath to abstain from doing harm, should we offer TMS before atypicals?

Some have argued that the high cost of TMS is reason not to offer it. But what is the cost of developing type 2 diabetes mellitus? Should we put patients at risk for such a disorder without giving them the option to choose a modality that doesn’t confer such risk?

The language used in Drs. Desseilles, Fava, Mischoulon, and Freeman’s “Comments & Controversies” response suggesting TMS was in the “same vein” as vagus nerve stimulation and deep brain stimulation concerned me. Such a comment—hopefully inadvertently—suggests a failure to recognize our oath to first, do no harm. Do the authors really believe that such invasive procedures confer no greater risk of harm than TMS? Are such modalities in the same vein as TMS, or do they take us to a new level of treatment risk and complexity?

Although no evidence suggests TMS is a panacea that successfully treats all patients with treatment-resistant depression, we can say with great confidence it is the safest of all somatic treatments and confers the least risk of harm. Because no evidence demonstrates that any other somatic treatment provides greater efficacy, do our ethics not require us to offer TMS as part of informed consent, before starting atypical antipsychotics, which carry a risk of metabolic syndrome, type 2 diabetes mellitus, sexual dysfunction, parkinsonism, and a host of other potentially life-altering problems and complications?

Timothy R. Jennings, MD, FAPA
President, TMS Chattanooga
Adjunct Faculty
University of Tennessee College of Medicine
Chattanooga, TN

Dr. Nasrallah responds

Dr. Jennings is correct in reminding us that above all, physicians must do no harm. However, there are certain other principles in medicine: 1) the lack of treatment for severe illness can result in serious harm, and 2) there always is a side-effect burden with any treatment. The risk-benefit considerations are complicated when dealing with chronically suffering, disabled, or suicidal patients with refractory depression.

Bold new interventions must be developed for such desperate cases at the cost of side effects, which must not be unacceptably severe. That’s why controlled studies to prove the usefulness of a new therapy are conducted in a few hundred patients so that millions of others can benefit from a new treatment mechanism. That’s how medical science advances, always balancing risks and benefits. It’s up to the clinician to determine which intervention is the best and least harmful for each patient. However, what may be considered an effective treatment may quickly be discarded when better and less harmful treatments are found, such as abandoning prefrontal lobotomy for aggressive psychotic patients shortly after chlorpromazine was discovered.

The authors respond

We thank Dr. Jennings for his comments and appreciate his concern to offer patients pharmacologic or nonpharmacologic treatments with the least amount of side effects. We also recognize the diversity of clinical situations, which, according to factors such as the degree of depression severity, the therapeutic choice of the patient, and the availability of treatments, lead the clinician to suggest an antidepressant treatment that is the most efficient and least harmful as possible.

By proposing that the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire consider the diversity of antidepressant treatments that various clinical situations have necessitated, we by no means encourage the use of antidepressant treatments that are inefficient and harmful to the patient. We look to provide clinicians with tools that take into consideration the therapeutic interventions available for treatment-resistant depression. In the same manner, we have not established a hierarchy of pharmacologic options, because we hope clinicians will identify the multiple treatments that the patient needs. If it is essential to “abstain from doing harm,” we must not forget that if healing is an ideal objective, we often only “treat” our patients with the best available methods.

As Dr. Jennings suggests, the least harmful treatments often are those that target depression’s physiopathology with the highest degree of specificity. In the same vein, neuromodulation treatments target the different neurobiologic mechanisms underlying depression. However, response predictors of TMS include age, degrees of treatment resistance, and the absence of comorbid anxiety or psychotic symptoms.^{Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/FTE612). This so-called side effect may be the central antidepressant effect, because short-term memory loss may be a central effect in any seizure therapy for depression.}

John S. Kafka, MD
Private Practice
Emeritus Professor of Psychiatry and Behavioral Sciences
George Washington University School of Medicine and Health Sciences
Washington, DC

Dr. Nasrallah responds

Memory loss with regular and heavy ketamine use or with a course of bilateral electroconvulsive therapy (ECT) is widely regarded as an undesirable side effect, not a therapeutic effect or mechanism. The side effects of short-term ketamine use in refractory depression studies included dissociation and unusual beliefs—such as conspiracy theories—as well as full-fledged delusions.

Both ketamine and ECT increase brain-derived neurotrophic factor (BDNF), which has been found to significantly decline in depression. The BDNF deficit is emerging as the leading mechanism of antidepressant therapy, both pharmacologic and non-pharmacologic, in both animal models and clinical populations.

Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV) and the authors’ response to a letter on treating resistant depression (Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR) remind us of depression’s complexity and the wide range of treatments available. I question whether in our zeal to help our patients we have forgotten the bedrock principle of medicine: Primum non nocere (First, do no harm).

Do we as psychiatrists make this principle a staple of our daily practice? Do we ask, “Which treatment modality offers the greatest likelihood of restoring wellness with the least risk of harm?” or do we restrict such inquiry to the confines of pharmacotherapy, considering only which medicine is least harmful? Is it not common practice to prescribe atypical antipsychotics to patients who have failed antidepressants? Do we offer modalities such as transcranial magnetic stimulation (TMS) before introducing atypical antipsychotics? If we keep our oath to abstain from doing harm, should we offer TMS before atypicals?

Some have argued that the high cost of TMS is reason not to offer it. But what is the cost of developing type 2 diabetes mellitus? Should we put patients at risk for such a disorder without giving them the option to choose a modality that doesn’t confer such risk?

The language used in Drs. Desseilles, Fava, Mischoulon, and Freeman’s “Comments & Controversies” response suggesting TMS was in the “same vein” as vagus nerve stimulation and deep brain stimulation concerned me. Such a comment—hopefully inadvertently—suggests a failure to recognize our oath to first, do no harm. Do the authors really believe that such invasive procedures confer no greater risk of harm than TMS? Are such modalities in the same vein as TMS, or do they take us to a new level of treatment risk and complexity?

Although no evidence suggests TMS is a panacea that successfully treats all patients with treatment-resistant depression, we can say with great confidence it is the safest of all somatic treatments and confers the least risk of harm. Because no evidence demonstrates that any other somatic treatment provides greater efficacy, do our ethics not require us to offer TMS as part of informed consent, before starting atypical antipsychotics, which carry a risk of metabolic syndrome, type 2 diabetes mellitus, sexual dysfunction, parkinsonism, and a host of other potentially life-altering problems and complications?

Timothy R. Jennings, MD, FAPA
President, TMS Chattanooga
Adjunct Faculty
University of Tennessee College of Medicine
Chattanooga, TN

Dr. Nasrallah responds

Dr. Jennings is correct in reminding us that above all, physicians must do no harm. However, there are certain other principles in medicine: 1) the lack of treatment for severe illness can result in serious harm, and 2) there always is a side-effect burden with any treatment. The risk-benefit considerations are complicated when dealing with chronically suffering, disabled, or suicidal patients with refractory depression.

Bold new interventions must be developed for such desperate cases at the cost of side effects, which must not be unacceptably severe. That’s why controlled studies to prove the usefulness of a new therapy are conducted in a few hundred patients so that millions of others can benefit from a new treatment mechanism. That’s how medical science advances, always balancing risks and benefits. It’s up to the clinician to determine which intervention is the best and least harmful for each patient. However, what may be considered an effective treatment may quickly be discarded when better and less harmful treatments are found, such as abandoning prefrontal lobotomy for aggressive psychotic patients shortly after chlorpromazine was discovered.

The authors respond

We thank Dr. Jennings for his comments and appreciate his concern to offer patients pharmacologic or nonpharmacologic treatments with the least amount of side effects. We also recognize the diversity of clinical situations, which, according to factors such as the degree of depression severity, the therapeutic choice of the patient, and the availability of treatments, lead the clinician to suggest an antidepressant treatment that is the most efficient and least harmful as possible.

By proposing that the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire consider the diversity of antidepressant treatments that various clinical situations have necessitated, we by no means encourage the use of antidepressant treatments that are inefficient and harmful to the patient. We look to provide clinicians with tools that take into consideration the therapeutic interventions available for treatment-resistant depression. In the same manner, we have not established a hierarchy of pharmacologic options, because we hope clinicians will identify the multiple treatments that the patient needs. If it is essential to “abstain from doing harm,” we must not forget that if healing is an ideal objective, we often only “treat” our patients with the best available methods.

As Dr. Jennings suggests, the least harmful treatments often are those that target depression’s physiopathology with the highest degree of specificity. In the same vein, neuromodulation treatments target the different neurobiologic mechanisms underlying depression. However, response predictors of TMS include age, degrees of treatment resistance, and the absence of comorbid anxiety or psychotic symptoms.^{Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/FTE612). This so-called side effect may be the central antidepressant effect, because short-term memory loss may be a central effect in any seizure therapy for depression.}

John S. Kafka, MD
Private Practice
Emeritus Professor of Psychiatry and Behavioral Sciences
George Washington University School of Medicine and Health Sciences
Washington, DC

Dr. Nasrallah responds

Memory loss with regular and heavy ketamine use or with a course of bilateral electroconvulsive therapy (ECT) is widely regarded as an undesirable side effect, not a therapeutic effect or mechanism. The side effects of short-term ketamine use in refractory depression studies included dissociation and unusual beliefs—such as conspiracy theories—as well as full-fledged delusions.

Both ketamine and ECT increase brain-derived neurotrophic factor (BDNF), which has been found to significantly decline in depression. The BDNF deficit is emerging as the leading mechanism of antidepressant therapy, both pharmacologic and non-pharmacologic, in both animal models and clinical populations.

CASE: Seizure-like symptoms

Ms. T, age 20, is brought to the emergency room (ER) by her father because she refuses to eat and drink, is unable to function at home, lies in bed all day, and does not attend to her activities of daily living (ADLs). Ms. T lives with her family, is not enrolled in school, and is unemployed. In the ER she initially is uncooperative and mute and then suddenly becomes agitated and has a seizure-like episode characterized by jerking of her trunk followed by random, asymmetrical movements of her legs and arms, closing both eyes, weeping, foaming at the mouth, moaning, and marked unresponsiveness. The episode lasts for >5 minutes.

The authors’ observations

Based on Ms. T’s presentation, the medical team considered acute epileptic seizures. Asymmetrical jerking of the body may be seen in frontal lobe epilepsy or seizures of the supplementary sensorimotor area. Frontal lobe epilepsy can present with bilateral asynchronous motor activity with consciousness during the event and a lack of postictal confusion.¹ Seizures of the supplementary sensorimotor area—also known as the secondary motor area—are particularly problematic because typically they present with bilateral asymmetric tonic posturing followed by a few clonic movements, intact consciousness, and rarely postictal confusion. Adding to the diagnostic uncertainty, some “soft signs” thought to indicate PNES (eg, pelvic thrusting, crying) are common with frontal lobe epilepsy.^1,2

PNES are episodes of altered movement, sensation, or experience that may be mistaken for epileptic seizures but are not a consequence of abnormal cortical discharges. Instead they are caused by physiological or psychological factors.³ Behaviors or signs that strongly suggest PNES include:

• gradual onset or termination
• pseudosleep, when the patient appears to be asleep but electroencephalography (EEG) findings indicate he or she is awake
• discontinuous (stop-and-go), irregular, or asynchronous (out-of-phase) activity—including side-to-side head movement, pelvic thrusting, and opisthotonic posturing—stuttering, and weeping⁴
• eye closure.⁵

Ms. T’s father said his daughter had been hospitalized several times for episodes characterized by pelvic thrusting, stuttering, and pseudosleep, which raised the possibility of PNES. Definitive diagnosis of PNES comes from video EEG when a patient is observed having typical seizures without accompanying EEG abnormalities.⁶

EVALUATION: Inconclusive data

Ms. T is admitted to the medical unit to rule out a seizure disorder. Physical examination is unremarkable and laboratory tests are within normal limits. The neurology service requests a head MRI, which is inconclusive. Inpatient video EEG with 24-hour monitoring does not indicate acute epileptic seizures. Ms. T’s father says that she has experienced many paroxysmal motor episodes and all neurologic tests, exams, and labs have failed to find a cause for these episodes. She did not receive any antiepileptic medications. A psychiatric consult is requested to clarify the diagnosis. Ms. T is transferred to an inpatient psychiatric unit for further evaluation and management.

The authors’ observations

Fleisher et al⁷ suggested that traumatic events may lead to presentations similar to PNES. Because Ms. T was molested by a family friend as a child, we considered posttraumatic stress disorder (PTSD) in the differential diagnosis, although she has not reported symptoms of intrusive recollections, avoidance, numbing, or hyperarousal.

We also considered conversion disorder and dissociative disorder. Patients with conversion disorder have ≥1 symptoms or signs that affect voluntary motor or sensory function that cannot be explained by a neurologic or general medical condition.⁸ Dissociative disorder is a disruption in usually integrated functions of consciousness, memory, identity, or perception of the environment.⁸ The presentation of patients with PNES may resemble that of patients with dissociative disorder.⁸ In a study of 45 adult PNES patients, Bowman et al⁸ found that PNES often are comorbid with other psychiatric disorders, including somatoform disorders (89%), dissociative disorders (91%), affective disorders (64%), personality disorders (62%), PTSD (49%), and other anxiety disorders (47%).

TREATMENT: Managing aggression

In the psychiatric unit, Ms. T initially is irritable and disorganized with poor oral intake and regressed behavior; she often is found in the fetal position, crying and talking in a childish manner. Throughout her admission, she receives several anxiolytics and antipsychotics—including lorazepam, up to 6 mg/d, clonazepam, up to 3 mg/d, haloperidol, up to 10 mg/d, and quetiapine, up to 200 mg/d—to help manage her aggressive behaviors after her seizure-like episodes. Further evaluation reveals that Ms. T has no psychotic symptoms, overt delusions, or perceptual disturbances and her thought process is coherent and clear. She has no history of substance abuse. Her ability to perform ADLs improves within a few days. She complains of depressed mood and engages in head banging, which requires close observation.

Ms. T has a history of mood and behavioral problems since early childhood characterized by episodic dysphoric mood, anxiety, and agitation. She has had trials of several antidepressants, including sertraline, fluoxetine, venlafaxine, and escitalopram, and anxiolytics, including lorazepam, clonazepam, and alprazolam. Her outpatient psychiatrist describes a history of physical and sexual abuse starting at age 7. At age 9, after her mother died from breast cancer, Ms. T and her siblings were moved to foster care, where she was physically abused by the staff. She remained in foster care until age 18.

The authors’ observations

PNES pose a diagnostic and therapeutic challenge. Many PNES patients seek medical attention for their seizures. PNES patients misdiagnosed as having epilepsy have a worse prognosis because they do not receive appropriate treatment⁹ and may experience side effects if antiepileptics are prescribed.¹⁰ Finally, the financial burden of medical care can be significant. Ms. T had several hospitalizations, including extensive neurologic workup, intensive care unit admissions for intubation, and use of antiepileptics with almost no benefit.

Psychosocial assessments of PNES patients have revealed that sexual abuse, family conflicts, and death of a family member often play an important role.¹¹ It is possible that as a result of childhood trauma, Ms. T exhibited a regressed and primitive defense mechanism to deal with the trauma. PNES usually are considered when a patient presents with:

• absence of therapeutic response to antiepileptics
• loss of response (therapeutic failure) to antiepileptics
• paradoxical response to antiepileptics (worsening or unexpected responses)
• atypical, multiple, or inconsistent seizures
• seizures that occur soon after emotional stress.¹²

We concluded Ms. T had PNES because of the unusual presentations of her seizures, negative video EEG findings, failure to respond to antiepileptics, lack of risk factors for epilepsy, and aggressive behaviors before or after the seizures ( Table ).^4,10,11,13 Diagnosing PNES early allows clinicians to focus on appropriate treatment modalities (eg, psychotherapy, antidepressants), prevents costly neurologic workups and treatments (eg, routine EEGs, trials of several antiepileptics), and provides patients with diagnostic assurance.¹⁰

Table

Characteristics of psychogenic nonepileptic seizures

3 components of treatment

Presenting the PNES diagnosis to the patient. The neurologist and the psychiatrist should convey to the patient that they see the symptoms as “real” and not “all in your head.”¹⁴

Withdrawing antiepileptic medications. Antiepileptic medication withdrawal is recommended when a thorough diagnostic workup shows no evidence of epileptic seizures.¹⁵ Oto et al¹⁶ reported 49% of PNES patients became seizure-free 12 months after discontinuing antiepileptics.

Psychotherapy and pharmacotherapy. Open-label studies of psychological treatments for PNES have demonstrated that a cognitive-behavioral therapy-based approach and brief augmented psychodynamic interpersonal therapy could reduce seizures.¹⁷ In a pilot, randomized, placebo-controlled trial, PNES patients who received flexibly dosed sertraline reported a 45% reduction in seizures compared with an 8% increase in the placebo group.¹⁸ Similar improvements in seizure frequency have been reported in PNES patients with anxiety or depression treated with venlafaxine.¹⁹

OUTCOME: Support, improvement

During the next several days, Ms. T has random episodes of seizures with foaming of the mouth and unresponsiveness. These episodes last from 5 to 30 minutes and require transfer to the ER. After each episode, Ms. T is medically cleared and sent back to the psychiatric unit. The neurologist recommends avoiding antiepileptics. Ms. T responds well to the structured inpatient setting and supportive psychotherapy. Her episodes decrease and her mood becomes more stable. She refrains from self-injurious behaviors and is discharged home with outpatient follow-up.

Related Resource

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-35.

Drug Brand Names

• Alprazolam • Xanax
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

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

CASE: Seizure-like symptoms

Ms. T, age 20, is brought to the emergency room (ER) by her father because she refuses to eat and drink, is unable to function at home, lies in bed all day, and does not attend to her activities of daily living (ADLs). Ms. T lives with her family, is not enrolled in school, and is unemployed. In the ER she initially is uncooperative and mute and then suddenly becomes agitated and has a seizure-like episode characterized by jerking of her trunk followed by random, asymmetrical movements of her legs and arms, closing both eyes, weeping, foaming at the mouth, moaning, and marked unresponsiveness. The episode lasts for >5 minutes.

The authors’ observations

Based on Ms. T’s presentation, the medical team considered acute epileptic seizures. Asymmetrical jerking of the body may be seen in frontal lobe epilepsy or seizures of the supplementary sensorimotor area. Frontal lobe epilepsy can present with bilateral asynchronous motor activity with consciousness during the event and a lack of postictal confusion.¹ Seizures of the supplementary sensorimotor area—also known as the secondary motor area—are particularly problematic because typically they present with bilateral asymmetric tonic posturing followed by a few clonic movements, intact consciousness, and rarely postictal confusion. Adding to the diagnostic uncertainty, some “soft signs” thought to indicate PNES (eg, pelvic thrusting, crying) are common with frontal lobe epilepsy.^1,2

PNES are episodes of altered movement, sensation, or experience that may be mistaken for epileptic seizures but are not a consequence of abnormal cortical discharges. Instead they are caused by physiological or psychological factors.³ Behaviors or signs that strongly suggest PNES include:

• gradual onset or termination
• pseudosleep, when the patient appears to be asleep but electroencephalography (EEG) findings indicate he or she is awake
• discontinuous (stop-and-go), irregular, or asynchronous (out-of-phase) activity—including side-to-side head movement, pelvic thrusting, and opisthotonic posturing—stuttering, and weeping⁴
• eye closure.⁵

Ms. T’s father said his daughter had been hospitalized several times for episodes characterized by pelvic thrusting, stuttering, and pseudosleep, which raised the possibility of PNES. Definitive diagnosis of PNES comes from video EEG when a patient is observed having typical seizures without accompanying EEG abnormalities.⁶

EVALUATION: Inconclusive data

Ms. T is admitted to the medical unit to rule out a seizure disorder. Physical examination is unremarkable and laboratory tests are within normal limits. The neurology service requests a head MRI, which is inconclusive. Inpatient video EEG with 24-hour monitoring does not indicate acute epileptic seizures. Ms. T’s father says that she has experienced many paroxysmal motor episodes and all neurologic tests, exams, and labs have failed to find a cause for these episodes. She did not receive any antiepileptic medications. A psychiatric consult is requested to clarify the diagnosis. Ms. T is transferred to an inpatient psychiatric unit for further evaluation and management.

The authors’ observations

Fleisher et al⁷ suggested that traumatic events may lead to presentations similar to PNES. Because Ms. T was molested by a family friend as a child, we considered posttraumatic stress disorder (PTSD) in the differential diagnosis, although she has not reported symptoms of intrusive recollections, avoidance, numbing, or hyperarousal.

We also considered conversion disorder and dissociative disorder. Patients with conversion disorder have ≥1 symptoms or signs that affect voluntary motor or sensory function that cannot be explained by a neurologic or general medical condition.⁸ Dissociative disorder is a disruption in usually integrated functions of consciousness, memory, identity, or perception of the environment.⁸ The presentation of patients with PNES may resemble that of patients with dissociative disorder.⁸ In a study of 45 adult PNES patients, Bowman et al⁸ found that PNES often are comorbid with other psychiatric disorders, including somatoform disorders (89%), dissociative disorders (91%), affective disorders (64%), personality disorders (62%), PTSD (49%), and other anxiety disorders (47%).

TREATMENT: Managing aggression

In the psychiatric unit, Ms. T initially is irritable and disorganized with poor oral intake and regressed behavior; she often is found in the fetal position, crying and talking in a childish manner. Throughout her admission, she receives several anxiolytics and antipsychotics—including lorazepam, up to 6 mg/d, clonazepam, up to 3 mg/d, haloperidol, up to 10 mg/d, and quetiapine, up to 200 mg/d—to help manage her aggressive behaviors after her seizure-like episodes. Further evaluation reveals that Ms. T has no psychotic symptoms, overt delusions, or perceptual disturbances and her thought process is coherent and clear. She has no history of substance abuse. Her ability to perform ADLs improves within a few days. She complains of depressed mood and engages in head banging, which requires close observation.

Ms. T has a history of mood and behavioral problems since early childhood characterized by episodic dysphoric mood, anxiety, and agitation. She has had trials of several antidepressants, including sertraline, fluoxetine, venlafaxine, and escitalopram, and anxiolytics, including lorazepam, clonazepam, and alprazolam. Her outpatient psychiatrist describes a history of physical and sexual abuse starting at age 7. At age 9, after her mother died from breast cancer, Ms. T and her siblings were moved to foster care, where she was physically abused by the staff. She remained in foster care until age 18.

The authors’ observations

PNES pose a diagnostic and therapeutic challenge. Many PNES patients seek medical attention for their seizures. PNES patients misdiagnosed as having epilepsy have a worse prognosis because they do not receive appropriate treatment⁹ and may experience side effects if antiepileptics are prescribed.¹⁰ Finally, the financial burden of medical care can be significant. Ms. T had several hospitalizations, including extensive neurologic workup, intensive care unit admissions for intubation, and use of antiepileptics with almost no benefit.

Psychosocial assessments of PNES patients have revealed that sexual abuse, family conflicts, and death of a family member often play an important role.¹¹ It is possible that as a result of childhood trauma, Ms. T exhibited a regressed and primitive defense mechanism to deal with the trauma. PNES usually are considered when a patient presents with:

• absence of therapeutic response to antiepileptics
• loss of response (therapeutic failure) to antiepileptics
• paradoxical response to antiepileptics (worsening or unexpected responses)
• atypical, multiple, or inconsistent seizures
• seizures that occur soon after emotional stress.¹²

We concluded Ms. T had PNES because of the unusual presentations of her seizures, negative video EEG findings, failure to respond to antiepileptics, lack of risk factors for epilepsy, and aggressive behaviors before or after the seizures ( Table ).^4,10,11,13 Diagnosing PNES early allows clinicians to focus on appropriate treatment modalities (eg, psychotherapy, antidepressants), prevents costly neurologic workups and treatments (eg, routine EEGs, trials of several antiepileptics), and provides patients with diagnostic assurance.¹⁰

Table

Characteristics of psychogenic nonepileptic seizures

3 components of treatment

Presenting the PNES diagnosis to the patient. The neurologist and the psychiatrist should convey to the patient that they see the symptoms as “real” and not “all in your head.”¹⁴

Withdrawing antiepileptic medications. Antiepileptic medication withdrawal is recommended when a thorough diagnostic workup shows no evidence of epileptic seizures.¹⁵ Oto et al¹⁶ reported 49% of PNES patients became seizure-free 12 months after discontinuing antiepileptics.

Psychotherapy and pharmacotherapy. Open-label studies of psychological treatments for PNES have demonstrated that a cognitive-behavioral therapy-based approach and brief augmented psychodynamic interpersonal therapy could reduce seizures.¹⁷ In a pilot, randomized, placebo-controlled trial, PNES patients who received flexibly dosed sertraline reported a 45% reduction in seizures compared with an 8% increase in the placebo group.¹⁸ Similar improvements in seizure frequency have been reported in PNES patients with anxiety or depression treated with venlafaxine.¹⁹

OUTCOME: Support, improvement

During the next several days, Ms. T has random episodes of seizures with foaming of the mouth and unresponsiveness. These episodes last from 5 to 30 minutes and require transfer to the ER. After each episode, Ms. T is medically cleared and sent back to the psychiatric unit. The neurologist recommends avoiding antiepileptics. Ms. T responds well to the structured inpatient setting and supportive psychotherapy. Her episodes decrease and her mood becomes more stable. She refrains from self-injurious behaviors and is discharged home with outpatient follow-up.

Related Resource

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-35.

Drug Brand Names

• Alprazolam • Xanax
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

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

CASE: Seizure-like symptoms

Ms. T, age 20, is brought to the emergency room (ER) by her father because she refuses to eat and drink, is unable to function at home, lies in bed all day, and does not attend to her activities of daily living (ADLs). Ms. T lives with her family, is not enrolled in school, and is unemployed. In the ER she initially is uncooperative and mute and then suddenly becomes agitated and has a seizure-like episode characterized by jerking of her trunk followed by random, asymmetrical movements of her legs and arms, closing both eyes, weeping, foaming at the mouth, moaning, and marked unresponsiveness. The episode lasts for >5 minutes.

The authors’ observations

Based on Ms. T’s presentation, the medical team considered acute epileptic seizures. Asymmetrical jerking of the body may be seen in frontal lobe epilepsy or seizures of the supplementary sensorimotor area. Frontal lobe epilepsy can present with bilateral asynchronous motor activity with consciousness during the event and a lack of postictal confusion.¹ Seizures of the supplementary sensorimotor area—also known as the secondary motor area—are particularly problematic because typically they present with bilateral asymmetric tonic posturing followed by a few clonic movements, intact consciousness, and rarely postictal confusion. Adding to the diagnostic uncertainty, some “soft signs” thought to indicate PNES (eg, pelvic thrusting, crying) are common with frontal lobe epilepsy.^1,2

PNES are episodes of altered movement, sensation, or experience that may be mistaken for epileptic seizures but are not a consequence of abnormal cortical discharges. Instead they are caused by physiological or psychological factors.³ Behaviors or signs that strongly suggest PNES include:

• gradual onset or termination
• pseudosleep, when the patient appears to be asleep but electroencephalography (EEG) findings indicate he or she is awake
• discontinuous (stop-and-go), irregular, or asynchronous (out-of-phase) activity—including side-to-side head movement, pelvic thrusting, and opisthotonic posturing—stuttering, and weeping⁴
• eye closure.⁵

Ms. T’s father said his daughter had been hospitalized several times for episodes characterized by pelvic thrusting, stuttering, and pseudosleep, which raised the possibility of PNES. Definitive diagnosis of PNES comes from video EEG when a patient is observed having typical seizures without accompanying EEG abnormalities.⁶

EVALUATION: Inconclusive data

Ms. T is admitted to the medical unit to rule out a seizure disorder. Physical examination is unremarkable and laboratory tests are within normal limits. The neurology service requests a head MRI, which is inconclusive. Inpatient video EEG with 24-hour monitoring does not indicate acute epileptic seizures. Ms. T’s father says that she has experienced many paroxysmal motor episodes and all neurologic tests, exams, and labs have failed to find a cause for these episodes. She did not receive any antiepileptic medications. A psychiatric consult is requested to clarify the diagnosis. Ms. T is transferred to an inpatient psychiatric unit for further evaluation and management.

The authors’ observations

Fleisher et al⁷ suggested that traumatic events may lead to presentations similar to PNES. Because Ms. T was molested by a family friend as a child, we considered posttraumatic stress disorder (PTSD) in the differential diagnosis, although she has not reported symptoms of intrusive recollections, avoidance, numbing, or hyperarousal.

We also considered conversion disorder and dissociative disorder. Patients with conversion disorder have ≥1 symptoms or signs that affect voluntary motor or sensory function that cannot be explained by a neurologic or general medical condition.⁸ Dissociative disorder is a disruption in usually integrated functions of consciousness, memory, identity, or perception of the environment.⁸ The presentation of patients with PNES may resemble that of patients with dissociative disorder.⁸ In a study of 45 adult PNES patients, Bowman et al⁸ found that PNES often are comorbid with other psychiatric disorders, including somatoform disorders (89%), dissociative disorders (91%), affective disorders (64%), personality disorders (62%), PTSD (49%), and other anxiety disorders (47%).

TREATMENT: Managing aggression

In the psychiatric unit, Ms. T initially is irritable and disorganized with poor oral intake and regressed behavior; she often is found in the fetal position, crying and talking in a childish manner. Throughout her admission, she receives several anxiolytics and antipsychotics—including lorazepam, up to 6 mg/d, clonazepam, up to 3 mg/d, haloperidol, up to 10 mg/d, and quetiapine, up to 200 mg/d—to help manage her aggressive behaviors after her seizure-like episodes. Further evaluation reveals that Ms. T has no psychotic symptoms, overt delusions, or perceptual disturbances and her thought process is coherent and clear. She has no history of substance abuse. Her ability to perform ADLs improves within a few days. She complains of depressed mood and engages in head banging, which requires close observation.

Ms. T has a history of mood and behavioral problems since early childhood characterized by episodic dysphoric mood, anxiety, and agitation. She has had trials of several antidepressants, including sertraline, fluoxetine, venlafaxine, and escitalopram, and anxiolytics, including lorazepam, clonazepam, and alprazolam. Her outpatient psychiatrist describes a history of physical and sexual abuse starting at age 7. At age 9, after her mother died from breast cancer, Ms. T and her siblings were moved to foster care, where she was physically abused by the staff. She remained in foster care until age 18.

The authors’ observations

PNES pose a diagnostic and therapeutic challenge. Many PNES patients seek medical attention for their seizures. PNES patients misdiagnosed as having epilepsy have a worse prognosis because they do not receive appropriate treatment⁹ and may experience side effects if antiepileptics are prescribed.¹⁰ Finally, the financial burden of medical care can be significant. Ms. T had several hospitalizations, including extensive neurologic workup, intensive care unit admissions for intubation, and use of antiepileptics with almost no benefit.

Psychosocial assessments of PNES patients have revealed that sexual abuse, family conflicts, and death of a family member often play an important role.¹¹ It is possible that as a result of childhood trauma, Ms. T exhibited a regressed and primitive defense mechanism to deal with the trauma. PNES usually are considered when a patient presents with:

• absence of therapeutic response to antiepileptics
• loss of response (therapeutic failure) to antiepileptics
• paradoxical response to antiepileptics (worsening or unexpected responses)
• atypical, multiple, or inconsistent seizures
• seizures that occur soon after emotional stress.¹²

We concluded Ms. T had PNES because of the unusual presentations of her seizures, negative video EEG findings, failure to respond to antiepileptics, lack of risk factors for epilepsy, and aggressive behaviors before or after the seizures ( Table ).^4,10,11,13 Diagnosing PNES early allows clinicians to focus on appropriate treatment modalities (eg, psychotherapy, antidepressants), prevents costly neurologic workups and treatments (eg, routine EEGs, trials of several antiepileptics), and provides patients with diagnostic assurance.¹⁰

Table

Characteristics of psychogenic nonepileptic seizures

3 components of treatment

Presenting the PNES diagnosis to the patient. The neurologist and the psychiatrist should convey to the patient that they see the symptoms as “real” and not “all in your head.”¹⁴

Withdrawing antiepileptic medications. Antiepileptic medication withdrawal is recommended when a thorough diagnostic workup shows no evidence of epileptic seizures.¹⁵ Oto et al¹⁶ reported 49% of PNES patients became seizure-free 12 months after discontinuing antiepileptics.

Psychotherapy and pharmacotherapy. Open-label studies of psychological treatments for PNES have demonstrated that a cognitive-behavioral therapy-based approach and brief augmented psychodynamic interpersonal therapy could reduce seizures.¹⁷ In a pilot, randomized, placebo-controlled trial, PNES patients who received flexibly dosed sertraline reported a 45% reduction in seizures compared with an 8% increase in the placebo group.¹⁸ Similar improvements in seizure frequency have been reported in PNES patients with anxiety or depression treated with venlafaxine.¹⁹

OUTCOME: Support, improvement

During the next several days, Ms. T has random episodes of seizures with foaming of the mouth and unresponsiveness. These episodes last from 5 to 30 minutes and require transfer to the ER. After each episode, Ms. T is medically cleared and sent back to the psychiatric unit. The neurologist recommends avoiding antiepileptics. Ms. T responds well to the structured inpatient setting and supportive psychotherapy. Her episodes decrease and her mood becomes more stable. She refrains from self-injurious behaviors and is discharged home with outpatient follow-up.

Related Resource

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-35.

Drug Brand Names

• Alprazolam • Xanax
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

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

I want to correct an error in a recent letter regarding the use of transcranial magnetic stimulation (TMS) in treatment-resistant depression (TRD) (Comments & Controversies, Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR). The letter writers assert that a March 2012 article in Current Psychiatry should have included TMS as a treatment for TRD because it is “FDA-approved for TRD.” TMS is FDA-approved for the treatment of unipolar depression in patients who failed to respond to a single antidepressant trial. There are various definitions of TRD, but failing to respond to 1 antidepressant trial would not satisfy criteria for any such definition. A pivotal study of TMS, upon which the FDA approval was based, found that patients who had failed to respond to a single antidepressant were significantly more likely to respond to TMS than those who failed 2 to 4 antidepressant trials (P = .021).¹ Therefore, TMS is of questionable utility in treating TRD.

Brian Feldman, MD
Boca Raton Psychiatric Group
Boca Raton, FL

The authors respond

We appreciate Dr. Feldman noting our technical error. He is correct that TMS is FDA-approved for treating unipolar depression in individuals who had failed 1 adequate antidepressant trial during their current episode. However, Dr. Feldman is not correct that by no definition would this constitute TRD. For example, Fava¹ stated TRD “typically refers to inadequate response to at least one antidepressant trial of adequate doses and duration.”

Based on the research literature, we also disagree with Dr. Feldman’s assertion of “questionable utility” of TMS in TRD. As part of research presented to the FDA, O’Reardon et al² characterized the study sample as having failed an average of 1.6 adequate antidepressant treatment trial, with approximately one-half having failed ≥2 treatments in their current episode. Connolly et al³ described results in treating 100 consecutive depressed patients with TMS as equivalent to research findings. Most patients had >1 failed adequate antidepressant trial in their current episode. The Agency for Healthcare Research and Quality concluded that evidence supported use of TMS.⁴ Overall, the panel concluded that there is a substantial and well-replicated body of evidence that TMS is beneficial compared with controls in severity of symptoms, response rate, and remission rate. In a head-to-head comparison with electroconvulsive therapy, TMS was equally effective. TMS is a valuable addition to the therapeutic armamentarium that can help patients early in an illness not fall into a treatment-resistant state, and can offer another chance for those who have.

Gordon Baumbacher MD
Caroline Mulder, MD
Private Practice
Corte Madera, CA

Richard Bermudes, MD
Private Practice
Sacramento, CA

Jennifer Beck, MD
Private Practice
Santa Rosa, CA

I want to correct an error in a recent letter regarding the use of transcranial magnetic stimulation (TMS) in treatment-resistant depression (TRD) (Comments & Controversies, Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR). The letter writers assert that a March 2012 article in Current Psychiatry should have included TMS as a treatment for TRD because it is “FDA-approved for TRD.” TMS is FDA-approved for the treatment of unipolar depression in patients who failed to respond to a single antidepressant trial. There are various definitions of TRD, but failing to respond to 1 antidepressant trial would not satisfy criteria for any such definition. A pivotal study of TMS, upon which the FDA approval was based, found that patients who had failed to respond to a single antidepressant were significantly more likely to respond to TMS than those who failed 2 to 4 antidepressant trials (P = .021).¹ Therefore, TMS is of questionable utility in treating TRD.

Brian Feldman, MD
Boca Raton Psychiatric Group
Boca Raton, FL

The authors respond

We appreciate Dr. Feldman noting our technical error. He is correct that TMS is FDA-approved for treating unipolar depression in individuals who had failed 1 adequate antidepressant trial during their current episode. However, Dr. Feldman is not correct that by no definition would this constitute TRD. For example, Fava¹ stated TRD “typically refers to inadequate response to at least one antidepressant trial of adequate doses and duration.”

Based on the research literature, we also disagree with Dr. Feldman’s assertion of “questionable utility” of TMS in TRD. As part of research presented to the FDA, O’Reardon et al² characterized the study sample as having failed an average of 1.6 adequate antidepressant treatment trial, with approximately one-half having failed ≥2 treatments in their current episode. Connolly et al³ described results in treating 100 consecutive depressed patients with TMS as equivalent to research findings. Most patients had >1 failed adequate antidepressant trial in their current episode. The Agency for Healthcare Research and Quality concluded that evidence supported use of TMS.⁴ Overall, the panel concluded that there is a substantial and well-replicated body of evidence that TMS is beneficial compared with controls in severity of symptoms, response rate, and remission rate. In a head-to-head comparison with electroconvulsive therapy, TMS was equally effective. TMS is a valuable addition to the therapeutic armamentarium that can help patients early in an illness not fall into a treatment-resistant state, and can offer another chance for those who have.

Gordon Baumbacher MD
Caroline Mulder, MD
Private Practice
Corte Madera, CA

Richard Bermudes, MD
Private Practice
Sacramento, CA

Jennifer Beck, MD
Private Practice
Santa Rosa, CA

I want to correct an error in a recent letter regarding the use of transcranial magnetic stimulation (TMS) in treatment-resistant depression (TRD) (Comments & Controversies, Current Psychiatry, June 2012, p. 19; http://bit.ly/1QU1sOR). The letter writers assert that a March 2012 article in Current Psychiatry should have included TMS as a treatment for TRD because it is “FDA-approved for TRD.” TMS is FDA-approved for the treatment of unipolar depression in patients who failed to respond to a single antidepressant trial. There are various definitions of TRD, but failing to respond to 1 antidepressant trial would not satisfy criteria for any such definition. A pivotal study of TMS, upon which the FDA approval was based, found that patients who had failed to respond to a single antidepressant were significantly more likely to respond to TMS than those who failed 2 to 4 antidepressant trials (P = .021).¹ Therefore, TMS is of questionable utility in treating TRD.

Brian Feldman, MD
Boca Raton Psychiatric Group
Boca Raton, FL

The authors respond

We appreciate Dr. Feldman noting our technical error. He is correct that TMS is FDA-approved for treating unipolar depression in individuals who had failed 1 adequate antidepressant trial during their current episode. However, Dr. Feldman is not correct that by no definition would this constitute TRD. For example, Fava¹ stated TRD “typically refers to inadequate response to at least one antidepressant trial of adequate doses and duration.”

Based on the research literature, we also disagree with Dr. Feldman’s assertion of “questionable utility” of TMS in TRD. As part of research presented to the FDA, O’Reardon et al² characterized the study sample as having failed an average of 1.6 adequate antidepressant treatment trial, with approximately one-half having failed ≥2 treatments in their current episode. Connolly et al³ described results in treating 100 consecutive depressed patients with TMS as equivalent to research findings. Most patients had >1 failed adequate antidepressant trial in their current episode. The Agency for Healthcare Research and Quality concluded that evidence supported use of TMS.⁴ Overall, the panel concluded that there is a substantial and well-replicated body of evidence that TMS is beneficial compared with controls in severity of symptoms, response rate, and remission rate. In a head-to-head comparison with electroconvulsive therapy, TMS was equally effective. TMS is a valuable addition to the therapeutic armamentarium that can help patients early in an illness not fall into a treatment-resistant state, and can offer another chance for those who have.

Gordon Baumbacher MD
Caroline Mulder, MD
Private Practice
Corte Madera, CA

Richard Bermudes, MD
Private Practice
Sacramento, CA

Jennifer Beck, MD
Private Practice
Santa Rosa, CA

On July 20 of every year, I recall the transcendent wonder I felt on that day in 1969 when the entire world and I were glued to our television sets, witnessing one of the greatest achievements in the history of the human race: American astronauts landing on the moon and beaming pictures of their extraordinary celestial expedition to the billions of earthlings sitting on the edge of their seats.

Every year on July 20, I ponder the supreme and brilliant abilities of the human brain that transformed walking on the moon from an absurd fantasy to a thrilling reality. After becoming a psychiatrist, trained to observe everything through the prism of mind and brain, the moon landing represented the zenith achievement of the divinely evolved human neocortex, especially the prefrontal lobe of President John F. Kennedy, who established that lofty goal, and the advanced brains of thousands of NASA scientists and engineers, who set out to fulfill that towering expectation in less than a decade. That’s why every year on July 20, my abiding faith in the limitless capacities of the human brain to do great things is confirmed and reinforced.

However, this year was different as July 20 took on a much darker meaning. The tragic shooting in Aurora, CO that killed 12 people and wounded 58 others—perpetrated by the bizarre machinations of a graduate school student who had been receiving psychiatric treatment when he suddenly dropped out—rudely reminded me how, like the moon, the human brain has a dark side. A healthy brain that can envision, plan, and execute a magnificent moon landing is capable, when perturbed, of carrying out a dreadfully heinous crime. So henceforth, July 20 always will remind me of the zenith vs nadir dichotomy of the human mind potential in health and disease.

As a longtime academic psychiatrist, I have repeatedly witnessed the tragic disability my patients suffer when the frontal lobe—the most advanced component of their brains— becomes seriously impaired, rendering them dysfunctional. Unless driven by an intense delusion or command hallucinations, patients with schizophrenia rarely commit a murder. However, the media often has linked psychosis with violent crime, whether in movies¹ or in news reporting, which has led to public misconception that every person suffering from psychosis is a potential mass murderer. The truth is that the vast majority of murders are committed by nonpsychotic criminals with severe antisocial traits.

Because of the shocking killings in Aurora, July 20 may become an annual reminder that perpetuates the unfair and ignorant notion that mental illness always is associated with horrendous crimes. That would further darken the discriminatory stigma of mental illness and may foster a hatred of and aversion to mentally ill individuals, the vast majority of whom are law-abiding citizens. Even the legally mandated “not guilty by reason of insanity” defense is being described as a spurious “excuse” and is under assault, which may lead to death sentences for medically ill persons whose actions are triggered by a severe brain pathology that impairs judgment and distorts reality testing of what is right or wrong.

The devastated families of the victims also are very much on my mind. For them, July 20 will become a dark anniversary of how their loved ones—most of whom were in the prime of life—lost theirs lives while watching a movie called The Dark Knight Rises. Their annual grief on July 20 will for many years reopen the deep wounds inflicted on their souls.

In the future, on July 20 I will no longer be merely inspired by the human brain’s potential for achievements. I now also will remember the potential for despicable and murderous actions when a sickened human brain and its convoluted mind go terribly awry. As an academic investigator dedicated to finding a cure for schizophrenia and related disorders, I regard the tragic events in Aurora on July 20, 2012 as another call to escalate the commitment of researchers to restore normalcy to the blighted brains of those afflicted by this cruel disease, or, better yet, to ultimately discover how to prevent schizophrenia from developing. Only then will the darkness of severe mental illness finally ebb and vanish.

Editor's Note: This editorial was written before Neil Armstrong, the first man to walk on the moon, died on August 25, 2012.

On July 20 of every year, I recall the transcendent wonder I felt on that day in 1969 when the entire world and I were glued to our television sets, witnessing one of the greatest achievements in the history of the human race: American astronauts landing on the moon and beaming pictures of their extraordinary celestial expedition to the billions of earthlings sitting on the edge of their seats.

Every year on July 20, I ponder the supreme and brilliant abilities of the human brain that transformed walking on the moon from an absurd fantasy to a thrilling reality. After becoming a psychiatrist, trained to observe everything through the prism of mind and brain, the moon landing represented the zenith achievement of the divinely evolved human neocortex, especially the prefrontal lobe of President John F. Kennedy, who established that lofty goal, and the advanced brains of thousands of NASA scientists and engineers, who set out to fulfill that towering expectation in less than a decade. That’s why every year on July 20, my abiding faith in the limitless capacities of the human brain to do great things is confirmed and reinforced.

However, this year was different as July 20 took on a much darker meaning. The tragic shooting in Aurora, CO that killed 12 people and wounded 58 others—perpetrated by the bizarre machinations of a graduate school student who had been receiving psychiatric treatment when he suddenly dropped out—rudely reminded me how, like the moon, the human brain has a dark side. A healthy brain that can envision, plan, and execute a magnificent moon landing is capable, when perturbed, of carrying out a dreadfully heinous crime. So henceforth, July 20 always will remind me of the zenith vs nadir dichotomy of the human mind potential in health and disease.

As a longtime academic psychiatrist, I have repeatedly witnessed the tragic disability my patients suffer when the frontal lobe—the most advanced component of their brains— becomes seriously impaired, rendering them dysfunctional. Unless driven by an intense delusion or command hallucinations, patients with schizophrenia rarely commit a murder. However, the media often has linked psychosis with violent crime, whether in movies¹ or in news reporting, which has led to public misconception that every person suffering from psychosis is a potential mass murderer. The truth is that the vast majority of murders are committed by nonpsychotic criminals with severe antisocial traits.

Because of the shocking killings in Aurora, July 20 may become an annual reminder that perpetuates the unfair and ignorant notion that mental illness always is associated with horrendous crimes. That would further darken the discriminatory stigma of mental illness and may foster a hatred of and aversion to mentally ill individuals, the vast majority of whom are law-abiding citizens. Even the legally mandated “not guilty by reason of insanity” defense is being described as a spurious “excuse” and is under assault, which may lead to death sentences for medically ill persons whose actions are triggered by a severe brain pathology that impairs judgment and distorts reality testing of what is right or wrong.

The devastated families of the victims also are very much on my mind. For them, July 20 will become a dark anniversary of how their loved ones—most of whom were in the prime of life—lost theirs lives while watching a movie called The Dark Knight Rises. Their annual grief on July 20 will for many years reopen the deep wounds inflicted on their souls.

In the future, on July 20 I will no longer be merely inspired by the human brain’s potential for achievements. I now also will remember the potential for despicable and murderous actions when a sickened human brain and its convoluted mind go terribly awry. As an academic investigator dedicated to finding a cure for schizophrenia and related disorders, I regard the tragic events in Aurora on July 20, 2012 as another call to escalate the commitment of researchers to restore normalcy to the blighted brains of those afflicted by this cruel disease, or, better yet, to ultimately discover how to prevent schizophrenia from developing. Only then will the darkness of severe mental illness finally ebb and vanish.

Editor's Note: This editorial was written before Neil Armstrong, the first man to walk on the moon, died on August 25, 2012.

On July 20 of every year, I recall the transcendent wonder I felt on that day in 1969 when the entire world and I were glued to our television sets, witnessing one of the greatest achievements in the history of the human race: American astronauts landing on the moon and beaming pictures of their extraordinary celestial expedition to the billions of earthlings sitting on the edge of their seats.

Every year on July 20, I ponder the supreme and brilliant abilities of the human brain that transformed walking on the moon from an absurd fantasy to a thrilling reality. After becoming a psychiatrist, trained to observe everything through the prism of mind and brain, the moon landing represented the zenith achievement of the divinely evolved human neocortex, especially the prefrontal lobe of President John F. Kennedy, who established that lofty goal, and the advanced brains of thousands of NASA scientists and engineers, who set out to fulfill that towering expectation in less than a decade. That’s why every year on July 20, my abiding faith in the limitless capacities of the human brain to do great things is confirmed and reinforced.

However, this year was different as July 20 took on a much darker meaning. The tragic shooting in Aurora, CO that killed 12 people and wounded 58 others—perpetrated by the bizarre machinations of a graduate school student who had been receiving psychiatric treatment when he suddenly dropped out—rudely reminded me how, like the moon, the human brain has a dark side. A healthy brain that can envision, plan, and execute a magnificent moon landing is capable, when perturbed, of carrying out a dreadfully heinous crime. So henceforth, July 20 always will remind me of the zenith vs nadir dichotomy of the human mind potential in health and disease.

As a longtime academic psychiatrist, I have repeatedly witnessed the tragic disability my patients suffer when the frontal lobe—the most advanced component of their brains— becomes seriously impaired, rendering them dysfunctional. Unless driven by an intense delusion or command hallucinations, patients with schizophrenia rarely commit a murder. However, the media often has linked psychosis with violent crime, whether in movies¹ or in news reporting, which has led to public misconception that every person suffering from psychosis is a potential mass murderer. The truth is that the vast majority of murders are committed by nonpsychotic criminals with severe antisocial traits.

Because of the shocking killings in Aurora, July 20 may become an annual reminder that perpetuates the unfair and ignorant notion that mental illness always is associated with horrendous crimes. That would further darken the discriminatory stigma of mental illness and may foster a hatred of and aversion to mentally ill individuals, the vast majority of whom are law-abiding citizens. Even the legally mandated “not guilty by reason of insanity” defense is being described as a spurious “excuse” and is under assault, which may lead to death sentences for medically ill persons whose actions are triggered by a severe brain pathology that impairs judgment and distorts reality testing of what is right or wrong.

The devastated families of the victims also are very much on my mind. For them, July 20 will become a dark anniversary of how their loved ones—most of whom were in the prime of life—lost theirs lives while watching a movie called The Dark Knight Rises. Their annual grief on July 20 will for many years reopen the deep wounds inflicted on their souls.

In the future, on July 20 I will no longer be merely inspired by the human brain’s potential for achievements. I now also will remember the potential for despicable and murderous actions when a sickened human brain and its convoluted mind go terribly awry. As an academic investigator dedicated to finding a cure for schizophrenia and related disorders, I regard the tragic events in Aurora on July 20, 2012 as another call to escalate the commitment of researchers to restore normalcy to the blighted brains of those afflicted by this cruel disease, or, better yet, to ultimately discover how to prevent schizophrenia from developing. Only then will the darkness of severe mental illness finally ebb and vanish.

Editor's Note: This editorial was written before Neil Armstrong, the first man to walk on the moon, died on August 25, 2012.

Most psychiatrists are aware that some antidepressants can cause clinically significant drug interactions, especially through the cytochrome P450 (CYP450) hepatic enzyme system. Antidepressants’ potential for drug interactions is especially important for patients who take >1 other medication, including cardiovascular agents.¹

Unfortunately, drug interactions can be difficult to remember and are commonly missed. One strategy to help remember a list of antidepressants with a relatively low potential for CYP450 drug interactions is to use the mnemonic Various Medicines Definitely Commingle Very Easily (VMDCVE) to recall venlafaxine, mirtazapine, desvenlafaxine,² citalopram, vilazodone,³ and escitalopram. The order in which these medications are listed does not indicate a preference for any of the 6 antidepressants. Bupropion and duloxetine are not included in this list because they are moderately potent inhibitors of the 2D6 isoenzyme.^4,5

A few caveats

There are some important caveats in using this mnemonic:

• None of these antidepressants is completely devoid of effects on the CYP450 system. However, compared with the antidepressants included in this mnemonic, fluoxetine, paroxetine, fluvoxamine, duloxetine, bupropion, and nefazodone are more likely to have clinically significant effects on CYP450.^4,5
• Although sertraline has a lower potential for CYP450-mediated drug interactions at low doses, it is not included in this mnemonic because it may have greater effects on 2D6 inhibition in some patients, especially at higher doses, such as ≥150 mg/d.⁵ Also, sertraline may significantly increase lamotrigine levels through a different mechanism: inhibition of uridine 5’-diphosphate glucuronosyltransferase 1A4.⁴
• Antidepressants also may be the substrates for CYP450 drug interactions caused by other medications.
• This mnemonic refers only to CYP450-mediated drug interactions. Antidepressants included in this mnemonic may have a high potential for drug interactions mediated by displacement from carrier proteins— eg, with digoxin or warfarin.
• Pharmacodynamic drug interactions also are possible—eg, serotonin syndrome as a result of combining a selective serotonin reuptake inhibitor with another serotonergic medication.

To remain vigilant for drug-drug interactions, routinely use a drug interaction software, in addition to this mnemonic.

Disclosure

Dr. Mago receives grant/research, support from Bristol-Myers Squibb, Eli Lilly and Company, and NARSAD.

Most psychiatrists are aware that some antidepressants can cause clinically significant drug interactions, especially through the cytochrome P450 (CYP450) hepatic enzyme system. Antidepressants’ potential for drug interactions is especially important for patients who take >1 other medication, including cardiovascular agents.¹

Unfortunately, drug interactions can be difficult to remember and are commonly missed. One strategy to help remember a list of antidepressants with a relatively low potential for CYP450 drug interactions is to use the mnemonic Various Medicines Definitely Commingle Very Easily (VMDCVE) to recall venlafaxine, mirtazapine, desvenlafaxine,² citalopram, vilazodone,³ and escitalopram. The order in which these medications are listed does not indicate a preference for any of the 6 antidepressants. Bupropion and duloxetine are not included in this list because they are moderately potent inhibitors of the 2D6 isoenzyme.^4,5

A few caveats

There are some important caveats in using this mnemonic:

• None of these antidepressants is completely devoid of effects on the CYP450 system. However, compared with the antidepressants included in this mnemonic, fluoxetine, paroxetine, fluvoxamine, duloxetine, bupropion, and nefazodone are more likely to have clinically significant effects on CYP450.^4,5
• Although sertraline has a lower potential for CYP450-mediated drug interactions at low doses, it is not included in this mnemonic because it may have greater effects on 2D6 inhibition in some patients, especially at higher doses, such as ≥150 mg/d.⁵ Also, sertraline may significantly increase lamotrigine levels through a different mechanism: inhibition of uridine 5’-diphosphate glucuronosyltransferase 1A4.⁴
• Antidepressants also may be the substrates for CYP450 drug interactions caused by other medications.
• This mnemonic refers only to CYP450-mediated drug interactions. Antidepressants included in this mnemonic may have a high potential for drug interactions mediated by displacement from carrier proteins— eg, with digoxin or warfarin.
• Pharmacodynamic drug interactions also are possible—eg, serotonin syndrome as a result of combining a selective serotonin reuptake inhibitor with another serotonergic medication.

To remain vigilant for drug-drug interactions, routinely use a drug interaction software, in addition to this mnemonic.

Disclosure

Dr. Mago receives grant/research, support from Bristol-Myers Squibb, Eli Lilly and Company, and NARSAD.

Most psychiatrists are aware that some antidepressants can cause clinically significant drug interactions, especially through the cytochrome P450 (CYP450) hepatic enzyme system. Antidepressants’ potential for drug interactions is especially important for patients who take >1 other medication, including cardiovascular agents.¹

Unfortunately, drug interactions can be difficult to remember and are commonly missed. One strategy to help remember a list of antidepressants with a relatively low potential for CYP450 drug interactions is to use the mnemonic Various Medicines Definitely Commingle Very Easily (VMDCVE) to recall venlafaxine, mirtazapine, desvenlafaxine,² citalopram, vilazodone,³ and escitalopram. The order in which these medications are listed does not indicate a preference for any of the 6 antidepressants. Bupropion and duloxetine are not included in this list because they are moderately potent inhibitors of the 2D6 isoenzyme.^4,5

A few caveats

There are some important caveats in using this mnemonic:

• None of these antidepressants is completely devoid of effects on the CYP450 system. However, compared with the antidepressants included in this mnemonic, fluoxetine, paroxetine, fluvoxamine, duloxetine, bupropion, and nefazodone are more likely to have clinically significant effects on CYP450.^4,5
• Although sertraline has a lower potential for CYP450-mediated drug interactions at low doses, it is not included in this mnemonic because it may have greater effects on 2D6 inhibition in some patients, especially at higher doses, such as ≥150 mg/d.⁵ Also, sertraline may significantly increase lamotrigine levels through a different mechanism: inhibition of uridine 5’-diphosphate glucuronosyltransferase 1A4.⁴
• Antidepressants also may be the substrates for CYP450 drug interactions caused by other medications.
• This mnemonic refers only to CYP450-mediated drug interactions. Antidepressants included in this mnemonic may have a high potential for drug interactions mediated by displacement from carrier proteins— eg, with digoxin or warfarin.
• Pharmacodynamic drug interactions also are possible—eg, serotonin syndrome as a result of combining a selective serotonin reuptake inhibitor with another serotonergic medication.

To remain vigilant for drug-drug interactions, routinely use a drug interaction software, in addition to this mnemonic.

Disclosure

Dr. Mago receives grant/research, support from Bristol-Myers Squibb, Eli Lilly and Company, and NARSAD.