Current Psychiatry

Dr. Keenan is associate professor, department of medicine, University of California, Davis.

Principal Source: U.S. Preventive Services Task Force. Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;148(11):846-854.—Discussant: Craig R. Keenan, MD

Psychiatric patients—especially those with schizophrenia or taking atypical antipsychotics—are at risk for developing type 2 diabetes mellitus (T2DM) and prediabetes conditions. T2DM can be present for years without significant symptoms and even asymptomatic conditions increase the risk of cardiovascular, renal, retinal, and neurologic complications.

Despite a need for T2DM screening and treatment, expert guidelines disagree on who and how to screen (Table 1). Although testing patients who have diabetes symptoms—including polyuria, polydipsia, and weight loss—is indicated, some medical groups advocate screening asymptomatic persons for T2DM.

Screening recommendations

Consensus guidelines. In 2004, the American Diabetes Association (ADA), American Psychiatric Association (APA), American Association of Clinical Endocrinologists (AACE), and North American Association for the Study of Obesity (NAASO) created consensus guidelines for screening psychiatric patients receiving atypical antipsychotics. In addition to diabetes risk, psychiatric patients are at higher risk for metabolic syndrome, dyslipidemia, obesity, and hypertension.¹ The ADA, APA, AACE, and NAASO recommend regularly screening for weight gain and dyslipidemia, obtaining baseline values of fasting plasma glucose (FPG), rechecking FPG after 3 months, and then screening annually for diabetes or prediabetes. For patients with risk factors for diabetes and those who develop diabetes or prediabetes while taking an atypical antipsychotic, consider an atypical with a lower risk of diabetes—specifically aripiprazole or ziprasidone.¹ For psychiatric patients who do not take atypicals, there is no consensus on who and how to screen for T2DM.

The U.S. Preventive Services Task Force (USPSTF) recommends screening only adults with hypertension.² Its review found insufficient evidence that early detection and treatment leads to improved clinical outcomes in asymptomatic adults.

The ADA recommends more liberal screening, including individuals age ≥45 or anyone age <45 who is overweight and has any other diabetes risk factors.³ The ADA admits that no trials show a benefit of screening asymptomatic patients but notes that the duration of glycemic burden predicts adverse outcomes and effective interventions for diabetes and prediabetes are available.

AACE guidelines recommend screening starting at age 30 if the patient has risk factors for T2DM. This is the only group that includes psychiatric illness as a risk factor.⁴

European Association for the Study of Diabetes (EASD) guidelines calculate a risk score based on common risk factors to determine who should be screened and recommend using the oral glucose tolerance test (OGTT) rather the FPG.⁵ The OGTT identifies more cases of diabetes and pre-diabetes but takes >2 hours to administer.

Table 1

General population screening recommendations for type 2 diabetes mellitus or prediabetes

Discussion

Despite a lack evidence showing benefit to the screened population, treating diabetes and its comorbidities improves outcomes, and the potential risks of therapy are low. Therefore, it seems reasonable to screen more patients than the USPSTF recommends.

Using the EASD risk score is intriguing, but difficult to implement in a busy practice. Therefore, I recommend following the AACE guidelines, which recognize psychiatric illness as a risk factor, for screening psychiatric patients who are not receiving atypicals.

Annually screen psychiatric patients age ≥30, especially those with schizophrenia or affective disorders. I also follow the ADA guidelines and screen overweight adults age ≤30 if they have any of the other risk factors listed in Table 2. The most common risk factors seen in practice are being a member of a high-risk ethnic group, hypertension, lipid abnormalities, and cardiovascular disease. For overweight adults without other risk factors, I start screening at age 30.

Other practitioners can be more or less conservative and still be within accepted guidelines. The FPG—glucose level drawn from a vein after at least 8 hours of fasting—is probably the easiest screening test in practice. Any patient with a value >100mg/dL should be referred to the patient’s primary care physician. Any patient who develops diabetes symptoms—including polyuria, polydipsia, and weight loss—should be tested immediately. The hemoglobin A1C test is not recommended for screening.

Table 2

Risk factors identified for diabetes or prediabetes

Clinical presentation

Screening detects overt diabetes and can identify prediabetes. Prediabetes includes conditions of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). IFG is defined as a fasting glucose of 100 to 125 mg/dL, and IGT is defined as having a 2-hour glucose of 140 to 199 mg/dL on an OGTT.

Approximately one-quarter of the adult population has prediabetes, and interventions can prevent the progression of prediabetes to overt diabetes and reverse prediabetes. The Diabetes Prevention Trial found that lifestyle measures—including exercise and diet—were most effective, with a 53% reduction in the rate of progression to diabetes.⁶ Metformin also was effective, but less so than lifestyle measures alone.

Treatment slows the development or progression of microvascular complications, such as retinopathy, nephropathy, and neuropathy. Aggressive treatment of comorbid conditions, including hyperlipidemia and hypertension, also reduces the risk of cardiovascular events.

Drug brand names

• Aripiprazole • Abilify
• Metformin • Glucophage
• Ziprasidone • Geodon

Related resources

• American Diabetes Association. Diabetes risk calculator. www.diabetes.org/risk-test.jsp.
• Dagogo-Jack S. The role of antipsychotic agents in the development of diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(1):22-23. Quick, up-to-date review of the association between atypical antipsychotics and diabetes mellitus.

Disclosure

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

Dr. Keenan is associate professor, department of medicine, University of California, Davis.

Principal Source: U.S. Preventive Services Task Force. Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;148(11):846-854.—Discussant: Craig R. Keenan, MD

Psychiatric patients—especially those with schizophrenia or taking atypical antipsychotics—are at risk for developing type 2 diabetes mellitus (T2DM) and prediabetes conditions. T2DM can be present for years without significant symptoms and even asymptomatic conditions increase the risk of cardiovascular, renal, retinal, and neurologic complications.

Despite a need for T2DM screening and treatment, expert guidelines disagree on who and how to screen (Table 1). Although testing patients who have diabetes symptoms—including polyuria, polydipsia, and weight loss—is indicated, some medical groups advocate screening asymptomatic persons for T2DM.

Screening recommendations

Consensus guidelines. In 2004, the American Diabetes Association (ADA), American Psychiatric Association (APA), American Association of Clinical Endocrinologists (AACE), and North American Association for the Study of Obesity (NAASO) created consensus guidelines for screening psychiatric patients receiving atypical antipsychotics. In addition to diabetes risk, psychiatric patients are at higher risk for metabolic syndrome, dyslipidemia, obesity, and hypertension.¹ The ADA, APA, AACE, and NAASO recommend regularly screening for weight gain and dyslipidemia, obtaining baseline values of fasting plasma glucose (FPG), rechecking FPG after 3 months, and then screening annually for diabetes or prediabetes. For patients with risk factors for diabetes and those who develop diabetes or prediabetes while taking an atypical antipsychotic, consider an atypical with a lower risk of diabetes—specifically aripiprazole or ziprasidone.¹ For psychiatric patients who do not take atypicals, there is no consensus on who and how to screen for T2DM.

The U.S. Preventive Services Task Force (USPSTF) recommends screening only adults with hypertension.² Its review found insufficient evidence that early detection and treatment leads to improved clinical outcomes in asymptomatic adults.

The ADA recommends more liberal screening, including individuals age ≥45 or anyone age <45 who is overweight and has any other diabetes risk factors.³ The ADA admits that no trials show a benefit of screening asymptomatic patients but notes that the duration of glycemic burden predicts adverse outcomes and effective interventions for diabetes and prediabetes are available.

AACE guidelines recommend screening starting at age 30 if the patient has risk factors for T2DM. This is the only group that includes psychiatric illness as a risk factor.⁴

European Association for the Study of Diabetes (EASD) guidelines calculate a risk score based on common risk factors to determine who should be screened and recommend using the oral glucose tolerance test (OGTT) rather the FPG.⁵ The OGTT identifies more cases of diabetes and pre-diabetes but takes >2 hours to administer.

Table 1

General population screening recommendations for type 2 diabetes mellitus or prediabetes

Discussion

Despite a lack evidence showing benefit to the screened population, treating diabetes and its comorbidities improves outcomes, and the potential risks of therapy are low. Therefore, it seems reasonable to screen more patients than the USPSTF recommends.

Using the EASD risk score is intriguing, but difficult to implement in a busy practice. Therefore, I recommend following the AACE guidelines, which recognize psychiatric illness as a risk factor, for screening psychiatric patients who are not receiving atypicals.

Annually screen psychiatric patients age ≥30, especially those with schizophrenia or affective disorders. I also follow the ADA guidelines and screen overweight adults age ≤30 if they have any of the other risk factors listed in Table 2. The most common risk factors seen in practice are being a member of a high-risk ethnic group, hypertension, lipid abnormalities, and cardiovascular disease. For overweight adults without other risk factors, I start screening at age 30.

Other practitioners can be more or less conservative and still be within accepted guidelines. The FPG—glucose level drawn from a vein after at least 8 hours of fasting—is probably the easiest screening test in practice. Any patient with a value >100mg/dL should be referred to the patient’s primary care physician. Any patient who develops diabetes symptoms—including polyuria, polydipsia, and weight loss—should be tested immediately. The hemoglobin A1C test is not recommended for screening.

Table 2

Risk factors identified for diabetes or prediabetes

Clinical presentation

Screening detects overt diabetes and can identify prediabetes. Prediabetes includes conditions of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). IFG is defined as a fasting glucose of 100 to 125 mg/dL, and IGT is defined as having a 2-hour glucose of 140 to 199 mg/dL on an OGTT.

Approximately one-quarter of the adult population has prediabetes, and interventions can prevent the progression of prediabetes to overt diabetes and reverse prediabetes. The Diabetes Prevention Trial found that lifestyle measures—including exercise and diet—were most effective, with a 53% reduction in the rate of progression to diabetes.⁶ Metformin also was effective, but less so than lifestyle measures alone.

Treatment slows the development or progression of microvascular complications, such as retinopathy, nephropathy, and neuropathy. Aggressive treatment of comorbid conditions, including hyperlipidemia and hypertension, also reduces the risk of cardiovascular events.

Drug brand names

• Aripiprazole • Abilify
• Metformin • Glucophage
• Ziprasidone • Geodon

Related resources

• American Diabetes Association. Diabetes risk calculator. www.diabetes.org/risk-test.jsp.
• Dagogo-Jack S. The role of antipsychotic agents in the development of diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(1):22-23. Quick, up-to-date review of the association between atypical antipsychotics and diabetes mellitus.

Disclosure

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

Dr. Keenan is associate professor, department of medicine, University of California, Davis.

Principal Source: U.S. Preventive Services Task Force. Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;148(11):846-854.—Discussant: Craig R. Keenan, MD

Psychiatric patients—especially those with schizophrenia or taking atypical antipsychotics—are at risk for developing type 2 diabetes mellitus (T2DM) and prediabetes conditions. T2DM can be present for years without significant symptoms and even asymptomatic conditions increase the risk of cardiovascular, renal, retinal, and neurologic complications.

Despite a need for T2DM screening and treatment, expert guidelines disagree on who and how to screen (Table 1). Although testing patients who have diabetes symptoms—including polyuria, polydipsia, and weight loss—is indicated, some medical groups advocate screening asymptomatic persons for T2DM.

Screening recommendations

Consensus guidelines. In 2004, the American Diabetes Association (ADA), American Psychiatric Association (APA), American Association of Clinical Endocrinologists (AACE), and North American Association for the Study of Obesity (NAASO) created consensus guidelines for screening psychiatric patients receiving atypical antipsychotics. In addition to diabetes risk, psychiatric patients are at higher risk for metabolic syndrome, dyslipidemia, obesity, and hypertension.¹ The ADA, APA, AACE, and NAASO recommend regularly screening for weight gain and dyslipidemia, obtaining baseline values of fasting plasma glucose (FPG), rechecking FPG after 3 months, and then screening annually for diabetes or prediabetes. For patients with risk factors for diabetes and those who develop diabetes or prediabetes while taking an atypical antipsychotic, consider an atypical with a lower risk of diabetes—specifically aripiprazole or ziprasidone.¹ For psychiatric patients who do not take atypicals, there is no consensus on who and how to screen for T2DM.

The U.S. Preventive Services Task Force (USPSTF) recommends screening only adults with hypertension.² Its review found insufficient evidence that early detection and treatment leads to improved clinical outcomes in asymptomatic adults.

The ADA recommends more liberal screening, including individuals age ≥45 or anyone age <45 who is overweight and has any other diabetes risk factors.³ The ADA admits that no trials show a benefit of screening asymptomatic patients but notes that the duration of glycemic burden predicts adverse outcomes and effective interventions for diabetes and prediabetes are available.

AACE guidelines recommend screening starting at age 30 if the patient has risk factors for T2DM. This is the only group that includes psychiatric illness as a risk factor.⁴

European Association for the Study of Diabetes (EASD) guidelines calculate a risk score based on common risk factors to determine who should be screened and recommend using the oral glucose tolerance test (OGTT) rather the FPG.⁵ The OGTT identifies more cases of diabetes and pre-diabetes but takes >2 hours to administer.

Table 1

General population screening recommendations for type 2 diabetes mellitus or prediabetes

Discussion

Despite a lack evidence showing benefit to the screened population, treating diabetes and its comorbidities improves outcomes, and the potential risks of therapy are low. Therefore, it seems reasonable to screen more patients than the USPSTF recommends.

Using the EASD risk score is intriguing, but difficult to implement in a busy practice. Therefore, I recommend following the AACE guidelines, which recognize psychiatric illness as a risk factor, for screening psychiatric patients who are not receiving atypicals.

Annually screen psychiatric patients age ≥30, especially those with schizophrenia or affective disorders. I also follow the ADA guidelines and screen overweight adults age ≤30 if they have any of the other risk factors listed in Table 2. The most common risk factors seen in practice are being a member of a high-risk ethnic group, hypertension, lipid abnormalities, and cardiovascular disease. For overweight adults without other risk factors, I start screening at age 30.

Other practitioners can be more or less conservative and still be within accepted guidelines. The FPG—glucose level drawn from a vein after at least 8 hours of fasting—is probably the easiest screening test in practice. Any patient with a value >100mg/dL should be referred to the patient’s primary care physician. Any patient who develops diabetes symptoms—including polyuria, polydipsia, and weight loss—should be tested immediately. The hemoglobin A1C test is not recommended for screening.

Table 2

Risk factors identified for diabetes or prediabetes

Clinical presentation

Screening detects overt diabetes and can identify prediabetes. Prediabetes includes conditions of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). IFG is defined as a fasting glucose of 100 to 125 mg/dL, and IGT is defined as having a 2-hour glucose of 140 to 199 mg/dL on an OGTT.

Approximately one-quarter of the adult population has prediabetes, and interventions can prevent the progression of prediabetes to overt diabetes and reverse prediabetes. The Diabetes Prevention Trial found that lifestyle measures—including exercise and diet—were most effective, with a 53% reduction in the rate of progression to diabetes.⁶ Metformin also was effective, but less so than lifestyle measures alone.

Treatment slows the development or progression of microvascular complications, such as retinopathy, nephropathy, and neuropathy. Aggressive treatment of comorbid conditions, including hyperlipidemia and hypertension, also reduces the risk of cardiovascular events.

Drug brand names

• Aripiprazole • Abilify
• Metformin • Glucophage
• Ziprasidone • Geodon

Related resources

• American Diabetes Association. Diabetes risk calculator. www.diabetes.org/risk-test.jsp.
• Dagogo-Jack S. The role of antipsychotic agents in the development of diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(1):22-23. Quick, up-to-date review of the association between atypical antipsychotics and diabetes mellitus.

Disclosure

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

Finding the best clozapine dosage for your psychotic patient can be challenging because any given dose of the drug yields highly variable clozapine serum levels. This interindividual variability reflects clozapine’s complex metabolism.

Obtaining serum levels will help you determine if your patient remains psychotic because of insufficient dosing or if your asymptomatic patient can safely receive a lower dose to minimize side effects without risking psychotic relapse. Following these guidelines will help you make the ban use of clozapine drug levels.

Obtaining clozapine levels

Measure clozapine as steady-state trough levels. I usually draw them 12 hours after the last dose (such as in the morning after the nightly dose) and several days after treatment begins.

When you order a clozapine level, most laboratories report 3 numbers: clozapine, norclozapine, and their sum. The literature addresses only the clinical use of clozapine levels and ignores the much less active metabolite, norclozapine.

Interpreting clozapine levels

Although there is no simple relationship among clozapine levels, therapeutic efficacy, and toxicity, a randomized clinical trial of patients with chronic schizophrenia¹ compared 3 non-overlapping ranges and found:

• “medium” range (200 to 300 ng/mL) is a good initial target
• low range (50 to 150 ng/mL) is not as effective as medium or high levels
• high range (350 to 450 ng/mL) can be tried if clinical response is insufficient, although the high range was no more effective than the medium range
• overy high levels (ie >1,000 ng/mL combined clozapine and norclozapine levels) have no proven benefit and increase seizure risk.

These guidelines are based on bid or tid dosing. If your patient receives clozapine only at night, take into account the higher morning level compared with the same dose administered on a split schedule.

Adjusting clozapine dose

Now that you have an accurate drug level, take advantage of clozapine’s linear pharmacokinetics. If you double the dose, you double the level; if you halve the dose, you halve the level.

For example, consider the case of a schizophrenia patient who remains psychotic despite a clozapine dose of 200 mg bid (400 mg/d). His clozapine level is 100 ng/mL (ie, low range) and his norclozapine level is 50 ng/mL. This patient would need double his dose (800 mg/d) to achieve a clozapine level at the low end of the medium range (200 ng/mL). Note that the norclozapine level is ignored for this calculation.

Finding the best clozapine dosage for your psychotic patient can be challenging because any given dose of the drug yields highly variable clozapine serum levels. This interindividual variability reflects clozapine’s complex metabolism.

Obtaining serum levels will help you determine if your patient remains psychotic because of insufficient dosing or if your asymptomatic patient can safely receive a lower dose to minimize side effects without risking psychotic relapse. Following these guidelines will help you make the ban use of clozapine drug levels.

Obtaining clozapine levels

Measure clozapine as steady-state trough levels. I usually draw them 12 hours after the last dose (such as in the morning after the nightly dose) and several days after treatment begins.

When you order a clozapine level, most laboratories report 3 numbers: clozapine, norclozapine, and their sum. The literature addresses only the clinical use of clozapine levels and ignores the much less active metabolite, norclozapine.

Interpreting clozapine levels

Although there is no simple relationship among clozapine levels, therapeutic efficacy, and toxicity, a randomized clinical trial of patients with chronic schizophrenia¹ compared 3 non-overlapping ranges and found:

• “medium” range (200 to 300 ng/mL) is a good initial target
• low range (50 to 150 ng/mL) is not as effective as medium or high levels
• high range (350 to 450 ng/mL) can be tried if clinical response is insufficient, although the high range was no more effective than the medium range
• overy high levels (ie >1,000 ng/mL combined clozapine and norclozapine levels) have no proven benefit and increase seizure risk.

These guidelines are based on bid or tid dosing. If your patient receives clozapine only at night, take into account the higher morning level compared with the same dose administered on a split schedule.

Adjusting clozapine dose

Now that you have an accurate drug level, take advantage of clozapine’s linear pharmacokinetics. If you double the dose, you double the level; if you halve the dose, you halve the level.

For example, consider the case of a schizophrenia patient who remains psychotic despite a clozapine dose of 200 mg bid (400 mg/d). His clozapine level is 100 ng/mL (ie, low range) and his norclozapine level is 50 ng/mL. This patient would need double his dose (800 mg/d) to achieve a clozapine level at the low end of the medium range (200 ng/mL). Note that the norclozapine level is ignored for this calculation.

Finding the best clozapine dosage for your psychotic patient can be challenging because any given dose of the drug yields highly variable clozapine serum levels. This interindividual variability reflects clozapine’s complex metabolism.

Obtaining serum levels will help you determine if your patient remains psychotic because of insufficient dosing or if your asymptomatic patient can safely receive a lower dose to minimize side effects without risking psychotic relapse. Following these guidelines will help you make the ban use of clozapine drug levels.

Obtaining clozapine levels

Measure clozapine as steady-state trough levels. I usually draw them 12 hours after the last dose (such as in the morning after the nightly dose) and several days after treatment begins.

When you order a clozapine level, most laboratories report 3 numbers: clozapine, norclozapine, and their sum. The literature addresses only the clinical use of clozapine levels and ignores the much less active metabolite, norclozapine.

Interpreting clozapine levels

Although there is no simple relationship among clozapine levels, therapeutic efficacy, and toxicity, a randomized clinical trial of patients with chronic schizophrenia¹ compared 3 non-overlapping ranges and found:

• “medium” range (200 to 300 ng/mL) is a good initial target
• low range (50 to 150 ng/mL) is not as effective as medium or high levels
• high range (350 to 450 ng/mL) can be tried if clinical response is insufficient, although the high range was no more effective than the medium range
• overy high levels (ie >1,000 ng/mL combined clozapine and norclozapine levels) have no proven benefit and increase seizure risk.

These guidelines are based on bid or tid dosing. If your patient receives clozapine only at night, take into account the higher morning level compared with the same dose administered on a split schedule.

Adjusting clozapine dose

Now that you have an accurate drug level, take advantage of clozapine’s linear pharmacokinetics. If you double the dose, you double the level; if you halve the dose, you halve the level.

For example, consider the case of a schizophrenia patient who remains psychotic despite a clozapine dose of 200 mg bid (400 mg/d). His clozapine level is 100 ng/mL (ie, low range) and his norclozapine level is 50 ng/mL. This patient would need double his dose (800 mg/d) to achieve a clozapine level at the low end of the medium range (200 ng/mL). Note that the norclozapine level is ignored for this calculation.

Comment on this article

You may have noticed the buzz about Charles Darwin in the news: 2009 marks the 200th anniversary of his birth and the 150th anniversary of his monumental description of evolution in On the Origin of Species. Celebrations are scheduled around the world to honor the scientist who coined the phrase “natural selection” to explain the heritable process by which adaptive evolution occurs.

But is Darwin’s theory of evolution still relevant? The “game-changer” that is transforming evolution is the genetic mutation that led to dramatic growth in the primate cortex—especially the frontal lobe—culminating in the emergence of Homo sapiens. The overdeveloped brain that has helped our species adapt and survive may be transforming us into predators of all other species and a hazard to our planet.

Survival regardless of ‘fitness’

Humans are discovering so much about biology and treatment of disease that we are disrupting natural selection and undermining the tyranny of “survival of the fittest.” A triumph of modern medicine (the antithesis of eugenics) is salvaging those who in Darwin’s day would have died and allowing them to survive and perpetuate their genes:

• Children born with metabolic errors no longer are doomed to succumb before their childbearing years.
• Premature 1-pound infants who never would have survived before are routinely doing so now.
• Women can conceive in their 60s, well after menopause.
• Medical advances have enabled humans to parry the deadly assaults of bacteria, viruses, and parasites.
• Future scientific advances will certainly include genetic engineering, which will eliminate the sometimes grim determinism of heredity.

Conversely, humans’ intelligence has enabled us to wreak havoc on other species. Tens of thousands of animals and plants have vanished because flourishing humans have survived and wittingly or unwittingly exploited, polluted, and injured the environment. Of course, a pathologic evolution may backfire on us, despite our highly evolved brain. However, humans may still adapt and survive, albeit in a dramatically altered, even inhospitable world. Or maybe not, as war and weapons of mass destruction appear to be unique inventions of the human brain.

Darwin’s psychiatric challenges

What does this have to do with psychiatry? Disorders of thought, emotions, cognition, and volition are probably the price humans paid for a dramatically evolved brain. Evolutionary psychiatrists have linked these disorders to traits that may have survival value in carriers but cause maladaptive behaviors in some individuals.

Darwin’s own struggles with disabling mental illness^1-5 are perhaps the most eloquent testimonial that classic evolutionary principles may not apply to humans. His symptoms included panic attacks, agoraphobia, social anxiety, depersonalization, obsessions and compulsions, depression, suicidal impulses, visual hallucinations, and psychosomatic complaints (eczema, dizziness, and irritable bowel syndrome). Beginning in his 20s, he confined himself to his home for decades, undergoing futile interventions (such as water therapy) and taking antiquated remedies for his afflictions.

Yet Darwin’s genius was never compromised by his lack of psychiatric or physical fitness. His explanation for evolution—which made him one of the most famous scientists of all time—emerged in the midst of and despite his overwhelming health problems.

Thus, Darwin’s achievements embody the notion that the mutation that led to the hyper-developed human brain is the nemesis of evolution as he conceived it. He also serves as an inspiration to everyone who suffers from mental illness. His landmark contribution to science is a forceful rebuttal to anyone who regards psychiatric illness as synonymous with “lack of fitness.”

Happy birthday, Darwin!

Comment on this article

You may have noticed the buzz about Charles Darwin in the news: 2009 marks the 200th anniversary of his birth and the 150th anniversary of his monumental description of evolution in On the Origin of Species. Celebrations are scheduled around the world to honor the scientist who coined the phrase “natural selection” to explain the heritable process by which adaptive evolution occurs.

But is Darwin’s theory of evolution still relevant? The “game-changer” that is transforming evolution is the genetic mutation that led to dramatic growth in the primate cortex—especially the frontal lobe—culminating in the emergence of Homo sapiens. The overdeveloped brain that has helped our species adapt and survive may be transforming us into predators of all other species and a hazard to our planet.

Survival regardless of ‘fitness’

Humans are discovering so much about biology and treatment of disease that we are disrupting natural selection and undermining the tyranny of “survival of the fittest.” A triumph of modern medicine (the antithesis of eugenics) is salvaging those who in Darwin’s day would have died and allowing them to survive and perpetuate their genes:

• Children born with metabolic errors no longer are doomed to succumb before their childbearing years.
• Premature 1-pound infants who never would have survived before are routinely doing so now.
• Women can conceive in their 60s, well after menopause.
• Medical advances have enabled humans to parry the deadly assaults of bacteria, viruses, and parasites.
• Future scientific advances will certainly include genetic engineering, which will eliminate the sometimes grim determinism of heredity.

Conversely, humans’ intelligence has enabled us to wreak havoc on other species. Tens of thousands of animals and plants have vanished because flourishing humans have survived and wittingly or unwittingly exploited, polluted, and injured the environment. Of course, a pathologic evolution may backfire on us, despite our highly evolved brain. However, humans may still adapt and survive, albeit in a dramatically altered, even inhospitable world. Or maybe not, as war and weapons of mass destruction appear to be unique inventions of the human brain.

Darwin’s psychiatric challenges

What does this have to do with psychiatry? Disorders of thought, emotions, cognition, and volition are probably the price humans paid for a dramatically evolved brain. Evolutionary psychiatrists have linked these disorders to traits that may have survival value in carriers but cause maladaptive behaviors in some individuals.

Darwin’s own struggles with disabling mental illness^1-5 are perhaps the most eloquent testimonial that classic evolutionary principles may not apply to humans. His symptoms included panic attacks, agoraphobia, social anxiety, depersonalization, obsessions and compulsions, depression, suicidal impulses, visual hallucinations, and psychosomatic complaints (eczema, dizziness, and irritable bowel syndrome). Beginning in his 20s, he confined himself to his home for decades, undergoing futile interventions (such as water therapy) and taking antiquated remedies for his afflictions.

Yet Darwin’s genius was never compromised by his lack of psychiatric or physical fitness. His explanation for evolution—which made him one of the most famous scientists of all time—emerged in the midst of and despite his overwhelming health problems.

Thus, Darwin’s achievements embody the notion that the mutation that led to the hyper-developed human brain is the nemesis of evolution as he conceived it. He also serves as an inspiration to everyone who suffers from mental illness. His landmark contribution to science is a forceful rebuttal to anyone who regards psychiatric illness as synonymous with “lack of fitness.”

Happy birthday, Darwin!

Comment on this article

You may have noticed the buzz about Charles Darwin in the news: 2009 marks the 200th anniversary of his birth and the 150th anniversary of his monumental description of evolution in On the Origin of Species. Celebrations are scheduled around the world to honor the scientist who coined the phrase “natural selection” to explain the heritable process by which adaptive evolution occurs.

But is Darwin’s theory of evolution still relevant? The “game-changer” that is transforming evolution is the genetic mutation that led to dramatic growth in the primate cortex—especially the frontal lobe—culminating in the emergence of Homo sapiens. The overdeveloped brain that has helped our species adapt and survive may be transforming us into predators of all other species and a hazard to our planet.

Survival regardless of ‘fitness’

Humans are discovering so much about biology and treatment of disease that we are disrupting natural selection and undermining the tyranny of “survival of the fittest.” A triumph of modern medicine (the antithesis of eugenics) is salvaging those who in Darwin’s day would have died and allowing them to survive and perpetuate their genes:

• Children born with metabolic errors no longer are doomed to succumb before their childbearing years.
• Premature 1-pound infants who never would have survived before are routinely doing so now.
• Women can conceive in their 60s, well after menopause.
• Medical advances have enabled humans to parry the deadly assaults of bacteria, viruses, and parasites.
• Future scientific advances will certainly include genetic engineering, which will eliminate the sometimes grim determinism of heredity.

Conversely, humans’ intelligence has enabled us to wreak havoc on other species. Tens of thousands of animals and plants have vanished because flourishing humans have survived and wittingly or unwittingly exploited, polluted, and injured the environment. Of course, a pathologic evolution may backfire on us, despite our highly evolved brain. However, humans may still adapt and survive, albeit in a dramatically altered, even inhospitable world. Or maybe not, as war and weapons of mass destruction appear to be unique inventions of the human brain.

Darwin’s psychiatric challenges

What does this have to do with psychiatry? Disorders of thought, emotions, cognition, and volition are probably the price humans paid for a dramatically evolved brain. Evolutionary psychiatrists have linked these disorders to traits that may have survival value in carriers but cause maladaptive behaviors in some individuals.

Darwin’s own struggles with disabling mental illness^1-5 are perhaps the most eloquent testimonial that classic evolutionary principles may not apply to humans. His symptoms included panic attacks, agoraphobia, social anxiety, depersonalization, obsessions and compulsions, depression, suicidal impulses, visual hallucinations, and psychosomatic complaints (eczema, dizziness, and irritable bowel syndrome). Beginning in his 20s, he confined himself to his home for decades, undergoing futile interventions (such as water therapy) and taking antiquated remedies for his afflictions.

Yet Darwin’s genius was never compromised by his lack of psychiatric or physical fitness. His explanation for evolution—which made him one of the most famous scientists of all time—emerged in the midst of and despite his overwhelming health problems.

Thus, Darwin’s achievements embody the notion that the mutation that led to the hyper-developed human brain is the nemesis of evolution as he conceived it. He also serves as an inspiration to everyone who suffers from mental illness. His landmark contribution to science is a forceful rebuttal to anyone who regards psychiatric illness as synonymous with “lack of fitness.”

Happy birthday, Darwin!

Case: Worsening psychosis

Ms. R, age 21, is admitted to our psychiatric facility while experiencing paranoid delusions and auditory hallucinations. Upon admission, she is agitated and her mood is labile.

Ms. R has 4 previous brief psychiatric admissions and was diagnosed with schizoaffective disorder, bipolar type and moderate mental retardation. Her family history is positive for psychiatric illness, as her mother was diagnosed with schizophrenia. Prior to admission, Ms. R was taking ziprasidone, 160 mg/d, and lithium, 450 mg/d, for 11 months. Both were discontinued during the first week of admission because Ms. R was not responding.

During this admission, the treating psychiatrist assesses Ms. R using the Schedules for Clinicians’ Interview in Psychiatry (SCIP), an instrument developed by the lead author (AA) for psychiatrists to use in conjunction with their routine clinical interviews in inpatient and outpatient settings (see Related Resources). The SCIP includes a 25-question screening section and a diagnostic section that consists of 7 modules that represent major psychiatric diagnoses defined by DSM and International Classification of Diseases criteria.¹

During the first week of admission, we monitor Ms. R and administer haloperidol as needed, 10 mg total. Eight days after admission, she develops severe catatonia. On the catatonia scale of the SCIP, Ms. R scores the maximum on measures of immobility, catalepsy/waxy flexibility, and mutism (Table).

How would you treat Ms. R’s catatonia?

Table

Patient’s catatonia symptoms: Response to pharmacotherapy

The authors’ observations

DSM-IV-TR recognizes catatonia as a schizophrenia subtype, as a descriptor for mania and major depression, and as being caused by various medical conditions, such as neuroleptic malignant syndrome, encephalopathy, or renal failure.² Kahlbaum initially described catatonia in 1873 as a brain disease characterized by motor abnormalities such as akinesia, rigidity, negativism, mutism, grimacing, posturing, catalepsy, waxy flexibility, and verbigerations.³ Catatonia is characterized by hypo- and hyperkinetic features. Catalepsy, stupor, rigidity, and catatonic posturing with waxy flexibility might alternate with violent catatonic excitement.⁴

Catatonia can be life-threatening; patients might not be able to eat or chew food, which puts them at risk for aspiration. Those with immobility might not move to urinate or defecate. During the first half of the 20th century, catatonia was documented in up to 50% of patients with schizophrenia.⁵ Since then, the incidence of catatonia has decreased, possibly the result of advances in psychopharmacology.⁶

Two days after Ms. R develops catatonia, we transfer her to a local hospital for evaluation to rule out a medical cause of her catatonic symptoms.

EVALUATION: No medical cause

At the hospital, physical examination, electroencephalography, drug screening, and liver and thyroid function tests are within normal limits, eliminating an organic cause of Ms. R’s catatonia. MRI of the head shows a 3-mm mass at the base of the infundibulum, which is unchanged from a prior MRI. Ms. R received 7 mg total of lorazepam over 4 days without relief of her catatonia. She is transferred back to our facility.

The authors’ observations

Benzodiazepines and ECT are effective treatments for catatonia.⁷ Benzodiazepines are considered first-line treatment because of their efficacy and favorable side-effect profile.⁷ Lorazepam frequently is used to treat catatonia in the short term.⁸ Long-term use of benzodiazepines, however, is associated with tolerance, addiction, and rebound phenomena.^8,9

Patients with catatonia who do not respond to benzodiazepines may benefit from ECT.⁹ ECT can cause serious side effects, however, including memory impairment, confusion, delirium, and cardiac arrhythmias.¹⁰

Atypical antipsychotics may alleviate motor symptoms of catatonia by virtue of their 5-HT2A receptor antagonistic action.⁹ In 2 case reports, risperidone successfully treated catatonia.^4,11 Kopala et al¹¹ found risperidone, 4 mg/d, was effective in treating severe, first-episode catatonic schizophrenia in a neuroleptic-naive young man. This efficacy was sustained over a 3.5-year outpatient follow-up.

In another report, risperidone, 6 mg/d, effectively treated catatonia and prevented further episodes in a patient with schizophrenia who developed severe catatonia after receiving adequate treatment for Lyme disease with encephalitis.⁴ Two relapses of catatonic syndrome occurred when risperidone was reduced to 2 mg/d, and remission occurred after risperidone was increased to 6 mg/d. Risperidone’s antagonistic activity of the 5-HT2/D2 receptors may be relevant to its anticatatonic effect.¹²

TREATMENT: Trying risperidone

Based on case reports showing risperidone’s efficacy for catatonia, we start Ms. R on risperidone, 4 mg/d, and lorazepam, 4 mg/d. Eight days later, her catatonic symptoms decrease substantially—she scores 2/6 on the SCIP catatonia scale (Table)—and she starts to talk with the staff.

We continue this regimen for 30 days, then discontinue lorazepam to avoid long-term side effects—such as dependence—and titrate risperidone to 8 mg/d. Ms. R continues to improve while taking risperidone only. Twenty-three days after stopping lorazepam, she is free of catatonic symptoms, scoring 0/6 on the SCIP catatonia scale.

We discharge Ms. R on risperidone. Because she has a history of medication nonadherence, we prescribe risperidone long-acting injection, 37.5 mg every 2 weeks, while continuing oral risperidone for 3 weeks after the first injection. She does well on this medication, experiencing no catatonic symptoms or adverse effects over the next 15 months as measured by the SCIP assessment.

The authors’ observations

This is the third case report in the literature to show that risperidone is effective in short- and long-term treatment of catatonia.^4,11 Although Ms. R’s initial response can be attributed at least partially to lorazepam—which is known to be effective in treating catatonia—she continued to show improvement while taking risperidone only and remained free from catatonic symptoms for 15 months, until she was readmitted for reasons unrelated to catatonia.

We recommend using risperidone to treat catatonia in patients who do not respond to a benzodiazepine, especially those with other psychotic symptoms such as delusions or hallucinations. While administering risperidone, watch for long-term side effects, such as hyperlipidemia, weight gain, and diabetes. For catatonia in patients who cannot tolerate risperidone, consider olanzapine or ziprasidone.

Related resources

• Schedules for Clinicians’ Interview in Psychiatry (SCIP). Available from Ahmed Aboraya, [email protected].
  
• Valevski A, Loebl T, Keren T, et al. Response of catatonia to risperidone: two case reports. Clin Neuropharmacol. 2001;24(4):228-231.
  
• Van Den Eede F, Van Hecke J, Van Dalfsen A, et al. The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry. 2005;20(5-6):422-429.
  

• Haloperidol • Haldol
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Ziprasidone • Geodon
  

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

Case: Worsening psychosis

Ms. R, age 21, is admitted to our psychiatric facility while experiencing paranoid delusions and auditory hallucinations. Upon admission, she is agitated and her mood is labile.

Ms. R has 4 previous brief psychiatric admissions and was diagnosed with schizoaffective disorder, bipolar type and moderate mental retardation. Her family history is positive for psychiatric illness, as her mother was diagnosed with schizophrenia. Prior to admission, Ms. R was taking ziprasidone, 160 mg/d, and lithium, 450 mg/d, for 11 months. Both were discontinued during the first week of admission because Ms. R was not responding.

During this admission, the treating psychiatrist assesses Ms. R using the Schedules for Clinicians’ Interview in Psychiatry (SCIP), an instrument developed by the lead author (AA) for psychiatrists to use in conjunction with their routine clinical interviews in inpatient and outpatient settings (see Related Resources). The SCIP includes a 25-question screening section and a diagnostic section that consists of 7 modules that represent major psychiatric diagnoses defined by DSM and International Classification of Diseases criteria.¹

During the first week of admission, we monitor Ms. R and administer haloperidol as needed, 10 mg total. Eight days after admission, she develops severe catatonia. On the catatonia scale of the SCIP, Ms. R scores the maximum on measures of immobility, catalepsy/waxy flexibility, and mutism (Table).

How would you treat Ms. R’s catatonia?

Table

Patient’s catatonia symptoms: Response to pharmacotherapy

The authors’ observations

DSM-IV-TR recognizes catatonia as a schizophrenia subtype, as a descriptor for mania and major depression, and as being caused by various medical conditions, such as neuroleptic malignant syndrome, encephalopathy, or renal failure.² Kahlbaum initially described catatonia in 1873 as a brain disease characterized by motor abnormalities such as akinesia, rigidity, negativism, mutism, grimacing, posturing, catalepsy, waxy flexibility, and verbigerations.³ Catatonia is characterized by hypo- and hyperkinetic features. Catalepsy, stupor, rigidity, and catatonic posturing with waxy flexibility might alternate with violent catatonic excitement.⁴

Catatonia can be life-threatening; patients might not be able to eat or chew food, which puts them at risk for aspiration. Those with immobility might not move to urinate or defecate. During the first half of the 20th century, catatonia was documented in up to 50% of patients with schizophrenia.⁵ Since then, the incidence of catatonia has decreased, possibly the result of advances in psychopharmacology.⁶

Two days after Ms. R develops catatonia, we transfer her to a local hospital for evaluation to rule out a medical cause of her catatonic symptoms.

EVALUATION: No medical cause

At the hospital, physical examination, electroencephalography, drug screening, and liver and thyroid function tests are within normal limits, eliminating an organic cause of Ms. R’s catatonia. MRI of the head shows a 3-mm mass at the base of the infundibulum, which is unchanged from a prior MRI. Ms. R received 7 mg total of lorazepam over 4 days without relief of her catatonia. She is transferred back to our facility.

The authors’ observations

Benzodiazepines and ECT are effective treatments for catatonia.⁷ Benzodiazepines are considered first-line treatment because of their efficacy and favorable side-effect profile.⁷ Lorazepam frequently is used to treat catatonia in the short term.⁸ Long-term use of benzodiazepines, however, is associated with tolerance, addiction, and rebound phenomena.^8,9

Patients with catatonia who do not respond to benzodiazepines may benefit from ECT.⁹ ECT can cause serious side effects, however, including memory impairment, confusion, delirium, and cardiac arrhythmias.¹⁰

Atypical antipsychotics may alleviate motor symptoms of catatonia by virtue of their 5-HT2A receptor antagonistic action.⁹ In 2 case reports, risperidone successfully treated catatonia.^4,11 Kopala et al¹¹ found risperidone, 4 mg/d, was effective in treating severe, first-episode catatonic schizophrenia in a neuroleptic-naive young man. This efficacy was sustained over a 3.5-year outpatient follow-up.

In another report, risperidone, 6 mg/d, effectively treated catatonia and prevented further episodes in a patient with schizophrenia who developed severe catatonia after receiving adequate treatment for Lyme disease with encephalitis.⁴ Two relapses of catatonic syndrome occurred when risperidone was reduced to 2 mg/d, and remission occurred after risperidone was increased to 6 mg/d. Risperidone’s antagonistic activity of the 5-HT2/D2 receptors may be relevant to its anticatatonic effect.¹²

TREATMENT: Trying risperidone

Based on case reports showing risperidone’s efficacy for catatonia, we start Ms. R on risperidone, 4 mg/d, and lorazepam, 4 mg/d. Eight days later, her catatonic symptoms decrease substantially—she scores 2/6 on the SCIP catatonia scale (Table)—and she starts to talk with the staff.

We continue this regimen for 30 days, then discontinue lorazepam to avoid long-term side effects—such as dependence—and titrate risperidone to 8 mg/d. Ms. R continues to improve while taking risperidone only. Twenty-three days after stopping lorazepam, she is free of catatonic symptoms, scoring 0/6 on the SCIP catatonia scale.

We discharge Ms. R on risperidone. Because she has a history of medication nonadherence, we prescribe risperidone long-acting injection, 37.5 mg every 2 weeks, while continuing oral risperidone for 3 weeks after the first injection. She does well on this medication, experiencing no catatonic symptoms or adverse effects over the next 15 months as measured by the SCIP assessment.

The authors’ observations

This is the third case report in the literature to show that risperidone is effective in short- and long-term treatment of catatonia.^4,11 Although Ms. R’s initial response can be attributed at least partially to lorazepam—which is known to be effective in treating catatonia—she continued to show improvement while taking risperidone only and remained free from catatonic symptoms for 15 months, until she was readmitted for reasons unrelated to catatonia.

We recommend using risperidone to treat catatonia in patients who do not respond to a benzodiazepine, especially those with other psychotic symptoms such as delusions or hallucinations. While administering risperidone, watch for long-term side effects, such as hyperlipidemia, weight gain, and diabetes. For catatonia in patients who cannot tolerate risperidone, consider olanzapine or ziprasidone.

Related resources

• Schedules for Clinicians’ Interview in Psychiatry (SCIP). Available from Ahmed Aboraya, [email protected].
  
• Valevski A, Loebl T, Keren T, et al. Response of catatonia to risperidone: two case reports. Clin Neuropharmacol. 2001;24(4):228-231.
  
• Van Den Eede F, Van Hecke J, Van Dalfsen A, et al. The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry. 2005;20(5-6):422-429.
  

• Haloperidol • Haldol
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Ziprasidone • Geodon
  

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

Case: Worsening psychosis

Ms. R, age 21, is admitted to our psychiatric facility while experiencing paranoid delusions and auditory hallucinations. Upon admission, she is agitated and her mood is labile.

Ms. R has 4 previous brief psychiatric admissions and was diagnosed with schizoaffective disorder, bipolar type and moderate mental retardation. Her family history is positive for psychiatric illness, as her mother was diagnosed with schizophrenia. Prior to admission, Ms. R was taking ziprasidone, 160 mg/d, and lithium, 450 mg/d, for 11 months. Both were discontinued during the first week of admission because Ms. R was not responding.

During this admission, the treating psychiatrist assesses Ms. R using the Schedules for Clinicians’ Interview in Psychiatry (SCIP), an instrument developed by the lead author (AA) for psychiatrists to use in conjunction with their routine clinical interviews in inpatient and outpatient settings (see Related Resources). The SCIP includes a 25-question screening section and a diagnostic section that consists of 7 modules that represent major psychiatric diagnoses defined by DSM and International Classification of Diseases criteria.¹

During the first week of admission, we monitor Ms. R and administer haloperidol as needed, 10 mg total. Eight days after admission, she develops severe catatonia. On the catatonia scale of the SCIP, Ms. R scores the maximum on measures of immobility, catalepsy/waxy flexibility, and mutism (Table).

How would you treat Ms. R’s catatonia?

Table

Patient’s catatonia symptoms: Response to pharmacotherapy

The authors’ observations

DSM-IV-TR recognizes catatonia as a schizophrenia subtype, as a descriptor for mania and major depression, and as being caused by various medical conditions, such as neuroleptic malignant syndrome, encephalopathy, or renal failure.² Kahlbaum initially described catatonia in 1873 as a brain disease characterized by motor abnormalities such as akinesia, rigidity, negativism, mutism, grimacing, posturing, catalepsy, waxy flexibility, and verbigerations.³ Catatonia is characterized by hypo- and hyperkinetic features. Catalepsy, stupor, rigidity, and catatonic posturing with waxy flexibility might alternate with violent catatonic excitement.⁴

Catatonia can be life-threatening; patients might not be able to eat or chew food, which puts them at risk for aspiration. Those with immobility might not move to urinate or defecate. During the first half of the 20th century, catatonia was documented in up to 50% of patients with schizophrenia.⁵ Since then, the incidence of catatonia has decreased, possibly the result of advances in psychopharmacology.⁶

Two days after Ms. R develops catatonia, we transfer her to a local hospital for evaluation to rule out a medical cause of her catatonic symptoms.

EVALUATION: No medical cause

At the hospital, physical examination, electroencephalography, drug screening, and liver and thyroid function tests are within normal limits, eliminating an organic cause of Ms. R’s catatonia. MRI of the head shows a 3-mm mass at the base of the infundibulum, which is unchanged from a prior MRI. Ms. R received 7 mg total of lorazepam over 4 days without relief of her catatonia. She is transferred back to our facility.

The authors’ observations

Benzodiazepines and ECT are effective treatments for catatonia.⁷ Benzodiazepines are considered first-line treatment because of their efficacy and favorable side-effect profile.⁷ Lorazepam frequently is used to treat catatonia in the short term.⁸ Long-term use of benzodiazepines, however, is associated with tolerance, addiction, and rebound phenomena.^8,9

Patients with catatonia who do not respond to benzodiazepines may benefit from ECT.⁹ ECT can cause serious side effects, however, including memory impairment, confusion, delirium, and cardiac arrhythmias.¹⁰

Atypical antipsychotics may alleviate motor symptoms of catatonia by virtue of their 5-HT2A receptor antagonistic action.⁹ In 2 case reports, risperidone successfully treated catatonia.^4,11 Kopala et al¹¹ found risperidone, 4 mg/d, was effective in treating severe, first-episode catatonic schizophrenia in a neuroleptic-naive young man. This efficacy was sustained over a 3.5-year outpatient follow-up.

In another report, risperidone, 6 mg/d, effectively treated catatonia and prevented further episodes in a patient with schizophrenia who developed severe catatonia after receiving adequate treatment for Lyme disease with encephalitis.⁴ Two relapses of catatonic syndrome occurred when risperidone was reduced to 2 mg/d, and remission occurred after risperidone was increased to 6 mg/d. Risperidone’s antagonistic activity of the 5-HT2/D2 receptors may be relevant to its anticatatonic effect.¹²

TREATMENT: Trying risperidone

Based on case reports showing risperidone’s efficacy for catatonia, we start Ms. R on risperidone, 4 mg/d, and lorazepam, 4 mg/d. Eight days later, her catatonic symptoms decrease substantially—she scores 2/6 on the SCIP catatonia scale (Table)—and she starts to talk with the staff.

We continue this regimen for 30 days, then discontinue lorazepam to avoid long-term side effects—such as dependence—and titrate risperidone to 8 mg/d. Ms. R continues to improve while taking risperidone only. Twenty-three days after stopping lorazepam, she is free of catatonic symptoms, scoring 0/6 on the SCIP catatonia scale.

We discharge Ms. R on risperidone. Because she has a history of medication nonadherence, we prescribe risperidone long-acting injection, 37.5 mg every 2 weeks, while continuing oral risperidone for 3 weeks after the first injection. She does well on this medication, experiencing no catatonic symptoms or adverse effects over the next 15 months as measured by the SCIP assessment.

The authors’ observations

This is the third case report in the literature to show that risperidone is effective in short- and long-term treatment of catatonia.^4,11 Although Ms. R’s initial response can be attributed at least partially to lorazepam—which is known to be effective in treating catatonia—she continued to show improvement while taking risperidone only and remained free from catatonic symptoms for 15 months, until she was readmitted for reasons unrelated to catatonia.

We recommend using risperidone to treat catatonia in patients who do not respond to a benzodiazepine, especially those with other psychotic symptoms such as delusions or hallucinations. While administering risperidone, watch for long-term side effects, such as hyperlipidemia, weight gain, and diabetes. For catatonia in patients who cannot tolerate risperidone, consider olanzapine or ziprasidone.

Related resources

• Schedules for Clinicians’ Interview in Psychiatry (SCIP). Available from Ahmed Aboraya, [email protected].
  
• Valevski A, Loebl T, Keren T, et al. Response of catatonia to risperidone: two case reports. Clin Neuropharmacol. 2001;24(4):228-231.
  
• Van Den Eede F, Van Hecke J, Van Dalfsen A, et al. The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry. 2005;20(5-6):422-429.
  

• Haloperidol • Haldol
  
• Lithium • Eskalith, Lithobid
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Ziprasidone • Geodon
  

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

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"Is fibromyalgia a somatoform disorder?

Comment on this article

Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Fibromyalgia: Structured interview for diagnosis

Differentiating fibromyalgia from illnesses with similar symptoms

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.

WEB AUDIO
Listen to Dr. Stanford discuss,
"Is fibromyalgia a somatoform disorder?

Comment on this article

Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Fibromyalgia: Structured interview for diagnosis

Differentiating fibromyalgia from illnesses with similar symptoms

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.

WEB AUDIO
Listen to Dr. Stanford discuss,
"Is fibromyalgia a somatoform disorder?

Comment on this article

Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Fibromyalgia: Structured interview for diagnosis

Differentiating fibromyalgia from illnesses with similar symptoms

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.

Comment on this article

Oral habits such as bruxism—compulsive grinding or clenching of the teeth—can be a manifestation of obsessive-compulsive disorder (OCD) and other anxiety disorders.¹ Bruxism also may be a side effect of selective serotonin reuptake inhibitors (SSRIs)^2,3 used to treat OCD⁴ and depression. Other oral conditions can complicate treatment of these disorders (Table 1).

Potentially serious sequelae of bruxism and similar behaviors include:

• wearing down of teeth (more common)
• necrosis of the pulpal tissues that results in non-vital teeth (less common).

The following case underlines the need for early referral to a dentist and close follow-up for patients who have tooth-related behaviors or are taking medications associated with a risk for such behaviors.

Table 1

Oral conditions associated with anxiety disorders and depression

CASE REPORT: A compulsive oral habit

Mr. G, age 26, presents to our school of dental medicine with the chief complaint that he needs a crown. On clinical intraoral examination, we find he has multiple restorations, some areas of recurrent tooth decay, and a fractured cusp on a maxillary molar. His mandibular incisors show greater wear on their incisal surfaces than would be expected for a patient his age. This is especially true of his mandibular right lateral incisor (tooth #26) and canine (tooth #27) (Photo 1).

Clinical examination also reveals a restoration on tooth #26 that was consistent with an access cavity drilled for endodontic (root canal) therapy (Photo 2). This finding is consistent with his dental history. Soft tissue examination is within normal limits. He reports that he saw a dentist 7 months earlier but could not afford the fees.

During his medical history, Mr. G states he has mild Tourette’s syndrome that was diagnosed when he was 10. In the early 1990s he tried several medications, including haloperidol and pimozide, as a subject in research studies of Tourette’s. He could not recall the dosages of the medications or for how long he took them. Because these medications did not improve his symptoms, he stopped taking them after the studies ended.

Photo 1 Unexpected tooth wear: A clue to an anxiety-related oral habit

Teeth of a 26-year-old man show greater than expected wear, particularly on the mandibular right lateral incisor (tooth #26) and canine (tooth #27).

Photo 2 Radiographic evidence of tooth non-vitality

Radiolucencies (dark areas) in the bone at the apices of the tooth roots are a radiographic sign of non-vitality. Tooth #26 has undergone root canal.Mr. G reports that when he was in second grade, a psychiatrist diagnosed him with OCD, and has received treatment since then. We observe that while Mr. G is seated, he continually raises his right arm above his head and rubs his fingers together. He reports and demonstrates numerous other compulsive rituals, including head movements and rubbing his elbows against his side. His right elbow has a large scab.

He has been taking sertraline, 150 mg/d, for the past month. He says his psychiatrist prescribed this medication to help him break out of what he describes as episodes where he “gets into a mental loop.” Sertraline has improved Mr. G’s symptoms but they have not resolved.

He further reports that he has begun to “grind” his anterior teeth. Technically, he does not engage in grinding or bruxing; he has a habit of pushing his mandible forward so that his mandibular (lower) teeth are anterior to the maxillary (top) teeth, then forcefully pulling his mandible back so that the lingual (back) surfaces of the mandibular incisors push up against the buccal (outside) surfaces of the maxillary incisors (Photo 3). He states that he engaged in this habit frequently from approximately age 19 to 22. When Mr. G was 22, his dentist reduced the height of tooth #23, which Mr. G says he used “to set things in motion.” The dentist’s maneuver cut down but did not eliminate Mr. G’s habit.

Mr. G had not complained of nor had any clinician asked him about his bruxism-like behavior. He noted that the oral habit began prior to sertraline treatment, thus suggesting no relationship between the medication and the behavior. Interestingly, although some studies have reported bruxism as a side effect of SSRIs,^2,3 at least 1 case report found that SSRIs reduced nocturnal bruxism.¹²

Photo 3 Obsessive-compulsive disorder manifested in Mr. G’s oral habit

Starting with his mandible pushed forward so that his mandibular (lower) teeth were anterior to the maxillary (upper) teeth, the patient would forcefully pull his mandible back so that the lingual (back) surfaces of the mandibular incisors pushed against the buccal (outside) surfaces of the maxillary incisors.As part of Mr. G’s dental examination, we take a full series of intraoral radiographs. These reveal radiolucencies at the apices of teeth #23 through #26 (Photo 2). The films also show root canal therapy on tooth #26.

Differential diagnosis for lesions in the periapical region of the mandibular incisors includes periapical cemental dysplasia (PCD), which typically is found in middle-aged African-American females,⁵ and lesions resulting from non-vitality of the teeth. Histopathologically, lesions resulting from the latter include an apical abscess, cyst, or granuloma.

As is customary when periapical lesions are noted, we test the vitality of the affected teeth. None of the affected teeth responded to cold or electric pulp testing, which indicated they were non-vital. Tooth vitality is not affected in PCD, which allowed us to exclude this condition.

Non-vital teeth indicate that the pulpal tissue is necrotic. Most commonly, non-vitality occurs when decay has penetrated the pulp chamber or as a complication of physical trauma. No decay was present on Mr. G’s mandibular anterior teeth and he denied a history of trauma such as a blow to the teeth. This left his oral habit as the likely cause of non-vitality.

Treatment for a non-vital tooth is a root canal, which had been done on tooth #26. We successfully performed root canal on Mr. G’s other non-vital teeth. We informed the patient of reason for his non-vital teeth, and made a protective occlusal guard to try to prevent additional trauma to the affected teeth.

Recognizing oral habits

Restoration of worn teeth, particularly those of the mandibular anterior, is technically difficult and—depending on the nature of the restoration—quite expensive. Endodontic therapy is more successful in teeth without periapical disease.⁶ Thus, preventing tooth-related problems in patients who grind their teeth or engage in other destructive dental behaviors is important.

As this case illustrates, teeth can become non-vital without clinical evidence of tooth wear; clinical evidence may be subtle or nonexistent (note teeth #23, #24, and #25 in Photo 2). Absence of tooth wear is not a reliable sign of tooth vitality. Mild to moderate tooth wear usually goes unnoticed by patients and clinicians.⁷

Patients with bruxism may complain of masticatory muscle soreness or increased wear of the teeth.⁷ In extreme cases, they may self-extract teeth as a result of bruxism.⁸

Screen patients who have anxiety disorders or depression for signs of bruxism or related behaviors (Table 2). If you detect signs of bruxism or related behavior, refer the patient to a dentist. Ask the dentist to look for signs of wear and perform vitality testing of teeth on a regular basis (twice a year is reasonable). Any signs of changes in pulp vitality should be followed up with intraoral periapical radiographs, which these patients might need more frequently than FDA guidelines recommend.⁹

Table 2

Screening for bruxism: 3 questions for patients

An occlusal guard may provide the most definitive tooth protection for patients who engage in bruxism or similar behaviors. Occlusal guards are made of material that is softer than enamel, so the patient will wear away the guard rather than tooth structure. When the guard is worn away, the patient needs a new one.

Pharmacologic strategies for bruxism or related oral habits involving the teeth are not well developed. One short-term, placebo-controlled trial for acute treatment in 10 drug-free patients with sleep bruxism consisted of a predrug night, a placebo night, and a clonazepam night. Clonazepam, 1 mg 30 minutes before bedtime, significantly improved bruxism and sleep quality as determined by objective and subjective measures.¹⁰

Kast¹¹ reported 4 cases in which tiagabine suppressed nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. This gammaaminobutyric acid reuptake inhibitor anticonvulsant approved for treating partial seizures was dosed at 4 to 8 mg at bedtime. These dosages are lower than those used to treat seizures.

Related resources

• American Dental Association. www.ada.org.

Drug brand names

• Clonazepam • Klonopin
• Haloperidol • Haldol
• Pimozide • Orap
• Sertraline • Zoloft
• Tiagabine • Gabitril

Disclosure

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

Comment on this article

Oral habits such as bruxism—compulsive grinding or clenching of the teeth—can be a manifestation of obsessive-compulsive disorder (OCD) and other anxiety disorders.¹ Bruxism also may be a side effect of selective serotonin reuptake inhibitors (SSRIs)^2,3 used to treat OCD⁴ and depression. Other oral conditions can complicate treatment of these disorders (Table 1).

Potentially serious sequelae of bruxism and similar behaviors include:

• wearing down of teeth (more common)
• necrosis of the pulpal tissues that results in non-vital teeth (less common).

The following case underlines the need for early referral to a dentist and close follow-up for patients who have tooth-related behaviors or are taking medications associated with a risk for such behaviors.

Table 1

Oral conditions associated with anxiety disorders and depression

CASE REPORT: A compulsive oral habit

Mr. G, age 26, presents to our school of dental medicine with the chief complaint that he needs a crown. On clinical intraoral examination, we find he has multiple restorations, some areas of recurrent tooth decay, and a fractured cusp on a maxillary molar. His mandibular incisors show greater wear on their incisal surfaces than would be expected for a patient his age. This is especially true of his mandibular right lateral incisor (tooth #26) and canine (tooth #27) (Photo 1).

Clinical examination also reveals a restoration on tooth #26 that was consistent with an access cavity drilled for endodontic (root canal) therapy (Photo 2). This finding is consistent with his dental history. Soft tissue examination is within normal limits. He reports that he saw a dentist 7 months earlier but could not afford the fees.

During his medical history, Mr. G states he has mild Tourette’s syndrome that was diagnosed when he was 10. In the early 1990s he tried several medications, including haloperidol and pimozide, as a subject in research studies of Tourette’s. He could not recall the dosages of the medications or for how long he took them. Because these medications did not improve his symptoms, he stopped taking them after the studies ended.

Photo 1 Unexpected tooth wear: A clue to an anxiety-related oral habit

Teeth of a 26-year-old man show greater than expected wear, particularly on the mandibular right lateral incisor (tooth #26) and canine (tooth #27).

Photo 2 Radiographic evidence of tooth non-vitality

Radiolucencies (dark areas) in the bone at the apices of the tooth roots are a radiographic sign of non-vitality. Tooth #26 has undergone root canal.Mr. G reports that when he was in second grade, a psychiatrist diagnosed him with OCD, and has received treatment since then. We observe that while Mr. G is seated, he continually raises his right arm above his head and rubs his fingers together. He reports and demonstrates numerous other compulsive rituals, including head movements and rubbing his elbows against his side. His right elbow has a large scab.

He has been taking sertraline, 150 mg/d, for the past month. He says his psychiatrist prescribed this medication to help him break out of what he describes as episodes where he “gets into a mental loop.” Sertraline has improved Mr. G’s symptoms but they have not resolved.

He further reports that he has begun to “grind” his anterior teeth. Technically, he does not engage in grinding or bruxing; he has a habit of pushing his mandible forward so that his mandibular (lower) teeth are anterior to the maxillary (top) teeth, then forcefully pulling his mandible back so that the lingual (back) surfaces of the mandibular incisors push up against the buccal (outside) surfaces of the maxillary incisors (Photo 3). He states that he engaged in this habit frequently from approximately age 19 to 22. When Mr. G was 22, his dentist reduced the height of tooth #23, which Mr. G says he used “to set things in motion.” The dentist’s maneuver cut down but did not eliminate Mr. G’s habit.

Mr. G had not complained of nor had any clinician asked him about his bruxism-like behavior. He noted that the oral habit began prior to sertraline treatment, thus suggesting no relationship between the medication and the behavior. Interestingly, although some studies have reported bruxism as a side effect of SSRIs,^2,3 at least 1 case report found that SSRIs reduced nocturnal bruxism.¹²

Photo 3 Obsessive-compulsive disorder manifested in Mr. G’s oral habit

Starting with his mandible pushed forward so that his mandibular (lower) teeth were anterior to the maxillary (upper) teeth, the patient would forcefully pull his mandible back so that the lingual (back) surfaces of the mandibular incisors pushed against the buccal (outside) surfaces of the maxillary incisors.As part of Mr. G’s dental examination, we take a full series of intraoral radiographs. These reveal radiolucencies at the apices of teeth #23 through #26 (Photo 2). The films also show root canal therapy on tooth #26.

Differential diagnosis for lesions in the periapical region of the mandibular incisors includes periapical cemental dysplasia (PCD), which typically is found in middle-aged African-American females,⁵ and lesions resulting from non-vitality of the teeth. Histopathologically, lesions resulting from the latter include an apical abscess, cyst, or granuloma.

As is customary when periapical lesions are noted, we test the vitality of the affected teeth. None of the affected teeth responded to cold or electric pulp testing, which indicated they were non-vital. Tooth vitality is not affected in PCD, which allowed us to exclude this condition.

Non-vital teeth indicate that the pulpal tissue is necrotic. Most commonly, non-vitality occurs when decay has penetrated the pulp chamber or as a complication of physical trauma. No decay was present on Mr. G’s mandibular anterior teeth and he denied a history of trauma such as a blow to the teeth. This left his oral habit as the likely cause of non-vitality.

Treatment for a non-vital tooth is a root canal, which had been done on tooth #26. We successfully performed root canal on Mr. G’s other non-vital teeth. We informed the patient of reason for his non-vital teeth, and made a protective occlusal guard to try to prevent additional trauma to the affected teeth.

Recognizing oral habits

Restoration of worn teeth, particularly those of the mandibular anterior, is technically difficult and—depending on the nature of the restoration—quite expensive. Endodontic therapy is more successful in teeth without periapical disease.⁶ Thus, preventing tooth-related problems in patients who grind their teeth or engage in other destructive dental behaviors is important.

As this case illustrates, teeth can become non-vital without clinical evidence of tooth wear; clinical evidence may be subtle or nonexistent (note teeth #23, #24, and #25 in Photo 2). Absence of tooth wear is not a reliable sign of tooth vitality. Mild to moderate tooth wear usually goes unnoticed by patients and clinicians.⁷

Patients with bruxism may complain of masticatory muscle soreness or increased wear of the teeth.⁷ In extreme cases, they may self-extract teeth as a result of bruxism.⁸

Screen patients who have anxiety disorders or depression for signs of bruxism or related behaviors (Table 2). If you detect signs of bruxism or related behavior, refer the patient to a dentist. Ask the dentist to look for signs of wear and perform vitality testing of teeth on a regular basis (twice a year is reasonable). Any signs of changes in pulp vitality should be followed up with intraoral periapical radiographs, which these patients might need more frequently than FDA guidelines recommend.⁹

Table 2

Screening for bruxism: 3 questions for patients

An occlusal guard may provide the most definitive tooth protection for patients who engage in bruxism or similar behaviors. Occlusal guards are made of material that is softer than enamel, so the patient will wear away the guard rather than tooth structure. When the guard is worn away, the patient needs a new one.

Pharmacologic strategies for bruxism or related oral habits involving the teeth are not well developed. One short-term, placebo-controlled trial for acute treatment in 10 drug-free patients with sleep bruxism consisted of a predrug night, a placebo night, and a clonazepam night. Clonazepam, 1 mg 30 minutes before bedtime, significantly improved bruxism and sleep quality as determined by objective and subjective measures.¹⁰

Kast¹¹ reported 4 cases in which tiagabine suppressed nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. This gammaaminobutyric acid reuptake inhibitor anticonvulsant approved for treating partial seizures was dosed at 4 to 8 mg at bedtime. These dosages are lower than those used to treat seizures.

Related resources

• American Dental Association. www.ada.org.

Drug brand names

• Clonazepam • Klonopin
• Haloperidol • Haldol
• Pimozide • Orap
• Sertraline • Zoloft
• Tiagabine • Gabitril

Disclosure

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

Comment on this article

Oral habits such as bruxism—compulsive grinding or clenching of the teeth—can be a manifestation of obsessive-compulsive disorder (OCD) and other anxiety disorders.¹ Bruxism also may be a side effect of selective serotonin reuptake inhibitors (SSRIs)^2,3 used to treat OCD⁴ and depression. Other oral conditions can complicate treatment of these disorders (Table 1).

Potentially serious sequelae of bruxism and similar behaviors include:

• wearing down of teeth (more common)
• necrosis of the pulpal tissues that results in non-vital teeth (less common).

The following case underlines the need for early referral to a dentist and close follow-up for patients who have tooth-related behaviors or are taking medications associated with a risk for such behaviors.

Table 1

Oral conditions associated with anxiety disorders and depression

CASE REPORT: A compulsive oral habit

Mr. G, age 26, presents to our school of dental medicine with the chief complaint that he needs a crown. On clinical intraoral examination, we find he has multiple restorations, some areas of recurrent tooth decay, and a fractured cusp on a maxillary molar. His mandibular incisors show greater wear on their incisal surfaces than would be expected for a patient his age. This is especially true of his mandibular right lateral incisor (tooth #26) and canine (tooth #27) (Photo 1).

Clinical examination also reveals a restoration on tooth #26 that was consistent with an access cavity drilled for endodontic (root canal) therapy (Photo 2). This finding is consistent with his dental history. Soft tissue examination is within normal limits. He reports that he saw a dentist 7 months earlier but could not afford the fees.

During his medical history, Mr. G states he has mild Tourette’s syndrome that was diagnosed when he was 10. In the early 1990s he tried several medications, including haloperidol and pimozide, as a subject in research studies of Tourette’s. He could not recall the dosages of the medications or for how long he took them. Because these medications did not improve his symptoms, he stopped taking them after the studies ended.

Photo 1 Unexpected tooth wear: A clue to an anxiety-related oral habit

Teeth of a 26-year-old man show greater than expected wear, particularly on the mandibular right lateral incisor (tooth #26) and canine (tooth #27).

Photo 2 Radiographic evidence of tooth non-vitality

Radiolucencies (dark areas) in the bone at the apices of the tooth roots are a radiographic sign of non-vitality. Tooth #26 has undergone root canal.Mr. G reports that when he was in second grade, a psychiatrist diagnosed him with OCD, and has received treatment since then. We observe that while Mr. G is seated, he continually raises his right arm above his head and rubs his fingers together. He reports and demonstrates numerous other compulsive rituals, including head movements and rubbing his elbows against his side. His right elbow has a large scab.

He has been taking sertraline, 150 mg/d, for the past month. He says his psychiatrist prescribed this medication to help him break out of what he describes as episodes where he “gets into a mental loop.” Sertraline has improved Mr. G’s symptoms but they have not resolved.

He further reports that he has begun to “grind” his anterior teeth. Technically, he does not engage in grinding or bruxing; he has a habit of pushing his mandible forward so that his mandibular (lower) teeth are anterior to the maxillary (top) teeth, then forcefully pulling his mandible back so that the lingual (back) surfaces of the mandibular incisors push up against the buccal (outside) surfaces of the maxillary incisors (Photo 3). He states that he engaged in this habit frequently from approximately age 19 to 22. When Mr. G was 22, his dentist reduced the height of tooth #23, which Mr. G says he used “to set things in motion.” The dentist’s maneuver cut down but did not eliminate Mr. G’s habit.

Mr. G had not complained of nor had any clinician asked him about his bruxism-like behavior. He noted that the oral habit began prior to sertraline treatment, thus suggesting no relationship between the medication and the behavior. Interestingly, although some studies have reported bruxism as a side effect of SSRIs,^2,3 at least 1 case report found that SSRIs reduced nocturnal bruxism.¹²

Photo 3 Obsessive-compulsive disorder manifested in Mr. G’s oral habit

Starting with his mandible pushed forward so that his mandibular (lower) teeth were anterior to the maxillary (upper) teeth, the patient would forcefully pull his mandible back so that the lingual (back) surfaces of the mandibular incisors pushed against the buccal (outside) surfaces of the maxillary incisors.As part of Mr. G’s dental examination, we take a full series of intraoral radiographs. These reveal radiolucencies at the apices of teeth #23 through #26 (Photo 2). The films also show root canal therapy on tooth #26.

Differential diagnosis for lesions in the periapical region of the mandibular incisors includes periapical cemental dysplasia (PCD), which typically is found in middle-aged African-American females,⁵ and lesions resulting from non-vitality of the teeth. Histopathologically, lesions resulting from the latter include an apical abscess, cyst, or granuloma.

As is customary when periapical lesions are noted, we test the vitality of the affected teeth. None of the affected teeth responded to cold or electric pulp testing, which indicated they were non-vital. Tooth vitality is not affected in PCD, which allowed us to exclude this condition.

Non-vital teeth indicate that the pulpal tissue is necrotic. Most commonly, non-vitality occurs when decay has penetrated the pulp chamber or as a complication of physical trauma. No decay was present on Mr. G’s mandibular anterior teeth and he denied a history of trauma such as a blow to the teeth. This left his oral habit as the likely cause of non-vitality.

Treatment for a non-vital tooth is a root canal, which had been done on tooth #26. We successfully performed root canal on Mr. G’s other non-vital teeth. We informed the patient of reason for his non-vital teeth, and made a protective occlusal guard to try to prevent additional trauma to the affected teeth.

Recognizing oral habits

Restoration of worn teeth, particularly those of the mandibular anterior, is technically difficult and—depending on the nature of the restoration—quite expensive. Endodontic therapy is more successful in teeth without periapical disease.⁶ Thus, preventing tooth-related problems in patients who grind their teeth or engage in other destructive dental behaviors is important.

As this case illustrates, teeth can become non-vital without clinical evidence of tooth wear; clinical evidence may be subtle or nonexistent (note teeth #23, #24, and #25 in Photo 2). Absence of tooth wear is not a reliable sign of tooth vitality. Mild to moderate tooth wear usually goes unnoticed by patients and clinicians.⁷

Patients with bruxism may complain of masticatory muscle soreness or increased wear of the teeth.⁷ In extreme cases, they may self-extract teeth as a result of bruxism.⁸

Screen patients who have anxiety disorders or depression for signs of bruxism or related behaviors (Table 2). If you detect signs of bruxism or related behavior, refer the patient to a dentist. Ask the dentist to look for signs of wear and perform vitality testing of teeth on a regular basis (twice a year is reasonable). Any signs of changes in pulp vitality should be followed up with intraoral periapical radiographs, which these patients might need more frequently than FDA guidelines recommend.⁹

Table 2

Screening for bruxism: 3 questions for patients

An occlusal guard may provide the most definitive tooth protection for patients who engage in bruxism or similar behaviors. Occlusal guards are made of material that is softer than enamel, so the patient will wear away the guard rather than tooth structure. When the guard is worn away, the patient needs a new one.

Pharmacologic strategies for bruxism or related oral habits involving the teeth are not well developed. One short-term, placebo-controlled trial for acute treatment in 10 drug-free patients with sleep bruxism consisted of a predrug night, a placebo night, and a clonazepam night. Clonazepam, 1 mg 30 minutes before bedtime, significantly improved bruxism and sleep quality as determined by objective and subjective measures.¹⁰

Kast¹¹ reported 4 cases in which tiagabine suppressed nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. This gammaaminobutyric acid reuptake inhibitor anticonvulsant approved for treating partial seizures was dosed at 4 to 8 mg at bedtime. These dosages are lower than those used to treat seizures.

Related resources

• American Dental Association. www.ada.org.

Drug brand names

• Clonazepam • Klonopin
• Haloperidol • Haldol
• Pimozide • Orap
• Sertraline • Zoloft
• Tiagabine • Gabitril

Disclosure

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

Comment on this article

In June 2001, Andrea Yates drowned her 5 children ages 6 months to 7 years in the bathtub of their home. She had delusions that her house was bugged and television cameras were monitoring her mothering skills. She came to believe that “the one and only Satan” was within her, and that her children would burn in hell if she did not save their souls while they were still innocent.

Her conviction of capital murder in her first trial was overturned on appeal. She was found not guilty by reason of insanity at her retrial in 2006 and committed to a Texas state mental hospital.¹

Postpartum psychosis (PPP) presents dramatically days to weeks after delivery, with wide-ranging symptoms that can include dysphoric mania and delirium. Because untreated PPP has an estimated 4% risk of infanticide (murder of the infant in the first year of life),² and a 5% risk of suicide,³ psychiatric hospitalization usually is required to protect the mother and her baby.

The diagnosis may be missed, however, because postpartum psychotic symptoms wax and wane and suspiciousness or poor insight cause some women—such as Andrea Yates—to hide their delusional thinking from their families. This article discusses the risk factors, prevention, and treatment of PPP, including a review of:

• infanticide and suicide risks in the postpartum period
  
• increased susceptibility to PPP in women with bipolar disorder and other psychiatric disorders
  
• hospitalization for support and safety of the mother and her infant.
  

Risks of infanticide and suicide

A number of motives exist for infanticide (Table 1).⁴ Psychiatric literature shows that mothers who kill their children often have experienced psychosis, suicidality, depression, and considerable life stress.⁵ Common factors include alcohol use, limited social support, and a personal history of abuse. Studies on infanticide found a significant increase in common psychiatric disorders and financial stress among the mothers. Neonaticide (murder of the infant in the first day of life) generally is not related to PPP because PPP usually does not begin until after the day of delivery.⁶

Among women who develop psychiatric illness, homicidal ideation is more frequent in those with a perinatal onset of psychopathology.⁷ Infanticidal ideas and behavior are associated with psychotic ideas about the infant.⁸ Suicide is the cause of up to 20% of postpartum deaths.⁹

Table 1

Motives for infanticide: Mental illness or something else?

The bipolar connection

Many factors can elevate the risk of PPP, including sleep deprivation in susceptible women, the hormonal shifts after birth, and psychiatric comorbidity (Table 2). Nearly three-fourths (>72%) of mothers with PPP have bipolar disorder or schizoaffective disorder, whereas 12% have schizophrenia.¹⁰ Some authors consider PPP to be bipolar disorder until proven otherwise. Mothers with a history of bipolar disorder or PPP have a 100-fold increase in rates of psychiatric hospitalization in the postpartum period.¹¹

Presentation. PPP is relatively rare, occurring at a rate of 1 to 3 cases per 1,000 births. Symptoms often have an abrupt onset, within days to weeks of delivery.¹⁰ In at least one-half of cases, symptoms begin by the third postpartum day,¹³ when many mothers have been discharged home and may be solely responsible for their infants.

Symptoms include confusion, bizarre behaviors, hallucinations (including rarer types such as tactile and olfactory), mood lability (ranging from euphoria to depression), decreased need for sleep or insomnia, restlessness, agitation, disorganized thinking, and bizarre delusions of relatively rapid onset.¹³ One mother might believe God wants her baby to be sacrificed as the second coming of the Messiah, a second may believe she has special powers, and a third that her baby is defective.

Table 2

Postpartum psychosis: Risk factors supported by evidence

Differential diagnosis

When evaluating a postpartum woman with psychotic symptoms, stay in contact with her obstetrician and the child’s pediatrician. Rule out delirium and organic causes of the mother’s symptoms (Box).¹¹

Postpartum depression (PPD) occurs in approximately 10% to 15% of new mothers.¹⁴ Depressive symptoms occur within weeks to months after delivery and often coexist with anxious symptoms. Some women with severe depression may present with psychotic symptoms. A mother may experience insomnia, sometimes not being able to sleep when the baby is sleeping. She may lack interest in caring for her baby and experience difficulty bonding.

At times it can be difficult to distinguish PPD from PPP. When evaluating a mother who is referred for “postpartum depression,” consider PPP in the differential diagnosis. A woman with PPD or PPP may report depressed mood, but in PPP this symptom usually is related to rapid mood changes. Other clinical features that point toward PPP are abnormal hallucinations (such as olfactory or tactile), hypomanic or mixed mood symptoms, and confusion.

Box

Psychosis vs OCD. Psychotic thinking and behaviors also must be differentiated from obsessive thoughts and compulsions.^10,16 Obsessive compulsive disorder (OCD) may be exacerbated or emerge for the first time during the perinatal period.¹⁷

In postpartum OCD, women may experience intrusive thoughts of accidental or purposeful harm to their baby. As opposed to women with PPP, mothers with OCD are not out of touch with reality and their thoughts are ego-dystonic.¹⁷ When these mothers have thoughts of their infants being harmed, they realize that these thoughts are not plans but fears and they try to avoid the thoughts.

Preventing PPP

Bipolar disorder is one of the most difficult disorders to treat during pregnancy because the serious risks of untreated illness must be balanced against the potential teratogenic risk of medications. Nevertheless, proactively managing bipolar disorder during pregnancy may reduce the risk of PPP.¹⁰

Closely monitor women with a history of bipolar disorder or PPP. During pregnancy, counsel them—and their partners—to:

• anticipate that depressive or psychotic symptoms could develop within days after delivery¹⁸
  
• seek treatment immediately if this occurs.
  

A retrospective study examined the course of women with bipolar disorder, some of whom were given prophylactic mood stabilizers immediately in the postpartum. One of 14 who received antimanic agents relapsed within the first 3 months postpartum, compared with 8 of 13 who were not so treated.¹⁸

Compared with antiepileptics, less information is available about the use of atypical antipsychotics in pregnancy and lactation. Antipsychotics’ potential advantage in women at risk for PPP is that these agents may help prevent or treat both manic and psychotic symptoms.

In a small, naturalistic, prospective study, 11 women at risk for PPP received olanzapine alone or with an antidepressant or mood stabilizer for at least 4 weeks after delivery. Two (18%) experienced a postpartum mood episode, compared with 8 (57%) of 14 other at-risk women who received antidepressants, mood stabilizers, or no medication.²⁰

When you discuss breast-feeding, consider possible risks to the neonate as well as potential sleep interruption for the mother. If a mother has a supportive partner, the partner might be put in charge of night-time feedings in a routine combining breast-feeding and bottle-feeding. In some cases you may need to recommend cessation of lactation.²¹

Table 3

Treating postpartum psychosis: Consider 3 components

Managing PPP

Early symptoms. Because of its severity and rapid evolution, PPP often presents as a psychiatric emergency. Monitor atrisk patients’ sleep patterns and mood for early signs of psychosis.²² Watch especially for hypomanic symptoms such as elevated or mixed mood and decreased judgment, which are common early in PPP.¹³

A mother with few signs of abnormal mood, good social support, and close follow-up may potentially be safely managed as an outpatient. Initial evaluation and management of PPP usually requires hospitalization, however, because of the risks of suicide, infanticide, and child maltreatment.²³

Hospitalization. Mother-infant bonding is important, but safety is paramount if a mother is psychotic—especially if she is experiencing psychotic thoughts about her infant. If possible, the infant should remain with family members during the mother’s hospitalization. Supervised mother-infant visits are often arranged, as appropriate.

Mood-stabilizing medications, including antipsychotics, are mainstays of treatment.²⁴ In some cases, conventional antipsychotics such as haloperidol may be useful because of a lower risk of weight gain or of sedation that could impair a mother’s ability to respond to her infant. Electroconvulsive therapy often yields rapid symptomatic improvement for mothers with postpartum mood or psychotic symptoms.²⁵

Discharge planning. Assuming that the mother adheres to prescribed treatment, discharge may occur within 1 week. Plan discharge arrangements carefully (Table 4).²⁸ A team approach can be very useful within the outpatient clinic. In the model of the Perinatal Psychiatry Clinic of Connections in suburban Cleveland, OH, the mother’s treatment team includes perinatal psychiatrists, nurses, counsellors, case managers (who do home visits), and peer counselors.

Outpatient civil commitment, in which patients are mandated to accept treatment, is an option in some jurisdictions and could help ensure that patients receive treatment consistently.

Table 4

Discharge planning for safety of mother and infant