LAS VEGAS– A newly introduced statement proposes to change how obesity is diagnosed and treated.

The American Association of Clinical Endocrinologists and the American College of Endocrinology are suggesting algorithms to determine stages for the disease, each of which comes with a set of therapy recommendations. 

"Right now it’s obesity, or overweight/obesity, or Class 1, 2, 3 obesity – it’s all [body mass index]. BMI doesn’t convey actionability. It doesn’t convey a medical meaning," said Dr. W. Timothy Garvey, chair of the AACE Obesity Scientific Committee at the annual meeting of the American Association of Clinical Endocrinologists.

Naseem Miller/Frontline Medical News

AACE/ACE leaders hope that their new diagnostic algorithm will fill that gap.

"We’re using weight loss therapy to treat the complications of obesity in a medical model," Dr. Garvey said.

According to the framework, which is not finalized yet, the diagnostic categories of obesity will be:

• Overweight: BMI of 25-29.9 kg/m², with no obesity-related complications.

• Obesity Stage 0: BMI of at least 30, with no obesity-related complications.

• Obesity Stage 1: BMI of at least 25 and one or more complications that are mild to moderate in severity.

• Obesity stage 2: BMI of greater than or equal to 25 and one or more severe complications.

Also, a four-step diagnosis and treatment approach is recommended for all patients:

1. BMI screening and adjusting for ethnic differences.

2. Clinical evaluation for the presence of obesity-related complications, by using a checklist.

3. Staging for the severity of complications using complication-specific criteria.

4. Selection of prevention and/or intervention strategies targeting specific complications guided by the AACE/ACE obesity management algorithm.

AACE/ACE leaders pointed out that today there are better tools to treat obesity than ever before, including improvements in lifestyle intervention, new medications, and improvements in bariatric surgery, yet there’s limited access and penetrance of these tools in the clinic. They said they hoped the new algorithm would help incorporate available therapies into treating obese patients.

The algorithm emerged from the AACE/ACE 2014 Consensus Conference on Obesity, which included medical professionals, industry representatives, advocacy groups, and regulators. One of the findings that everyone agreed on was that the diagnostic definition of obesity needed to improve.

The current definition of obesity "didn’t give all the stakeholders a reason to buy into a concerted plan." Employers would say, "I bring somebody down from a BMI of 38 to 34. But what does that mean? "How is it benefiting me? How is it benefiting my company? Why would I want to invest in that? But if they’re treating Stage 2, that’s telling them that that person is overweight, has excessive body fat, and it’s impacting their health and they have complications that can be remedied by weight loss and use of more aggressive therapies. All of that is embedded in that simple term," Dr. Garvey said. 

The AACE/ACE is not the first to issue a diagnosis or treatment guideline for obesity, which was declared a disease by the American Medical Association in 2013. 

There are a lot of commonalities to the guidelines," said Dr. Garvey, professor and chair at the department of Nutrition Sciences at the University of Alabama at Birmingham. They’re all addressing obesity and therapy and attempt to improve patients’ health. "I think we’re more focused on using weight loss as a therapy to treat obesity-related complications," Dr. Garvey said. 

AACE/ACE is holding another consensus conference later this year as a step toward finalizing the framework.

Dr. Garvey is a consultant for Daiichi Sankyo, Liposcience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, Astra Zeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @naseemmiller

LAS VEGAS– A newly introduced statement proposes to change how obesity is diagnosed and treated.

The American Association of Clinical Endocrinologists and the American College of Endocrinology are suggesting algorithms to determine stages for the disease, each of which comes with a set of therapy recommendations. 

"Right now it’s obesity, or overweight/obesity, or Class 1, 2, 3 obesity – it’s all [body mass index]. BMI doesn’t convey actionability. It doesn’t convey a medical meaning," said Dr. W. Timothy Garvey, chair of the AACE Obesity Scientific Committee at the annual meeting of the American Association of Clinical Endocrinologists.

Naseem Miller/Frontline Medical News

AACE/ACE leaders hope that their new diagnostic algorithm will fill that gap.

"We’re using weight loss therapy to treat the complications of obesity in a medical model," Dr. Garvey said.

According to the framework, which is not finalized yet, the diagnostic categories of obesity will be:

• Overweight: BMI of 25-29.9 kg/m², with no obesity-related complications.

• Obesity Stage 0: BMI of at least 30, with no obesity-related complications.

• Obesity Stage 1: BMI of at least 25 and one or more complications that are mild to moderate in severity.

• Obesity stage 2: BMI of greater than or equal to 25 and one or more severe complications.

Also, a four-step diagnosis and treatment approach is recommended for all patients:

1. BMI screening and adjusting for ethnic differences.

2. Clinical evaluation for the presence of obesity-related complications, by using a checklist.

3. Staging for the severity of complications using complication-specific criteria.

4. Selection of prevention and/or intervention strategies targeting specific complications guided by the AACE/ACE obesity management algorithm.

AACE/ACE leaders pointed out that today there are better tools to treat obesity than ever before, including improvements in lifestyle intervention, new medications, and improvements in bariatric surgery, yet there’s limited access and penetrance of these tools in the clinic. They said they hoped the new algorithm would help incorporate available therapies into treating obese patients.

The algorithm emerged from the AACE/ACE 2014 Consensus Conference on Obesity, which included medical professionals, industry representatives, advocacy groups, and regulators. One of the findings that everyone agreed on was that the diagnostic definition of obesity needed to improve.

The current definition of obesity "didn’t give all the stakeholders a reason to buy into a concerted plan." Employers would say, "I bring somebody down from a BMI of 38 to 34. But what does that mean? "How is it benefiting me? How is it benefiting my company? Why would I want to invest in that? But if they’re treating Stage 2, that’s telling them that that person is overweight, has excessive body fat, and it’s impacting their health and they have complications that can be remedied by weight loss and use of more aggressive therapies. All of that is embedded in that simple term," Dr. Garvey said. 

The AACE/ACE is not the first to issue a diagnosis or treatment guideline for obesity, which was declared a disease by the American Medical Association in 2013. 

There are a lot of commonalities to the guidelines," said Dr. Garvey, professor and chair at the department of Nutrition Sciences at the University of Alabama at Birmingham. They’re all addressing obesity and therapy and attempt to improve patients’ health. "I think we’re more focused on using weight loss as a therapy to treat obesity-related complications," Dr. Garvey said. 

AACE/ACE is holding another consensus conference later this year as a step toward finalizing the framework.

Dr. Garvey is a consultant for Daiichi Sankyo, Liposcience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, Astra Zeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @naseemmiller

LAS VEGAS– A newly introduced statement proposes to change how obesity is diagnosed and treated.

The American Association of Clinical Endocrinologists and the American College of Endocrinology are suggesting algorithms to determine stages for the disease, each of which comes with a set of therapy recommendations. 

"Right now it’s obesity, or overweight/obesity, or Class 1, 2, 3 obesity – it’s all [body mass index]. BMI doesn’t convey actionability. It doesn’t convey a medical meaning," said Dr. W. Timothy Garvey, chair of the AACE Obesity Scientific Committee at the annual meeting of the American Association of Clinical Endocrinologists.

Naseem Miller/Frontline Medical News

AACE/ACE leaders hope that their new diagnostic algorithm will fill that gap.

"We’re using weight loss therapy to treat the complications of obesity in a medical model," Dr. Garvey said.

According to the framework, which is not finalized yet, the diagnostic categories of obesity will be:

• Overweight: BMI of 25-29.9 kg/m², with no obesity-related complications.

• Obesity Stage 0: BMI of at least 30, with no obesity-related complications.

• Obesity Stage 1: BMI of at least 25 and one or more complications that are mild to moderate in severity.

• Obesity stage 2: BMI of greater than or equal to 25 and one or more severe complications.

Also, a four-step diagnosis and treatment approach is recommended for all patients:

1. BMI screening and adjusting for ethnic differences.

2. Clinical evaluation for the presence of obesity-related complications, by using a checklist.

3. Staging for the severity of complications using complication-specific criteria.

4. Selection of prevention and/or intervention strategies targeting specific complications guided by the AACE/ACE obesity management algorithm.

AACE/ACE leaders pointed out that today there are better tools to treat obesity than ever before, including improvements in lifestyle intervention, new medications, and improvements in bariatric surgery, yet there’s limited access and penetrance of these tools in the clinic. They said they hoped the new algorithm would help incorporate available therapies into treating obese patients.

The algorithm emerged from the AACE/ACE 2014 Consensus Conference on Obesity, which included medical professionals, industry representatives, advocacy groups, and regulators. One of the findings that everyone agreed on was that the diagnostic definition of obesity needed to improve.

The current definition of obesity "didn’t give all the stakeholders a reason to buy into a concerted plan." Employers would say, "I bring somebody down from a BMI of 38 to 34. But what does that mean? "How is it benefiting me? How is it benefiting my company? Why would I want to invest in that? But if they’re treating Stage 2, that’s telling them that that person is overweight, has excessive body fat, and it’s impacting their health and they have complications that can be remedied by weight loss and use of more aggressive therapies. All of that is embedded in that simple term," Dr. Garvey said. 

The AACE/ACE is not the first to issue a diagnosis or treatment guideline for obesity, which was declared a disease by the American Medical Association in 2013. 

There are a lot of commonalities to the guidelines," said Dr. Garvey, professor and chair at the department of Nutrition Sciences at the University of Alabama at Birmingham. They’re all addressing obesity and therapy and attempt to improve patients’ health. "I think we’re more focused on using weight loss as a therapy to treat obesity-related complications," Dr. Garvey said. 

AACE/ACE is holding another consensus conference later this year as a step toward finalizing the framework.

Dr. Garvey is a consultant for Daiichi Sankyo, Liposcience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, Astra Zeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @naseemmiller

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

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

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

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

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

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

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Individualized case conceptualization lays the foundation for the course of CBT, and may be thought of as a map for therapy. Case conceptualization brings in several domains of assessment including symp­toms and diagnosis, the patient’s strengths, formative experiences (including biopsy­chosocial aspects), contextual factors, and cognitive factors that influence diagnosis and treatment, such as automatic thoughts or schemas. The case formulation leads to a working hypothesis about the optimal course and focus of CBT.

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

 

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

 

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

 

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

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

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Individualized case conceptualization lays the foundation for the course of CBT, and may be thought of as a map for therapy. Case conceptualization brings in several domains of assessment including symp­toms and diagnosis, the patient’s strengths, formative experiences (including biopsy­chosocial aspects), contextual factors, and cognitive factors that influence diagnosis and treatment, such as automatic thoughts or schemas. The case formulation leads to a working hypothesis about the optimal course and focus of CBT.

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

 

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

 

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

 

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

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

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Individualized case conceptualization lays the foundation for the course of CBT, and may be thought of as a map for therapy. Case conceptualization brings in several domains of assessment including symp­toms and diagnosis, the patient’s strengths, formative experiences (including biopsy­chosocial aspects), contextual factors, and cognitive factors that influence diagnosis and treatment, such as automatic thoughts or schemas. The case formulation leads to a working hypothesis about the optimal course and focus of CBT.

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

 

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

 

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

 

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

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

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

Neuroimaging
The basic purpose of CT and MRI of the head in the workup of cognitive impairment is to rule out a lesion in the brain, such as a tumor or hemorrhage, as the cause of, or contribu­tor to, the impairment. Several neuroimag­ing studies are available to aid in diagnosing AD and distinguishing it from other causes of dementia, including:
   • Fludeoxyglucose (FDG) positron-emission tomography (PET) scanning
   • MRI
   • Florbetapir F 18 Injection for PET.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

 

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

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

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

Neuroimaging
The basic purpose of CT and MRI of the head in the workup of cognitive impairment is to rule out a lesion in the brain, such as a tumor or hemorrhage, as the cause of, or contribu­tor to, the impairment. Several neuroimag­ing studies are available to aid in diagnosing AD and distinguishing it from other causes of dementia, including:
   • Fludeoxyglucose (FDG) positron-emission tomography (PET) scanning
   • MRI
   • Florbetapir F 18 Injection for PET.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

 

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

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

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

Neuroimaging
The basic purpose of CT and MRI of the head in the workup of cognitive impairment is to rule out a lesion in the brain, such as a tumor or hemorrhage, as the cause of, or contribu­tor to, the impairment. Several neuroimag­ing studies are available to aid in diagnosing AD and distinguishing it from other causes of dementia, including:
   • Fludeoxyglucose (FDG) positron-emission tomography (PET) scanning
   • MRI
   • Florbetapir F 18 Injection for PET.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

 

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

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