Re-experiencing a previous life-threatening stress through nightmares or recurrent memories is a hallmark of posttraumatic stress disorder (PTSD). In the United States, the lifetime risk of PTSD is 10.1% and the 12-month prevalence is 3.7%.¹ The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA-approved for treating PTSD; clinicians commonly use any SSRI for this disorder. Although SSRIs can alleviate many PTSD symptoms, at times patients experience only a partial response, which necessitates other interventions.

Rationale for using topiramate

The anticonvulsant topiramate blocks voltage-sensitive sodium channels, augments γ-aminobutyric acid type A, antagonizes the glutamate receptor, and inhibits carbonic anhydrase. Researchers have hypothesized that limbic nuclei become sensitized and “kindled” after exposure to a traumatic event. Anticonvulsants such as topiramate may help mitigate stress-activated kindling in PTSD.^2,3

What does the evidence say?

Although less compelling than double-blind, placebo-controlled trials, small open-label studies and some case reports indicate a potential role for topiramate in PTSD for specific populations.^4,5 In an 8-week open- label study, Alderman et al⁶ found adjunctive topiramate led to a statistically significant reduction in Clinician-Administered PTSD Scale (CAPS) scores and nightmares in 43 male veterans with combat-related PTSD. There was a nonsignificant decrease in high-risk alcohol use.

In a 2002 retrospective case series, Berlant et al⁷ found topiramate as monotherapy or adjunctive therapy reduced nightmares in 35 patients with chronic, non-combat PTSD. Nightmares decreased in 79% of patients and flashbacks decreased in 86%, with symptom improvement in a median of 4 days. Limitations of this study included lack of placebo control, a low number of participants, and a high dropout rate (9/35).

Two years later, Berlant⁸ used the PTSD Checklist-Civilian version (PCL-C) to assess response to topiramate in an open-label study of 33 patients with chronic, non-hallucinatory PTSD. Twenty-eight patients used topiramate as add-on therapy. PCL-C scores decreased by ≥30% in 77% of patients in 4 weeks, with a median dose of 50 mg/d and a median response time of 9 days.

In a double-blind, placebo-controlled trial, Tucker et al⁹ assessed 38 civilian patients who took topiramate monotherapy for PTSD. Using the CAPS, researchers concluded that topiramate reduced re-experiencing symptoms, but the effect was not statistically significant.⁹

Lindley et al¹⁰ conducted a randomized, double-blind, placebo-controlled trial to study the effect of add-on topiramate in 40 patients with chronic, combat-related PTSD. Because many patients in this study had a history of depression and substance use disorders, topiramate was added to antidepressants; no anticonvulsants, antipsychotics, or benzodiazepines were used. Similar to previous studies, researchers found no statistically significant effect on PTSD symptom severity or global symptom improvement. However, the small number of participants and a high dropout rate limited this study.¹⁰

In a 12-week, double-blind, placebo-controlled study of 35 men and women age 18 to 62 with PTSD, Yeh et al¹¹ found that topiramate (mean dose: 102.94 mg/d) lead to a statistically significant overall CAPS score reduction, with significant improvements in re-experiencing symptoms, such as nightmares.

Our opinion

FDA-approved treatments such as SSRIs should be the first pharmacologic intervention for PTSD. If a patient’s response is partial or inadequate, consider additional treatment options. For patients with persistent re-experiencing symptoms, evidence and experience with prazosin and trazodone are more robust than that for topiramate.¹²

Using topiramate to reduce re-experiencing symptoms such as nightmares in PTSD is not supported by statistically significant evidence from double-blind, placebo- controlled trials. However, numerous open-label studies and case reports suggest that there may be a role for topiramate in PTSD patients who do not respond to other treatments. Data indicate that topiramate may be helpful for PTSD patients who have high-risk alcohol use⁶ or migraine headaches.¹³ Because some patients who take topiramate lose weight, the medication may be useful for PTSD patients who are overweight.¹³

Disclosure

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

Related Resource

• U.S. Department of Veterans Affairs. Nightmares and PTSD. www.ptsd.va.gov/public/pages/nightmares.asp.

Drug Brand Names

• Paroxetine • Paxil
• Sertraline • Zoloft
• Prazosin • Minipress
• Topiramate • Topamax
• Trazodone • Desyrel, Oleptro

Re-experiencing a previous life-threatening stress through nightmares or recurrent memories is a hallmark of posttraumatic stress disorder (PTSD). In the United States, the lifetime risk of PTSD is 10.1% and the 12-month prevalence is 3.7%.¹ The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA-approved for treating PTSD; clinicians commonly use any SSRI for this disorder. Although SSRIs can alleviate many PTSD symptoms, at times patients experience only a partial response, which necessitates other interventions.

Rationale for using topiramate

The anticonvulsant topiramate blocks voltage-sensitive sodium channels, augments γ-aminobutyric acid type A, antagonizes the glutamate receptor, and inhibits carbonic anhydrase. Researchers have hypothesized that limbic nuclei become sensitized and “kindled” after exposure to a traumatic event. Anticonvulsants such as topiramate may help mitigate stress-activated kindling in PTSD.^2,3

What does the evidence say?

Although less compelling than double-blind, placebo-controlled trials, small open-label studies and some case reports indicate a potential role for topiramate in PTSD for specific populations.^4,5 In an 8-week open- label study, Alderman et al⁶ found adjunctive topiramate led to a statistically significant reduction in Clinician-Administered PTSD Scale (CAPS) scores and nightmares in 43 male veterans with combat-related PTSD. There was a nonsignificant decrease in high-risk alcohol use.

In a 2002 retrospective case series, Berlant et al⁷ found topiramate as monotherapy or adjunctive therapy reduced nightmares in 35 patients with chronic, non-combat PTSD. Nightmares decreased in 79% of patients and flashbacks decreased in 86%, with symptom improvement in a median of 4 days. Limitations of this study included lack of placebo control, a low number of participants, and a high dropout rate (9/35).

Two years later, Berlant⁸ used the PTSD Checklist-Civilian version (PCL-C) to assess response to topiramate in an open-label study of 33 patients with chronic, non-hallucinatory PTSD. Twenty-eight patients used topiramate as add-on therapy. PCL-C scores decreased by ≥30% in 77% of patients in 4 weeks, with a median dose of 50 mg/d and a median response time of 9 days.

In a double-blind, placebo-controlled trial, Tucker et al⁹ assessed 38 civilian patients who took topiramate monotherapy for PTSD. Using the CAPS, researchers concluded that topiramate reduced re-experiencing symptoms, but the effect was not statistically significant.⁹

Lindley et al¹⁰ conducted a randomized, double-blind, placebo-controlled trial to study the effect of add-on topiramate in 40 patients with chronic, combat-related PTSD. Because many patients in this study had a history of depression and substance use disorders, topiramate was added to antidepressants; no anticonvulsants, antipsychotics, or benzodiazepines were used. Similar to previous studies, researchers found no statistically significant effect on PTSD symptom severity or global symptom improvement. However, the small number of participants and a high dropout rate limited this study.¹⁰

In a 12-week, double-blind, placebo-controlled study of 35 men and women age 18 to 62 with PTSD, Yeh et al¹¹ found that topiramate (mean dose: 102.94 mg/d) lead to a statistically significant overall CAPS score reduction, with significant improvements in re-experiencing symptoms, such as nightmares.

Our opinion

FDA-approved treatments such as SSRIs should be the first pharmacologic intervention for PTSD. If a patient’s response is partial or inadequate, consider additional treatment options. For patients with persistent re-experiencing symptoms, evidence and experience with prazosin and trazodone are more robust than that for topiramate.¹²

Using topiramate to reduce re-experiencing symptoms such as nightmares in PTSD is not supported by statistically significant evidence from double-blind, placebo- controlled trials. However, numerous open-label studies and case reports suggest that there may be a role for topiramate in PTSD patients who do not respond to other treatments. Data indicate that topiramate may be helpful for PTSD patients who have high-risk alcohol use⁶ or migraine headaches.¹³ Because some patients who take topiramate lose weight, the medication may be useful for PTSD patients who are overweight.¹³

Disclosure

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

Related Resource

• U.S. Department of Veterans Affairs. Nightmares and PTSD. www.ptsd.va.gov/public/pages/nightmares.asp.

Drug Brand Names

• Paroxetine • Paxil
• Sertraline • Zoloft
• Prazosin • Minipress
• Topiramate • Topamax
• Trazodone • Desyrel, Oleptro

Re-experiencing a previous life-threatening stress through nightmares or recurrent memories is a hallmark of posttraumatic stress disorder (PTSD). In the United States, the lifetime risk of PTSD is 10.1% and the 12-month prevalence is 3.7%.¹ The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA-approved for treating PTSD; clinicians commonly use any SSRI for this disorder. Although SSRIs can alleviate many PTSD symptoms, at times patients experience only a partial response, which necessitates other interventions.

Rationale for using topiramate

The anticonvulsant topiramate blocks voltage-sensitive sodium channels, augments γ-aminobutyric acid type A, antagonizes the glutamate receptor, and inhibits carbonic anhydrase. Researchers have hypothesized that limbic nuclei become sensitized and “kindled” after exposure to a traumatic event. Anticonvulsants such as topiramate may help mitigate stress-activated kindling in PTSD.^2,3

What does the evidence say?

Although less compelling than double-blind, placebo-controlled trials, small open-label studies and some case reports indicate a potential role for topiramate in PTSD for specific populations.^4,5 In an 8-week open- label study, Alderman et al⁶ found adjunctive topiramate led to a statistically significant reduction in Clinician-Administered PTSD Scale (CAPS) scores and nightmares in 43 male veterans with combat-related PTSD. There was a nonsignificant decrease in high-risk alcohol use.

In a 2002 retrospective case series, Berlant et al⁷ found topiramate as monotherapy or adjunctive therapy reduced nightmares in 35 patients with chronic, non-combat PTSD. Nightmares decreased in 79% of patients and flashbacks decreased in 86%, with symptom improvement in a median of 4 days. Limitations of this study included lack of placebo control, a low number of participants, and a high dropout rate (9/35).

Two years later, Berlant⁸ used the PTSD Checklist-Civilian version (PCL-C) to assess response to topiramate in an open-label study of 33 patients with chronic, non-hallucinatory PTSD. Twenty-eight patients used topiramate as add-on therapy. PCL-C scores decreased by ≥30% in 77% of patients in 4 weeks, with a median dose of 50 mg/d and a median response time of 9 days.

In a double-blind, placebo-controlled trial, Tucker et al⁹ assessed 38 civilian patients who took topiramate monotherapy for PTSD. Using the CAPS, researchers concluded that topiramate reduced re-experiencing symptoms, but the effect was not statistically significant.⁹

Lindley et al¹⁰ conducted a randomized, double-blind, placebo-controlled trial to study the effect of add-on topiramate in 40 patients with chronic, combat-related PTSD. Because many patients in this study had a history of depression and substance use disorders, topiramate was added to antidepressants; no anticonvulsants, antipsychotics, or benzodiazepines were used. Similar to previous studies, researchers found no statistically significant effect on PTSD symptom severity or global symptom improvement. However, the small number of participants and a high dropout rate limited this study.¹⁰

In a 12-week, double-blind, placebo-controlled study of 35 men and women age 18 to 62 with PTSD, Yeh et al¹¹ found that topiramate (mean dose: 102.94 mg/d) lead to a statistically significant overall CAPS score reduction, with significant improvements in re-experiencing symptoms, such as nightmares.

Our opinion

FDA-approved treatments such as SSRIs should be the first pharmacologic intervention for PTSD. If a patient’s response is partial or inadequate, consider additional treatment options. For patients with persistent re-experiencing symptoms, evidence and experience with prazosin and trazodone are more robust than that for topiramate.¹²

Using topiramate to reduce re-experiencing symptoms such as nightmares in PTSD is not supported by statistically significant evidence from double-blind, placebo- controlled trials. However, numerous open-label studies and case reports suggest that there may be a role for topiramate in PTSD patients who do not respond to other treatments. Data indicate that topiramate may be helpful for PTSD patients who have high-risk alcohol use⁶ or migraine headaches.¹³ Because some patients who take topiramate lose weight, the medication may be useful for PTSD patients who are overweight.¹³

Disclosure

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

Related Resource

• U.S. Department of Veterans Affairs. Nightmares and PTSD. www.ptsd.va.gov/public/pages/nightmares.asp.

Drug Brand Names

• Paroxetine • Paxil
• Sertraline • Zoloft
• Prazosin • Minipress
• Topiramate • Topamax
• Trazodone • Desyrel, Oleptro

Some older patients with depression, anxiety, or insomnia may be reluctant to turn to pharmacotherapy and may prefer psychotherapeutic treatments.¹ Evidence has established cognitive-behavioral therapy (CBT) as an effective intervention for several psychiatric disorders and CBT should be considered when treating geriatric patients (Table 1).²

Table 1

Indications for CBT

Research evaluating the efficacy of CBT for depression in older adults was first published in the early 1980s. Since then, research and application of CBT with older adults has expanded to include other psychiatric disorders and researchers have suggested changes to increase the efficacy of CBT for these patients. This article provides:

• an overview of CBT’s efficacy for older adults with depression, anxiety, and insomnia
• modifications to employ when providing CBT to older patients.

The cognitive model of CBT

In the 1970s, Aaron T. Beck, MD, developed CBT while working with depressed patients. Beck’s patients reported thoughts characterized by inaccuracies and distortions in association with their depressed mood. He found these thoughts could be brought to the patient’s conscious attention and modified to improve the patient’s depression. This finding led to the development of CBT.

CBT is based on a cognitive model of the relationship among cognition, emotion, and behavior. Mood and behavior are viewed as determined by a person’s perception and interpretation of events, which manifest as a stream of automatically generated thoughts (Figure).³ These automatic thoughts have their origins in an underlying network of beliefs or schema. Patients with psychiatric disorders such as anxiety and depression typically have frequent automatic thoughts that characteristically lack validity because they arise from dysfunctional beliefs. The therapeutic process consists of helping the patient become aware of his or her internal stream of thoughts when distressed, and to identify and modify the dysfunctional thoughts. Behavioral techniques are used to bring about functional changes in behavior, regulate emotion, and help the cognitive restructuring process. Modifying the patient’s underlying dysfunctional beliefs leads to lasting improvements. In this structured therapy, the therapist and patient work collaboratively to use an approach that features reality testing and experimentation.⁴

Figure

The cognitive model of CBT

CBT: cognitive-behavioral therapy
Source: Adapted from reference 3

Indications for CBT in older adults

Depression. Among psychotherapies used in older adults, CBT has received the most research for late-life depression.⁵ Randomized controlled trials (RCTs) have found CBT is superior to treatment as usual in depressed adults age ≥60.⁶ It also has been found to be superior to wait-list control⁷ and talking as control.^6,8 Meta-analyses have shown above-average effect sizes for CBT in treating late-life depression.^9,10 A follow-up study found improvement was maintained up to 2 years after CBT, which suggests CBT’s impact is likely to be long lasting.¹¹

Thompson et al¹² compared 102 depressed patients age >60 who were treated with CBT alone, desipramine alone, or a combination of the 2. A combination of medication and CBT worked best for severely depressed patients; CBT alone or a combination of CBT and medication worked best for moderately depressed patients.

CBT is an option when treating depressed medically ill older adults. Research indicates that CBT could reduce depression in older patients with Parkinson’s disease¹³ and chronic obstructive pulmonary disease.¹⁴

As patients get older, cognitive impairment with comorbid depression can make treatment challenging. Limited research suggests CBT applied in a modified format that involves caregivers and uses problem solving and behavioral strategies can significantly reduce depression in patients with dementia.¹⁵

Anxiety. Researchers have examined the efficacy of variants of CBT in treating older adults with anxiety disorders—commonly, generalized anxiety disorder (GAD), panic disorder, agoraphobia, subjective anxiety, or a combination of these illnesses.^16,17 Randomized trials have supported CBT’s efficacy for older patients with GAD and mixed anxiety states; gains made in CBT were maintained over a 1-year follow-up.^18,19 In a meta-analysis of 15 studies using cognitive and behavioral methods of treating anxiety in older patients, Nordhus and Pallesen¹⁶ reported a significant effect size of 0.55. In a 2008 meta-analysis that included only RCTs, CBT was superior to wait-list conditions as well as active control conditions in treating anxious older patients.²⁰

However, some research suggests that CBT for GAD may not be as effective for older adults as it is for younger adults. In a study of CBT for GAD in older adults, Stanley et al¹⁹ reported smaller effect sizes compared with CBT for younger adults. Researchers have found relatively few differences between CBT and comparison conditions—supportive psychotherapy or active control conditions—in treating GAD in older adults.²¹ Modified, more effective formats of CBT for GAD in older adults need to be established.²² Mohlman et al²³ supplemented standard CBT for late-life GAD with memory and learning aids—weekly reading assignments, graphing exercises to chart mood ratings, reminder phone calls from therapists, and homework compliance requirement. This approach improved the response rate from 40% to 75%.²³

Insomnia. Studies have found CBT to be an effective means of treating insomnia in geriatric patients. Although sleep problems occur more frequently among older patients, only 15% of chronic insomnia patients receive treatment; psychotherapy rarely is used.²⁴ CBT for insomnia (CBT-I) should be considered for older adults because managing insomnia with medications may be problematic and these patients may prefer nonpharmacologic treatment.² CBT-I typically incorporates cognitive strategies with established behavioral techniques, including sleep hygiene education, cognitive restructuring, relaxation training, stimulus control, and/or sleep restriction. The CBT-I multicomponent treatment package meets all criteria to be considered an evidence-based treatment for late-life insomnia.²⁵

RCTs have reported significant improvements in late-life insomnia with CBT-I.^26,27 Reviews and meta-analyses have also concluded that cognitive-behavioral treatments are effective for treating insomnia in older adults.^25,28 Most insomnia cases in geriatric patients are reported to occur secondary to other medical or psychiatric conditions that are judged as causing the insomnia.²⁵ In these cases, direct treatment of the insomnia usually is delayed or omitted.²⁸ Studies evaluating the efficacy of CBT packages for treating insomnia occurring in conjunction with other medical or psychiatric illnesses have reported significant improvement of insomnia.^28,29 Because insomnia frequently occurs in older patients with medical illnesses and psychiatric disorders, CBT-I could be beneficial for such patients.

Good candidates for CBT

Clinical experience indicates that older adults in relatively good health with no significant cognitive decline are good candidates for CBT. These patients tend to comply with their assignments, are interested in applying the learned strategies, and are motivated to read self-help books. CBT’s structured, goal-oriented approach makes it a short-term treatment, which makes it cost effective. Insomnia patients may improve after 6 to 8 CBT-I sessions and patients with anxiety or depression may need to undergo 15 to 20 CBT sessions. Patients age ≥65 have basic Medicare coverage that includes mental health care and psychotherapy.

There are no absolute contraindications for CBT, but the greater the cognitive impairment, the less the patient will benefit from CBT (Table 2). Similarly, severe depression and anxiety might make it difficult for patients to participate meaningfully, although CBT may be incorporated gradually as patients improve with medication. Severe medical illnesses and sensory losses such as visual and hearing loss would make it difficult to carry out CBT effectively.

Table 2

Contraindications for CBT

Adapting CBT for older patients

When using CBT with older patients, it is important to keep in mind characteristics that define the geriatric population. Laidlaw et al³⁰ developed a model to help clinicians develop a more appropriate conceptualization of older patients that focuses on significant events and related cognitions associated with physical health, changes in role investments, and interactions with younger generations. It emphasizes the need to explore beliefs about aging viewed through each patient’s socio-cultural lens and examine cognitions in the context of the time period in which the individual has lived.

Losses and transitions. For many older patients, the latter years of life are characterized by losses and transitions.³¹ According to Thompson,³¹ these losses and transitions can trigger thoughts of missed opportunities or unresolved relationships and reflection on unachieved goals.³¹ CBT for older adults should focus on the meaning the patient gives to these losses and transitions. For example, depressed patients could view their retirement as a loss of self worth as they become less productive. CBT can help patients identify ways of thinking about the situation that will enable them to adapt to these losses and transitions.

Changes in cognition. Changes in cognitive functioning with aging are not universal and there’s considerable variability, but it’s important to make appropriate adaptations when needed. Patients may experience a decline in cognitive speed, working memory, selective attention, and fluid intelligence. This would require that information be presented slowly, with frequent repetitions and summaries. Also, it might be helpful to present information in alternate ways and to encourage patients to take notes during sessions. To accommodate for a decline in fluid intelligence, presenting new information in the context of previous experiences will help promote learning. Recordings of important information and conclusions from cognitive restructuring that patients can listen to between sessions could serve as helpful reminders that will help patients progress. Phone prompts or alarms can remind patients to carry out certain therapeutic measures, such as breathing exercises. Caretakers can attend sessions to become familiar with strategies performed during CBT and act as a co-therapist at home; however, their inclusion must be done with the consent of both parties and only if it’s viewed as necessary for the patient’s progress.

Additional strategies. For patients with substantial cognitive decline, cognitive restructuring might not be as effective as behavioral strategies—activity scheduling, graded task assignment, graded exposure, and rehearsals. Because older adults often have strengthened dysfunctional beliefs over a long time, modifying them takes longer, which is why the tapering process usually takes longer for older patients than for younger patients. The lengthier tapering ensures learning is well established and the process of modifying dysfunctional beliefs to functional beliefs continues. Collaborating with other professionals—physicians, social workers, and case managers—will help ensure a shared care process in which common goals are met.

The websites of the Academy of Cognitive Therapy, American Psychological Association, and Association for Behavioral and Cognitive Therapies can help clinicians who do not offer CBT to locate a qualified therapist for their patients (Related Resources).

Related Resources

• Academy of Cognitive Therapy. www.academyofct.org.
• American Psychological Association. www.apa.org.
• Association for Behavioral and Cognitive Therapies. www.abct.org.
• Laidlaw K, Thompson LW, Dick-Siskin L, et al. Cognitive behaviour therapy with older people. West Sussex, England: John Wiley & Sons, Ltd; 2003.

Drug Brand Name

• Desipramine • Norpramin

Disclosure

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

Some older patients with depression, anxiety, or insomnia may be reluctant to turn to pharmacotherapy and may prefer psychotherapeutic treatments.¹ Evidence has established cognitive-behavioral therapy (CBT) as an effective intervention for several psychiatric disorders and CBT should be considered when treating geriatric patients (Table 1).²

Table 1

Indications for CBT

Research evaluating the efficacy of CBT for depression in older adults was first published in the early 1980s. Since then, research and application of CBT with older adults has expanded to include other psychiatric disorders and researchers have suggested changes to increase the efficacy of CBT for these patients. This article provides:

• an overview of CBT’s efficacy for older adults with depression, anxiety, and insomnia
• modifications to employ when providing CBT to older patients.

The cognitive model of CBT

In the 1970s, Aaron T. Beck, MD, developed CBT while working with depressed patients. Beck’s patients reported thoughts characterized by inaccuracies and distortions in association with their depressed mood. He found these thoughts could be brought to the patient’s conscious attention and modified to improve the patient’s depression. This finding led to the development of CBT.

CBT is based on a cognitive model of the relationship among cognition, emotion, and behavior. Mood and behavior are viewed as determined by a person’s perception and interpretation of events, which manifest as a stream of automatically generated thoughts (Figure).³ These automatic thoughts have their origins in an underlying network of beliefs or schema. Patients with psychiatric disorders such as anxiety and depression typically have frequent automatic thoughts that characteristically lack validity because they arise from dysfunctional beliefs. The therapeutic process consists of helping the patient become aware of his or her internal stream of thoughts when distressed, and to identify and modify the dysfunctional thoughts. Behavioral techniques are used to bring about functional changes in behavior, regulate emotion, and help the cognitive restructuring process. Modifying the patient’s underlying dysfunctional beliefs leads to lasting improvements. In this structured therapy, the therapist and patient work collaboratively to use an approach that features reality testing and experimentation.⁴

Figure

The cognitive model of CBT

CBT: cognitive-behavioral therapy
Source: Adapted from reference 3

Indications for CBT in older adults

Depression. Among psychotherapies used in older adults, CBT has received the most research for late-life depression.⁵ Randomized controlled trials (RCTs) have found CBT is superior to treatment as usual in depressed adults age ≥60.⁶ It also has been found to be superior to wait-list control⁷ and talking as control.^6,8 Meta-analyses have shown above-average effect sizes for CBT in treating late-life depression.^9,10 A follow-up study found improvement was maintained up to 2 years after CBT, which suggests CBT’s impact is likely to be long lasting.¹¹

Thompson et al¹² compared 102 depressed patients age >60 who were treated with CBT alone, desipramine alone, or a combination of the 2. A combination of medication and CBT worked best for severely depressed patients; CBT alone or a combination of CBT and medication worked best for moderately depressed patients.

CBT is an option when treating depressed medically ill older adults. Research indicates that CBT could reduce depression in older patients with Parkinson’s disease¹³ and chronic obstructive pulmonary disease.¹⁴

As patients get older, cognitive impairment with comorbid depression can make treatment challenging. Limited research suggests CBT applied in a modified format that involves caregivers and uses problem solving and behavioral strategies can significantly reduce depression in patients with dementia.¹⁵

Anxiety. Researchers have examined the efficacy of variants of CBT in treating older adults with anxiety disorders—commonly, generalized anxiety disorder (GAD), panic disorder, agoraphobia, subjective anxiety, or a combination of these illnesses.^16,17 Randomized trials have supported CBT’s efficacy for older patients with GAD and mixed anxiety states; gains made in CBT were maintained over a 1-year follow-up.^18,19 In a meta-analysis of 15 studies using cognitive and behavioral methods of treating anxiety in older patients, Nordhus and Pallesen¹⁶ reported a significant effect size of 0.55. In a 2008 meta-analysis that included only RCTs, CBT was superior to wait-list conditions as well as active control conditions in treating anxious older patients.²⁰

However, some research suggests that CBT for GAD may not be as effective for older adults as it is for younger adults. In a study of CBT for GAD in older adults, Stanley et al¹⁹ reported smaller effect sizes compared with CBT for younger adults. Researchers have found relatively few differences between CBT and comparison conditions—supportive psychotherapy or active control conditions—in treating GAD in older adults.²¹ Modified, more effective formats of CBT for GAD in older adults need to be established.²² Mohlman et al²³ supplemented standard CBT for late-life GAD with memory and learning aids—weekly reading assignments, graphing exercises to chart mood ratings, reminder phone calls from therapists, and homework compliance requirement. This approach improved the response rate from 40% to 75%.²³

Insomnia. Studies have found CBT to be an effective means of treating insomnia in geriatric patients. Although sleep problems occur more frequently among older patients, only 15% of chronic insomnia patients receive treatment; psychotherapy rarely is used.²⁴ CBT for insomnia (CBT-I) should be considered for older adults because managing insomnia with medications may be problematic and these patients may prefer nonpharmacologic treatment.² CBT-I typically incorporates cognitive strategies with established behavioral techniques, including sleep hygiene education, cognitive restructuring, relaxation training, stimulus control, and/or sleep restriction. The CBT-I multicomponent treatment package meets all criteria to be considered an evidence-based treatment for late-life insomnia.²⁵

RCTs have reported significant improvements in late-life insomnia with CBT-I.^26,27 Reviews and meta-analyses have also concluded that cognitive-behavioral treatments are effective for treating insomnia in older adults.^25,28 Most insomnia cases in geriatric patients are reported to occur secondary to other medical or psychiatric conditions that are judged as causing the insomnia.²⁵ In these cases, direct treatment of the insomnia usually is delayed or omitted.²⁸ Studies evaluating the efficacy of CBT packages for treating insomnia occurring in conjunction with other medical or psychiatric illnesses have reported significant improvement of insomnia.^28,29 Because insomnia frequently occurs in older patients with medical illnesses and psychiatric disorders, CBT-I could be beneficial for such patients.

Good candidates for CBT

Clinical experience indicates that older adults in relatively good health with no significant cognitive decline are good candidates for CBT. These patients tend to comply with their assignments, are interested in applying the learned strategies, and are motivated to read self-help books. CBT’s structured, goal-oriented approach makes it a short-term treatment, which makes it cost effective. Insomnia patients may improve after 6 to 8 CBT-I sessions and patients with anxiety or depression may need to undergo 15 to 20 CBT sessions. Patients age ≥65 have basic Medicare coverage that includes mental health care and psychotherapy.

There are no absolute contraindications for CBT, but the greater the cognitive impairment, the less the patient will benefit from CBT (Table 2). Similarly, severe depression and anxiety might make it difficult for patients to participate meaningfully, although CBT may be incorporated gradually as patients improve with medication. Severe medical illnesses and sensory losses such as visual and hearing loss would make it difficult to carry out CBT effectively.

Table 2

Contraindications for CBT

Adapting CBT for older patients

When using CBT with older patients, it is important to keep in mind characteristics that define the geriatric population. Laidlaw et al³⁰ developed a model to help clinicians develop a more appropriate conceptualization of older patients that focuses on significant events and related cognitions associated with physical health, changes in role investments, and interactions with younger generations. It emphasizes the need to explore beliefs about aging viewed through each patient’s socio-cultural lens and examine cognitions in the context of the time period in which the individual has lived.

Losses and transitions. For many older patients, the latter years of life are characterized by losses and transitions.³¹ According to Thompson,³¹ these losses and transitions can trigger thoughts of missed opportunities or unresolved relationships and reflection on unachieved goals.³¹ CBT for older adults should focus on the meaning the patient gives to these losses and transitions. For example, depressed patients could view their retirement as a loss of self worth as they become less productive. CBT can help patients identify ways of thinking about the situation that will enable them to adapt to these losses and transitions.

Changes in cognition. Changes in cognitive functioning with aging are not universal and there’s considerable variability, but it’s important to make appropriate adaptations when needed. Patients may experience a decline in cognitive speed, working memory, selective attention, and fluid intelligence. This would require that information be presented slowly, with frequent repetitions and summaries. Also, it might be helpful to present information in alternate ways and to encourage patients to take notes during sessions. To accommodate for a decline in fluid intelligence, presenting new information in the context of previous experiences will help promote learning. Recordings of important information and conclusions from cognitive restructuring that patients can listen to between sessions could serve as helpful reminders that will help patients progress. Phone prompts or alarms can remind patients to carry out certain therapeutic measures, such as breathing exercises. Caretakers can attend sessions to become familiar with strategies performed during CBT and act as a co-therapist at home; however, their inclusion must be done with the consent of both parties and only if it’s viewed as necessary for the patient’s progress.

Additional strategies. For patients with substantial cognitive decline, cognitive restructuring might not be as effective as behavioral strategies—activity scheduling, graded task assignment, graded exposure, and rehearsals. Because older adults often have strengthened dysfunctional beliefs over a long time, modifying them takes longer, which is why the tapering process usually takes longer for older patients than for younger patients. The lengthier tapering ensures learning is well established and the process of modifying dysfunctional beliefs to functional beliefs continues. Collaborating with other professionals—physicians, social workers, and case managers—will help ensure a shared care process in which common goals are met.

The websites of the Academy of Cognitive Therapy, American Psychological Association, and Association for Behavioral and Cognitive Therapies can help clinicians who do not offer CBT to locate a qualified therapist for their patients (Related Resources).

Related Resources

• Academy of Cognitive Therapy. www.academyofct.org.
• American Psychological Association. www.apa.org.
• Association for Behavioral and Cognitive Therapies. www.abct.org.
• Laidlaw K, Thompson LW, Dick-Siskin L, et al. Cognitive behaviour therapy with older people. West Sussex, England: John Wiley & Sons, Ltd; 2003.

Drug Brand Name

• Desipramine • Norpramin

Disclosure

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

Some older patients with depression, anxiety, or insomnia may be reluctant to turn to pharmacotherapy and may prefer psychotherapeutic treatments.¹ Evidence has established cognitive-behavioral therapy (CBT) as an effective intervention for several psychiatric disorders and CBT should be considered when treating geriatric patients (Table 1).²

Table 1

Indications for CBT

Research evaluating the efficacy of CBT for depression in older adults was first published in the early 1980s. Since then, research and application of CBT with older adults has expanded to include other psychiatric disorders and researchers have suggested changes to increase the efficacy of CBT for these patients. This article provides:

• an overview of CBT’s efficacy for older adults with depression, anxiety, and insomnia
• modifications to employ when providing CBT to older patients.

The cognitive model of CBT

In the 1970s, Aaron T. Beck, MD, developed CBT while working with depressed patients. Beck’s patients reported thoughts characterized by inaccuracies and distortions in association with their depressed mood. He found these thoughts could be brought to the patient’s conscious attention and modified to improve the patient’s depression. This finding led to the development of CBT.

CBT is based on a cognitive model of the relationship among cognition, emotion, and behavior. Mood and behavior are viewed as determined by a person’s perception and interpretation of events, which manifest as a stream of automatically generated thoughts (Figure).³ These automatic thoughts have their origins in an underlying network of beliefs or schema. Patients with psychiatric disorders such as anxiety and depression typically have frequent automatic thoughts that characteristically lack validity because they arise from dysfunctional beliefs. The therapeutic process consists of helping the patient become aware of his or her internal stream of thoughts when distressed, and to identify and modify the dysfunctional thoughts. Behavioral techniques are used to bring about functional changes in behavior, regulate emotion, and help the cognitive restructuring process. Modifying the patient’s underlying dysfunctional beliefs leads to lasting improvements. In this structured therapy, the therapist and patient work collaboratively to use an approach that features reality testing and experimentation.⁴

Figure

The cognitive model of CBT

CBT: cognitive-behavioral therapy
Source: Adapted from reference 3

Indications for CBT in older adults

Depression. Among psychotherapies used in older adults, CBT has received the most research for late-life depression.⁵ Randomized controlled trials (RCTs) have found CBT is superior to treatment as usual in depressed adults age ≥60.⁶ It also has been found to be superior to wait-list control⁷ and talking as control.^6,8 Meta-analyses have shown above-average effect sizes for CBT in treating late-life depression.^9,10 A follow-up study found improvement was maintained up to 2 years after CBT, which suggests CBT’s impact is likely to be long lasting.¹¹

Thompson et al¹² compared 102 depressed patients age >60 who were treated with CBT alone, desipramine alone, or a combination of the 2. A combination of medication and CBT worked best for severely depressed patients; CBT alone or a combination of CBT and medication worked best for moderately depressed patients.

CBT is an option when treating depressed medically ill older adults. Research indicates that CBT could reduce depression in older patients with Parkinson’s disease¹³ and chronic obstructive pulmonary disease.¹⁴

As patients get older, cognitive impairment with comorbid depression can make treatment challenging. Limited research suggests CBT applied in a modified format that involves caregivers and uses problem solving and behavioral strategies can significantly reduce depression in patients with dementia.¹⁵

Anxiety. Researchers have examined the efficacy of variants of CBT in treating older adults with anxiety disorders—commonly, generalized anxiety disorder (GAD), panic disorder, agoraphobia, subjective anxiety, or a combination of these illnesses.^16,17 Randomized trials have supported CBT’s efficacy for older patients with GAD and mixed anxiety states; gains made in CBT were maintained over a 1-year follow-up.^18,19 In a meta-analysis of 15 studies using cognitive and behavioral methods of treating anxiety in older patients, Nordhus and Pallesen¹⁶ reported a significant effect size of 0.55. In a 2008 meta-analysis that included only RCTs, CBT was superior to wait-list conditions as well as active control conditions in treating anxious older patients.²⁰

However, some research suggests that CBT for GAD may not be as effective for older adults as it is for younger adults. In a study of CBT for GAD in older adults, Stanley et al¹⁹ reported smaller effect sizes compared with CBT for younger adults. Researchers have found relatively few differences between CBT and comparison conditions—supportive psychotherapy or active control conditions—in treating GAD in older adults.²¹ Modified, more effective formats of CBT for GAD in older adults need to be established.²² Mohlman et al²³ supplemented standard CBT for late-life GAD with memory and learning aids—weekly reading assignments, graphing exercises to chart mood ratings, reminder phone calls from therapists, and homework compliance requirement. This approach improved the response rate from 40% to 75%.²³

Insomnia. Studies have found CBT to be an effective means of treating insomnia in geriatric patients. Although sleep problems occur more frequently among older patients, only 15% of chronic insomnia patients receive treatment; psychotherapy rarely is used.²⁴ CBT for insomnia (CBT-I) should be considered for older adults because managing insomnia with medications may be problematic and these patients may prefer nonpharmacologic treatment.² CBT-I typically incorporates cognitive strategies with established behavioral techniques, including sleep hygiene education, cognitive restructuring, relaxation training, stimulus control, and/or sleep restriction. The CBT-I multicomponent treatment package meets all criteria to be considered an evidence-based treatment for late-life insomnia.²⁵

RCTs have reported significant improvements in late-life insomnia with CBT-I.^26,27 Reviews and meta-analyses have also concluded that cognitive-behavioral treatments are effective for treating insomnia in older adults.^25,28 Most insomnia cases in geriatric patients are reported to occur secondary to other medical or psychiatric conditions that are judged as causing the insomnia.²⁵ In these cases, direct treatment of the insomnia usually is delayed or omitted.²⁸ Studies evaluating the efficacy of CBT packages for treating insomnia occurring in conjunction with other medical or psychiatric illnesses have reported significant improvement of insomnia.^28,29 Because insomnia frequently occurs in older patients with medical illnesses and psychiatric disorders, CBT-I could be beneficial for such patients.

Good candidates for CBT

Clinical experience indicates that older adults in relatively good health with no significant cognitive decline are good candidates for CBT. These patients tend to comply with their assignments, are interested in applying the learned strategies, and are motivated to read self-help books. CBT’s structured, goal-oriented approach makes it a short-term treatment, which makes it cost effective. Insomnia patients may improve after 6 to 8 CBT-I sessions and patients with anxiety or depression may need to undergo 15 to 20 CBT sessions. Patients age ≥65 have basic Medicare coverage that includes mental health care and psychotherapy.

There are no absolute contraindications for CBT, but the greater the cognitive impairment, the less the patient will benefit from CBT (Table 2). Similarly, severe depression and anxiety might make it difficult for patients to participate meaningfully, although CBT may be incorporated gradually as patients improve with medication. Severe medical illnesses and sensory losses such as visual and hearing loss would make it difficult to carry out CBT effectively.

Table 2

Contraindications for CBT

Adapting CBT for older patients

When using CBT with older patients, it is important to keep in mind characteristics that define the geriatric population. Laidlaw et al³⁰ developed a model to help clinicians develop a more appropriate conceptualization of older patients that focuses on significant events and related cognitions associated with physical health, changes in role investments, and interactions with younger generations. It emphasizes the need to explore beliefs about aging viewed through each patient’s socio-cultural lens and examine cognitions in the context of the time period in which the individual has lived.

Losses and transitions. For many older patients, the latter years of life are characterized by losses and transitions.³¹ According to Thompson,³¹ these losses and transitions can trigger thoughts of missed opportunities or unresolved relationships and reflection on unachieved goals.³¹ CBT for older adults should focus on the meaning the patient gives to these losses and transitions. For example, depressed patients could view their retirement as a loss of self worth as they become less productive. CBT can help patients identify ways of thinking about the situation that will enable them to adapt to these losses and transitions.

Changes in cognition. Changes in cognitive functioning with aging are not universal and there’s considerable variability, but it’s important to make appropriate adaptations when needed. Patients may experience a decline in cognitive speed, working memory, selective attention, and fluid intelligence. This would require that information be presented slowly, with frequent repetitions and summaries. Also, it might be helpful to present information in alternate ways and to encourage patients to take notes during sessions. To accommodate for a decline in fluid intelligence, presenting new information in the context of previous experiences will help promote learning. Recordings of important information and conclusions from cognitive restructuring that patients can listen to between sessions could serve as helpful reminders that will help patients progress. Phone prompts or alarms can remind patients to carry out certain therapeutic measures, such as breathing exercises. Caretakers can attend sessions to become familiar with strategies performed during CBT and act as a co-therapist at home; however, their inclusion must be done with the consent of both parties and only if it’s viewed as necessary for the patient’s progress.

Additional strategies. For patients with substantial cognitive decline, cognitive restructuring might not be as effective as behavioral strategies—activity scheduling, graded task assignment, graded exposure, and rehearsals. Because older adults often have strengthened dysfunctional beliefs over a long time, modifying them takes longer, which is why the tapering process usually takes longer for older patients than for younger patients. The lengthier tapering ensures learning is well established and the process of modifying dysfunctional beliefs to functional beliefs continues. Collaborating with other professionals—physicians, social workers, and case managers—will help ensure a shared care process in which common goals are met.

The websites of the Academy of Cognitive Therapy, American Psychological Association, and Association for Behavioral and Cognitive Therapies can help clinicians who do not offer CBT to locate a qualified therapist for their patients (Related Resources).

Related Resources

• Academy of Cognitive Therapy. www.academyofct.org.
• American Psychological Association. www.apa.org.
• Association for Behavioral and Cognitive Therapies. www.abct.org.
• Laidlaw K, Thompson LW, Dick-Siskin L, et al. Cognitive behaviour therapy with older people. West Sussex, England: John Wiley & Sons, Ltd; 2003.

Drug Brand Name

• Desipramine • Norpramin

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Nauseous and full

Ms. O, age 48, presents to the emergency department reporting a 3-day history of vomiting approximately 5 minutes after consuming solids or liquids. She’s had 10 vomiting episodes, which were associated with “fullness” and an “aching” sensation she rates as 6 on a 10-point scale pain scale that is diffuse over the upper epigastric area, with no palliative factors. Ms. O has not had a bowel movement for 3 days and her last menstrual period was 8 days ago. She is taking lorazepam, 1 mg/d. Her medical and psychiatric history includes anxiety, depression, personality disorder symptoms of affective dysregulation, obesity (270 lbs; medium height), and pica. She was 352 lbs when she underwent a Roux-en-Y gastric bypass 2 years ago. One year earlier, she had a laparoscopic gastric bezoar removal and an incisional hernia repair. Ms. O had no pica-related surgeries before undergoing gastric bypass surgery.

Ms. O denies shortness of breath, chest pain, allergies, smoking, or alcohol abuse, but reports uncontrollable cravings for paper products, specifically cardboard, which she describes as “just so delicious.” This craving led her to consume large amounts of cardboard and newspaper in the days before she began vomiting.

What may be causing Ms. O’s pica symptoms?

1. iron deficiency anemia
2. complications from gastric bypass surgery
3. personality disorder
4. generalized anxiety disorder (GAD)

The authors’ observations

DSM-IV-TR diagnostic criteria for pica include the persistent eating of non-nutritive substances for ≥1 month that is inappropriate for the level of a person’s development and not an acceptable part of one’s culture.¹ If pica occurs with other mental disorders, it must be severe enough to indicate further clinical assessment to receive a separate diagnosis. Often associated with pregnancy, iron deficiency anemia, early development, and mental retardation, pica has been observed in post-gastric bypass surgery patients, all of whom presented with pagophagia (compulsive ice eating), and in one case was associated with a bezoar causing obstruction of the GI tract.^1,2 With the dramatic increase in gastric bypass surgery and the required presurgical mental health evaluation, the consequences of failing to screen patients for pica behaviors can be devastating.

EVALUATION: Low iron

Ms. O’s vital signs on admission are stable, and physical exam is notable for mild abdominal distention with no guarding, tenderness, rigidity, or masses. No rebound tenderness is elicited. CT scan shows evidence of post-surgical changes involving the small bowel consistent with gastric bypass surgery and a hiatal hernia, but no obstruction, focal inflammation, free fluids, or gas. Lab values for amylase, lipase, urinalysis, coagulation studies, cardiac enzymes, and complete metabolic profile are within normal limits. Although not anemic, Ms. O is iron deficient, with ferritin, 10 ng/mL (normal 10 to 120 ng/mL); B12, 299 pg/mL (normal 100 to 700 pg/mL); and iron, 25 μg/dL (normal 50 to 170 μg/dL).

A foreign body is removed endoscopically and the specimen is sent to pathology. It is determined to be a gastric bezoar, yellowish-green in color, measuring 2.5 cm × 1 cm × 0.8 cm. After bezoar removal, Ms. O tolerates food and is discharged home on vitamin B12, 1,000 mcg/d for 2 weeks; folate, 1 mg/d for 1 month; calcium with vitamin D, 1 g/d; and esomeprazole, 40 mg/d for frequent heartburn. She is referred to psychiatry for behavioral modification therapy and medication management.

How would you treat Ms. O?

1. start a selective serotonin reuptake inhibitor (SSRI)
2. prescribe an atypical antipsychotic
3. continue lorazepam
4. begin behavioral therapy

HISTORY: Pica during pregnancy

During psychiatric workup, Ms. O admits to having pica urges most of her life, but experienced an uncontrollable exacerbation after gastric bypass surgery. This led to intense, chaotic periods of pica, resulting in a previous bezoar removal. She is particularly attracted to cardboard and newspaper cartoons, but notes she also has felt the urge to eat charcoal, moist soil, clay, chalk, pencils, and new shoes, which she chews on. In the past, her extreme anxiety and preoccupation with these urges had lead to diagnoses of personality disorder not otherwise specified, GAD, and obsessive-compulsive disorder.

Her first experience with pica was during her first pregnancy at age 15, when she had an impulse to eat soil. The urges briefly stopped until she became pregnant again. During each of her 5 pregnancies her pica symptoms returned. At one point during her last pregnancy she reports having felt out of control, eating 2 to 3 pencils with the eraser per day, after which she would feel intense relaxation. Her mother also exhibited symptoms of pica toward charcoal and soil. Ms. O had been taking unknown dosages of lorazepam for anxiety and fluoxetine for depression, both of which she stopped because she feared side effects during her last pregnancy. However, she never experienced any side effects.

The authors’ observations

Although pica is most commonly observed in young children, it sometimes is seen in pregnant women.¹ Pica frequently is associated with other mental disorders, such as pervasive developmental disorder and mental retardation,¹ and can be associated with premorbid psychosis and anxiety disorders. Occasional vitamin and mineral deficiencies, such as iron or zinc, have been reported, but usually patients’ lab values are normal. Treatment usually is initiated in the context of medical complications, such as iron deficiency anemia. In Ms. O’s case, the precipitating event was mechanical bowel obstruction due to a bezoar.

Several theories about the origins of pica have been proposed, but none truly are explanatory or satisfactory. The nutritional theory—that patients eat non-nutritive substances to compensate for mineral deficiencies—is popular because of pica’s frequent association with mineral deficiencies, but it is unknown whether pica is the cause or the result of the deficiency. An example of this is anemia due to eating clay instead of foods that contain iron. Another theory is that because pica is normal in early childhood development, it may be a manifestation of delayed development or mental retardation. The cultural theory is attractive because pregnant women in several cultures eat starch or clay as a part of their native rituals, and the incidence of pica is relatively high among pregnant African American women who live in rural areas.³ In the Roux-en-Y procedure, bypass of the duodenum and proximal jejunum can significantly decrease a patient’s iron uptake, leading to iron deficiency anemia, and could trigger pica in a susceptible patient.⁴

Exacerbation after gastric bypass

Kushner et al⁴ describes re-emergent pica after bariatric surgery in 2 patients with pagophagia associated with concomitant iron deficiency anemia. A 41-year-old white woman presented with pagophagia and a history of childhood consumption of dirt, chalk, and clay. Another patient, a 34-year-old African American woman, suffered from a lifelong desire to eat dirt, which she was able to resist, but experienced pagophagia during pregnancy and later when she developed iron deficiency anemia.⁴ In another case series, Kushner et al⁵ describes a 35-year-old woman with iron deficiency anemia with pagophagia presenting 2 years after Roux-en-Y. Her history was significant for eating clay as a child, but this new-onset pagophagia was so intense she purchased 2 snow cone machines, one for home and one for work, to feed her urges. Another patient, a 45-year-old African American woman, had an irresistible craving for calcium carbonate antacids, eating 40 to 50 a day, as well as several 30-ounce cups of ice.⁵ A third case report details a 33-year-old woman with iron deficiency anemia who presented with nocturnal pagophagia after Roux-en-Y anastomosis. She repeatedly rose during the night to eat the frost off the ice maker in her refrigerator.⁶ Another case described a female patient who ate cardboard after having a Roux-en-Y.²

Common themes in these case reports are female sex, Roux-en-Y, and dramatic resurgence of previously noted pica behaviors after gastric bypass surgery. Several studies have shown that pagophagia and pica in patients who are iron deficient or have iron deficiency anemia can be rapidly curbed with iron supplements.⁵ Ms. O, who has low iron, is taking iron supplementation, yet continues to experience pica cravings, albeit less severely. Her pica could be psychiatric in origin, perhaps related to her history of anxiety.

OUTCOME: Combination therapy

We start Ms. O on ziprasidone, 80 mg twice a day, restart lorazepam, 1 mg/d, and schedule monthly follow-up appointments to monitor her pica symptoms. We prescribe ziprasidone because it could treat paranoia and preoccupations and is considered to be weight-neutral. She continues her supplements, including ferrous sulfate, 325 mg 3 times daily. Ms. O attends weekly behavioral therapy sessions, during which the therapist monitors her mood and cravings with response prevention, which entails purposely avoiding behaviors after initiating a distressing stimulus. Ms. O responds well to medication and psychotherapy 1 month after the gastric bezoar removal, and she reports a decreased urge to eat cardboard. She is able to increase the amount of time she can go without eating non-nutritive substances—once daily, rather than repeatedly throughout the day.

The authors’ observations

Each patient with pica likely needs customized care. Children need to be supervised to prevent ingestion of lead-containing substances such as paint chips. Iron supplements are recommended for iron deficiency anemia and prophylaxis for iron deficiency anemia in Roux-en-Y patients.^3,4 Pica in pregnant patients should be addressed to maintain adequate nutrition and prevent accidental poisonings.⁷ Behavioral intervention strategies are based on positive reinforcement and punishment (Table).⁸ A report of 3 young children with pica noted successful treatment of one with automatic reinforcement, and the other 2 with a combination of social and automatic reinforcement.⁹ There are no FDA-approved medications for pica. Positive effects have been seen with SSRIs, bupropion, atypical antipsychotics, buprenorphine, and chlorimipramine.¹⁰ Olanzapine has shown positive results as a treatment for pica.¹¹ Most pica patients need concurrent psychotherapy.¹⁰

Table

Behavioral interventions for pica

Related Resources

• Blinder BJ, Salama C. An update on pica: prevalence, contributing causes, and treatment. Psychiatric Times. www.psychiatrictimes.com/display/article/10168/1159376?pageNumber=1. Published May 1, 2008.
• Nurcombe B. Developmental disorders of attachment, feeding, elimination, & sleeping. In: Ebert MH, Loosen PT, Nurcombe B, et al, eds. CURRENT diagnosis & treatment: psychiatry. 2nd ed. New York, NY: McGraw Hill; 2008.

Drug Brand Names

• Buprenorphine • Subutex
• Bupropion • Wellbutrin, Zyban
• Chlorimipramine • Anafranil
• Esomeprazole • Nexium
• Fluoxetine • Prozac
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Nauseous and full

Ms. O, age 48, presents to the emergency department reporting a 3-day history of vomiting approximately 5 minutes after consuming solids or liquids. She’s had 10 vomiting episodes, which were associated with “fullness” and an “aching” sensation she rates as 6 on a 10-point scale pain scale that is diffuse over the upper epigastric area, with no palliative factors. Ms. O has not had a bowel movement for 3 days and her last menstrual period was 8 days ago. She is taking lorazepam, 1 mg/d. Her medical and psychiatric history includes anxiety, depression, personality disorder symptoms of affective dysregulation, obesity (270 lbs; medium height), and pica. She was 352 lbs when she underwent a Roux-en-Y gastric bypass 2 years ago. One year earlier, she had a laparoscopic gastric bezoar removal and an incisional hernia repair. Ms. O had no pica-related surgeries before undergoing gastric bypass surgery.

Ms. O denies shortness of breath, chest pain, allergies, smoking, or alcohol abuse, but reports uncontrollable cravings for paper products, specifically cardboard, which she describes as “just so delicious.” This craving led her to consume large amounts of cardboard and newspaper in the days before she began vomiting.

What may be causing Ms. O’s pica symptoms?

1. iron deficiency anemia
2. complications from gastric bypass surgery
3. personality disorder
4. generalized anxiety disorder (GAD)

The authors’ observations

DSM-IV-TR diagnostic criteria for pica include the persistent eating of non-nutritive substances for ≥1 month that is inappropriate for the level of a person’s development and not an acceptable part of one’s culture.¹ If pica occurs with other mental disorders, it must be severe enough to indicate further clinical assessment to receive a separate diagnosis. Often associated with pregnancy, iron deficiency anemia, early development, and mental retardation, pica has been observed in post-gastric bypass surgery patients, all of whom presented with pagophagia (compulsive ice eating), and in one case was associated with a bezoar causing obstruction of the GI tract.^1,2 With the dramatic increase in gastric bypass surgery and the required presurgical mental health evaluation, the consequences of failing to screen patients for pica behaviors can be devastating.

EVALUATION: Low iron

Ms. O’s vital signs on admission are stable, and physical exam is notable for mild abdominal distention with no guarding, tenderness, rigidity, or masses. No rebound tenderness is elicited. CT scan shows evidence of post-surgical changes involving the small bowel consistent with gastric bypass surgery and a hiatal hernia, but no obstruction, focal inflammation, free fluids, or gas. Lab values for amylase, lipase, urinalysis, coagulation studies, cardiac enzymes, and complete metabolic profile are within normal limits. Although not anemic, Ms. O is iron deficient, with ferritin, 10 ng/mL (normal 10 to 120 ng/mL); B12, 299 pg/mL (normal 100 to 700 pg/mL); and iron, 25 μg/dL (normal 50 to 170 μg/dL).

A foreign body is removed endoscopically and the specimen is sent to pathology. It is determined to be a gastric bezoar, yellowish-green in color, measuring 2.5 cm × 1 cm × 0.8 cm. After bezoar removal, Ms. O tolerates food and is discharged home on vitamin B12, 1,000 mcg/d for 2 weeks; folate, 1 mg/d for 1 month; calcium with vitamin D, 1 g/d; and esomeprazole, 40 mg/d for frequent heartburn. She is referred to psychiatry for behavioral modification therapy and medication management.

How would you treat Ms. O?

1. start a selective serotonin reuptake inhibitor (SSRI)
2. prescribe an atypical antipsychotic
3. continue lorazepam
4. begin behavioral therapy

HISTORY: Pica during pregnancy

During psychiatric workup, Ms. O admits to having pica urges most of her life, but experienced an uncontrollable exacerbation after gastric bypass surgery. This led to intense, chaotic periods of pica, resulting in a previous bezoar removal. She is particularly attracted to cardboard and newspaper cartoons, but notes she also has felt the urge to eat charcoal, moist soil, clay, chalk, pencils, and new shoes, which she chews on. In the past, her extreme anxiety and preoccupation with these urges had lead to diagnoses of personality disorder not otherwise specified, GAD, and obsessive-compulsive disorder.

Her first experience with pica was during her first pregnancy at age 15, when she had an impulse to eat soil. The urges briefly stopped until she became pregnant again. During each of her 5 pregnancies her pica symptoms returned. At one point during her last pregnancy she reports having felt out of control, eating 2 to 3 pencils with the eraser per day, after which she would feel intense relaxation. Her mother also exhibited symptoms of pica toward charcoal and soil. Ms. O had been taking unknown dosages of lorazepam for anxiety and fluoxetine for depression, both of which she stopped because she feared side effects during her last pregnancy. However, she never experienced any side effects.

The authors’ observations

Although pica is most commonly observed in young children, it sometimes is seen in pregnant women.¹ Pica frequently is associated with other mental disorders, such as pervasive developmental disorder and mental retardation,¹ and can be associated with premorbid psychosis and anxiety disorders. Occasional vitamin and mineral deficiencies, such as iron or zinc, have been reported, but usually patients’ lab values are normal. Treatment usually is initiated in the context of medical complications, such as iron deficiency anemia. In Ms. O’s case, the precipitating event was mechanical bowel obstruction due to a bezoar.

Several theories about the origins of pica have been proposed, but none truly are explanatory or satisfactory. The nutritional theory—that patients eat non-nutritive substances to compensate for mineral deficiencies—is popular because of pica’s frequent association with mineral deficiencies, but it is unknown whether pica is the cause or the result of the deficiency. An example of this is anemia due to eating clay instead of foods that contain iron. Another theory is that because pica is normal in early childhood development, it may be a manifestation of delayed development or mental retardation. The cultural theory is attractive because pregnant women in several cultures eat starch or clay as a part of their native rituals, and the incidence of pica is relatively high among pregnant African American women who live in rural areas.³ In the Roux-en-Y procedure, bypass of the duodenum and proximal jejunum can significantly decrease a patient’s iron uptake, leading to iron deficiency anemia, and could trigger pica in a susceptible patient.⁴

Exacerbation after gastric bypass

Kushner et al⁴ describes re-emergent pica after bariatric surgery in 2 patients with pagophagia associated with concomitant iron deficiency anemia. A 41-year-old white woman presented with pagophagia and a history of childhood consumption of dirt, chalk, and clay. Another patient, a 34-year-old African American woman, suffered from a lifelong desire to eat dirt, which she was able to resist, but experienced pagophagia during pregnancy and later when she developed iron deficiency anemia.⁴ In another case series, Kushner et al⁵ describes a 35-year-old woman with iron deficiency anemia with pagophagia presenting 2 years after Roux-en-Y. Her history was significant for eating clay as a child, but this new-onset pagophagia was so intense she purchased 2 snow cone machines, one for home and one for work, to feed her urges. Another patient, a 45-year-old African American woman, had an irresistible craving for calcium carbonate antacids, eating 40 to 50 a day, as well as several 30-ounce cups of ice.⁵ A third case report details a 33-year-old woman with iron deficiency anemia who presented with nocturnal pagophagia after Roux-en-Y anastomosis. She repeatedly rose during the night to eat the frost off the ice maker in her refrigerator.⁶ Another case described a female patient who ate cardboard after having a Roux-en-Y.²

Common themes in these case reports are female sex, Roux-en-Y, and dramatic resurgence of previously noted pica behaviors after gastric bypass surgery. Several studies have shown that pagophagia and pica in patients who are iron deficient or have iron deficiency anemia can be rapidly curbed with iron supplements.⁵ Ms. O, who has low iron, is taking iron supplementation, yet continues to experience pica cravings, albeit less severely. Her pica could be psychiatric in origin, perhaps related to her history of anxiety.

OUTCOME: Combination therapy

We start Ms. O on ziprasidone, 80 mg twice a day, restart lorazepam, 1 mg/d, and schedule monthly follow-up appointments to monitor her pica symptoms. We prescribe ziprasidone because it could treat paranoia and preoccupations and is considered to be weight-neutral. She continues her supplements, including ferrous sulfate, 325 mg 3 times daily. Ms. O attends weekly behavioral therapy sessions, during which the therapist monitors her mood and cravings with response prevention, which entails purposely avoiding behaviors after initiating a distressing stimulus. Ms. O responds well to medication and psychotherapy 1 month after the gastric bezoar removal, and she reports a decreased urge to eat cardboard. She is able to increase the amount of time she can go without eating non-nutritive substances—once daily, rather than repeatedly throughout the day.

The authors’ observations

Each patient with pica likely needs customized care. Children need to be supervised to prevent ingestion of lead-containing substances such as paint chips. Iron supplements are recommended for iron deficiency anemia and prophylaxis for iron deficiency anemia in Roux-en-Y patients.^3,4 Pica in pregnant patients should be addressed to maintain adequate nutrition and prevent accidental poisonings.⁷ Behavioral intervention strategies are based on positive reinforcement and punishment (Table).⁸ A report of 3 young children with pica noted successful treatment of one with automatic reinforcement, and the other 2 with a combination of social and automatic reinforcement.⁹ There are no FDA-approved medications for pica. Positive effects have been seen with SSRIs, bupropion, atypical antipsychotics, buprenorphine, and chlorimipramine.¹⁰ Olanzapine has shown positive results as a treatment for pica.¹¹ Most pica patients need concurrent psychotherapy.¹⁰

Table

Behavioral interventions for pica

Related Resources

• Blinder BJ, Salama C. An update on pica: prevalence, contributing causes, and treatment. Psychiatric Times. www.psychiatrictimes.com/display/article/10168/1159376?pageNumber=1. Published May 1, 2008.
• Nurcombe B. Developmental disorders of attachment, feeding, elimination, & sleeping. In: Ebert MH, Loosen PT, Nurcombe B, et al, eds. CURRENT diagnosis & treatment: psychiatry. 2nd ed. New York, NY: McGraw Hill; 2008.

Drug Brand Names

• Buprenorphine • Subutex
• Bupropion • Wellbutrin, Zyban
• Chlorimipramine • Anafranil
• Esomeprazole • Nexium
• Fluoxetine • Prozac
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Nauseous and full

Ms. O, age 48, presents to the emergency department reporting a 3-day history of vomiting approximately 5 minutes after consuming solids or liquids. She’s had 10 vomiting episodes, which were associated with “fullness” and an “aching” sensation she rates as 6 on a 10-point scale pain scale that is diffuse over the upper epigastric area, with no palliative factors. Ms. O has not had a bowel movement for 3 days and her last menstrual period was 8 days ago. She is taking lorazepam, 1 mg/d. Her medical and psychiatric history includes anxiety, depression, personality disorder symptoms of affective dysregulation, obesity (270 lbs; medium height), and pica. She was 352 lbs when she underwent a Roux-en-Y gastric bypass 2 years ago. One year earlier, she had a laparoscopic gastric bezoar removal and an incisional hernia repair. Ms. O had no pica-related surgeries before undergoing gastric bypass surgery.

Ms. O denies shortness of breath, chest pain, allergies, smoking, or alcohol abuse, but reports uncontrollable cravings for paper products, specifically cardboard, which she describes as “just so delicious.” This craving led her to consume large amounts of cardboard and newspaper in the days before she began vomiting.

What may be causing Ms. O’s pica symptoms?

1. iron deficiency anemia
2. complications from gastric bypass surgery
3. personality disorder
4. generalized anxiety disorder (GAD)

The authors’ observations

DSM-IV-TR diagnostic criteria for pica include the persistent eating of non-nutritive substances for ≥1 month that is inappropriate for the level of a person’s development and not an acceptable part of one’s culture.¹ If pica occurs with other mental disorders, it must be severe enough to indicate further clinical assessment to receive a separate diagnosis. Often associated with pregnancy, iron deficiency anemia, early development, and mental retardation, pica has been observed in post-gastric bypass surgery patients, all of whom presented with pagophagia (compulsive ice eating), and in one case was associated with a bezoar causing obstruction of the GI tract.^1,2 With the dramatic increase in gastric bypass surgery and the required presurgical mental health evaluation, the consequences of failing to screen patients for pica behaviors can be devastating.

EVALUATION: Low iron

Ms. O’s vital signs on admission are stable, and physical exam is notable for mild abdominal distention with no guarding, tenderness, rigidity, or masses. No rebound tenderness is elicited. CT scan shows evidence of post-surgical changes involving the small bowel consistent with gastric bypass surgery and a hiatal hernia, but no obstruction, focal inflammation, free fluids, or gas. Lab values for amylase, lipase, urinalysis, coagulation studies, cardiac enzymes, and complete metabolic profile are within normal limits. Although not anemic, Ms. O is iron deficient, with ferritin, 10 ng/mL (normal 10 to 120 ng/mL); B12, 299 pg/mL (normal 100 to 700 pg/mL); and iron, 25 μg/dL (normal 50 to 170 μg/dL).

A foreign body is removed endoscopically and the specimen is sent to pathology. It is determined to be a gastric bezoar, yellowish-green in color, measuring 2.5 cm × 1 cm × 0.8 cm. After bezoar removal, Ms. O tolerates food and is discharged home on vitamin B12, 1,000 mcg/d for 2 weeks; folate, 1 mg/d for 1 month; calcium with vitamin D, 1 g/d; and esomeprazole, 40 mg/d for frequent heartburn. She is referred to psychiatry for behavioral modification therapy and medication management.

How would you treat Ms. O?

1. start a selective serotonin reuptake inhibitor (SSRI)
2. prescribe an atypical antipsychotic
3. continue lorazepam
4. begin behavioral therapy

HISTORY: Pica during pregnancy

During psychiatric workup, Ms. O admits to having pica urges most of her life, but experienced an uncontrollable exacerbation after gastric bypass surgery. This led to intense, chaotic periods of pica, resulting in a previous bezoar removal. She is particularly attracted to cardboard and newspaper cartoons, but notes she also has felt the urge to eat charcoal, moist soil, clay, chalk, pencils, and new shoes, which she chews on. In the past, her extreme anxiety and preoccupation with these urges had lead to diagnoses of personality disorder not otherwise specified, GAD, and obsessive-compulsive disorder.

Her first experience with pica was during her first pregnancy at age 15, when she had an impulse to eat soil. The urges briefly stopped until she became pregnant again. During each of her 5 pregnancies her pica symptoms returned. At one point during her last pregnancy she reports having felt out of control, eating 2 to 3 pencils with the eraser per day, after which she would feel intense relaxation. Her mother also exhibited symptoms of pica toward charcoal and soil. Ms. O had been taking unknown dosages of lorazepam for anxiety and fluoxetine for depression, both of which she stopped because she feared side effects during her last pregnancy. However, she never experienced any side effects.

The authors’ observations

Although pica is most commonly observed in young children, it sometimes is seen in pregnant women.¹ Pica frequently is associated with other mental disorders, such as pervasive developmental disorder and mental retardation,¹ and can be associated with premorbid psychosis and anxiety disorders. Occasional vitamin and mineral deficiencies, such as iron or zinc, have been reported, but usually patients’ lab values are normal. Treatment usually is initiated in the context of medical complications, such as iron deficiency anemia. In Ms. O’s case, the precipitating event was mechanical bowel obstruction due to a bezoar.

Several theories about the origins of pica have been proposed, but none truly are explanatory or satisfactory. The nutritional theory—that patients eat non-nutritive substances to compensate for mineral deficiencies—is popular because of pica’s frequent association with mineral deficiencies, but it is unknown whether pica is the cause or the result of the deficiency. An example of this is anemia due to eating clay instead of foods that contain iron. Another theory is that because pica is normal in early childhood development, it may be a manifestation of delayed development or mental retardation. The cultural theory is attractive because pregnant women in several cultures eat starch or clay as a part of their native rituals, and the incidence of pica is relatively high among pregnant African American women who live in rural areas.³ In the Roux-en-Y procedure, bypass of the duodenum and proximal jejunum can significantly decrease a patient’s iron uptake, leading to iron deficiency anemia, and could trigger pica in a susceptible patient.⁴

Exacerbation after gastric bypass

Kushner et al⁴ describes re-emergent pica after bariatric surgery in 2 patients with pagophagia associated with concomitant iron deficiency anemia. A 41-year-old white woman presented with pagophagia and a history of childhood consumption of dirt, chalk, and clay. Another patient, a 34-year-old African American woman, suffered from a lifelong desire to eat dirt, which she was able to resist, but experienced pagophagia during pregnancy and later when she developed iron deficiency anemia.⁴ In another case series, Kushner et al⁵ describes a 35-year-old woman with iron deficiency anemia with pagophagia presenting 2 years after Roux-en-Y. Her history was significant for eating clay as a child, but this new-onset pagophagia was so intense she purchased 2 snow cone machines, one for home and one for work, to feed her urges. Another patient, a 45-year-old African American woman, had an irresistible craving for calcium carbonate antacids, eating 40 to 50 a day, as well as several 30-ounce cups of ice.⁵ A third case report details a 33-year-old woman with iron deficiency anemia who presented with nocturnal pagophagia after Roux-en-Y anastomosis. She repeatedly rose during the night to eat the frost off the ice maker in her refrigerator.⁶ Another case described a female patient who ate cardboard after having a Roux-en-Y.²

Common themes in these case reports are female sex, Roux-en-Y, and dramatic resurgence of previously noted pica behaviors after gastric bypass surgery. Several studies have shown that pagophagia and pica in patients who are iron deficient or have iron deficiency anemia can be rapidly curbed with iron supplements.⁵ Ms. O, who has low iron, is taking iron supplementation, yet continues to experience pica cravings, albeit less severely. Her pica could be psychiatric in origin, perhaps related to her history of anxiety.

OUTCOME: Combination therapy

We start Ms. O on ziprasidone, 80 mg twice a day, restart lorazepam, 1 mg/d, and schedule monthly follow-up appointments to monitor her pica symptoms. We prescribe ziprasidone because it could treat paranoia and preoccupations and is considered to be weight-neutral. She continues her supplements, including ferrous sulfate, 325 mg 3 times daily. Ms. O attends weekly behavioral therapy sessions, during which the therapist monitors her mood and cravings with response prevention, which entails purposely avoiding behaviors after initiating a distressing stimulus. Ms. O responds well to medication and psychotherapy 1 month after the gastric bezoar removal, and she reports a decreased urge to eat cardboard. She is able to increase the amount of time she can go without eating non-nutritive substances—once daily, rather than repeatedly throughout the day.

The authors’ observations

Each patient with pica likely needs customized care. Children need to be supervised to prevent ingestion of lead-containing substances such as paint chips. Iron supplements are recommended for iron deficiency anemia and prophylaxis for iron deficiency anemia in Roux-en-Y patients.^3,4 Pica in pregnant patients should be addressed to maintain adequate nutrition and prevent accidental poisonings.⁷ Behavioral intervention strategies are based on positive reinforcement and punishment (Table).⁸ A report of 3 young children with pica noted successful treatment of one with automatic reinforcement, and the other 2 with a combination of social and automatic reinforcement.⁹ There are no FDA-approved medications for pica. Positive effects have been seen with SSRIs, bupropion, atypical antipsychotics, buprenorphine, and chlorimipramine.¹⁰ Olanzapine has shown positive results as a treatment for pica.¹¹ Most pica patients need concurrent psychotherapy.¹⁰

Table

Behavioral interventions for pica

Related Resources

• Blinder BJ, Salama C. An update on pica: prevalence, contributing causes, and treatment. Psychiatric Times. www.psychiatrictimes.com/display/article/10168/1159376?pageNumber=1. Published May 1, 2008.
• Nurcombe B. Developmental disorders of attachment, feeding, elimination, & sleeping. In: Ebert MH, Loosen PT, Nurcombe B, et al, eds. CURRENT diagnosis & treatment: psychiatry. 2nd ed. New York, NY: McGraw Hill; 2008.

Drug Brand Names

• Buprenorphine • Subutex
• Bupropion • Wellbutrin, Zyban
• Chlorimipramine • Anafranil
• Esomeprazole • Nexium
• Fluoxetine • Prozac
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected]. 

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected]. 

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected]. 

ANSWER
The radiograph shows a lucency within the lateral tibial plateau and tibial metaphysis, consistent with a fracture. It is mildly depressed and slightly comminuted.

Fluid collection is also evident on the lateral view, likely reflecting a lipohemarthrosis. The patient was placed in a knee immobilizer and made non–weight-bearing. She was instructed to follow up with an orthopedist when she returned home (as she was visiting from out of town).

ANSWER
The radiograph shows a lucency within the lateral tibial plateau and tibial metaphysis, consistent with a fracture. It is mildly depressed and slightly comminuted.

Fluid collection is also evident on the lateral view, likely reflecting a lipohemarthrosis. The patient was placed in a knee immobilizer and made non–weight-bearing. She was instructed to follow up with an orthopedist when she returned home (as she was visiting from out of town).

ANSWER
The radiograph shows a lucency within the lateral tibial plateau and tibial metaphysis, consistent with a fracture. It is mildly depressed and slightly comminuted.

Fluid collection is also evident on the lateral view, likely reflecting a lipohemarthrosis. The patient was placed in a knee immobilizer and made non–weight-bearing. She was instructed to follow up with an orthopedist when she returned home (as she was visiting from out of town).

ANSWER
This ECG is remarkable for ventricular pacing at a rate of 70 beats/min, with an underlying sinus rhythm at the same rate as the pacemaker but dissociated from ventricular pacing. Ventricular pacing is evidenced by the presence of a pacing spike before each QRS complex, and the fact that each QRS complex in all leads is wide (200 ms) and does not demonstrate variability within an ECG lead. The T waves are similar in each lead as well. A left-axis deviation of –83° is attributable to pacing from the right ventricle.

What is interesting to note is that P waves are visible and are at a rate very close to that of the ventricular paced beats; however, they show no association with the pacing spike or the QRS complexes. This is most evident in lead V₁ and the rhythm strip of lead I, which shows the P waves marching through the QRS and T-wave complexes without being associated with any ventricular conduction. This is an unusual situation in which the sinus rate and the paced ventricular rate are very similar. 

Interrogation of the pacemaker generator revealed that the programming had been inadvertently changed from DDDR at a rate of 60 beats/min to VVI at a rate of 70 beats/min. After the device was reprogrammed to its original settings, the patient’s symptoms resolved.

ANSWER
This ECG is remarkable for ventricular pacing at a rate of 70 beats/min, with an underlying sinus rhythm at the same rate as the pacemaker but dissociated from ventricular pacing. Ventricular pacing is evidenced by the presence of a pacing spike before each QRS complex, and the fact that each QRS complex in all leads is wide (200 ms) and does not demonstrate variability within an ECG lead. The T waves are similar in each lead as well. A left-axis deviation of –83° is attributable to pacing from the right ventricle.

What is interesting to note is that P waves are visible and are at a rate very close to that of the ventricular paced beats; however, they show no association with the pacing spike or the QRS complexes. This is most evident in lead V₁ and the rhythm strip of lead I, which shows the P waves marching through the QRS and T-wave complexes without being associated with any ventricular conduction. This is an unusual situation in which the sinus rate and the paced ventricular rate are very similar. 

Interrogation of the pacemaker generator revealed that the programming had been inadvertently changed from DDDR at a rate of 60 beats/min to VVI at a rate of 70 beats/min. After the device was reprogrammed to its original settings, the patient’s symptoms resolved.

ANSWER
This ECG is remarkable for ventricular pacing at a rate of 70 beats/min, with an underlying sinus rhythm at the same rate as the pacemaker but dissociated from ventricular pacing. Ventricular pacing is evidenced by the presence of a pacing spike before each QRS complex, and the fact that each QRS complex in all leads is wide (200 ms) and does not demonstrate variability within an ECG lead. The T waves are similar in each lead as well. A left-axis deviation of –83° is attributable to pacing from the right ventricle.

What is interesting to note is that P waves are visible and are at a rate very close to that of the ventricular paced beats; however, they show no association with the pacing spike or the QRS complexes. This is most evident in lead V₁ and the rhythm strip of lead I, which shows the P waves marching through the QRS and T-wave complexes without being associated with any ventricular conduction. This is an unusual situation in which the sinus rate and the paced ventricular rate are very similar. 

Interrogation of the pacemaker generator revealed that the programming had been inadvertently changed from DDDR at a rate of 60 beats/min to VVI at a rate of 70 beats/min. After the device was reprogrammed to its original settings, the patient’s symptoms resolved.

ANSWER
The correct answer is pityriasis rosea (PR; choice “d”), which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

Lichen planus (LP; choice “a”) can mimic PR but lacks the peculiar centripetal scale and oval shape. Furthermore, it does not present with a herald patch.

Guttate psoriasis (choice “b”) could easily be confused for PR. However, it displays heavier white uniform scales with a salmon-pink base, tends to have a distinctly round configuration, and does not involve the appearance of a herald patch.

Secondary syphilis (choice “c”) can usually be ruled out by the sexual history, but also by the lack of a herald patch and the absence of centripetal scaling. Highly variable in appearance, the lesions of secondary syphilis are often seen on the palms.

DISCUSSION
PR was first described in 1860 by Camille Gibert, who used the term pityriasis to describe the fine scale seen with this condition, and chose the term rosea to denote the rosy or pink color.

For a variety of reasons, PR is assumed to be a viral exanthema since, as with many such eruptions, its incidence clusters in the fall and spring, it occurs in close contacts and families, and it is commonly seen in immunocompromised patients. In addition, acquiring the condition appears to confer lifelong immunity.

However, the jury is still out with regard to the exact virus responsible for the disease. Human herpesviruses 6 and 7 are the strongest candidates in terms of antibody production, but no herpesviral particles have been detected in tissue samples.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.” In the author’s experience, the most consistent diagnostic finding is the centripetal scaling seen in at least a few lesions.

Since secondary syphilis is a major item in the differential, obtaining a careful sexual history is essential. If this is uncertain, or if the lesions are not a good fit for PR, obtaining a punch biopsy and serum rapid plasma reagin is necessary. The biopsy in secondary syphilis will show an infiltrate largely composed of plasma cells.

TREATMENT
Once the diagnosis of PR is made, patient education is essential. Affected patients should be reassured about the benign and self-limiting nature of the problem, but also about the likelihood that the condition will persist for up to nine weeks. Darker-skinned patients need to understand that the hyperpigmentation will last for months after the condition has resolved.

Relief of the itching experienced by 75% of PR patients can be achieved with topical steroids (eg, triamcinolone 0.1% cream) and oral antihistamines at bedtime (eg, hydroxyzine 25 to 50 mg) and/or during the daytime (cetirizine 10 mg/d), plus the liberal use of soothing OTC lotions (eg, those containing camphor and menthol). Systemic steroids appear to prolong the condition and are not terribly helpful in controlling the symptoms. In severe cases, phototherapy (narrow-band UVB) can be useful in controlling the itching.

ANSWER
The correct answer is pityriasis rosea (PR; choice “d”), which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

Lichen planus (LP; choice “a”) can mimic PR but lacks the peculiar centripetal scale and oval shape. Furthermore, it does not present with a herald patch.

Guttate psoriasis (choice “b”) could easily be confused for PR. However, it displays heavier white uniform scales with a salmon-pink base, tends to have a distinctly round configuration, and does not involve the appearance of a herald patch.

Secondary syphilis (choice “c”) can usually be ruled out by the sexual history, but also by the lack of a herald patch and the absence of centripetal scaling. Highly variable in appearance, the lesions of secondary syphilis are often seen on the palms.

DISCUSSION
PR was first described in 1860 by Camille Gibert, who used the term pityriasis to describe the fine scale seen with this condition, and chose the term rosea to denote the rosy or pink color.

For a variety of reasons, PR is assumed to be a viral exanthema since, as with many such eruptions, its incidence clusters in the fall and spring, it occurs in close contacts and families, and it is commonly seen in immunocompromised patients. In addition, acquiring the condition appears to confer lifelong immunity.

However, the jury is still out with regard to the exact virus responsible for the disease. Human herpesviruses 6 and 7 are the strongest candidates in terms of antibody production, but no herpesviral particles have been detected in tissue samples.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.” In the author’s experience, the most consistent diagnostic finding is the centripetal scaling seen in at least a few lesions.

Since secondary syphilis is a major item in the differential, obtaining a careful sexual history is essential. If this is uncertain, or if the lesions are not a good fit for PR, obtaining a punch biopsy and serum rapid plasma reagin is necessary. The biopsy in secondary syphilis will show an infiltrate largely composed of plasma cells.

TREATMENT
Once the diagnosis of PR is made, patient education is essential. Affected patients should be reassured about the benign and self-limiting nature of the problem, but also about the likelihood that the condition will persist for up to nine weeks. Darker-skinned patients need to understand that the hyperpigmentation will last for months after the condition has resolved.

Relief of the itching experienced by 75% of PR patients can be achieved with topical steroids (eg, triamcinolone 0.1% cream) and oral antihistamines at bedtime (eg, hydroxyzine 25 to 50 mg) and/or during the daytime (cetirizine 10 mg/d), plus the liberal use of soothing OTC lotions (eg, those containing camphor and menthol). Systemic steroids appear to prolong the condition and are not terribly helpful in controlling the symptoms. In severe cases, phototherapy (narrow-band UVB) can be useful in controlling the itching.

ANSWER
The correct answer is pityriasis rosea (PR; choice “d”), which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

Lichen planus (LP; choice “a”) can mimic PR but lacks the peculiar centripetal scale and oval shape. Furthermore, it does not present with a herald patch.

Guttate psoriasis (choice “b”) could easily be confused for PR. However, it displays heavier white uniform scales with a salmon-pink base, tends to have a distinctly round configuration, and does not involve the appearance of a herald patch.

Secondary syphilis (choice “c”) can usually be ruled out by the sexual history, but also by the lack of a herald patch and the absence of centripetal scaling. Highly variable in appearance, the lesions of secondary syphilis are often seen on the palms.

DISCUSSION
PR was first described in 1860 by Camille Gibert, who used the term pityriasis to describe the fine scale seen with this condition, and chose the term rosea to denote the rosy or pink color.

For a variety of reasons, PR is assumed to be a viral exanthema since, as with many such eruptions, its incidence clusters in the fall and spring, it occurs in close contacts and families, and it is commonly seen in immunocompromised patients. In addition, acquiring the condition appears to confer lifelong immunity.

However, the jury is still out with regard to the exact virus responsible for the disease. Human herpesviruses 6 and 7 are the strongest candidates in terms of antibody production, but no herpesviral particles have been detected in tissue samples.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.” In the author’s experience, the most consistent diagnostic finding is the centripetal scaling seen in at least a few lesions.

Since secondary syphilis is a major item in the differential, obtaining a careful sexual history is essential. If this is uncertain, or if the lesions are not a good fit for PR, obtaining a punch biopsy and serum rapid plasma reagin is necessary. The biopsy in secondary syphilis will show an infiltrate largely composed of plasma cells.

TREATMENT
Once the diagnosis of PR is made, patient education is essential. Affected patients should be reassured about the benign and self-limiting nature of the problem, but also about the likelihood that the condition will persist for up to nine weeks. Darker-skinned patients need to understand that the hyperpigmentation will last for months after the condition has resolved.

Relief of the itching experienced by 75% of PR patients can be achieved with topical steroids (eg, triamcinolone 0.1% cream) and oral antihistamines at bedtime (eg, hydroxyzine 25 to 50 mg) and/or during the daytime (cetirizine 10 mg/d), plus the liberal use of soothing OTC lotions (eg, those containing camphor and menthol). Systemic steroids appear to prolong the condition and are not terribly helpful in controlling the symptoms. In severe cases, phototherapy (narrow-band UVB) can be useful in controlling the itching.

With the looming federal "sequestration" threatening drastic spending cuts, our nation’s leaders are finally confronting the main drivers of our deficit dilemma: government "entitlement" programs such as Social Security, Medicare, and Medicaid.

Meanwhile, there is broad consensus that many of our runaway health care costs are avoidable. Our current fee-for-service health care payment system rewards higher-intensity care in greater volume, with no consequence for lack of coordination. It is a significant reason that our health care system is fragmented, inefficient, and too costly.

Federal government receipts total approximately 19% of our nation’s gross domestic product. Yet if our health care spending trends remain unchecked, by 2035 Medicare and Medicaid alone are predicted to consume 13% of GDP. By 2080, Medicare and Medicaid will consume all federal taxes, while total public and private health spending will claim almost 50% of GDP. We will have to borrow to pay for the rest of the federal government’s obligations: defense, education, transportation, etc.

As of 2012, our nation is already $16 trillion in the hole and counting. Sticking with the status quo would be a disastrous choice.

However, if medical providers work together and accept new payment incentives that reward value instead of volume, we can help fix America’s broken health care system.

That cannot be done remotely in Washington. It requires health care providers in each community cooperating to increase health care quality and cut cumulative costs.

Quality, savings, and patient satisfaction all must be achieved for providers to receive incentive payments under the new health care payment model, called "value-based reimbursement."

There is plenty of waste to be found and eliminated. Last summer, the Institute of Medicine concluded that America wastes about 30% of its health care spending – some $750 billion a year – on unneeded care, excessive paperwork, fraud, and other inefficiencies.

With basic health care becoming unaffordable for many ordinary working families and individuals, that amount of waste is unacceptable.

Although no one can hope to eradicate it overnight, it’s time somebody did something about it. America is asking physicians to step up and form teams, teams such as accountable care organizations.

By doing so, you can help ensure access, improve patient care, promote efficiency, stretch health care dollars, and make patients more of a partner in their treatment. ACOs typically receive 50% of the savings they create, which should be considered compensation to you for professional services.

As healers with a calling to serve, you have an opportunity to do your part to enhance patient care while helping to improve our nation’s fiscal health. Besides empowering, and paying, physicians to regain control of the physician/patient relationship, your patients, your profession, and your nation need you.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected], or at 919-821-6612.

With the looming federal "sequestration" threatening drastic spending cuts, our nation’s leaders are finally confronting the main drivers of our deficit dilemma: government "entitlement" programs such as Social Security, Medicare, and Medicaid.

Meanwhile, there is broad consensus that many of our runaway health care costs are avoidable. Our current fee-for-service health care payment system rewards higher-intensity care in greater volume, with no consequence for lack of coordination. It is a significant reason that our health care system is fragmented, inefficient, and too costly.

Federal government receipts total approximately 19% of our nation’s gross domestic product. Yet if our health care spending trends remain unchecked, by 2035 Medicare and Medicaid alone are predicted to consume 13% of GDP. By 2080, Medicare and Medicaid will consume all federal taxes, while total public and private health spending will claim almost 50% of GDP. We will have to borrow to pay for the rest of the federal government’s obligations: defense, education, transportation, etc.

As of 2012, our nation is already $16 trillion in the hole and counting. Sticking with the status quo would be a disastrous choice.

However, if medical providers work together and accept new payment incentives that reward value instead of volume, we can help fix America’s broken health care system.

That cannot be done remotely in Washington. It requires health care providers in each community cooperating to increase health care quality and cut cumulative costs.

Quality, savings, and patient satisfaction all must be achieved for providers to receive incentive payments under the new health care payment model, called "value-based reimbursement."

There is plenty of waste to be found and eliminated. Last summer, the Institute of Medicine concluded that America wastes about 30% of its health care spending – some $750 billion a year – on unneeded care, excessive paperwork, fraud, and other inefficiencies.

With basic health care becoming unaffordable for many ordinary working families and individuals, that amount of waste is unacceptable.

Although no one can hope to eradicate it overnight, it’s time somebody did something about it. America is asking physicians to step up and form teams, teams such as accountable care organizations.

By doing so, you can help ensure access, improve patient care, promote efficiency, stretch health care dollars, and make patients more of a partner in their treatment. ACOs typically receive 50% of the savings they create, which should be considered compensation to you for professional services.

As healers with a calling to serve, you have an opportunity to do your part to enhance patient care while helping to improve our nation’s fiscal health. Besides empowering, and paying, physicians to regain control of the physician/patient relationship, your patients, your profession, and your nation need you.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected], or at 919-821-6612.

With the looming federal "sequestration" threatening drastic spending cuts, our nation’s leaders are finally confronting the main drivers of our deficit dilemma: government "entitlement" programs such as Social Security, Medicare, and Medicaid.

Meanwhile, there is broad consensus that many of our runaway health care costs are avoidable. Our current fee-for-service health care payment system rewards higher-intensity care in greater volume, with no consequence for lack of coordination. It is a significant reason that our health care system is fragmented, inefficient, and too costly.

Federal government receipts total approximately 19% of our nation’s gross domestic product. Yet if our health care spending trends remain unchecked, by 2035 Medicare and Medicaid alone are predicted to consume 13% of GDP. By 2080, Medicare and Medicaid will consume all federal taxes, while total public and private health spending will claim almost 50% of GDP. We will have to borrow to pay for the rest of the federal government’s obligations: defense, education, transportation, etc.

As of 2012, our nation is already $16 trillion in the hole and counting. Sticking with the status quo would be a disastrous choice.

However, if medical providers work together and accept new payment incentives that reward value instead of volume, we can help fix America’s broken health care system.

That cannot be done remotely in Washington. It requires health care providers in each community cooperating to increase health care quality and cut cumulative costs.

Quality, savings, and patient satisfaction all must be achieved for providers to receive incentive payments under the new health care payment model, called "value-based reimbursement."

There is plenty of waste to be found and eliminated. Last summer, the Institute of Medicine concluded that America wastes about 30% of its health care spending – some $750 billion a year – on unneeded care, excessive paperwork, fraud, and other inefficiencies.

With basic health care becoming unaffordable for many ordinary working families and individuals, that amount of waste is unacceptable.

Although no one can hope to eradicate it overnight, it’s time somebody did something about it. America is asking physicians to step up and form teams, teams such as accountable care organizations.

By doing so, you can help ensure access, improve patient care, promote efficiency, stretch health care dollars, and make patients more of a partner in their treatment. ACOs typically receive 50% of the savings they create, which should be considered compensation to you for professional services.

As healers with a calling to serve, you have an opportunity to do your part to enhance patient care while helping to improve our nation’s fiscal health. Besides empowering, and paying, physicians to regain control of the physician/patient relationship, your patients, your profession, and your nation need you.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected], or at 919-821-6612.

Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

[email protected]

Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

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Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

[email protected]

Despite all the discussion of meaningful use of EHRs to earn federal incentives, what physicians seem most frustrated with is the lack of optimal use of their EHRs. In this podcast, Dr. Skolnik and Dr. Notte talk about what you can do to optimize your EHR and make your interactions with it easier and more effective throughout the clinical day.

To download the podcast, right-click here.

To read the related column, click here.

To listen via this Web page, click on the player below:

Despite all the discussion of meaningful use of EHRs to earn federal incentives, what physicians seem most frustrated with is the lack of optimal use of their EHRs. In this podcast, Dr. Skolnik and Dr. Notte talk about what you can do to optimize your EHR and make your interactions with it easier and more effective throughout the clinical day.

To download the podcast, right-click here.

To read the related column, click here.

To listen via this Web page, click on the player below:

Despite all the discussion of meaningful use of EHRs to earn federal incentives, what physicians seem most frustrated with is the lack of optimal use of their EHRs. In this podcast, Dr. Skolnik and Dr. Notte talk about what you can do to optimize your EHR and make your interactions with it easier and more effective throughout the clinical day.

To download the podcast, right-click here.

To read the related column, click here.

To listen via this Web page, click on the player below: