Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

Disruptive mood dysregulation disorder (DMDD)—a childhood condition of extreme irritability, anger, and frequent, intense temper outbursts—has been a source of controversy among clinicians in the field of pediatric mental health. Before DSM-5 was published, the validity of DMDD had been questioned because DMDD had failed a field trial; agreement between clinicians on the diagnosis of DMDD was poor.¹ Axelson² and Birmaher et al³ examined its validity in their COBY (Course and Outcome of Bipolar Youth) sample. They concluded that only 19% met the criteria for DMDD in 3 times of follow-up. Furthermore, most DMDD criteria overlap with those of other common pediatric psychiatric disorders, including oppositional defiant disorder (ODD), attention-deficit/hyperactivity disorder (ADHD), and pediatric bipolar disorder (BD). Because diagnosis of pediatric BD increased drastically from 2.9% to 15.1% between 1990 and 2000,⁴ it was believed that introducing DMDD as a diagnosis might lessen the overdiagnosis of pediatric BD by identifying children with chronic irritability and temper tantrums who previously would have been diagnosed with BD.

It is important to recognize that in pediatric patients, mood disorders present differently than they do in adults.⁵ In children/adolescents, mood disorders are less likely to present as distinct episodes (narrow band), but more likely to present as chronic, broad symptoms. Also, irritability is a common presentation in many pediatric psychiatric disorders, such as ODD, BD (irritability without elation),⁶ and depression. Thus, for many clinicians, determining the correct mood disorder diagnosis in pediatric patients can be challenging.

This article describes the diagnosis of DMDD, and how its presentation is similar to—and different from—those of other common pediatric psychiatric disorders.

_

The origin of DMDD

Many researchers have investigated the broadband phenotypical presentation of pediatric mood disorders, which have been mostly diagnosed in the psychiatric community as pediatric BD. Leibenluft⁷ identified a subtype of mood disorder that they termed “severe mood dysregulation” (SMD). Compared with the narrow-band, clearly episodic BD, SMD has a different trajectory, outcome, and findings on brain imaging. SMD is characterized by chronic irritability with abnormal mood (anger or sadness) at least half of the day on most days, with 3 hyperarousal symptoms, including pressured speech, racing thoughts or flight of ideas, intrusiveness, distractibility, insomnia, and agitation.⁸ Eventually, SMD became the foundation of the development of DMDD.

DSM-5 diagnostic criteria for DMDD include severe recurrent temper outbursts that are out of proportion to the situation, inconsistent with developmental level, and occurring on average ≥3 times per week, plus persistently irritable or angry mood for most of the day nearly every day.⁹ Additional criteria include the presence of symptoms for at least 12 months (without a symptom-free period of at least 3 consecutive months) in ≥2 settings (at home, at school, or with peers) with onset before age 10. The course of DMDD typically is chronic with accompanying severe temperament. The estimated 6-month to 1-year prevalence is 2% to 5%; the diagnosis is more common among males and school-age children than it is in females and adolescents.^9,10

_

DMDD or bipolar disorder?

A patient cannot be dually diagnosed with both disorders. If a patient exhibits a manic episode for more than 1 day, that would null and void the DMDD diagnosis. However, in a study to evaluate BD in pediatric patients, researchers divided BD symptoms into BD-specific categories (elevated mood, grandiosity, and increased goal-directed activity) and nonspecific symptoms such as irritability and talkativeness, distractibility, and flight of ideas or racing thoughts. They found that in the absence of specific symptoms, a diagnosis of BD is unlikely to be the correct diagnosis.¹¹ Hence, as a nonspecific symptom, chronic irritability should be attributed to the symptom count for DMDD, rather than BD. Most epidemiologic studies have concluded that depression and anxiety, and not irritability, are typically the preceeding presentations prior to the development of BD in young adults.¹² Chronic irritability, however, predicts major depressive disorder and anxiety disorders in later adolescence and one’s early twenties.¹³ Furthermore, BD commonly presents with infrequent and discrete episodes and a later age of onset, while DMDD presents with chronic and frequent, severe temper outbursts. Some differences between DMDD and BD are illustrated in Table 1.^11-13

Continue to: CASE 1

Ms. N, age 16, is brought to the outpatient psychiatry clinic by her parents for evaluation of mood symptoms, including irritability. Her mother claims her daughter was an introverted, anxious, shy child, but by the beginning of middle school, she began to feel irritable and frequently stayed up at night with little sleep. In high school, Ms. N had displayed several episodes of risk-taking behaviors, including taking her father’s vehicle for a drive despite not having a driver’s permit, running away for 2 days, and having unprotected sex.

During her assessment, Ms. N is pleasant and claims she usually has a great mood. She fought with her mother several times this year, which led her to run away. Her parents had divorced when Ms. N was 5 years old and have shared custody. Ms. N is doing well in school despite her parents’ concerns.

Diagnosis. The most likely diagnosis is emerging BD. Notice that Ms. N may have had anxiety symptoms before she developed irritability. She had a relatively late onset of symptoms that were episodic in nature, which further supports a diagnosis of BD.

_

>

DMDD or oppositional defiant disorder?

DMDD and ODD cannot be dually diagnosed. However, if a patient meets the criteria for both DMDD and ODD, only the DMDD diagnosis should be considered. One of many issues of DMDD is its similarity to ODD. In fact, more than 70% of patients with DMDD also meet the diagnostic criteria for ODD.^10,14 Some researchers have conceptualized DMDD as a severe form of ODD. However, there are a few differences that clinicians can use to distinguish the 2 disorders.

Compared with patients with ODD, those with DMDD more frequently experience severe irritability.¹⁵ Patients with ODD may present with delinquent behaviors and trouble with authority figures. Moreover, comorbidity with ADHD is twice as common in ODD; more than 65% of patients with ADHD have ODD vs 30% who have DMDD.^10,16 Finally, in general, children with DMDD have more social impairments compared with those with ODD. Differences between DMDD and BD are illustrated in Table 2.^10,14-16

Continue to: CASE 2

Mr. R, age 14, is brought to the emergency department (ED) by his parents after becoming very aggressive with them. He punched a wall and vandalized his room after his parents grounded him because of his previous defiant behavior. He had been suspended from school that day for disrespecting his teacher after he was caught fighting another student.

His parents describe Mr. R as a strong-willed, stubborn child. He has difficulty with rules and refuses to follow them. He is grouchy and irritable around adults, including the ED staff. Mr. R enjoys being with his friends and playing video games. He had been diagnosed with ADHD when he was in kindergarten, when his teacher noticed he had a poor attention span and could not sit still. According to his parents, Mr. R has “blown up” a few times before, smashing items in his room and shouting obscenities. Mr. R’s parents noticed that he is more defiant in concurrence with discontinuing his ADHD stimulant medication.

Diagnosis. The most likely diagnosis for Mr. R is ODD. Notice the comorbidity of ADHD, which is more commonly associated with ODD. The frequency and severity of his outbursts and irritability symptoms were lower than that typically associated with DMDD.

_

Treatment strategies for DMDD

Management of DMDD should focus on helping children and adolescents improve their emotional dysregulation.

Clinicians should always consider behavioral therapy as a first-line intervention. The behavioral planning team may include (but is not limited to) a behavior specialist, child psychiatrist, psychologist, therapist, skills trainer, teachers, and the caregiver(s). The plan should be implemented across all settings, including home and school. Furthermore, social skills training is necessary for many children with DMDD, who may require intensive behavioral modification planning. Comorbidity with ADHD should be addressed with a combination of behavioral planning and stimulant medications.¹⁷ If available, parent training and parent-child interactive therapy can help to improve defiant behavior.

Pharmacotherapy
Currently, no medications are FDA-approved for treating DMDD. Most pharmacologic trials that included patients with DMDD focused on managing chronic irritability and/or stabilizing comorbid disorders (ie, ADHD, depression, and anxiety).

Continue to: Stimulants

Stimulants. Previous trials examined the benefit of CNS stimulant medications, alone or in conjunction with behavioral therapy, in treating DMDD and comorbid ADHD. Methylphenidate results in a significant reduction in aggression¹⁸ with a dosing recommendation range from 1 to 1.2 mg/kg/d. CNS stimulants should be considered as first-line pharmacotherapy for DMDD, especially for patients with comorbid ADHD.

Anticonvulsants. Divalproex sodium is superior to placebo in treating aggression in children and adolescents.¹⁹ Trials found that divalproex sodium reduces irritability and aggression whether it is prescribed as monotherapy or combined with stimulant medications.¹⁹

Lithium is one of the main treatment options for mania in BD. The benefits of lithium for controlling aggression in DMDD are still under investigation. Earlier studies found that lithium significantly improves aggressive behavior in hospitalized pediatric with conduct disorder.^20,21 However, a later study that evaluated lithium vs placebo for children with SMD (which arguably is phenotypically related to the DMDD) found there were no significant differences in improvement of irritability symptoms between groups.²² More research is needed to determine if lithium may play a role in treating patients with DMDD.

Antipsychotics. Aripiprazole and risperidone are FDA-approved for treating irritability in autism. A 2017 meta-analysis found both medications were effective in controlling irritability and aggression in other diagnoses as well.²³ Other antipsychotic medications did not show sufficient benefits in treating irritability.²³ When considering antipsychotics, clinicians should weigh the risks of metabolic adverse effects and follow practice guidelines.

Antidepressants. A systematic review did not find that selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors effectively reduce irritability.²⁴ However, in most of the studies evaluated, irritability was not the primary outcome measure.²⁴

Other medications. Alpha-2 agonists (guanfacine, clonidine), and atomoxetine may help irritability indirectly by improving ADHD symptoms.²⁵

Bottom Line

Disruptive mood dysregulation disorder (DMDD), bipolar disorder, and oppositional defiant disorder have similar presentations and diagnostic criteria. The frequency and severity of irritability can be a distinguishing factor. Behavioral therapy is a first-line treatment. No medications are FDA-approved for treating DMDD, but pharmacotherapy may help reduce irritability and aggression.

Related Resources

• Rao U. DSM-5: disruptive mood dysregulation disorder. Asian J Psychiatr. 2014;11:119-123.
• Roy AK, Lopes V, Klein RG. Disruptive mood dysregulation disorder: a new diagnostic approach to chronic irritability in youth. Am J Psychiatry. 2014;171(9):918-924.

Drug Brand Names
Aripiprazole • Abilify
Atomoxetine • Strattera
Clonidine • Catapres
Divalproex sodium • Depakote, Depakote ER
Guanfacine • Intuniv, Tenex
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta, Ritalin
Risperidone • Risperdal

Disruptive mood dysregulation disorder (DMDD)—a childhood condition of extreme irritability, anger, and frequent, intense temper outbursts—has been a source of controversy among clinicians in the field of pediatric mental health. Before DSM-5 was published, the validity of DMDD had been questioned because DMDD had failed a field trial; agreement between clinicians on the diagnosis of DMDD was poor.¹ Axelson² and Birmaher et al³ examined its validity in their COBY (Course and Outcome of Bipolar Youth) sample. They concluded that only 19% met the criteria for DMDD in 3 times of follow-up. Furthermore, most DMDD criteria overlap with those of other common pediatric psychiatric disorders, including oppositional defiant disorder (ODD), attention-deficit/hyperactivity disorder (ADHD), and pediatric bipolar disorder (BD). Because diagnosis of pediatric BD increased drastically from 2.9% to 15.1% between 1990 and 2000,⁴ it was believed that introducing DMDD as a diagnosis might lessen the overdiagnosis of pediatric BD by identifying children with chronic irritability and temper tantrums who previously would have been diagnosed with BD.

It is important to recognize that in pediatric patients, mood disorders present differently than they do in adults.⁵ In children/adolescents, mood disorders are less likely to present as distinct episodes (narrow band), but more likely to present as chronic, broad symptoms. Also, irritability is a common presentation in many pediatric psychiatric disorders, such as ODD, BD (irritability without elation),⁶ and depression. Thus, for many clinicians, determining the correct mood disorder diagnosis in pediatric patients can be challenging.

This article describes the diagnosis of DMDD, and how its presentation is similar to—and different from—those of other common pediatric psychiatric disorders.

_

The origin of DMDD

Many researchers have investigated the broadband phenotypical presentation of pediatric mood disorders, which have been mostly diagnosed in the psychiatric community as pediatric BD. Leibenluft⁷ identified a subtype of mood disorder that they termed “severe mood dysregulation” (SMD). Compared with the narrow-band, clearly episodic BD, SMD has a different trajectory, outcome, and findings on brain imaging. SMD is characterized by chronic irritability with abnormal mood (anger or sadness) at least half of the day on most days, with 3 hyperarousal symptoms, including pressured speech, racing thoughts or flight of ideas, intrusiveness, distractibility, insomnia, and agitation.⁸ Eventually, SMD became the foundation of the development of DMDD.

DSM-5 diagnostic criteria for DMDD include severe recurrent temper outbursts that are out of proportion to the situation, inconsistent with developmental level, and occurring on average ≥3 times per week, plus persistently irritable or angry mood for most of the day nearly every day.⁹ Additional criteria include the presence of symptoms for at least 12 months (without a symptom-free period of at least 3 consecutive months) in ≥2 settings (at home, at school, or with peers) with onset before age 10. The course of DMDD typically is chronic with accompanying severe temperament. The estimated 6-month to 1-year prevalence is 2% to 5%; the diagnosis is more common among males and school-age children than it is in females and adolescents.^9,10

_

DMDD or bipolar disorder?

A patient cannot be dually diagnosed with both disorders. If a patient exhibits a manic episode for more than 1 day, that would null and void the DMDD diagnosis. However, in a study to evaluate BD in pediatric patients, researchers divided BD symptoms into BD-specific categories (elevated mood, grandiosity, and increased goal-directed activity) and nonspecific symptoms such as irritability and talkativeness, distractibility, and flight of ideas or racing thoughts. They found that in the absence of specific symptoms, a diagnosis of BD is unlikely to be the correct diagnosis.¹¹ Hence, as a nonspecific symptom, chronic irritability should be attributed to the symptom count for DMDD, rather than BD. Most epidemiologic studies have concluded that depression and anxiety, and not irritability, are typically the preceeding presentations prior to the development of BD in young adults.¹² Chronic irritability, however, predicts major depressive disorder and anxiety disorders in later adolescence and one’s early twenties.¹³ Furthermore, BD commonly presents with infrequent and discrete episodes and a later age of onset, while DMDD presents with chronic and frequent, severe temper outbursts. Some differences between DMDD and BD are illustrated in Table 1.^11-13

Continue to: CASE 1

Ms. N, age 16, is brought to the outpatient psychiatry clinic by her parents for evaluation of mood symptoms, including irritability. Her mother claims her daughter was an introverted, anxious, shy child, but by the beginning of middle school, she began to feel irritable and frequently stayed up at night with little sleep. In high school, Ms. N had displayed several episodes of risk-taking behaviors, including taking her father’s vehicle for a drive despite not having a driver’s permit, running away for 2 days, and having unprotected sex.

During her assessment, Ms. N is pleasant and claims she usually has a great mood. She fought with her mother several times this year, which led her to run away. Her parents had divorced when Ms. N was 5 years old and have shared custody. Ms. N is doing well in school despite her parents’ concerns.

Diagnosis. The most likely diagnosis is emerging BD. Notice that Ms. N may have had anxiety symptoms before she developed irritability. She had a relatively late onset of symptoms that were episodic in nature, which further supports a diagnosis of BD.

_

>

DMDD or oppositional defiant disorder?

DMDD and ODD cannot be dually diagnosed. However, if a patient meets the criteria for both DMDD and ODD, only the DMDD diagnosis should be considered. One of many issues of DMDD is its similarity to ODD. In fact, more than 70% of patients with DMDD also meet the diagnostic criteria for ODD.^10,14 Some researchers have conceptualized DMDD as a severe form of ODD. However, there are a few differences that clinicians can use to distinguish the 2 disorders.

Compared with patients with ODD, those with DMDD more frequently experience severe irritability.¹⁵ Patients with ODD may present with delinquent behaviors and trouble with authority figures. Moreover, comorbidity with ADHD is twice as common in ODD; more than 65% of patients with ADHD have ODD vs 30% who have DMDD.^10,16 Finally, in general, children with DMDD have more social impairments compared with those with ODD. Differences between DMDD and BD are illustrated in Table 2.^10,14-16

Continue to: CASE 2

Mr. R, age 14, is brought to the emergency department (ED) by his parents after becoming very aggressive with them. He punched a wall and vandalized his room after his parents grounded him because of his previous defiant behavior. He had been suspended from school that day for disrespecting his teacher after he was caught fighting another student.

His parents describe Mr. R as a strong-willed, stubborn child. He has difficulty with rules and refuses to follow them. He is grouchy and irritable around adults, including the ED staff. Mr. R enjoys being with his friends and playing video games. He had been diagnosed with ADHD when he was in kindergarten, when his teacher noticed he had a poor attention span and could not sit still. According to his parents, Mr. R has “blown up” a few times before, smashing items in his room and shouting obscenities. Mr. R’s parents noticed that he is more defiant in concurrence with discontinuing his ADHD stimulant medication.

Diagnosis. The most likely diagnosis for Mr. R is ODD. Notice the comorbidity of ADHD, which is more commonly associated with ODD. The frequency and severity of his outbursts and irritability symptoms were lower than that typically associated with DMDD.

_

Treatment strategies for DMDD

Management of DMDD should focus on helping children and adolescents improve their emotional dysregulation.

Clinicians should always consider behavioral therapy as a first-line intervention. The behavioral planning team may include (but is not limited to) a behavior specialist, child psychiatrist, psychologist, therapist, skills trainer, teachers, and the caregiver(s). The plan should be implemented across all settings, including home and school. Furthermore, social skills training is necessary for many children with DMDD, who may require intensive behavioral modification planning. Comorbidity with ADHD should be addressed with a combination of behavioral planning and stimulant medications.¹⁷ If available, parent training and parent-child interactive therapy can help to improve defiant behavior.

Pharmacotherapy
Currently, no medications are FDA-approved for treating DMDD. Most pharmacologic trials that included patients with DMDD focused on managing chronic irritability and/or stabilizing comorbid disorders (ie, ADHD, depression, and anxiety).

Continue to: Stimulants

Stimulants. Previous trials examined the benefit of CNS stimulant medications, alone or in conjunction with behavioral therapy, in treating DMDD and comorbid ADHD. Methylphenidate results in a significant reduction in aggression¹⁸ with a dosing recommendation range from 1 to 1.2 mg/kg/d. CNS stimulants should be considered as first-line pharmacotherapy for DMDD, especially for patients with comorbid ADHD.

Anticonvulsants. Divalproex sodium is superior to placebo in treating aggression in children and adolescents.¹⁹ Trials found that divalproex sodium reduces irritability and aggression whether it is prescribed as monotherapy or combined with stimulant medications.¹⁹

Lithium is one of the main treatment options for mania in BD. The benefits of lithium for controlling aggression in DMDD are still under investigation. Earlier studies found that lithium significantly improves aggressive behavior in hospitalized pediatric with conduct disorder.^20,21 However, a later study that evaluated lithium vs placebo for children with SMD (which arguably is phenotypically related to the DMDD) found there were no significant differences in improvement of irritability symptoms between groups.²² More research is needed to determine if lithium may play a role in treating patients with DMDD.

Antipsychotics. Aripiprazole and risperidone are FDA-approved for treating irritability in autism. A 2017 meta-analysis found both medications were effective in controlling irritability and aggression in other diagnoses as well.²³ Other antipsychotic medications did not show sufficient benefits in treating irritability.²³ When considering antipsychotics, clinicians should weigh the risks of metabolic adverse effects and follow practice guidelines.

Antidepressants. A systematic review did not find that selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors effectively reduce irritability.²⁴ However, in most of the studies evaluated, irritability was not the primary outcome measure.²⁴

Other medications. Alpha-2 agonists (guanfacine, clonidine), and atomoxetine may help irritability indirectly by improving ADHD symptoms.²⁵

Bottom Line

Disruptive mood dysregulation disorder (DMDD), bipolar disorder, and oppositional defiant disorder have similar presentations and diagnostic criteria. The frequency and severity of irritability can be a distinguishing factor. Behavioral therapy is a first-line treatment. No medications are FDA-approved for treating DMDD, but pharmacotherapy may help reduce irritability and aggression.

Related Resources

• Rao U. DSM-5: disruptive mood dysregulation disorder. Asian J Psychiatr. 2014;11:119-123.
• Roy AK, Lopes V, Klein RG. Disruptive mood dysregulation disorder: a new diagnostic approach to chronic irritability in youth. Am J Psychiatry. 2014;171(9):918-924.

Drug Brand Names
Aripiprazole • Abilify
Atomoxetine • Strattera
Clonidine • Catapres
Divalproex sodium • Depakote, Depakote ER
Guanfacine • Intuniv, Tenex
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta, Ritalin
Risperidone • Risperdal

Disruptive mood dysregulation disorder (DMDD)—a childhood condition of extreme irritability, anger, and frequent, intense temper outbursts—has been a source of controversy among clinicians in the field of pediatric mental health. Before DSM-5 was published, the validity of DMDD had been questioned because DMDD had failed a field trial; agreement between clinicians on the diagnosis of DMDD was poor.¹ Axelson² and Birmaher et al³ examined its validity in their COBY (Course and Outcome of Bipolar Youth) sample. They concluded that only 19% met the criteria for DMDD in 3 times of follow-up. Furthermore, most DMDD criteria overlap with those of other common pediatric psychiatric disorders, including oppositional defiant disorder (ODD), attention-deficit/hyperactivity disorder (ADHD), and pediatric bipolar disorder (BD). Because diagnosis of pediatric BD increased drastically from 2.9% to 15.1% between 1990 and 2000,⁴ it was believed that introducing DMDD as a diagnosis might lessen the overdiagnosis of pediatric BD by identifying children with chronic irritability and temper tantrums who previously would have been diagnosed with BD.

It is important to recognize that in pediatric patients, mood disorders present differently than they do in adults.⁵ In children/adolescents, mood disorders are less likely to present as distinct episodes (narrow band), but more likely to present as chronic, broad symptoms. Also, irritability is a common presentation in many pediatric psychiatric disorders, such as ODD, BD (irritability without elation),⁶ and depression. Thus, for many clinicians, determining the correct mood disorder diagnosis in pediatric patients can be challenging.

This article describes the diagnosis of DMDD, and how its presentation is similar to—and different from—those of other common pediatric psychiatric disorders.

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The origin of DMDD

Many researchers have investigated the broadband phenotypical presentation of pediatric mood disorders, which have been mostly diagnosed in the psychiatric community as pediatric BD. Leibenluft⁷ identified a subtype of mood disorder that they termed “severe mood dysregulation” (SMD). Compared with the narrow-band, clearly episodic BD, SMD has a different trajectory, outcome, and findings on brain imaging. SMD is characterized by chronic irritability with abnormal mood (anger or sadness) at least half of the day on most days, with 3 hyperarousal symptoms, including pressured speech, racing thoughts or flight of ideas, intrusiveness, distractibility, insomnia, and agitation.⁸ Eventually, SMD became the foundation of the development of DMDD.

DSM-5 diagnostic criteria for DMDD include severe recurrent temper outbursts that are out of proportion to the situation, inconsistent with developmental level, and occurring on average ≥3 times per week, plus persistently irritable or angry mood for most of the day nearly every day.⁹ Additional criteria include the presence of symptoms for at least 12 months (without a symptom-free period of at least 3 consecutive months) in ≥2 settings (at home, at school, or with peers) with onset before age 10. The course of DMDD typically is chronic with accompanying severe temperament. The estimated 6-month to 1-year prevalence is 2% to 5%; the diagnosis is more common among males and school-age children than it is in females and adolescents.^9,10

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DMDD or bipolar disorder?

A patient cannot be dually diagnosed with both disorders. If a patient exhibits a manic episode for more than 1 day, that would null and void the DMDD diagnosis. However, in a study to evaluate BD in pediatric patients, researchers divided BD symptoms into BD-specific categories (elevated mood, grandiosity, and increased goal-directed activity) and nonspecific symptoms such as irritability and talkativeness, distractibility, and flight of ideas or racing thoughts. They found that in the absence of specific symptoms, a diagnosis of BD is unlikely to be the correct diagnosis.¹¹ Hence, as a nonspecific symptom, chronic irritability should be attributed to the symptom count for DMDD, rather than BD. Most epidemiologic studies have concluded that depression and anxiety, and not irritability, are typically the preceeding presentations prior to the development of BD in young adults.¹² Chronic irritability, however, predicts major depressive disorder and anxiety disorders in later adolescence and one’s early twenties.¹³ Furthermore, BD commonly presents with infrequent and discrete episodes and a later age of onset, while DMDD presents with chronic and frequent, severe temper outbursts. Some differences between DMDD and BD are illustrated in Table 1.^11-13

Continue to: CASE 1

Ms. N, age 16, is brought to the outpatient psychiatry clinic by her parents for evaluation of mood symptoms, including irritability. Her mother claims her daughter was an introverted, anxious, shy child, but by the beginning of middle school, she began to feel irritable and frequently stayed up at night with little sleep. In high school, Ms. N had displayed several episodes of risk-taking behaviors, including taking her father’s vehicle for a drive despite not having a driver’s permit, running away for 2 days, and having unprotected sex.

During her assessment, Ms. N is pleasant and claims she usually has a great mood. She fought with her mother several times this year, which led her to run away. Her parents had divorced when Ms. N was 5 years old and have shared custody. Ms. N is doing well in school despite her parents’ concerns.

Diagnosis. The most likely diagnosis is emerging BD. Notice that Ms. N may have had anxiety symptoms before she developed irritability. She had a relatively late onset of symptoms that were episodic in nature, which further supports a diagnosis of BD.

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DMDD or oppositional defiant disorder?

DMDD and ODD cannot be dually diagnosed. However, if a patient meets the criteria for both DMDD and ODD, only the DMDD diagnosis should be considered. One of many issues of DMDD is its similarity to ODD. In fact, more than 70% of patients with DMDD also meet the diagnostic criteria for ODD.^10,14 Some researchers have conceptualized DMDD as a severe form of ODD. However, there are a few differences that clinicians can use to distinguish the 2 disorders.

Compared with patients with ODD, those with DMDD more frequently experience severe irritability.¹⁵ Patients with ODD may present with delinquent behaviors and trouble with authority figures. Moreover, comorbidity with ADHD is twice as common in ODD; more than 65% of patients with ADHD have ODD vs 30% who have DMDD.^10,16 Finally, in general, children with DMDD have more social impairments compared with those with ODD. Differences between DMDD and BD are illustrated in Table 2.^10,14-16

Continue to: CASE 2

Mr. R, age 14, is brought to the emergency department (ED) by his parents after becoming very aggressive with them. He punched a wall and vandalized his room after his parents grounded him because of his previous defiant behavior. He had been suspended from school that day for disrespecting his teacher after he was caught fighting another student.

His parents describe Mr. R as a strong-willed, stubborn child. He has difficulty with rules and refuses to follow them. He is grouchy and irritable around adults, including the ED staff. Mr. R enjoys being with his friends and playing video games. He had been diagnosed with ADHD when he was in kindergarten, when his teacher noticed he had a poor attention span and could not sit still. According to his parents, Mr. R has “blown up” a few times before, smashing items in his room and shouting obscenities. Mr. R’s parents noticed that he is more defiant in concurrence with discontinuing his ADHD stimulant medication.

Diagnosis. The most likely diagnosis for Mr. R is ODD. Notice the comorbidity of ADHD, which is more commonly associated with ODD. The frequency and severity of his outbursts and irritability symptoms were lower than that typically associated with DMDD.

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Treatment strategies for DMDD

Management of DMDD should focus on helping children and adolescents improve their emotional dysregulation.

Clinicians should always consider behavioral therapy as a first-line intervention. The behavioral planning team may include (but is not limited to) a behavior specialist, child psychiatrist, psychologist, therapist, skills trainer, teachers, and the caregiver(s). The plan should be implemented across all settings, including home and school. Furthermore, social skills training is necessary for many children with DMDD, who may require intensive behavioral modification planning. Comorbidity with ADHD should be addressed with a combination of behavioral planning and stimulant medications.¹⁷ If available, parent training and parent-child interactive therapy can help to improve defiant behavior.

Pharmacotherapy
Currently, no medications are FDA-approved for treating DMDD. Most pharmacologic trials that included patients with DMDD focused on managing chronic irritability and/or stabilizing comorbid disorders (ie, ADHD, depression, and anxiety).

Continue to: Stimulants

Stimulants. Previous trials examined the benefit of CNS stimulant medications, alone or in conjunction with behavioral therapy, in treating DMDD and comorbid ADHD. Methylphenidate results in a significant reduction in aggression¹⁸ with a dosing recommendation range from 1 to 1.2 mg/kg/d. CNS stimulants should be considered as first-line pharmacotherapy for DMDD, especially for patients with comorbid ADHD.

Anticonvulsants. Divalproex sodium is superior to placebo in treating aggression in children and adolescents.¹⁹ Trials found that divalproex sodium reduces irritability and aggression whether it is prescribed as monotherapy or combined with stimulant medications.¹⁹

Lithium is one of the main treatment options for mania in BD. The benefits of lithium for controlling aggression in DMDD are still under investigation. Earlier studies found that lithium significantly improves aggressive behavior in hospitalized pediatric with conduct disorder.^20,21 However, a later study that evaluated lithium vs placebo for children with SMD (which arguably is phenotypically related to the DMDD) found there were no significant differences in improvement of irritability symptoms between groups.²² More research is needed to determine if lithium may play a role in treating patients with DMDD.

Antipsychotics. Aripiprazole and risperidone are FDA-approved for treating irritability in autism. A 2017 meta-analysis found both medications were effective in controlling irritability and aggression in other diagnoses as well.²³ Other antipsychotic medications did not show sufficient benefits in treating irritability.²³ When considering antipsychotics, clinicians should weigh the risks of metabolic adverse effects and follow practice guidelines.

Antidepressants. A systematic review did not find that selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors effectively reduce irritability.²⁴ However, in most of the studies evaluated, irritability was not the primary outcome measure.²⁴

Other medications. Alpha-2 agonists (guanfacine, clonidine), and atomoxetine may help irritability indirectly by improving ADHD symptoms.²⁵

Bottom Line

Disruptive mood dysregulation disorder (DMDD), bipolar disorder, and oppositional defiant disorder have similar presentations and diagnostic criteria. The frequency and severity of irritability can be a distinguishing factor. Behavioral therapy is a first-line treatment. No medications are FDA-approved for treating DMDD, but pharmacotherapy may help reduce irritability and aggression.

Related Resources

• Rao U. DSM-5: disruptive mood dysregulation disorder. Asian J Psychiatr. 2014;11:119-123.
• Roy AK, Lopes V, Klein RG. Disruptive mood dysregulation disorder: a new diagnostic approach to chronic irritability in youth. Am J Psychiatry. 2014;171(9):918-924.

Drug Brand Names
Aripiprazole • Abilify
Atomoxetine • Strattera
Clonidine • Catapres
Divalproex sodium • Depakote, Depakote ER
Guanfacine • Intuniv, Tenex
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta, Ritalin
Risperidone • Risperdal

Bright light therapy (BLT) refers to the use of bright light to treat symptoms of depression. BLT was initially prescribed as a treatment for patients with seasonal affective disorder.¹ It was later found helpful for nonseasonal depression,² premenstrual dysphoric disorder, postpartum depression, and phase shift circadian disorders, including for patients with dementia whose cognitive function improved after treatment with BLT.³ More recent studies suggest year-round benefit for nonseasonal depression.² The American Psychiatric Association practice guidelines for the treatment of depression list BLT as an alternative and/or addition to pharmacologic and psychological treatment.⁴ BLT also may be beneficial for patients who are in the depressive phase of bipolar illness.

This article describes the evidence, rationale for use, mechanism of action, benefits, and safety profile of BLT for treating patients with bipolar depression.

Circadian rhythm disruption in bipolar disorder

Clinical manifestation. Patients with bipolar disorder (BD) spend more time in depression than in mania.⁵ Sleep disturbance is a core symptom of BD; patients typically have little need for sleep during a manic episode, and excess sleepiness during a depressive episode. Sleep complaints can be both precipitating factors and consequences of mood disorders. Patients with seasonal depression have excess sleepiness and weight gain in the winter followed by hypomanic-like symptoms in the spring, including decreased need for sleep and weight loss with psychomotor activation. In a recent review of sleep problems in patients with BD, Steinan et al⁶ reported that 20% of patients with euthymic mood in bipolar disorder experience a sleep disorder. Circadian disruption and “eveningness” (being more active during the evening) have been associated with mood episodes, functional impairment, poor quality of life, and treatment resistance.^7-10

Pathophysiology. Existing hypotheses for the biological mechanism underlying dysregulation of circadian rhythm in BD include changes in melatonin levels, expression of melatonin receptors in the CNS, and daily cortisol profiles.¹¹ Genetic evidence also links circadian rhythm dysregulation with BD. Two polymorphisms on the circadian locomotor output cycles kaput (CLOCK) gene that control circadian rhythm—aryl hydrocarbon receptor nuclear translocator-like (ARNTL) and timeless circadian clock (TIMELESS)—have been linked to lithium responsiveness in BD.¹² In addition, Per2, Cry1, and Rev-Erbα expression—all components of the circadian clock—have been found to increase individual susceptibility to the therapeutic effects of lithium in mice.¹³ In addition, circadian rhythm dysregulation is associated with metabolic problems encountered by patients with BD, including weight gain, diabetes mellitus, and cardiovascular disease.¹⁴

Rationale for use

Regulation of a patient’s circadian rhythm disruption is a potential treatment for BD. Hashimoto et al¹⁵ demonstrated that midday bright light exposure can phase advance and increase the amplitude of nocturnal melatonin production in healthy individuals. Morning light therapy has been shown to increase blood serotonin throughout the day in both healthy individuals and in patients with nonseasonal depression; the effect was apparent with light intensities as low as 50 lux.¹⁶ Lithium may exert its therapeutic effect through its influence on the retino-hypothalamic-pineal tract and thus its effect on melatonin secretion.¹⁷

BLT is a logical choice to treat the depression phase of BD when exposure to sunlight is not feasible due to geographical location, season, or other factor. For patients who live in areas that receive frequent sunshine, an outside stroll for half an hour will likely achieve similar benefit to BLT.

The precise mechanism of action of BLT for bipolar depression has not yet been determined. It may be attributed to a phase-resetting effect via melanopsin and the suprachiasmatic nucleus (Box^18-24).

Continue to: BLT for BD...

Several studies and case reports have evaluated the use of BLT for bipolar depression. The number of participants in these studies is small, and there is no uniformity of methodology or patient selection.

Dauphinais et al (2012)²⁵ randomly assigned 44 patients with bipolar depression to BLT or a high-density or low-density negative ion generator for 8 weeks. They reported no difference in outcome between the various groups (50% vs 55.6%, remission and response rate). Only one patient in each group showed a switch to hypomania.

Carmadese et al (2015)²⁶ reported an open-label study of adjunctive BLT in 31 difficult-to-treat patients with depression (16 unipolar and 15 bipolar). Significant improvement was noted within 3 weeks and was sustained in 1 patient with bipolar depression 5 weeks after cessation of BLT.

Papatheodorou and Kutcher (1995)²⁷ treated 7 adolescents with bipolar depression with adjunctive BLT (10,000 lux twice per day). Three patients showed a marked response (>70% decrease from baseline Beck Depression Inventory and Symptom Check List scores). Two patients had a moderate response (40% to 47% decrease) and 2 patients obtained mild to no response. There were no reported adverse effects.

Benedetti et al (2014)²⁸ studied 141 patients with treatment-resistant bipolar depression. Approximately one-quarter (23%) had a history of attempted suicide, and 83% had a history of drug resistance. The authors found a combination of total sleep deprivation, BLT, and lithium rapidly decreased suicidality and improved patients’ depressive symptoms.

Liebenluft et al (1995)²⁹ administered 13 trials of BLT to 9 patients with rapid-cycling BD during a 3-month period. Five patients received the treatment in the morning, 5 around midday, and 3 in the evening. Patients who received BLT at midday had the best outcome, while 3 of the 5 patients who received morning BLT developed unstable mood. The authors recommended titrating the duration of light exposure so that patients could skip a treatment if their mood was trending toward hypomania.

Sit et al (2007)³⁰ evaluated BLT in a case series of 9 women with bipolar I or II disorder in the depression phase. Patients were exposed to 50 lux of red light for 2 weeks, and then they received 7,000 lux BLT for 15, 30, and 45 minutes daily for 2 weeks (4 patients received morning light and 5 received midday light). Mood was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale. Of the 4 patients receiving morning BLT, one patient had a full response and the other 3 developed hypomania. Of the 5 patients who received midday BLT, 2 achieved full response, 2 showed early improvement but required a dose increase, and one remained depressed but had a full response when she was switched to morning BLT.

Tseng et al (2016)³¹ reported a meta-analysis of BLT for bipolar depression that included a total of 567 patients from 11 studies. They reported significant improvement with BLT alone or in combination with antidepressants or total sleep deprivation. They also reported significant improvement with BLT in 130 patients who were not receiving other treatments. There was no difference in the frequency of mood shifts between patients on BLT alone or in combination with other modalities. The authors reported no mood shift in any of the patients receiving concurrent mood stabilizers. They also reported no difference with the color of light, gender, or duration of illness.

Yorguner et al (2017)³² conducted a 2-week randomized, single-blind study of BLT as an add-on treatment for 32 patients with bipolar depression. Patients were randomly assigned to BLT or dim light, which they were administered each morning for 30 mins for 2 weeks. Sixteen patients who received BLT showed a significantly greater reduction in Hamilton Depression Rating Scale scores (mean score of 24 at baseline down to 12) compared with 16 patients who received dim light (mean score of 24 at baseline down to 18). The authors also reported remission in 4 out of 4 patients who had seasonal depression, compared with 3 out of 12 who did not have seasonal depression (the other 9 showed response but not remission).

Zhou et al (2018)³³ conducted a multi-center, randomized, single-blind clinical trial of 63 patients with bipolar depression. Thirty-three patients received morning BLT, and 30 received dim red light therapy (control group). The authors reported a significantly higher response rate in the BLT group (78%) compared with the control group (43%).

Sit et al (2018)³⁴ conducted a 6-week randomized, double-blind, placebo-controlled trial of BLT vs dim red light in patients with bipolar I or II depression. Twenty-three patients were administered 7,000 lux bright white light, and 23 patients received 50 lux dim red light, at midday 5 days a week. The light dose was increased by 15 minutes every week up to 60 minutes by Week 4, unless the patient achieved remission. Patients were maintained on their usual medications, which included mood stabilizers and/or antidepressants. At Week 6, the group randomized to BLT had a significantly higher remission rate (68%) compared with patients who received dim red light (22%). Improvement was noted by Week 4. Patients receiving BLT also had significantly fewer depressive symptoms, and no mood polarity switch was noted.

Light box selection criteria. When selecting a light box or related BLT treatment apparatus, the Center for Environmental Therapeutics recommends consideration of the following factors³⁵:

• clinical efficacy
• ocular and dermatologic safety
• visual comfort.

The intensity of the light hitting the cornea depends on the distance from the light. In our experience, when the patient is facing the box it should provide 10,000 lux when he or she is 1 foot away at approximately a 45° angle (1 lux = 1 lumen per square meter). The light box selected should emit full spectrum white light with UV filter. The newest filters use LED, which is less expensive and more durable. Typically, we’ve found that it is most convenient for patients to use the light box in the morning before 9 am, but around noon is preferred for patients with BD. If using a light box is not feasible, we suggest the use of dawn light by the bedside before waking in the morning. Again, it is preferable to get some sunshine outdoors while taking a walk as long as geographical location and weather conditions permit.

Selecting a dose. The dose received is determined by the intensity emitted from the light source, distance from the light box, and duration of exposure.³⁶ Begin with midday light therapy between 12 noon and 2 pm at a daily dose of 15 minutes, and increase by 15 minutes every 2 weeks until the patient has achieved a euthymic mood.³⁴ Patients need not stare directly into the light source as long as the light is able to meet the eye at an angle of 30° to 60°.³⁵ The upper limit of midday light is 45 to 60 minutes, beyond which patients are more likely to have difficulty with adherence. Because morning BLT also may be effective, consider a change to morning light at a starting dose of 15 minutes for patients who respond partially or minimally to 45 to 60 mins of midday light, then increase it every week by an additional 7 to 15 mins.³⁵ For patients who respond to BLT, it is reasonable to continue light therapy for 12 months after remission to prevent relapses, similar to the recommendations for antidepressant therapy.³⁴

Monitor for adverse effects. Generally, BLT is well tolerated.³⁷ Adverse effects are rare; the most common ones include headache, eyestrain, nausea, and agitation.³⁸ One study found no adverse ocular effects from light therapy after 5 years of treatment.³⁹ Adverse effects tend to remit spontaneously or after dose reduction.³⁵ Evening administration of BLT may increase the incidence of sleep disturbances.⁴⁰ Like other biologic treatments for bipolar depression, BLT can precipitate manic/hypomanic and mixed states in susceptible patients, although the light dose can be titrated against emergent symptoms of hypomania.⁴¹

Bottom Line

Evidence suggests that bright light therapy is an effective, well tolerated, and affordable adjunct treatment for bipolar depression. Exposure to 5,000 to 7,000 lux around noon for 15 to 60 minutes will enhance the remission rate.

Related Resource

Mostert M, Dubovsky S. When bipolar treatment fails: what’s your next step? Current Psychiatry. 2008;7(1):39-46.

Drug Brand Name
Lithium • Eskalith, Lithobid

Bright light therapy (BLT) refers to the use of bright light to treat symptoms of depression. BLT was initially prescribed as a treatment for patients with seasonal affective disorder.¹ It was later found helpful for nonseasonal depression,² premenstrual dysphoric disorder, postpartum depression, and phase shift circadian disorders, including for patients with dementia whose cognitive function improved after treatment with BLT.³ More recent studies suggest year-round benefit for nonseasonal depression.² The American Psychiatric Association practice guidelines for the treatment of depression list BLT as an alternative and/or addition to pharmacologic and psychological treatment.⁴ BLT also may be beneficial for patients who are in the depressive phase of bipolar illness.

This article describes the evidence, rationale for use, mechanism of action, benefits, and safety profile of BLT for treating patients with bipolar depression.

Circadian rhythm disruption in bipolar disorder

Clinical manifestation. Patients with bipolar disorder (BD) spend more time in depression than in mania.⁵ Sleep disturbance is a core symptom of BD; patients typically have little need for sleep during a manic episode, and excess sleepiness during a depressive episode. Sleep complaints can be both precipitating factors and consequences of mood disorders. Patients with seasonal depression have excess sleepiness and weight gain in the winter followed by hypomanic-like symptoms in the spring, including decreased need for sleep and weight loss with psychomotor activation. In a recent review of sleep problems in patients with BD, Steinan et al⁶ reported that 20% of patients with euthymic mood in bipolar disorder experience a sleep disorder. Circadian disruption and “eveningness” (being more active during the evening) have been associated with mood episodes, functional impairment, poor quality of life, and treatment resistance.^7-10

Pathophysiology. Existing hypotheses for the biological mechanism underlying dysregulation of circadian rhythm in BD include changes in melatonin levels, expression of melatonin receptors in the CNS, and daily cortisol profiles.¹¹ Genetic evidence also links circadian rhythm dysregulation with BD. Two polymorphisms on the circadian locomotor output cycles kaput (CLOCK) gene that control circadian rhythm—aryl hydrocarbon receptor nuclear translocator-like (ARNTL) and timeless circadian clock (TIMELESS)—have been linked to lithium responsiveness in BD.¹² In addition, Per2, Cry1, and Rev-Erbα expression—all components of the circadian clock—have been found to increase individual susceptibility to the therapeutic effects of lithium in mice.¹³ In addition, circadian rhythm dysregulation is associated with metabolic problems encountered by patients with BD, including weight gain, diabetes mellitus, and cardiovascular disease.¹⁴

Rationale for use

Regulation of a patient’s circadian rhythm disruption is a potential treatment for BD. Hashimoto et al¹⁵ demonstrated that midday bright light exposure can phase advance and increase the amplitude of nocturnal melatonin production in healthy individuals. Morning light therapy has been shown to increase blood serotonin throughout the day in both healthy individuals and in patients with nonseasonal depression; the effect was apparent with light intensities as low as 50 lux.¹⁶ Lithium may exert its therapeutic effect through its influence on the retino-hypothalamic-pineal tract and thus its effect on melatonin secretion.¹⁷

BLT is a logical choice to treat the depression phase of BD when exposure to sunlight is not feasible due to geographical location, season, or other factor. For patients who live in areas that receive frequent sunshine, an outside stroll for half an hour will likely achieve similar benefit to BLT.

The precise mechanism of action of BLT for bipolar depression has not yet been determined. It may be attributed to a phase-resetting effect via melanopsin and the suprachiasmatic nucleus (Box^18-24).

Continue to: BLT for BD...

Several studies and case reports have evaluated the use of BLT for bipolar depression. The number of participants in these studies is small, and there is no uniformity of methodology or patient selection.

Dauphinais et al (2012)²⁵ randomly assigned 44 patients with bipolar depression to BLT or a high-density or low-density negative ion generator for 8 weeks. They reported no difference in outcome between the various groups (50% vs 55.6%, remission and response rate). Only one patient in each group showed a switch to hypomania.

Carmadese et al (2015)²⁶ reported an open-label study of adjunctive BLT in 31 difficult-to-treat patients with depression (16 unipolar and 15 bipolar). Significant improvement was noted within 3 weeks and was sustained in 1 patient with bipolar depression 5 weeks after cessation of BLT.

Papatheodorou and Kutcher (1995)²⁷ treated 7 adolescents with bipolar depression with adjunctive BLT (10,000 lux twice per day). Three patients showed a marked response (>70% decrease from baseline Beck Depression Inventory and Symptom Check List scores). Two patients had a moderate response (40% to 47% decrease) and 2 patients obtained mild to no response. There were no reported adverse effects.

Benedetti et al (2014)²⁸ studied 141 patients with treatment-resistant bipolar depression. Approximately one-quarter (23%) had a history of attempted suicide, and 83% had a history of drug resistance. The authors found a combination of total sleep deprivation, BLT, and lithium rapidly decreased suicidality and improved patients’ depressive symptoms.

Liebenluft et al (1995)²⁹ administered 13 trials of BLT to 9 patients with rapid-cycling BD during a 3-month period. Five patients received the treatment in the morning, 5 around midday, and 3 in the evening. Patients who received BLT at midday had the best outcome, while 3 of the 5 patients who received morning BLT developed unstable mood. The authors recommended titrating the duration of light exposure so that patients could skip a treatment if their mood was trending toward hypomania.

Sit et al (2007)³⁰ evaluated BLT in a case series of 9 women with bipolar I or II disorder in the depression phase. Patients were exposed to 50 lux of red light for 2 weeks, and then they received 7,000 lux BLT for 15, 30, and 45 minutes daily for 2 weeks (4 patients received morning light and 5 received midday light). Mood was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale. Of the 4 patients receiving morning BLT, one patient had a full response and the other 3 developed hypomania. Of the 5 patients who received midday BLT, 2 achieved full response, 2 showed early improvement but required a dose increase, and one remained depressed but had a full response when she was switched to morning BLT.

Tseng et al (2016)³¹ reported a meta-analysis of BLT for bipolar depression that included a total of 567 patients from 11 studies. They reported significant improvement with BLT alone or in combination with antidepressants or total sleep deprivation. They also reported significant improvement with BLT in 130 patients who were not receiving other treatments. There was no difference in the frequency of mood shifts between patients on BLT alone or in combination with other modalities. The authors reported no mood shift in any of the patients receiving concurrent mood stabilizers. They also reported no difference with the color of light, gender, or duration of illness.

Yorguner et al (2017)³² conducted a 2-week randomized, single-blind study of BLT as an add-on treatment for 32 patients with bipolar depression. Patients were randomly assigned to BLT or dim light, which they were administered each morning for 30 mins for 2 weeks. Sixteen patients who received BLT showed a significantly greater reduction in Hamilton Depression Rating Scale scores (mean score of 24 at baseline down to 12) compared with 16 patients who received dim light (mean score of 24 at baseline down to 18). The authors also reported remission in 4 out of 4 patients who had seasonal depression, compared with 3 out of 12 who did not have seasonal depression (the other 9 showed response but not remission).

Zhou et al (2018)³³ conducted a multi-center, randomized, single-blind clinical trial of 63 patients with bipolar depression. Thirty-three patients received morning BLT, and 30 received dim red light therapy (control group). The authors reported a significantly higher response rate in the BLT group (78%) compared with the control group (43%).

Sit et al (2018)³⁴ conducted a 6-week randomized, double-blind, placebo-controlled trial of BLT vs dim red light in patients with bipolar I or II depression. Twenty-three patients were administered 7,000 lux bright white light, and 23 patients received 50 lux dim red light, at midday 5 days a week. The light dose was increased by 15 minutes every week up to 60 minutes by Week 4, unless the patient achieved remission. Patients were maintained on their usual medications, which included mood stabilizers and/or antidepressants. At Week 6, the group randomized to BLT had a significantly higher remission rate (68%) compared with patients who received dim red light (22%). Improvement was noted by Week 4. Patients receiving BLT also had significantly fewer depressive symptoms, and no mood polarity switch was noted.

Light box selection criteria. When selecting a light box or related BLT treatment apparatus, the Center for Environmental Therapeutics recommends consideration of the following factors³⁵:

• clinical efficacy
• ocular and dermatologic safety
• visual comfort.

The intensity of the light hitting the cornea depends on the distance from the light. In our experience, when the patient is facing the box it should provide 10,000 lux when he or she is 1 foot away at approximately a 45° angle (1 lux = 1 lumen per square meter). The light box selected should emit full spectrum white light with UV filter. The newest filters use LED, which is less expensive and more durable. Typically, we’ve found that it is most convenient for patients to use the light box in the morning before 9 am, but around noon is preferred for patients with BD. If using a light box is not feasible, we suggest the use of dawn light by the bedside before waking in the morning. Again, it is preferable to get some sunshine outdoors while taking a walk as long as geographical location and weather conditions permit.

Selecting a dose. The dose received is determined by the intensity emitted from the light source, distance from the light box, and duration of exposure.³⁶ Begin with midday light therapy between 12 noon and 2 pm at a daily dose of 15 minutes, and increase by 15 minutes every 2 weeks until the patient has achieved a euthymic mood.³⁴ Patients need not stare directly into the light source as long as the light is able to meet the eye at an angle of 30° to 60°.³⁵ The upper limit of midday light is 45 to 60 minutes, beyond which patients are more likely to have difficulty with adherence. Because morning BLT also may be effective, consider a change to morning light at a starting dose of 15 minutes for patients who respond partially or minimally to 45 to 60 mins of midday light, then increase it every week by an additional 7 to 15 mins.³⁵ For patients who respond to BLT, it is reasonable to continue light therapy for 12 months after remission to prevent relapses, similar to the recommendations for antidepressant therapy.³⁴

Monitor for adverse effects. Generally, BLT is well tolerated.³⁷ Adverse effects are rare; the most common ones include headache, eyestrain, nausea, and agitation.³⁸ One study found no adverse ocular effects from light therapy after 5 years of treatment.³⁹ Adverse effects tend to remit spontaneously or after dose reduction.³⁵ Evening administration of BLT may increase the incidence of sleep disturbances.⁴⁰ Like other biologic treatments for bipolar depression, BLT can precipitate manic/hypomanic and mixed states in susceptible patients, although the light dose can be titrated against emergent symptoms of hypomania.⁴¹

Bottom Line

Evidence suggests that bright light therapy is an effective, well tolerated, and affordable adjunct treatment for bipolar depression. Exposure to 5,000 to 7,000 lux around noon for 15 to 60 minutes will enhance the remission rate.

Related Resource

Mostert M, Dubovsky S. When bipolar treatment fails: what’s your next step? Current Psychiatry. 2008;7(1):39-46.

Drug Brand Name
Lithium • Eskalith, Lithobid

Bright light therapy (BLT) refers to the use of bright light to treat symptoms of depression. BLT was initially prescribed as a treatment for patients with seasonal affective disorder.¹ It was later found helpful for nonseasonal depression,² premenstrual dysphoric disorder, postpartum depression, and phase shift circadian disorders, including for patients with dementia whose cognitive function improved after treatment with BLT.³ More recent studies suggest year-round benefit for nonseasonal depression.² The American Psychiatric Association practice guidelines for the treatment of depression list BLT as an alternative and/or addition to pharmacologic and psychological treatment.⁴ BLT also may be beneficial for patients who are in the depressive phase of bipolar illness.

This article describes the evidence, rationale for use, mechanism of action, benefits, and safety profile of BLT for treating patients with bipolar depression.

Circadian rhythm disruption in bipolar disorder

Clinical manifestation. Patients with bipolar disorder (BD) spend more time in depression than in mania.⁵ Sleep disturbance is a core symptom of BD; patients typically have little need for sleep during a manic episode, and excess sleepiness during a depressive episode. Sleep complaints can be both precipitating factors and consequences of mood disorders. Patients with seasonal depression have excess sleepiness and weight gain in the winter followed by hypomanic-like symptoms in the spring, including decreased need for sleep and weight loss with psychomotor activation. In a recent review of sleep problems in patients with BD, Steinan et al⁶ reported that 20% of patients with euthymic mood in bipolar disorder experience a sleep disorder. Circadian disruption and “eveningness” (being more active during the evening) have been associated with mood episodes, functional impairment, poor quality of life, and treatment resistance.^7-10

Pathophysiology. Existing hypotheses for the biological mechanism underlying dysregulation of circadian rhythm in BD include changes in melatonin levels, expression of melatonin receptors in the CNS, and daily cortisol profiles.¹¹ Genetic evidence also links circadian rhythm dysregulation with BD. Two polymorphisms on the circadian locomotor output cycles kaput (CLOCK) gene that control circadian rhythm—aryl hydrocarbon receptor nuclear translocator-like (ARNTL) and timeless circadian clock (TIMELESS)—have been linked to lithium responsiveness in BD.¹² In addition, Per2, Cry1, and Rev-Erbα expression—all components of the circadian clock—have been found to increase individual susceptibility to the therapeutic effects of lithium in mice.¹³ In addition, circadian rhythm dysregulation is associated with metabolic problems encountered by patients with BD, including weight gain, diabetes mellitus, and cardiovascular disease.¹⁴

Rationale for use

Regulation of a patient’s circadian rhythm disruption is a potential treatment for BD. Hashimoto et al¹⁵ demonstrated that midday bright light exposure can phase advance and increase the amplitude of nocturnal melatonin production in healthy individuals. Morning light therapy has been shown to increase blood serotonin throughout the day in both healthy individuals and in patients with nonseasonal depression; the effect was apparent with light intensities as low as 50 lux.¹⁶ Lithium may exert its therapeutic effect through its influence on the retino-hypothalamic-pineal tract and thus its effect on melatonin secretion.¹⁷

BLT is a logical choice to treat the depression phase of BD when exposure to sunlight is not feasible due to geographical location, season, or other factor. For patients who live in areas that receive frequent sunshine, an outside stroll for half an hour will likely achieve similar benefit to BLT.

The precise mechanism of action of BLT for bipolar depression has not yet been determined. It may be attributed to a phase-resetting effect via melanopsin and the suprachiasmatic nucleus (Box^18-24).

Continue to: BLT for BD...

Several studies and case reports have evaluated the use of BLT for bipolar depression. The number of participants in these studies is small, and there is no uniformity of methodology or patient selection.

Dauphinais et al (2012)²⁵ randomly assigned 44 patients with bipolar depression to BLT or a high-density or low-density negative ion generator for 8 weeks. They reported no difference in outcome between the various groups (50% vs 55.6%, remission and response rate). Only one patient in each group showed a switch to hypomania.

Carmadese et al (2015)²⁶ reported an open-label study of adjunctive BLT in 31 difficult-to-treat patients with depression (16 unipolar and 15 bipolar). Significant improvement was noted within 3 weeks and was sustained in 1 patient with bipolar depression 5 weeks after cessation of BLT.

Papatheodorou and Kutcher (1995)²⁷ treated 7 adolescents with bipolar depression with adjunctive BLT (10,000 lux twice per day). Three patients showed a marked response (>70% decrease from baseline Beck Depression Inventory and Symptom Check List scores). Two patients had a moderate response (40% to 47% decrease) and 2 patients obtained mild to no response. There were no reported adverse effects.

Benedetti et al (2014)²⁸ studied 141 patients with treatment-resistant bipolar depression. Approximately one-quarter (23%) had a history of attempted suicide, and 83% had a history of drug resistance. The authors found a combination of total sleep deprivation, BLT, and lithium rapidly decreased suicidality and improved patients’ depressive symptoms.

Liebenluft et al (1995)²⁹ administered 13 trials of BLT to 9 patients with rapid-cycling BD during a 3-month period. Five patients received the treatment in the morning, 5 around midday, and 3 in the evening. Patients who received BLT at midday had the best outcome, while 3 of the 5 patients who received morning BLT developed unstable mood. The authors recommended titrating the duration of light exposure so that patients could skip a treatment if their mood was trending toward hypomania.

Sit et al (2007)³⁰ evaluated BLT in a case series of 9 women with bipolar I or II disorder in the depression phase. Patients were exposed to 50 lux of red light for 2 weeks, and then they received 7,000 lux BLT for 15, 30, and 45 minutes daily for 2 weeks (4 patients received morning light and 5 received midday light). Mood was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale. Of the 4 patients receiving morning BLT, one patient had a full response and the other 3 developed hypomania. Of the 5 patients who received midday BLT, 2 achieved full response, 2 showed early improvement but required a dose increase, and one remained depressed but had a full response when she was switched to morning BLT.

Tseng et al (2016)³¹ reported a meta-analysis of BLT for bipolar depression that included a total of 567 patients from 11 studies. They reported significant improvement with BLT alone or in combination with antidepressants or total sleep deprivation. They also reported significant improvement with BLT in 130 patients who were not receiving other treatments. There was no difference in the frequency of mood shifts between patients on BLT alone or in combination with other modalities. The authors reported no mood shift in any of the patients receiving concurrent mood stabilizers. They also reported no difference with the color of light, gender, or duration of illness.

Yorguner et al (2017)³² conducted a 2-week randomized, single-blind study of BLT as an add-on treatment for 32 patients with bipolar depression. Patients were randomly assigned to BLT or dim light, which they were administered each morning for 30 mins for 2 weeks. Sixteen patients who received BLT showed a significantly greater reduction in Hamilton Depression Rating Scale scores (mean score of 24 at baseline down to 12) compared with 16 patients who received dim light (mean score of 24 at baseline down to 18). The authors also reported remission in 4 out of 4 patients who had seasonal depression, compared with 3 out of 12 who did not have seasonal depression (the other 9 showed response but not remission).

Zhou et al (2018)³³ conducted a multi-center, randomized, single-blind clinical trial of 63 patients with bipolar depression. Thirty-three patients received morning BLT, and 30 received dim red light therapy (control group). The authors reported a significantly higher response rate in the BLT group (78%) compared with the control group (43%).

Sit et al (2018)³⁴ conducted a 6-week randomized, double-blind, placebo-controlled trial of BLT vs dim red light in patients with bipolar I or II depression. Twenty-three patients were administered 7,000 lux bright white light, and 23 patients received 50 lux dim red light, at midday 5 days a week. The light dose was increased by 15 minutes every week up to 60 minutes by Week 4, unless the patient achieved remission. Patients were maintained on their usual medications, which included mood stabilizers and/or antidepressants. At Week 6, the group randomized to BLT had a significantly higher remission rate (68%) compared with patients who received dim red light (22%). Improvement was noted by Week 4. Patients receiving BLT also had significantly fewer depressive symptoms, and no mood polarity switch was noted.

Light box selection criteria. When selecting a light box or related BLT treatment apparatus, the Center for Environmental Therapeutics recommends consideration of the following factors³⁵:

• clinical efficacy
• ocular and dermatologic safety
• visual comfort.

The intensity of the light hitting the cornea depends on the distance from the light. In our experience, when the patient is facing the box it should provide 10,000 lux when he or she is 1 foot away at approximately a 45° angle (1 lux = 1 lumen per square meter). The light box selected should emit full spectrum white light with UV filter. The newest filters use LED, which is less expensive and more durable. Typically, we’ve found that it is most convenient for patients to use the light box in the morning before 9 am, but around noon is preferred for patients with BD. If using a light box is not feasible, we suggest the use of dawn light by the bedside before waking in the morning. Again, it is preferable to get some sunshine outdoors while taking a walk as long as geographical location and weather conditions permit.

Selecting a dose. The dose received is determined by the intensity emitted from the light source, distance from the light box, and duration of exposure.³⁶ Begin with midday light therapy between 12 noon and 2 pm at a daily dose of 15 minutes, and increase by 15 minutes every 2 weeks until the patient has achieved a euthymic mood.³⁴ Patients need not stare directly into the light source as long as the light is able to meet the eye at an angle of 30° to 60°.³⁵ The upper limit of midday light is 45 to 60 minutes, beyond which patients are more likely to have difficulty with adherence. Because morning BLT also may be effective, consider a change to morning light at a starting dose of 15 minutes for patients who respond partially or minimally to 45 to 60 mins of midday light, then increase it every week by an additional 7 to 15 mins.³⁵ For patients who respond to BLT, it is reasonable to continue light therapy for 12 months after remission to prevent relapses, similar to the recommendations for antidepressant therapy.³⁴

Monitor for adverse effects. Generally, BLT is well tolerated.³⁷ Adverse effects are rare; the most common ones include headache, eyestrain, nausea, and agitation.³⁸ One study found no adverse ocular effects from light therapy after 5 years of treatment.³⁹ Adverse effects tend to remit spontaneously or after dose reduction.³⁵ Evening administration of BLT may increase the incidence of sleep disturbances.⁴⁰ Like other biologic treatments for bipolar depression, BLT can precipitate manic/hypomanic and mixed states in susceptible patients, although the light dose can be titrated against emergent symptoms of hypomania.⁴¹

Bottom Line

Evidence suggests that bright light therapy is an effective, well tolerated, and affordable adjunct treatment for bipolar depression. Exposure to 5,000 to 7,000 lux around noon for 15 to 60 minutes will enhance the remission rate.

Related Resource

Mostert M, Dubovsky S. When bipolar treatment fails: what’s your next step? Current Psychiatry. 2008;7(1):39-46.

Drug Brand Name
Lithium • Eskalith, Lithobid

I very much enjoyed your fascinating case report “Xenomelia: Profile of a man with intense desire to amputate a healthy limb” (Current Psychiatry, August 2018, p. 34-36, 41-43) and your hypotheses regarding neurodevelopmental correlates to xenomelia and related disorders such as apotemnophilia and body dysmorphia. However, you comment that because your patient’s desire to have a limb removed began in early childhood, before genital sexual maturation, the condition must be “…independent of sexuality.” This omits Sigmund Freud’s adumbration of infantile sexuality (oral, anal, phallic stages) with the phallic stage of infantile sexuality reaching a period of strong arousal between age 3 and 5, which is at the height of the Oedipus and Electra complexes.

Your patient traced the history of his desire to amputate his leg (as do other individuals with xenomelia) to age 4, when he saw a man with a missing limb, which made a vivid impression on him. As you discuss, this was probably a moment when he had an intensely psychosexual imprinting of this perception. However, the actual memory of the man with the amputation may well have been a screen memory for other more arousing and traumatic experiences that the patient experienced at this early age, such as castration anxiety with or without actual overstimulation of the physical body.

Nathan Szajnberg, MD, and I reported a case of a man who desired that his partner pretend to be an amputee in order to strengthen sexual arousal, an arousal that he recalled having as early as age 5 or 6.¹ The report traced this fetish back to research films of his upbringing, which indicated heightened physical stimulation in very early life.² As we wrote, “The case provides unusual information about the manner in which early childhood events interdigitate with intrapsychic processes and mental structuralisation.” This has led me to wonder if similar mental processes are at work in the current wave of young people who are convinced that they are a different gender than the one indicated by their anatomy.

I very much enjoyed your fascinating case report “Xenomelia: Profile of a man with intense desire to amputate a healthy limb” (Current Psychiatry, August 2018, p. 34-36, 41-43) and your hypotheses regarding neurodevelopmental correlates to xenomelia and related disorders such as apotemnophilia and body dysmorphia. However, you comment that because your patient’s desire to have a limb removed began in early childhood, before genital sexual maturation, the condition must be “…independent of sexuality.” This omits Sigmund Freud’s adumbration of infantile sexuality (oral, anal, phallic stages) with the phallic stage of infantile sexuality reaching a period of strong arousal between age 3 and 5, which is at the height of the Oedipus and Electra complexes.

Your patient traced the history of his desire to amputate his leg (as do other individuals with xenomelia) to age 4, when he saw a man with a missing limb, which made a vivid impression on him. As you discuss, this was probably a moment when he had an intensely psychosexual imprinting of this perception. However, the actual memory of the man with the amputation may well have been a screen memory for other more arousing and traumatic experiences that the patient experienced at this early age, such as castration anxiety with or without actual overstimulation of the physical body.

Nathan Szajnberg, MD, and I reported a case of a man who desired that his partner pretend to be an amputee in order to strengthen sexual arousal, an arousal that he recalled having as early as age 5 or 6.¹ The report traced this fetish back to research films of his upbringing, which indicated heightened physical stimulation in very early life.² As we wrote, “The case provides unusual information about the manner in which early childhood events interdigitate with intrapsychic processes and mental structuralisation.” This has led me to wonder if similar mental processes are at work in the current wave of young people who are convinced that they are a different gender than the one indicated by their anatomy.

I very much enjoyed your fascinating case report “Xenomelia: Profile of a man with intense desire to amputate a healthy limb” (Current Psychiatry, August 2018, p. 34-36, 41-43) and your hypotheses regarding neurodevelopmental correlates to xenomelia and related disorders such as apotemnophilia and body dysmorphia. However, you comment that because your patient’s desire to have a limb removed began in early childhood, before genital sexual maturation, the condition must be “…independent of sexuality.” This omits Sigmund Freud’s adumbration of infantile sexuality (oral, anal, phallic stages) with the phallic stage of infantile sexuality reaching a period of strong arousal between age 3 and 5, which is at the height of the Oedipus and Electra complexes.

Your patient traced the history of his desire to amputate his leg (as do other individuals with xenomelia) to age 4, when he saw a man with a missing limb, which made a vivid impression on him. As you discuss, this was probably a moment when he had an intensely psychosexual imprinting of this perception. However, the actual memory of the man with the amputation may well have been a screen memory for other more arousing and traumatic experiences that the patient experienced at this early age, such as castration anxiety with or without actual overstimulation of the physical body.

Nathan Szajnberg, MD, and I reported a case of a man who desired that his partner pretend to be an amputee in order to strengthen sexual arousal, an arousal that he recalled having as early as age 5 or 6.¹ The report traced this fetish back to research films of his upbringing, which indicated heightened physical stimulation in very early life.² As we wrote, “The case provides unusual information about the manner in which early childhood events interdigitate with intrapsychic processes and mental structuralisation.” This has led me to wonder if similar mental processes are at work in the current wave of young people who are convinced that they are a different gender than the one indicated by their anatomy.

CASE Somnolent, confused, and hungry

Mr. G, age 14, presents to the emergency department (ED) for acute-onset hypersomnia that has gradually worsened over the course of a few days. Mr. G now sleeps most of the day, has altered mental status, and is experiencing emotional dysregulation with no clear etiology. His mother, who accompanies him to the ED, says that prior to the onset of these symptoms her son had been healthy. She notes that he has been eating more than usual, which she assumes is due to a growth spurt.

Mr. G’s symptoms began 4 days ago when he became increasingly fatigued, sleeping for 11 to 12 hours per day, with intermittent episodes of staring and unresponsiveness from which he rapidly returned to baseline. During the next 3 days, he became more confused and somnolent, and began to display bizarre behavior, including eating food out of the trash and attempting to microwave a full metal pot. He exhibited unexplained crying spells, calling out for his “mommy,” and saying he was “afraid I’m dying.”

During the 2 days before he came to our ED, Mr. G was seen at 2 other hospitals. Following extensive imaging and laboratory work-up, clinicians at these facilities attributed his symptoms to intoxication from an unknown substance. Mr. G has a history of marijuana use, and his mother reports that his friends had recently been using synthetic marijuana. However, no intoxicant was identified on urine or gas chromatography drug screening.

Mr. G’s history includes oppositional behavior, and a brief psychiatric hospitalization at age 5 for aggression. He has otherwise been healthy. His family history is significant for maternal substance use and anxiety disorders. In addition to sporadic cannabis use, Mr. G’s social history includes multiple recent family losses, previous foster care placement, and recent declining academic performance.

[polldaddy:10148168]

EVALUATION No red flags

On admission, Mr. G appears somnolent and displays disorganized speech, impulsivity, frequent disorientation, and intermittent agitation/anxiety; he sleeps 16 to 18 hours per day. Mr. G is admitted with a presumptive diagnosis of substance intoxication and transferred to the general pediatric inpatient unit. Upon arrival, he is found to be bradycardic (42 beats per minute), although afebrile with otherwise age-appropriate vitals. On exam, he is somnolent but arousable and follows simple commands.

Continue to: Mr. G undergoes a Monospot test...

Mr. G undergoes a Monospot test, which is positive, with subsequent evidence of a prior, but not active, Epstein-Barr virus (EBV) infection. He also has a mildly elevated CSF protein level, but subsequent CSF labs are negative for both infectious and non-infectious processes. An EEG reveals focal neuronal slowing.

During brief periods of wakefulness, Mr. G calls out to his mother and says, “I’m not going to make it to my birthday,” and “You’re going to have to let me go.” He occasionally becomes combative, pulling at IV lines and swearing at staff. His bradycardia resolves without intervention during his admission. On Day 8 of his hospitalization, Mr. G displays hypersexuality and makes sexually suggestive comments toward female staff members. He also experiences recurrence of hyperphagia.

On Day 10 of his stay on the pediatric unit, because of the emergence of hypersexuality and hyperphagia, along with a largely negative medical evaluation, Mr. G is transferred to the pediatric psychiatric unit for ongoing evaluation and management.

[polldaddy:10148172]

The authors’ observations

Given Mr. G’s rapid onset of confusion, hypersomnia, and emotional dysregulation, our differential diagnosis included delirium of unclear etiology, substance intoxication, autoimmune encephalitis, viral meningitis, heavy metal intoxication, primary psychotic disorder, and KLS. Mr. G underwent an extensive diagnostic evaluation, which was largely unremarkable (Table). He had a mildly elevated CSF protein level, but subsequent CSF labs were negative for both infectious and non-infectious processes. When Mr. G was transferred to the pediatric inpatient psychiatric unit on Day 10, the presumptive diagnosis was KLS.

KLS is a rare neurologic disorder, with an incidence of 1 to 5 in 1 million and a 4:1 male-to-female predominance.¹ It poses a diagnostic challenge due to its low prevalence and broad differential. The disorder typically presents in early adolescence and is characterized by episodes of severe hypersomnia with associated cognitive and/or behavioral disturbance² (Box^2-4). Bradycardia, as seen in Mr. G, and other forms of autonomic dysregulation have been reported in the literature, as has the focal neuronal slowing noted on Mr. G’s EEG.³

[polldaddy:10148174]

Continue to: TREATMENT Methylphenidate and a safety plan

On Day 11 of hospitalization, Mr. G is started on methylphenidate, 10 mg in the morning and 5 mg in the afternoon. After starting methylphenidate, he sustains more regular wakefulness, with improved thought organization, engagement, and fewer disruptive behaviors. He receives infrequent, as-needed doses of olanzapine, and by Day 14, he returns to his baseline behavior and cognition.

A safety plan is created for the family to address worsening symptoms or future episodes. The safety plan is developed with Mr. G and input from his family. It is to be administered in all settings and we particularly emphasized using it in the school setting, where staff may not be familiar with KLS. The safety plan involves a description of KLS, its symptoms, the risks for hypersomnolence, hypersexuality, and psychotic symptoms or behavioral dysregulation. It stresses close supervision of Mr. G, not allowing him to be unsupervised or unchaperoned on school trips or other outings, and lethal means restriction. It outlines a detailed plan if Mr. G’s behavior decompensates or escalates, including a step-wise approach to engaging psychological interventions and mental health resources, and securing crisis services as needed.

On Day 15, he is discharged to home in stable condition with outpatient mental health follow-up and continues to take the prescribed methylphenidate.

The authors’ observations

Management of KLS is primarily supportive. Stimulants may help reduce hypersomnia, impulsivity, and inattention early in the disease course.¹ However, in a systematic review, 89% of patients with KLS who received methylphenidate experienced worsening or no improvement, and 11% showed only partial improvement.² Amantadine was more promising, with 29% of patients with KLS showing partial benefit and 12% showing significant benefit.² Multiple other pharmacologic agents have been described with varying efficacy, including lithium, valproate, risperidone, bupropion, and immunoglobulins.² Furthermore, lithium and valproate have been suggested to be helpful in preventing recurrences in some cases.⁶

The circumstances surrounding Mr. G’s symptom onset are unclear and may have been multifactorial. It is possible that his prior EBV infection was a trigger for this KLS-associated episode, as EBV is a known precipitant for KLS episodes.³ Mr. G’s history of cannabis use may also have served as an early trigger for KLS.³

This case highlights the importance of multidisciplinary collaboration in a diagnostically challenging case. It emphasizes the need for a broad differential and the importance of challenging a previous diagnosis in the face of mounting evidence to the contrary. In this case, the patient’s history of irritability, aggression, and cannabis use resulted in multiple clinicians misattributing his symptoms to substance use or a primary psychiatric disorder. However, given his symptom acuity, progression, and the lack of findings on diagnostic evaluation to explain his presentation, these initial diagnoses did not explain the severity, nature, or duration of his symptoms. Keeping KLS in the differential is particularly important for patients with a prior history of psychiatric illness or substance use, because these patients are at higher risk for misattribution of symptoms to pre-existing psychiatric illness. Evolution of symptoms, a negative diagnostic evaluation, and maintaining a broad differential resulted in eventually reaching the final diagnosis of KLS and development of a longitudinal management plan.

While further work must be done to clearly define the pharmacologic approach to acute management of KLS episodes, nonpharmacologic aspects of care must not be neglected. Behavioral planning, adjustment of the environment, engagement with schools/community supports, and family education are valuable tools for facilitating the patient’s de-escalation, avoiding unneeded polypharmacy, reducing anxieties, and safeguarding the patient from unnecessary harm.⁷ Clinicians can support their patients’ transitions back into the community by ensuring careful outpatient follow-up for symptom monitoring and by communicating with patients’ schools and employers.

OUTCOME Asymptomatic; no recurrence of symptoms

Forty-six days after his symptoms began and 31 days after hospital discharge, Mr. G is asymptomatic with no recurrence of symptoms.

Bottom Line

Kleine-Levin syndrome (KLS) is a rare, often-overlooked condition that should be considered in the differential diagnosis for patients who present with hypersomnolence and altered mental status without a clear etiology. Rapid recognition of KLS can prevent misattribution of symptoms, unnecessary treatment, and missed opportunities for care.

CASE Somnolent, confused, and hungry

Mr. G, age 14, presents to the emergency department (ED) for acute-onset hypersomnia that has gradually worsened over the course of a few days. Mr. G now sleeps most of the day, has altered mental status, and is experiencing emotional dysregulation with no clear etiology. His mother, who accompanies him to the ED, says that prior to the onset of these symptoms her son had been healthy. She notes that he has been eating more than usual, which she assumes is due to a growth spurt.

Mr. G’s symptoms began 4 days ago when he became increasingly fatigued, sleeping for 11 to 12 hours per day, with intermittent episodes of staring and unresponsiveness from which he rapidly returned to baseline. During the next 3 days, he became more confused and somnolent, and began to display bizarre behavior, including eating food out of the trash and attempting to microwave a full metal pot. He exhibited unexplained crying spells, calling out for his “mommy,” and saying he was “afraid I’m dying.”

During the 2 days before he came to our ED, Mr. G was seen at 2 other hospitals. Following extensive imaging and laboratory work-up, clinicians at these facilities attributed his symptoms to intoxication from an unknown substance. Mr. G has a history of marijuana use, and his mother reports that his friends had recently been using synthetic marijuana. However, no intoxicant was identified on urine or gas chromatography drug screening.

Mr. G’s history includes oppositional behavior, and a brief psychiatric hospitalization at age 5 for aggression. He has otherwise been healthy. His family history is significant for maternal substance use and anxiety disorders. In addition to sporadic cannabis use, Mr. G’s social history includes multiple recent family losses, previous foster care placement, and recent declining academic performance.

[polldaddy:10148168]

EVALUATION No red flags

On admission, Mr. G appears somnolent and displays disorganized speech, impulsivity, frequent disorientation, and intermittent agitation/anxiety; he sleeps 16 to 18 hours per day. Mr. G is admitted with a presumptive diagnosis of substance intoxication and transferred to the general pediatric inpatient unit. Upon arrival, he is found to be bradycardic (42 beats per minute), although afebrile with otherwise age-appropriate vitals. On exam, he is somnolent but arousable and follows simple commands.

Continue to: Mr. G undergoes a Monospot test...

Mr. G undergoes a Monospot test, which is positive, with subsequent evidence of a prior, but not active, Epstein-Barr virus (EBV) infection. He also has a mildly elevated CSF protein level, but subsequent CSF labs are negative for both infectious and non-infectious processes. An EEG reveals focal neuronal slowing.

During brief periods of wakefulness, Mr. G calls out to his mother and says, “I’m not going to make it to my birthday,” and “You’re going to have to let me go.” He occasionally becomes combative, pulling at IV lines and swearing at staff. His bradycardia resolves without intervention during his admission. On Day 8 of his hospitalization, Mr. G displays hypersexuality and makes sexually suggestive comments toward female staff members. He also experiences recurrence of hyperphagia.

On Day 10 of his stay on the pediatric unit, because of the emergence of hypersexuality and hyperphagia, along with a largely negative medical evaluation, Mr. G is transferred to the pediatric psychiatric unit for ongoing evaluation and management.

[polldaddy:10148172]

The authors’ observations

Given Mr. G’s rapid onset of confusion, hypersomnia, and emotional dysregulation, our differential diagnosis included delirium of unclear etiology, substance intoxication, autoimmune encephalitis, viral meningitis, heavy metal intoxication, primary psychotic disorder, and KLS. Mr. G underwent an extensive diagnostic evaluation, which was largely unremarkable (Table). He had a mildly elevated CSF protein level, but subsequent CSF labs were negative for both infectious and non-infectious processes. When Mr. G was transferred to the pediatric inpatient psychiatric unit on Day 10, the presumptive diagnosis was KLS.

KLS is a rare neurologic disorder, with an incidence of 1 to 5 in 1 million and a 4:1 male-to-female predominance.¹ It poses a diagnostic challenge due to its low prevalence and broad differential. The disorder typically presents in early adolescence and is characterized by episodes of severe hypersomnia with associated cognitive and/or behavioral disturbance² (Box^2-4). Bradycardia, as seen in Mr. G, and other forms of autonomic dysregulation have been reported in the literature, as has the focal neuronal slowing noted on Mr. G’s EEG.³

[polldaddy:10148174]

Continue to: TREATMENT Methylphenidate and a safety plan

On Day 11 of hospitalization, Mr. G is started on methylphenidate, 10 mg in the morning and 5 mg in the afternoon. After starting methylphenidate, he sustains more regular wakefulness, with improved thought organization, engagement, and fewer disruptive behaviors. He receives infrequent, as-needed doses of olanzapine, and by Day 14, he returns to his baseline behavior and cognition.

A safety plan is created for the family to address worsening symptoms or future episodes. The safety plan is developed with Mr. G and input from his family. It is to be administered in all settings and we particularly emphasized using it in the school setting, where staff may not be familiar with KLS. The safety plan involves a description of KLS, its symptoms, the risks for hypersomnolence, hypersexuality, and psychotic symptoms or behavioral dysregulation. It stresses close supervision of Mr. G, not allowing him to be unsupervised or unchaperoned on school trips or other outings, and lethal means restriction. It outlines a detailed plan if Mr. G’s behavior decompensates or escalates, including a step-wise approach to engaging psychological interventions and mental health resources, and securing crisis services as needed.

On Day 15, he is discharged to home in stable condition with outpatient mental health follow-up and continues to take the prescribed methylphenidate.

The authors’ observations

Management of KLS is primarily supportive. Stimulants may help reduce hypersomnia, impulsivity, and inattention early in the disease course.¹ However, in a systematic review, 89% of patients with KLS who received methylphenidate experienced worsening or no improvement, and 11% showed only partial improvement.² Amantadine was more promising, with 29% of patients with KLS showing partial benefit and 12% showing significant benefit.² Multiple other pharmacologic agents have been described with varying efficacy, including lithium, valproate, risperidone, bupropion, and immunoglobulins.² Furthermore, lithium and valproate have been suggested to be helpful in preventing recurrences in some cases.⁶

The circumstances surrounding Mr. G’s symptom onset are unclear and may have been multifactorial. It is possible that his prior EBV infection was a trigger for this KLS-associated episode, as EBV is a known precipitant for KLS episodes.³ Mr. G’s history of cannabis use may also have served as an early trigger for KLS.³

This case highlights the importance of multidisciplinary collaboration in a diagnostically challenging case. It emphasizes the need for a broad differential and the importance of challenging a previous diagnosis in the face of mounting evidence to the contrary. In this case, the patient’s history of irritability, aggression, and cannabis use resulted in multiple clinicians misattributing his symptoms to substance use or a primary psychiatric disorder. However, given his symptom acuity, progression, and the lack of findings on diagnostic evaluation to explain his presentation, these initial diagnoses did not explain the severity, nature, or duration of his symptoms. Keeping KLS in the differential is particularly important for patients with a prior history of psychiatric illness or substance use, because these patients are at higher risk for misattribution of symptoms to pre-existing psychiatric illness. Evolution of symptoms, a negative diagnostic evaluation, and maintaining a broad differential resulted in eventually reaching the final diagnosis of KLS and development of a longitudinal management plan.

While further work must be done to clearly define the pharmacologic approach to acute management of KLS episodes, nonpharmacologic aspects of care must not be neglected. Behavioral planning, adjustment of the environment, engagement with schools/community supports, and family education are valuable tools for facilitating the patient’s de-escalation, avoiding unneeded polypharmacy, reducing anxieties, and safeguarding the patient from unnecessary harm.⁷ Clinicians can support their patients’ transitions back into the community by ensuring careful outpatient follow-up for symptom monitoring and by communicating with patients’ schools and employers.

OUTCOME Asymptomatic; no recurrence of symptoms

Forty-six days after his symptoms began and 31 days after hospital discharge, Mr. G is asymptomatic with no recurrence of symptoms.

Bottom Line

Kleine-Levin syndrome (KLS) is a rare, often-overlooked condition that should be considered in the differential diagnosis for patients who present with hypersomnolence and altered mental status without a clear etiology. Rapid recognition of KLS can prevent misattribution of symptoms, unnecessary treatment, and missed opportunities for care.

CASE Somnolent, confused, and hungry

Mr. G, age 14, presents to the emergency department (ED) for acute-onset hypersomnia that has gradually worsened over the course of a few days. Mr. G now sleeps most of the day, has altered mental status, and is experiencing emotional dysregulation with no clear etiology. His mother, who accompanies him to the ED, says that prior to the onset of these symptoms her son had been healthy. She notes that he has been eating more than usual, which she assumes is due to a growth spurt.

Mr. G’s symptoms began 4 days ago when he became increasingly fatigued, sleeping for 11 to 12 hours per day, with intermittent episodes of staring and unresponsiveness from which he rapidly returned to baseline. During the next 3 days, he became more confused and somnolent, and began to display bizarre behavior, including eating food out of the trash and attempting to microwave a full metal pot. He exhibited unexplained crying spells, calling out for his “mommy,” and saying he was “afraid I’m dying.”

During the 2 days before he came to our ED, Mr. G was seen at 2 other hospitals. Following extensive imaging and laboratory work-up, clinicians at these facilities attributed his symptoms to intoxication from an unknown substance. Mr. G has a history of marijuana use, and his mother reports that his friends had recently been using synthetic marijuana. However, no intoxicant was identified on urine or gas chromatography drug screening.

Mr. G’s history includes oppositional behavior, and a brief psychiatric hospitalization at age 5 for aggression. He has otherwise been healthy. His family history is significant for maternal substance use and anxiety disorders. In addition to sporadic cannabis use, Mr. G’s social history includes multiple recent family losses, previous foster care placement, and recent declining academic performance.

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EVALUATION No red flags

On admission, Mr. G appears somnolent and displays disorganized speech, impulsivity, frequent disorientation, and intermittent agitation/anxiety; he sleeps 16 to 18 hours per day. Mr. G is admitted with a presumptive diagnosis of substance intoxication and transferred to the general pediatric inpatient unit. Upon arrival, he is found to be bradycardic (42 beats per minute), although afebrile with otherwise age-appropriate vitals. On exam, he is somnolent but arousable and follows simple commands.

Continue to: Mr. G undergoes a Monospot test...

Mr. G undergoes a Monospot test, which is positive, with subsequent evidence of a prior, but not active, Epstein-Barr virus (EBV) infection. He also has a mildly elevated CSF protein level, but subsequent CSF labs are negative for both infectious and non-infectious processes. An EEG reveals focal neuronal slowing.

During brief periods of wakefulness, Mr. G calls out to his mother and says, “I’m not going to make it to my birthday,” and “You’re going to have to let me go.” He occasionally becomes combative, pulling at IV lines and swearing at staff. His bradycardia resolves without intervention during his admission. On Day 8 of his hospitalization, Mr. G displays hypersexuality and makes sexually suggestive comments toward female staff members. He also experiences recurrence of hyperphagia.

On Day 10 of his stay on the pediatric unit, because of the emergence of hypersexuality and hyperphagia, along with a largely negative medical evaluation, Mr. G is transferred to the pediatric psychiatric unit for ongoing evaluation and management.

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The authors’ observations

Given Mr. G’s rapid onset of confusion, hypersomnia, and emotional dysregulation, our differential diagnosis included delirium of unclear etiology, substance intoxication, autoimmune encephalitis, viral meningitis, heavy metal intoxication, primary psychotic disorder, and KLS. Mr. G underwent an extensive diagnostic evaluation, which was largely unremarkable (Table). He had a mildly elevated CSF protein level, but subsequent CSF labs were negative for both infectious and non-infectious processes. When Mr. G was transferred to the pediatric inpatient psychiatric unit on Day 10, the presumptive diagnosis was KLS.

KLS is a rare neurologic disorder, with an incidence of 1 to 5 in 1 million and a 4:1 male-to-female predominance.¹ It poses a diagnostic challenge due to its low prevalence and broad differential. The disorder typically presents in early adolescence and is characterized by episodes of severe hypersomnia with associated cognitive and/or behavioral disturbance² (Box^2-4). Bradycardia, as seen in Mr. G, and other forms of autonomic dysregulation have been reported in the literature, as has the focal neuronal slowing noted on Mr. G’s EEG.³

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Continue to: TREATMENT Methylphenidate and a safety plan

On Day 11 of hospitalization, Mr. G is started on methylphenidate, 10 mg in the morning and 5 mg in the afternoon. After starting methylphenidate, he sustains more regular wakefulness, with improved thought organization, engagement, and fewer disruptive behaviors. He receives infrequent, as-needed doses of olanzapine, and by Day 14, he returns to his baseline behavior and cognition.

A safety plan is created for the family to address worsening symptoms or future episodes. The safety plan is developed with Mr. G and input from his family. It is to be administered in all settings and we particularly emphasized using it in the school setting, where staff may not be familiar with KLS. The safety plan involves a description of KLS, its symptoms, the risks for hypersomnolence, hypersexuality, and psychotic symptoms or behavioral dysregulation. It stresses close supervision of Mr. G, not allowing him to be unsupervised or unchaperoned on school trips or other outings, and lethal means restriction. It outlines a detailed plan if Mr. G’s behavior decompensates or escalates, including a step-wise approach to engaging psychological interventions and mental health resources, and securing crisis services as needed.

On Day 15, he is discharged to home in stable condition with outpatient mental health follow-up and continues to take the prescribed methylphenidate.

The authors’ observations

Management of KLS is primarily supportive. Stimulants may help reduce hypersomnia, impulsivity, and inattention early in the disease course.¹ However, in a systematic review, 89% of patients with KLS who received methylphenidate experienced worsening or no improvement, and 11% showed only partial improvement.² Amantadine was more promising, with 29% of patients with KLS showing partial benefit and 12% showing significant benefit.² Multiple other pharmacologic agents have been described with varying efficacy, including lithium, valproate, risperidone, bupropion, and immunoglobulins.² Furthermore, lithium and valproate have been suggested to be helpful in preventing recurrences in some cases.⁶

The circumstances surrounding Mr. G’s symptom onset are unclear and may have been multifactorial. It is possible that his prior EBV infection was a trigger for this KLS-associated episode, as EBV is a known precipitant for KLS episodes.³ Mr. G’s history of cannabis use may also have served as an early trigger for KLS.³

This case highlights the importance of multidisciplinary collaboration in a diagnostically challenging case. It emphasizes the need for a broad differential and the importance of challenging a previous diagnosis in the face of mounting evidence to the contrary. In this case, the patient’s history of irritability, aggression, and cannabis use resulted in multiple clinicians misattributing his symptoms to substance use or a primary psychiatric disorder. However, given his symptom acuity, progression, and the lack of findings on diagnostic evaluation to explain his presentation, these initial diagnoses did not explain the severity, nature, or duration of his symptoms. Keeping KLS in the differential is particularly important for patients with a prior history of psychiatric illness or substance use, because these patients are at higher risk for misattribution of symptoms to pre-existing psychiatric illness. Evolution of symptoms, a negative diagnostic evaluation, and maintaining a broad differential resulted in eventually reaching the final diagnosis of KLS and development of a longitudinal management plan.

While further work must be done to clearly define the pharmacologic approach to acute management of KLS episodes, nonpharmacologic aspects of care must not be neglected. Behavioral planning, adjustment of the environment, engagement with schools/community supports, and family education are valuable tools for facilitating the patient’s de-escalation, avoiding unneeded polypharmacy, reducing anxieties, and safeguarding the patient from unnecessary harm.⁷ Clinicians can support their patients’ transitions back into the community by ensuring careful outpatient follow-up for symptom monitoring and by communicating with patients’ schools and employers.

OUTCOME Asymptomatic; no recurrence of symptoms

Forty-six days after his symptoms began and 31 days after hospital discharge, Mr. G is asymptomatic with no recurrence of symptoms.

Bottom Line

Kleine-Levin syndrome (KLS) is a rare, often-overlooked condition that should be considered in the differential diagnosis for patients who present with hypersomnolence and altered mental status without a clear etiology. Rapid recognition of KLS can prevent misattribution of symptoms, unnecessary treatment, and missed opportunities for care.

Clinical errors are common during shift changes in a hospital setting.^1-3 Clinicians on the outgoing shift may forget to communicate important details, such as medication dosages, critical laboratory orders, or other interventions, to the clinicians in the next shift. To help myself formally structure the sign-out process for each patient during a shift change in a psychiatric emergency room, I came up with the acronym COMPRESS for key questions to ask the outgoing provider:

Communicate. Did you communicate with this patient in any way at any time during your shift?

Orders. Did you write any orders for this patient? If not, had another clinician already written orders for this patient?

Medications. Did you review and reconcile the medication list for this patient? If not, had another clinician already reviewed and reconciled the medication list for this patient?

PRogrESs. Did you write a progress note for this patient? If not, had the attending clinician written a progress note for this patient within the last 24 hours?

Sign. Did you sign all of your orders and progress notes for this patient?

In my experience in the psychiatric emergency room, COMPRESS has helped me efficiently structure the outgoing clinicians’ reports about my patients by having them provide vital clinical sign-out information before they leave. I hope that other clinicians working in this setting also find these questions useful.

Clinical errors are common during shift changes in a hospital setting.^1-3 Clinicians on the outgoing shift may forget to communicate important details, such as medication dosages, critical laboratory orders, or other interventions, to the clinicians in the next shift. To help myself formally structure the sign-out process for each patient during a shift change in a psychiatric emergency room, I came up with the acronym COMPRESS for key questions to ask the outgoing provider:

Communicate. Did you communicate with this patient in any way at any time during your shift?

Orders. Did you write any orders for this patient? If not, had another clinician already written orders for this patient?

Medications. Did you review and reconcile the medication list for this patient? If not, had another clinician already reviewed and reconciled the medication list for this patient?

PRogrESs. Did you write a progress note for this patient? If not, had the attending clinician written a progress note for this patient within the last 24 hours?

Sign. Did you sign all of your orders and progress notes for this patient?

In my experience in the psychiatric emergency room, COMPRESS has helped me efficiently structure the outgoing clinicians’ reports about my patients by having them provide vital clinical sign-out information before they leave. I hope that other clinicians working in this setting also find these questions useful.

Clinical errors are common during shift changes in a hospital setting.^1-3 Clinicians on the outgoing shift may forget to communicate important details, such as medication dosages, critical laboratory orders, or other interventions, to the clinicians in the next shift. To help myself formally structure the sign-out process for each patient during a shift change in a psychiatric emergency room, I came up with the acronym COMPRESS for key questions to ask the outgoing provider:

Communicate. Did you communicate with this patient in any way at any time during your shift?

Orders. Did you write any orders for this patient? If not, had another clinician already written orders for this patient?

Medications. Did you review and reconcile the medication list for this patient? If not, had another clinician already reviewed and reconciled the medication list for this patient?

PRogrESs. Did you write a progress note for this patient? If not, had the attending clinician written a progress note for this patient within the last 24 hours?

Sign. Did you sign all of your orders and progress notes for this patient?

In my experience in the psychiatric emergency room, COMPRESS has helped me efficiently structure the outgoing clinicians’ reports about my patients by having them provide vital clinical sign-out information before they leave. I hope that other clinicians working in this setting also find these questions useful.

The rate of burnout among physicians is disturbingly high, and wellness promotion is needed at all levels of training. While rigorous clinical training is necessary to build competence for making life-or-death decisions, training should not cause an indifference toward life or death. Because many physicians experience burnout during residency, we all must commit to wellness, which directly leads to healthier professionals and improved patient care.

Ey et al¹ evaluated the feasibility and application of a wellness program for residents/fellows and faculty in an academic health center over 10 years. They concluded that a comprehensive model of care was viable and well-valued, based on high levels of physician satisfaction with the program. This model, which involves educational outreach, direct care, and consultation, inspired me to reflect on the resident burnout prevention strategies employed by the residency program in which I am currently training.

Even in situations where a formal wellness program does not exist, measures that promote resident well-being can be embedded and easily adapted:

• Education on recognizing the early signs of burnout or establishing a “buddy system” can promote a help-seeking culture and ease the transition into residency.
• Faculty who provide feedback in the “sandwich method” (praise followed by corrective feedback followed by more praise) can help promote self-confidence among residents.
• Process groups and monthly meetings with chief residents present opportunities for professional development and for residents to express concerns.
• Social gatherings that encourage team building and regular interaction among residents, attendings, and family members help build a comforting sense of community.
• A residency program director and faculty who adopt open-door policies and foster personal attention and guidance are also essential.

A recent cross-sectional analysis found that building competence, autonomy, coping mechanisms, adequate sleep, and social relatedness were associated with resident well-being.² Hence, these factors should be integrated within residency training programs.

Residency should be approached as an engagement between colleagues where autonomy and confidence are promoted while residents acquire clinical skills within a wellness-promoting, learning environment. Demanding schedules may limit access to a dedicated wellness program; however, it is essential that a system be established to quickly identify and mitigate burnout. We all strive to be the best in our respective fields, and we must re-evaluate how we achieve excellent training while developing proper skills for future success. As physicians, we are not machines; our humanity connects us with our patients, explains life-changing news, or consoles the bereaved when there is loss of life. We must embrace our humanity and be mindful that physicians experiencing burnout cannot deliver high-quality care. Early detection and prevention strategies during residency training are key.

The rate of burnout among physicians is disturbingly high, and wellness promotion is needed at all levels of training. While rigorous clinical training is necessary to build competence for making life-or-death decisions, training should not cause an indifference toward life or death. Because many physicians experience burnout during residency, we all must commit to wellness, which directly leads to healthier professionals and improved patient care.

Ey et al¹ evaluated the feasibility and application of a wellness program for residents/fellows and faculty in an academic health center over 10 years. They concluded that a comprehensive model of care was viable and well-valued, based on high levels of physician satisfaction with the program. This model, which involves educational outreach, direct care, and consultation, inspired me to reflect on the resident burnout prevention strategies employed by the residency program in which I am currently training.

Even in situations where a formal wellness program does not exist, measures that promote resident well-being can be embedded and easily adapted:

• Education on recognizing the early signs of burnout or establishing a “buddy system” can promote a help-seeking culture and ease the transition into residency.
• Faculty who provide feedback in the “sandwich method” (praise followed by corrective feedback followed by more praise) can help promote self-confidence among residents.
• Process groups and monthly meetings with chief residents present opportunities for professional development and for residents to express concerns.
• Social gatherings that encourage team building and regular interaction among residents, attendings, and family members help build a comforting sense of community.
• A residency program director and faculty who adopt open-door policies and foster personal attention and guidance are also essential.

A recent cross-sectional analysis found that building competence, autonomy, coping mechanisms, adequate sleep, and social relatedness were associated with resident well-being.² Hence, these factors should be integrated within residency training programs.

Residency should be approached as an engagement between colleagues where autonomy and confidence are promoted while residents acquire clinical skills within a wellness-promoting, learning environment. Demanding schedules may limit access to a dedicated wellness program; however, it is essential that a system be established to quickly identify and mitigate burnout. We all strive to be the best in our respective fields, and we must re-evaluate how we achieve excellent training while developing proper skills for future success. As physicians, we are not machines; our humanity connects us with our patients, explains life-changing news, or consoles the bereaved when there is loss of life. We must embrace our humanity and be mindful that physicians experiencing burnout cannot deliver high-quality care. Early detection and prevention strategies during residency training are key.

The rate of burnout among physicians is disturbingly high, and wellness promotion is needed at all levels of training. While rigorous clinical training is necessary to build competence for making life-or-death decisions, training should not cause an indifference toward life or death. Because many physicians experience burnout during residency, we all must commit to wellness, which directly leads to healthier professionals and improved patient care.

Ey et al¹ evaluated the feasibility and application of a wellness program for residents/fellows and faculty in an academic health center over 10 years. They concluded that a comprehensive model of care was viable and well-valued, based on high levels of physician satisfaction with the program. This model, which involves educational outreach, direct care, and consultation, inspired me to reflect on the resident burnout prevention strategies employed by the residency program in which I am currently training.

Even in situations where a formal wellness program does not exist, measures that promote resident well-being can be embedded and easily adapted:

• Education on recognizing the early signs of burnout or establishing a “buddy system” can promote a help-seeking culture and ease the transition into residency.
• Faculty who provide feedback in the “sandwich method” (praise followed by corrective feedback followed by more praise) can help promote self-confidence among residents.
• Process groups and monthly meetings with chief residents present opportunities for professional development and for residents to express concerns.
• Social gatherings that encourage team building and regular interaction among residents, attendings, and family members help build a comforting sense of community.
• A residency program director and faculty who adopt open-door policies and foster personal attention and guidance are also essential.

A recent cross-sectional analysis found that building competence, autonomy, coping mechanisms, adequate sleep, and social relatedness were associated with resident well-being.² Hence, these factors should be integrated within residency training programs.

Residency should be approached as an engagement between colleagues where autonomy and confidence are promoted while residents acquire clinical skills within a wellness-promoting, learning environment. Demanding schedules may limit access to a dedicated wellness program; however, it is essential that a system be established to quickly identify and mitigate burnout. We all strive to be the best in our respective fields, and we must re-evaluate how we achieve excellent training while developing proper skills for future success. As physicians, we are not machines; our humanity connects us with our patients, explains life-changing news, or consoles the bereaved when there is loss of life. We must embrace our humanity and be mindful that physicians experiencing burnout cannot deliver high-quality care. Early detection and prevention strategies during residency training are key.

Searching for someone on the Internet and viewing his or her social media profile is an effective way to obtain information about people, including patients. Following our patients’ “digital footprint” may help us understand the context of their lives, reconcile discrepancies in what they have told us, or allow us to confront denial and address incomplete reporting.¹ However, perusing our patients’ online profiles could negatively impact treatment and adherence. Consider these factors before looking up your patients’ online profiles^1-3:

Inaccurate information. Information on the Internet, especially what you can find on user-generated forums, is largely unregulated; as a result, the veracity of that information cannot be guaranteed.¹ Patients may choose to portray themselves inaccurately on their online profiles, and their identities often cannot be confirmed. Even if some information is accurate, you might discover things that you did not expect to learn about your patients, including important information that they did not share, or even something they lied about. This can create the conundrums of what to do with such information and how to discuss it at the next visit.

Impact on treatment. Despite patients’ online activities being displayed for the world to see, many patients do not expect their clinicians to access their online information. They might perceive such perusal as a breach of trust, which might lead some to view the doctor–patient relationship as adversarial. Accessing this information also could create a more intimate relationship than intended. Even if a clinician acquires consent to perform a search, patients may still feel coerced into allowing it because they might feel that declining to grant permission would make the clinician suspect that they have something to hide, or that the clinician would search without consent.²

In addition, if patients are aware that their psychiatrists are monitoring them, they might change their behavior. For example, they may delete certain data, add additional information that may not be accurate, or censor future social media posts. Knowing that their clinicians could be paying attention to them around the clock also might motivate certain patients to act out more or become withdrawn.

Possible medicolegal repercussions. If clinicians are able to access their patients’ electronic profiles, are they then legally obligated to monitor them? For example, if a patient who posts a picture with a noose around his neck later completes suicide, does the clinician who intermittently monitored this patient’s online profile face legal ramifications for not seeing the post? Do clinicians have to call 911 for vaguely suicidal tweets? What responsibilities does a clinician have at the first sign of an innocuous “sad” emoji? The sheer volume of online content that patients can create over different outlets is staggering. It can be overwhelming and ineffective to attempt to monitor patients’ online activities in addition to attending to one’s usual clinical duties, and the medicolegal repercussions of doing so are largely unknown.

Before searching the Internet to learn more about your patients, first consider the ramifications of doing so. While such searches could be helpful, they may lead to poor adherence, a lack of trust, or legal quagmires.

Searching for someone on the Internet and viewing his or her social media profile is an effective way to obtain information about people, including patients. Following our patients’ “digital footprint” may help us understand the context of their lives, reconcile discrepancies in what they have told us, or allow us to confront denial and address incomplete reporting.¹ However, perusing our patients’ online profiles could negatively impact treatment and adherence. Consider these factors before looking up your patients’ online profiles^1-3:

Inaccurate information. Information on the Internet, especially what you can find on user-generated forums, is largely unregulated; as a result, the veracity of that information cannot be guaranteed.¹ Patients may choose to portray themselves inaccurately on their online profiles, and their identities often cannot be confirmed. Even if some information is accurate, you might discover things that you did not expect to learn about your patients, including important information that they did not share, or even something they lied about. This can create the conundrums of what to do with such information and how to discuss it at the next visit.

Impact on treatment. Despite patients’ online activities being displayed for the world to see, many patients do not expect their clinicians to access their online information. They might perceive such perusal as a breach of trust, which might lead some to view the doctor–patient relationship as adversarial. Accessing this information also could create a more intimate relationship than intended. Even if a clinician acquires consent to perform a search, patients may still feel coerced into allowing it because they might feel that declining to grant permission would make the clinician suspect that they have something to hide, or that the clinician would search without consent.²

In addition, if patients are aware that their psychiatrists are monitoring them, they might change their behavior. For example, they may delete certain data, add additional information that may not be accurate, or censor future social media posts. Knowing that their clinicians could be paying attention to them around the clock also might motivate certain patients to act out more or become withdrawn.

Possible medicolegal repercussions. If clinicians are able to access their patients’ electronic profiles, are they then legally obligated to monitor them? For example, if a patient who posts a picture with a noose around his neck later completes suicide, does the clinician who intermittently monitored this patient’s online profile face legal ramifications for not seeing the post? Do clinicians have to call 911 for vaguely suicidal tweets? What responsibilities does a clinician have at the first sign of an innocuous “sad” emoji? The sheer volume of online content that patients can create over different outlets is staggering. It can be overwhelming and ineffective to attempt to monitor patients’ online activities in addition to attending to one’s usual clinical duties, and the medicolegal repercussions of doing so are largely unknown.

Before searching the Internet to learn more about your patients, first consider the ramifications of doing so. While such searches could be helpful, they may lead to poor adherence, a lack of trust, or legal quagmires.

Searching for someone on the Internet and viewing his or her social media profile is an effective way to obtain information about people, including patients. Following our patients’ “digital footprint” may help us understand the context of their lives, reconcile discrepancies in what they have told us, or allow us to confront denial and address incomplete reporting.¹ However, perusing our patients’ online profiles could negatively impact treatment and adherence. Consider these factors before looking up your patients’ online profiles^1-3:

Inaccurate information. Information on the Internet, especially what you can find on user-generated forums, is largely unregulated; as a result, the veracity of that information cannot be guaranteed.¹ Patients may choose to portray themselves inaccurately on their online profiles, and their identities often cannot be confirmed. Even if some information is accurate, you might discover things that you did not expect to learn about your patients, including important information that they did not share, or even something they lied about. This can create the conundrums of what to do with such information and how to discuss it at the next visit.

Impact on treatment. Despite patients’ online activities being displayed for the world to see, many patients do not expect their clinicians to access their online information. They might perceive such perusal as a breach of trust, which might lead some to view the doctor–patient relationship as adversarial. Accessing this information also could create a more intimate relationship than intended. Even if a clinician acquires consent to perform a search, patients may still feel coerced into allowing it because they might feel that declining to grant permission would make the clinician suspect that they have something to hide, or that the clinician would search without consent.²

In addition, if patients are aware that their psychiatrists are monitoring them, they might change their behavior. For example, they may delete certain data, add additional information that may not be accurate, or censor future social media posts. Knowing that their clinicians could be paying attention to them around the clock also might motivate certain patients to act out more or become withdrawn.

Possible medicolegal repercussions. If clinicians are able to access their patients’ electronic profiles, are they then legally obligated to monitor them? For example, if a patient who posts a picture with a noose around his neck later completes suicide, does the clinician who intermittently monitored this patient’s online profile face legal ramifications for not seeing the post? Do clinicians have to call 911 for vaguely suicidal tweets? What responsibilities does a clinician have at the first sign of an innocuous “sad” emoji? The sheer volume of online content that patients can create over different outlets is staggering. It can be overwhelming and ineffective to attempt to monitor patients’ online activities in addition to attending to one’s usual clinical duties, and the medicolegal repercussions of doing so are largely unknown.

Before searching the Internet to learn more about your patients, first consider the ramifications of doing so. While such searches could be helpful, they may lead to poor adherence, a lack of trust, or legal quagmires.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Photo by Rhoda Baer

A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).

Researchers found the timing and duration of corticosteroid use were both associated with FN.

The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.

On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.

Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.

“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”

With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.

Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.

In all, 4.3% of patients developed FN during their first cycle of chemotherapy.

Corticosteroid use

The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.

A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:

• 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
• 1.84 for treatment lasting 15 to 29 days (P<0.01)
• 2.27 for treatment lasting 30 to 44 days (P<0.01)
• 2.86 for treatment lasting 45 to 90 days (P<0.01).

More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:

• 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
• 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
• 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
• 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).

“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.

Other potential risk factors

The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).

In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.

IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).

On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.

Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.

As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):

• Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
• Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
• Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).

The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.

In closing, Dr. Chao and her colleagues said these results suggest cor­ticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be tak­en into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.

Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.

Image by Lance Liotta

Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.

Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.

Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.

Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.

The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.

When the researchers knocked down Spi1, the myeloid skewing diminished.

“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”

The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.

These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.

To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.

After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.

The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.

Suppression of erythropoiesis

The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.

Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.

They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.

Suppression of lymphopoiesis

The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.

And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.

EVI1 nearly eliminated the peripheral B cells completely, they noted.

Expansion of myelopoiesis

The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.

But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.

The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.

All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.

The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.

They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.

When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.

Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.

The authors had no competing interests to disclose. 

Image by Lance Liotta

Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.

Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.

Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.

Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.

The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.

When the researchers knocked down Spi1, the myeloid skewing diminished.

“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”

The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.

These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.

To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.

After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.

The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.

Suppression of erythropoiesis

The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.

Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.

They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.

Suppression of lymphopoiesis

The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.

And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.

EVI1 nearly eliminated the peripheral B cells completely, they noted.

Expansion of myelopoiesis

The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.

But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.

The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.

All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.

The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.

They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.

When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.

Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.

The authors had no competing interests to disclose. 

Image by Lance Liotta

Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.

Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.

Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.

Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.

The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.

When the researchers knocked down Spi1, the myeloid skewing diminished.

“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”

The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.

These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.

To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.

After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.

The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.

Suppression of erythropoiesis

The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.

Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.

They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.

Suppression of lymphopoiesis

The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.

And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.

EVI1 nearly eliminated the peripheral B cells completely, they noted.

Expansion of myelopoiesis

The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.

But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.

The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.

All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.

The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.

They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.

When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.

Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.

The authors had no competing interests to disclose.