Bipolar Disorder

Discuss this article at www.facebook.com/CurrentPsychiatry

Electroconvulsive therapy (ECT) has remained one of the most effective treatments for major depressive disorder (MDD) since it was introduced >70 years ago.¹ ECT’s primary indication is severe, treatment-resistant MDD but sometimes it is used to treat other disorders, including bipolar mania and schizophrenia. In ECT, electrical current is delivered to a patient’s brain via electrodes placed on the scalp to induce a seizure while the patient is under anesthesia and a muscle relaxant. ECT’s exact mechanism of action for MDD is unknown, but researchers believe it may relieve depressive symptoms by regulating functional disturbances in relevant neural circuits.²

Research has shown that 64% to 87% of patients with severe MDD respond to ECT, with response rates as high as 95% for patients with MDD with psychotic features.^3-5 Although patients may respond more quickly, 6 to 12 sessions typically are required to resolve a severe depressive episode.²

Despite ECT’s proven effectiveness, several factors have limited its widespread use, including limited access and expertise, adverse cognitive effects such as memory impairment, and negative public perception based on how ECT was administered decades ago.² This article describes current methods of administering ECT, and how these changes have helped minimize these concerns while retaining efficacy.

Modern ECT practices

Since ECT was first used in the 1930s, clinicians have made many modifications to improve its efficacy and safety. Refinements to how ECT is administered include changing waveform parameters, individualizing dosing to seizure threshold, and altering electrode placement.^6,7

Pulse width. Most ECT devices used today feature a constant-current output stimulator⁸ that allows continuous current regulation.⁷ Total charge, in millicoulombs (mC), is the common metric.⁷ Pulse width is a commonly altered waveform parameter in ECT delivery. Most research supports administering repeated brief or ultra-brief pulses (0.5 to 2 milliseconds), which is associated with greater charge efficiency and fewer side effects than traditional sine wave ECT dosing.^8,9 Using a brief or ultra-brief pulse width increases clinical efficiency and decreases side effects because it focuses the stimulus on brain regions that regulate mood while limiting stimulation of brain regions involved in cognitive functioning.⁷ With brief-pulse stimulus, a patient’s cognitive performance may return to baseline levels within 3 days of treatment.⁶ Increasing evidence demonstrates that using a larger number of pulses with a brief pulse width and amplitude enhances ECT’s antidepressant effects while reducing unwanted neurocognitive side effects.⁷

Acute therapy patients typically receive 2 to 3 treatments each week,^11,12 culminating in 12 to 18 treatments.^8,12 The optimum number of sessions administered is determined by the ratio of clinical improvement to the severity of cognitive adverse effects.³

Electrode placement. Spatial targeting of stimulus is crucial to maximize therapeutic benefits and minimize side effects. Concerns about cognitive side effects have led to variations in electrode placement to minimize the amount of brain parenchyma affected by electrical discharge (Table).^1,7,8 The most commonly used placements are:

• bitemporal (BT)—electrodes are placed midline between the eye and ear on both sides of the head
  
• right unilateral (RUL)—1 electrode is positioned just lateral to the vertex and the other at the right temple.⁷
  

Table

ECT electrodes: Bitemporal vs right unilateral placement

Addressing safety concerns

In addition to changes to waveforms, dosing, and electrode placement, using anesthesia, muscle relaxants, and other medications has dramatically reduced adverse effects of ECT.^8,10,13 See the Box^10,14,15 for the specific agents used and their purposes. Before these medications and electroencephalography and electrocardiography (ECG) monitoring were used during ECT, the mortality rate was approximately 0.1%.¹³ Today, ECT is considered a low-risk medical intervention, with a mortality rate of approximately 0.002%.^1,16 Before beginning an acute course of ECT, patients undergo laboratory testing, including a complete blood count, basic metabolic panel, and ECG. Spinal radiography and neuroimaging studies can be obtained to rule out preexisting vertebral injuries or neurologic disorders.^1,8

Hemodynamic changes in response to ECT-induced seizures can exacerbate preexisting cardiac conditions. Normal physiologic response to ECT consists of a brief parasympathetic outflow, inducing bradycardia for 10 to 15 seconds, followed by a prominent sympathetic response characterized by hypertension and tachycardia for approximately 5 minutes. Although these changes can induce myocardial ischemia or infarction,¹⁴ the most common cardiac disturbances caused by ECT are arrhythmias, primarily in patients with preexisting cardiac abnormalities.¹⁷

Memory impairment. The most prevalent adverse reaction to ECT is memory loss, although not all aspects of recall are impaired to the same degree.¹⁸ Memory impairment varies based on factors such as electrode placement,⁹ stimulus waveform,¹⁹ site of seizure initiation, and pattern of activation.²⁰ The risk of experiencing memory loss or other cognitive side effects following ECT can be decreased by using RUL electrode placement, brief pulses, and lower stimulus charge relative to seizure threshold.²¹ Memory deficits incurred by ECT usually are transient. In a study of 21 patients who received BT ECT for severe MDD, Meeter et al²² found that memory was stable and possibly improved at 3-month follow-up.

Procedural memory—memories of learned motor skills or mechanical tasks—often are left intact compared with semantic memory, which is general, declarative information recalled without context.¹⁸ The subsets of memory collectively regarded as declarative memory—the recollection of facts and events—may be most severely affected because this type of memory relies upon median temporal lobe structures, which are affected by ECT.²¹

Anterograde amnesia—the inability to form new memories—often is limited to the immediate posttreatment period and has been shown to become less pronounced at follow-up visits.²² Many clinicians and patients consider retrograde amnesia—forgetting memories that were formed before ECT—to be the most serious adverse effect of ECT. However, Mini-Mental State Examination scores tend to improve for patients who undergo ECT.^1,16 Retrograde amnesia usually improves within weeks to months after ECT.¹² Evidence suggests that retrograde amnesia mostly lifts during the recovery period and typically is not evident after 3 months.²² The best indicators of possible retrograde amnesic effects are preexisting cognitive deficits¹² and duration of disorientation after ECT.¹ Therefore, retrograde amnesia is more common among older adults, in whom age-related changes predispose patients to ECT’s adverse effects.²⁴

The conventionally accepted mechanism for memory deficits after ECT is excitotoxic damage in the pyramidal cell layer of neurons in the hippocampus that induces calcium influx, which damages cells and causes neuronal atrophy.¹² However, in animal studies, Dwork et al²⁵ found an absence of neuronal or glial loss in regions subserving memory or cognitive functions (ie, the hippocampus or frontal cortex). Even in regions exquisitely sensitive to neuronal damage—such as CA1 of the hippocampus—neither cell number or volume or density of neuronal or glial cells were detected at statistically significant levels.²⁵ Therefore, it is unlikely that ECT causes cell damage or atrophy in hippocampal neurons.

Box

• Leiknes KA, Jarosh-von Schweder L, Høie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012;2(3):283-344.
  
• Manka MV, Beyer JL, Weiner RD, et al. Clinical manual of electroconvulsive therapy. Arlington, VA: American Psychiatric Publishing; 2010.
  

• Esmolol • Brevibloc
  
• Etomidate • Amidate
  
• Glycopyrrolate • Robinul
  
• Ketorolac • Toradol
  
• Labetalol • Normodyne, Trandate
  
• Methohexital • Brevital
  
• Nicardipine • Cardene
  
• Succinylcholine • Anectine
  

Dr. Husain receives grant or research support from Brainsway, Cyberonics, MagStim, NARSAD, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute on Drug Abuse, NeoSync, Neuronetics, St. Jude Medical, and the Stanley Foundation.

Drs. Raza, Tirmizi, and Trevino report no relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Electroconvulsive therapy (ECT) has remained one of the most effective treatments for major depressive disorder (MDD) since it was introduced >70 years ago.¹ ECT’s primary indication is severe, treatment-resistant MDD but sometimes it is used to treat other disorders, including bipolar mania and schizophrenia. In ECT, electrical current is delivered to a patient’s brain via electrodes placed on the scalp to induce a seizure while the patient is under anesthesia and a muscle relaxant. ECT’s exact mechanism of action for MDD is unknown, but researchers believe it may relieve depressive symptoms by regulating functional disturbances in relevant neural circuits.²

Research has shown that 64% to 87% of patients with severe MDD respond to ECT, with response rates as high as 95% for patients with MDD with psychotic features.^3-5 Although patients may respond more quickly, 6 to 12 sessions typically are required to resolve a severe depressive episode.²

Despite ECT’s proven effectiveness, several factors have limited its widespread use, including limited access and expertise, adverse cognitive effects such as memory impairment, and negative public perception based on how ECT was administered decades ago.² This article describes current methods of administering ECT, and how these changes have helped minimize these concerns while retaining efficacy.

Modern ECT practices

Since ECT was first used in the 1930s, clinicians have made many modifications to improve its efficacy and safety. Refinements to how ECT is administered include changing waveform parameters, individualizing dosing to seizure threshold, and altering electrode placement.^6,7

Pulse width. Most ECT devices used today feature a constant-current output stimulator⁸ that allows continuous current regulation.⁷ Total charge, in millicoulombs (mC), is the common metric.⁷ Pulse width is a commonly altered waveform parameter in ECT delivery. Most research supports administering repeated brief or ultra-brief pulses (0.5 to 2 milliseconds), which is associated with greater charge efficiency and fewer side effects than traditional sine wave ECT dosing.^8,9 Using a brief or ultra-brief pulse width increases clinical efficiency and decreases side effects because it focuses the stimulus on brain regions that regulate mood while limiting stimulation of brain regions involved in cognitive functioning.⁷ With brief-pulse stimulus, a patient’s cognitive performance may return to baseline levels within 3 days of treatment.⁶ Increasing evidence demonstrates that using a larger number of pulses with a brief pulse width and amplitude enhances ECT’s antidepressant effects while reducing unwanted neurocognitive side effects.⁷

Acute therapy patients typically receive 2 to 3 treatments each week,^11,12 culminating in 12 to 18 treatments.^8,12 The optimum number of sessions administered is determined by the ratio of clinical improvement to the severity of cognitive adverse effects.³

Electrode placement. Spatial targeting of stimulus is crucial to maximize therapeutic benefits and minimize side effects. Concerns about cognitive side effects have led to variations in electrode placement to minimize the amount of brain parenchyma affected by electrical discharge (Table).^1,7,8 The most commonly used placements are:

• bitemporal (BT)—electrodes are placed midline between the eye and ear on both sides of the head
  
• right unilateral (RUL)—1 electrode is positioned just lateral to the vertex and the other at the right temple.⁷
  

Table

ECT electrodes: Bitemporal vs right unilateral placement

Addressing safety concerns

In addition to changes to waveforms, dosing, and electrode placement, using anesthesia, muscle relaxants, and other medications has dramatically reduced adverse effects of ECT.^8,10,13 See the Box^10,14,15 for the specific agents used and their purposes. Before these medications and electroencephalography and electrocardiography (ECG) monitoring were used during ECT, the mortality rate was approximately 0.1%.¹³ Today, ECT is considered a low-risk medical intervention, with a mortality rate of approximately 0.002%.^1,16 Before beginning an acute course of ECT, patients undergo laboratory testing, including a complete blood count, basic metabolic panel, and ECG. Spinal radiography and neuroimaging studies can be obtained to rule out preexisting vertebral injuries or neurologic disorders.^1,8

Hemodynamic changes in response to ECT-induced seizures can exacerbate preexisting cardiac conditions. Normal physiologic response to ECT consists of a brief parasympathetic outflow, inducing bradycardia for 10 to 15 seconds, followed by a prominent sympathetic response characterized by hypertension and tachycardia for approximately 5 minutes. Although these changes can induce myocardial ischemia or infarction,¹⁴ the most common cardiac disturbances caused by ECT are arrhythmias, primarily in patients with preexisting cardiac abnormalities.¹⁷

Memory impairment. The most prevalent adverse reaction to ECT is memory loss, although not all aspects of recall are impaired to the same degree.¹⁸ Memory impairment varies based on factors such as electrode placement,⁹ stimulus waveform,¹⁹ site of seizure initiation, and pattern of activation.²⁰ The risk of experiencing memory loss or other cognitive side effects following ECT can be decreased by using RUL electrode placement, brief pulses, and lower stimulus charge relative to seizure threshold.²¹ Memory deficits incurred by ECT usually are transient. In a study of 21 patients who received BT ECT for severe MDD, Meeter et al²² found that memory was stable and possibly improved at 3-month follow-up.

Procedural memory—memories of learned motor skills or mechanical tasks—often are left intact compared with semantic memory, which is general, declarative information recalled without context.¹⁸ The subsets of memory collectively regarded as declarative memory—the recollection of facts and events—may be most severely affected because this type of memory relies upon median temporal lobe structures, which are affected by ECT.²¹

Anterograde amnesia—the inability to form new memories—often is limited to the immediate posttreatment period and has been shown to become less pronounced at follow-up visits.²² Many clinicians and patients consider retrograde amnesia—forgetting memories that were formed before ECT—to be the most serious adverse effect of ECT. However, Mini-Mental State Examination scores tend to improve for patients who undergo ECT.^1,16 Retrograde amnesia usually improves within weeks to months after ECT.¹² Evidence suggests that retrograde amnesia mostly lifts during the recovery period and typically is not evident after 3 months.²² The best indicators of possible retrograde amnesic effects are preexisting cognitive deficits¹² and duration of disorientation after ECT.¹ Therefore, retrograde amnesia is more common among older adults, in whom age-related changes predispose patients to ECT’s adverse effects.²⁴

The conventionally accepted mechanism for memory deficits after ECT is excitotoxic damage in the pyramidal cell layer of neurons in the hippocampus that induces calcium influx, which damages cells and causes neuronal atrophy.¹² However, in animal studies, Dwork et al²⁵ found an absence of neuronal or glial loss in regions subserving memory or cognitive functions (ie, the hippocampus or frontal cortex). Even in regions exquisitely sensitive to neuronal damage—such as CA1 of the hippocampus—neither cell number or volume or density of neuronal or glial cells were detected at statistically significant levels.²⁵ Therefore, it is unlikely that ECT causes cell damage or atrophy in hippocampal neurons.

Box

• Leiknes KA, Jarosh-von Schweder L, Høie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012;2(3):283-344.
  
• Manka MV, Beyer JL, Weiner RD, et al. Clinical manual of electroconvulsive therapy. Arlington, VA: American Psychiatric Publishing; 2010.
  

• Esmolol • Brevibloc
  
• Etomidate • Amidate
  
• Glycopyrrolate • Robinul
  
• Ketorolac • Toradol
  
• Labetalol • Normodyne, Trandate
  
• Methohexital • Brevital
  
• Nicardipine • Cardene
  
• Succinylcholine • Anectine
  

Dr. Husain receives grant or research support from Brainsway, Cyberonics, MagStim, NARSAD, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute on Drug Abuse, NeoSync, Neuronetics, St. Jude Medical, and the Stanley Foundation.

Drs. Raza, Tirmizi, and Trevino report no relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Electroconvulsive therapy (ECT) has remained one of the most effective treatments for major depressive disorder (MDD) since it was introduced >70 years ago.¹ ECT’s primary indication is severe, treatment-resistant MDD but sometimes it is used to treat other disorders, including bipolar mania and schizophrenia. In ECT, electrical current is delivered to a patient’s brain via electrodes placed on the scalp to induce a seizure while the patient is under anesthesia and a muscle relaxant. ECT’s exact mechanism of action for MDD is unknown, but researchers believe it may relieve depressive symptoms by regulating functional disturbances in relevant neural circuits.²

Research has shown that 64% to 87% of patients with severe MDD respond to ECT, with response rates as high as 95% for patients with MDD with psychotic features.^3-5 Although patients may respond more quickly, 6 to 12 sessions typically are required to resolve a severe depressive episode.²

Despite ECT’s proven effectiveness, several factors have limited its widespread use, including limited access and expertise, adverse cognitive effects such as memory impairment, and negative public perception based on how ECT was administered decades ago.² This article describes current methods of administering ECT, and how these changes have helped minimize these concerns while retaining efficacy.

Modern ECT practices

Since ECT was first used in the 1930s, clinicians have made many modifications to improve its efficacy and safety. Refinements to how ECT is administered include changing waveform parameters, individualizing dosing to seizure threshold, and altering electrode placement.^6,7

Pulse width. Most ECT devices used today feature a constant-current output stimulator⁸ that allows continuous current regulation.⁷ Total charge, in millicoulombs (mC), is the common metric.⁷ Pulse width is a commonly altered waveform parameter in ECT delivery. Most research supports administering repeated brief or ultra-brief pulses (0.5 to 2 milliseconds), which is associated with greater charge efficiency and fewer side effects than traditional sine wave ECT dosing.^8,9 Using a brief or ultra-brief pulse width increases clinical efficiency and decreases side effects because it focuses the stimulus on brain regions that regulate mood while limiting stimulation of brain regions involved in cognitive functioning.⁷ With brief-pulse stimulus, a patient’s cognitive performance may return to baseline levels within 3 days of treatment.⁶ Increasing evidence demonstrates that using a larger number of pulses with a brief pulse width and amplitude enhances ECT’s antidepressant effects while reducing unwanted neurocognitive side effects.⁷

Acute therapy patients typically receive 2 to 3 treatments each week,^11,12 culminating in 12 to 18 treatments.^8,12 The optimum number of sessions administered is determined by the ratio of clinical improvement to the severity of cognitive adverse effects.³

Electrode placement. Spatial targeting of stimulus is crucial to maximize therapeutic benefits and minimize side effects. Concerns about cognitive side effects have led to variations in electrode placement to minimize the amount of brain parenchyma affected by electrical discharge (Table).^1,7,8 The most commonly used placements are:

• bitemporal (BT)—electrodes are placed midline between the eye and ear on both sides of the head
  
• right unilateral (RUL)—1 electrode is positioned just lateral to the vertex and the other at the right temple.⁷
  

Table

ECT electrodes: Bitemporal vs right unilateral placement

Addressing safety concerns

In addition to changes to waveforms, dosing, and electrode placement, using anesthesia, muscle relaxants, and other medications has dramatically reduced adverse effects of ECT.^8,10,13 See the Box^10,14,15 for the specific agents used and their purposes. Before these medications and electroencephalography and electrocardiography (ECG) monitoring were used during ECT, the mortality rate was approximately 0.1%.¹³ Today, ECT is considered a low-risk medical intervention, with a mortality rate of approximately 0.002%.^1,16 Before beginning an acute course of ECT, patients undergo laboratory testing, including a complete blood count, basic metabolic panel, and ECG. Spinal radiography and neuroimaging studies can be obtained to rule out preexisting vertebral injuries or neurologic disorders.^1,8

Hemodynamic changes in response to ECT-induced seizures can exacerbate preexisting cardiac conditions. Normal physiologic response to ECT consists of a brief parasympathetic outflow, inducing bradycardia for 10 to 15 seconds, followed by a prominent sympathetic response characterized by hypertension and tachycardia for approximately 5 minutes. Although these changes can induce myocardial ischemia or infarction,¹⁴ the most common cardiac disturbances caused by ECT are arrhythmias, primarily in patients with preexisting cardiac abnormalities.¹⁷

Memory impairment. The most prevalent adverse reaction to ECT is memory loss, although not all aspects of recall are impaired to the same degree.¹⁸ Memory impairment varies based on factors such as electrode placement,⁹ stimulus waveform,¹⁹ site of seizure initiation, and pattern of activation.²⁰ The risk of experiencing memory loss or other cognitive side effects following ECT can be decreased by using RUL electrode placement, brief pulses, and lower stimulus charge relative to seizure threshold.²¹ Memory deficits incurred by ECT usually are transient. In a study of 21 patients who received BT ECT for severe MDD, Meeter et al²² found that memory was stable and possibly improved at 3-month follow-up.

Procedural memory—memories of learned motor skills or mechanical tasks—often are left intact compared with semantic memory, which is general, declarative information recalled without context.¹⁸ The subsets of memory collectively regarded as declarative memory—the recollection of facts and events—may be most severely affected because this type of memory relies upon median temporal lobe structures, which are affected by ECT.²¹

Anterograde amnesia—the inability to form new memories—often is limited to the immediate posttreatment period and has been shown to become less pronounced at follow-up visits.²² Many clinicians and patients consider retrograde amnesia—forgetting memories that were formed before ECT—to be the most serious adverse effect of ECT. However, Mini-Mental State Examination scores tend to improve for patients who undergo ECT.^1,16 Retrograde amnesia usually improves within weeks to months after ECT.¹² Evidence suggests that retrograde amnesia mostly lifts during the recovery period and typically is not evident after 3 months.²² The best indicators of possible retrograde amnesic effects are preexisting cognitive deficits¹² and duration of disorientation after ECT.¹ Therefore, retrograde amnesia is more common among older adults, in whom age-related changes predispose patients to ECT’s adverse effects.²⁴

The conventionally accepted mechanism for memory deficits after ECT is excitotoxic damage in the pyramidal cell layer of neurons in the hippocampus that induces calcium influx, which damages cells and causes neuronal atrophy.¹² However, in animal studies, Dwork et al²⁵ found an absence of neuronal or glial loss in regions subserving memory or cognitive functions (ie, the hippocampus or frontal cortex). Even in regions exquisitely sensitive to neuronal damage—such as CA1 of the hippocampus—neither cell number or volume or density of neuronal or glial cells were detected at statistically significant levels.²⁵ Therefore, it is unlikely that ECT causes cell damage or atrophy in hippocampal neurons.

Box

• Leiknes KA, Jarosh-von Schweder L, Høie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012;2(3):283-344.
  
• Manka MV, Beyer JL, Weiner RD, et al. Clinical manual of electroconvulsive therapy. Arlington, VA: American Psychiatric Publishing; 2010.
  

• Esmolol • Brevibloc
  
• Etomidate • Amidate
  
• Glycopyrrolate • Robinul
  
• Ketorolac • Toradol
  
• Labetalol • Normodyne, Trandate
  
• Methohexital • Brevital
  
• Nicardipine • Cardene
  
• Succinylcholine • Anectine
  

Dr. Husain receives grant or research support from Brainsway, Cyberonics, MagStim, NARSAD, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute on Drug Abuse, NeoSync, Neuronetics, St. Jude Medical, and the Stanley Foundation.

Drs. Raza, Tirmizi, and Trevino report no relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX – The burden of comorbid medical illness is high, and is linked to increased prescribing of psychotropic drugs, in patients with bipolar I and II disorder, based on findings from the Lithium Treatment – Moderate Dose Use Study, or LiTMUS.

Clinically significant medical burden, defined by a score of 4 or more on the Cumulative Illness Rating Scale (CIRS), was present in 139 of 264 LiTMUS participants with available CIRS data. A score of 4 or higher on the 14-point scale indicates that a patient has at least two moderately disabling medical problems requiring first-line treatment, Dr. David E. Kemp of Case Western Reserve University, Cleveland, and his colleagues reported in a poster. They presented their findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The 139 patients with high medical comorbidity were significantly more likely than were those with low medical comorbidity to present in a current major depressive episode (71.3% vs. 57.8%), to have obsessive-compulsive disorder (14.4% vs. 5.6%), and to have previous mood episodes (66.5% vs. 37.7%), and previous manic or hypomanic episodes (34.9% vs. 18.3%), the investigators said.

Those with high medical comorbidity were also more likely to be female (61.9% vs. 50.4%) and to have previous depressive episodes (29.5% vs. 19.7%), although these measures did not reach statistical significance.

"Patients with high vs. low medical comorbidity burden experienced an average of 10 additional depressive episodes and 15 additional manic or hypomanic episodes over their lifetime," the investigators noted.

As for psychotropic medication use, those with high medical comorbidity were prescribed an average of 2.9 medications, compared with 2.3 for those with low medical comorbidity, a statistically significant difference, the investigators said.

The most common comorbid medical conditions in LiTMUS participants were migraines, hypertension, hyperlipidemia, and asthma, occurring in 24%, 17%, 15%, and 15% of study participants, respectively. The most common organ systems affected by medical comorbidity were the musculoskeletal, respiratory, and endocrine systems (in 33%, 27%, and 25% of participants, respectively).

Of note, hypertension and dyslipidemia were frequently underrecognized and undertreated in this population. Hypertension was diagnosed by a clinician in 44% of participants, but reported by only 17% of the patients; dyslipidemia was diagnosed by a clinician in 31% of participants, but reported by only 15%.

Additionally, 70% of the sample was overweight or obese. More males than females with bipolar I disorder were overweight, whereas more females than males with bipolar I disorder were obese. African Americans were the ethnic group with the highest rate (31%) of grade 2 obesity, defined as a body mass index of 35 kg/m² or greater, they noted.

LiTMUS was undertaken to estimate the prevalence and burden of general medical illnesses among patients with bipolar disorder and to identify the potential associations between those illnesses and the clinical features of bipolar disorder, the investigators said. Dr. Kemp and his colleagues explained that patients with bipolar disorder are known to have an increased risk for several general medical conditions, which contribute to an up to 30% shorter life expectancy in this population, compared with the general population.

Previous studies have identified links between cardiometabolic disorders and psychiatric illness severity suggestive of a genetic and pathophysiologic diathesis that predisposes vulnerable individuals to the concurrent development of mood symptoms and medical conditions, they said.

Participants were adults aged 18 years or older with bipolar I or II disorder and mood symptoms of at least mild severity that warranted a change in treatment. Having symptoms of at least mild severity was defined as a score of 3 or greater on the Clinical Global Impression Scale-Bipolar Version.

The findings reinforce the notion that bipolar disorder is associated with a high burden of comorbid medical illnesses, which appear to influence the course of the illness and psychotropic prescribing patterns, and they "highlight the multisystem involvement in bipolar disorder and the need for improved understanding of the relationships between psychiatric pathology and medical illness," the investigators concluded.

This study was funded by the National Institute of Mental Health. The authors had no disclosures.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.

PHOENIX – The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.

In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.

Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.

The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.

Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.

Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).

Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.

Treatment was followed by a 2-week safety follow-up period.

A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.

The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.

"Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics," she wrote.

In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.

The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.

Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.

PHILADELPHIA – Seeking to address issues of stigma surrounding bipolar disorder among patients and health care providers, a group of Canadian researchers and patient advocates commissioned a play aimed at giving a human face to someone who has succeeded at living with bipolar disorder.

The result was “That’s Just Crazy Talk,” an hour-long, one-woman performance by actor and playwright Victoria Maxwell, which premiered in performances in Vancouver and Toronto last July, was reprised several more times last year and this year, and is now available on DVD.

Courtesy Collaborative Research Team to Study Bipolar Disorder

The show’s development also was part of a research project that measured the impact that seeing a performance had on stigmatized feelings among people with bipolar disorder, the health care providers who deal with bipolar patients, and people with relatives or friends with bipolar disorder.

Survey results showed that seeing the show reduced stigma, especially among health care professionals, Dr. Sagar V. Parikh said at the annual meeting of the American Psychiatric Association.

The researchers surveyed 84 health care providers who deal with bipolar patients, both before and after the providers saw a performance. The providers’ average scores, as measured on a standard inventory known as the Day’s Mental Illness Stigma Scale (J. Applied Social Psych. 2007;37:2191-219), fell significantly in several categories, including treatability, relationship disturbance, and hygiene. The magnitude of the average effect size in these domains was comparable to the effect of “8 weeks of treatment with a mildly or moderately effective intervention, such as an antidepressant, or psychotherapy,” said Dr. Parikh, a professor of psychiatry at the University of Toronto.

Photo Mitchel L. Zoler/IMNG Medical Media

The responses of patients with bipolar disorder and those of their family members or friends were not as robust, but their stigma levels also seemed to be reduced when they saw the play.

“People said that the play made them think again about decisions they had made about treatment, how to handle treatment at work or in relationships, and how to deal with stigmatizing comments,” he said in an interview. “We think we have an intervention that works.”

“That’s Just Crazy Talk” was commissioned by Dr. Parikh and his associates using funds provided by the Canadian Institutes of Health Research, and with the participation of the Collaborative Research Team to Study Bipolar Disorder, and the Canadian Network for Mood and Anxiety Treatments. The project grew out of a desire to address the stigmas surrounding bipolar disorder, and a hunch that this could be done through a patient’s story told in a comedic and dramatic way. Victoria Maxwell’s prior work served as a catalyst for the concept. Ms. Maxwell is a bipolar disorder patient who had, for several years, incorporated stories about her illness and dealing with it into her performances.

“We knew of her and her work, which made us think of this project,” Dr. Parikh said. Plus, “we had the idea that a personal story could have an impact. Someone’s individual story is often very compelling. We have seen a number of shows and movies where mental illness is portrayed in various ways.

“We were struck that something via theater might be a powerful way to tell this story, and we had the happy circumstance of knowing of Victoria Maxwell. We approached her about creating a play centered on her struggles. For artistic reasons, we deliberately did not give her a list of things to say, but after her play was written we compared it with the key issues. We were prepared to say that some things might need strengthening, but that wasn’t necessary. She dealt with relationships, job discrimination, treatment, [and] adverse effects, and she models how a patient can negotiate a treatment plan that works. She talks about how she deals with life.”

A discussion period between the audience and Ms. Maxwell has followed each performance.

After the initial performances and Dr. Parikh’s assessments last summer, Ms. Maxwell performed her show several more times last year, and this year in Toronto and Vancouver, with additional performances scheduled for later this year and in other sites such as Ottawa and Boston. Also, in April the Collaborative Research Team to Study Bipolar Disorder began making available a DVD of the performance; the first public screening of the DVD occurred in Toronto in early May. The DVD comes with an associated discussion guide, and a future edition of the DVD will include a separate video of a postperformance discussion session.

Dr. Parikh said he had no disclosures.

PHILADELPHIA – Seeking to address issues of stigma surrounding bipolar disorder among patients and health care providers, a group of Canadian researchers and patient advocates commissioned a play aimed at giving a human face to someone who has succeeded at living with bipolar disorder.

The result was “That’s Just Crazy Talk,” an hour-long, one-woman performance by actor and playwright Victoria Maxwell, which premiered in performances in Vancouver and Toronto last July, was reprised several more times last year and this year, and is now available on DVD.

Courtesy Collaborative Research Team to Study Bipolar Disorder

The show’s development also was part of a research project that measured the impact that seeing a performance had on stigmatized feelings among people with bipolar disorder, the health care providers who deal with bipolar patients, and people with relatives or friends with bipolar disorder.

Survey results showed that seeing the show reduced stigma, especially among health care professionals, Dr. Sagar V. Parikh said at the annual meeting of the American Psychiatric Association.

The researchers surveyed 84 health care providers who deal with bipolar patients, both before and after the providers saw a performance. The providers’ average scores, as measured on a standard inventory known as the Day’s Mental Illness Stigma Scale (J. Applied Social Psych. 2007;37:2191-219), fell significantly in several categories, including treatability, relationship disturbance, and hygiene. The magnitude of the average effect size in these domains was comparable to the effect of “8 weeks of treatment with a mildly or moderately effective intervention, such as an antidepressant, or psychotherapy,” said Dr. Parikh, a professor of psychiatry at the University of Toronto.

Photo Mitchel L. Zoler/IMNG Medical Media

The responses of patients with bipolar disorder and those of their family members or friends were not as robust, but their stigma levels also seemed to be reduced when they saw the play.

“People said that the play made them think again about decisions they had made about treatment, how to handle treatment at work or in relationships, and how to deal with stigmatizing comments,” he said in an interview. “We think we have an intervention that works.”

“That’s Just Crazy Talk” was commissioned by Dr. Parikh and his associates using funds provided by the Canadian Institutes of Health Research, and with the participation of the Collaborative Research Team to Study Bipolar Disorder, and the Canadian Network for Mood and Anxiety Treatments. The project grew out of a desire to address the stigmas surrounding bipolar disorder, and a hunch that this could be done through a patient’s story told in a comedic and dramatic way. Victoria Maxwell’s prior work served as a catalyst for the concept. Ms. Maxwell is a bipolar disorder patient who had, for several years, incorporated stories about her illness and dealing with it into her performances.

“We knew of her and her work, which made us think of this project,” Dr. Parikh said. Plus, “we had the idea that a personal story could have an impact. Someone’s individual story is often very compelling. We have seen a number of shows and movies where mental illness is portrayed in various ways.

“We were struck that something via theater might be a powerful way to tell this story, and we had the happy circumstance of knowing of Victoria Maxwell. We approached her about creating a play centered on her struggles. For artistic reasons, we deliberately did not give her a list of things to say, but after her play was written we compared it with the key issues. We were prepared to say that some things might need strengthening, but that wasn’t necessary. She dealt with relationships, job discrimination, treatment, [and] adverse effects, and she models how a patient can negotiate a treatment plan that works. She talks about how she deals with life.”

A discussion period between the audience and Ms. Maxwell has followed each performance.

After the initial performances and Dr. Parikh’s assessments last summer, Ms. Maxwell performed her show several more times last year, and this year in Toronto and Vancouver, with additional performances scheduled for later this year and in other sites such as Ottawa and Boston. Also, in April the Collaborative Research Team to Study Bipolar Disorder began making available a DVD of the performance; the first public screening of the DVD occurred in Toronto in early May. The DVD comes with an associated discussion guide, and a future edition of the DVD will include a separate video of a postperformance discussion session.

Dr. Parikh said he had no disclosures.

PHILADELPHIA – Seeking to address issues of stigma surrounding bipolar disorder among patients and health care providers, a group of Canadian researchers and patient advocates commissioned a play aimed at giving a human face to someone who has succeeded at living with bipolar disorder.

The result was “That’s Just Crazy Talk,” an hour-long, one-woman performance by actor and playwright Victoria Maxwell, which premiered in performances in Vancouver and Toronto last July, was reprised several more times last year and this year, and is now available on DVD.

Courtesy Collaborative Research Team to Study Bipolar Disorder

The show’s development also was part of a research project that measured the impact that seeing a performance had on stigmatized feelings among people with bipolar disorder, the health care providers who deal with bipolar patients, and people with relatives or friends with bipolar disorder.

Survey results showed that seeing the show reduced stigma, especially among health care professionals, Dr. Sagar V. Parikh said at the annual meeting of the American Psychiatric Association.

The researchers surveyed 84 health care providers who deal with bipolar patients, both before and after the providers saw a performance. The providers’ average scores, as measured on a standard inventory known as the Day’s Mental Illness Stigma Scale (J. Applied Social Psych. 2007;37:2191-219), fell significantly in several categories, including treatability, relationship disturbance, and hygiene. The magnitude of the average effect size in these domains was comparable to the effect of “8 weeks of treatment with a mildly or moderately effective intervention, such as an antidepressant, or psychotherapy,” said Dr. Parikh, a professor of psychiatry at the University of Toronto.

Photo Mitchel L. Zoler/IMNG Medical Media

The responses of patients with bipolar disorder and those of their family members or friends were not as robust, but their stigma levels also seemed to be reduced when they saw the play.

“People said that the play made them think again about decisions they had made about treatment, how to handle treatment at work or in relationships, and how to deal with stigmatizing comments,” he said in an interview. “We think we have an intervention that works.”

“That’s Just Crazy Talk” was commissioned by Dr. Parikh and his associates using funds provided by the Canadian Institutes of Health Research, and with the participation of the Collaborative Research Team to Study Bipolar Disorder, and the Canadian Network for Mood and Anxiety Treatments. The project grew out of a desire to address the stigmas surrounding bipolar disorder, and a hunch that this could be done through a patient’s story told in a comedic and dramatic way. Victoria Maxwell’s prior work served as a catalyst for the concept. Ms. Maxwell is a bipolar disorder patient who had, for several years, incorporated stories about her illness and dealing with it into her performances.

“We knew of her and her work, which made us think of this project,” Dr. Parikh said. Plus, “we had the idea that a personal story could have an impact. Someone’s individual story is often very compelling. We have seen a number of shows and movies where mental illness is portrayed in various ways.

“We were struck that something via theater might be a powerful way to tell this story, and we had the happy circumstance of knowing of Victoria Maxwell. We approached her about creating a play centered on her struggles. For artistic reasons, we deliberately did not give her a list of things to say, but after her play was written we compared it with the key issues. We were prepared to say that some things might need strengthening, but that wasn’t necessary. She dealt with relationships, job discrimination, treatment, [and] adverse effects, and she models how a patient can negotiate a treatment plan that works. She talks about how she deals with life.”

A discussion period between the audience and Ms. Maxwell has followed each performance.

After the initial performances and Dr. Parikh’s assessments last summer, Ms. Maxwell performed her show several more times last year, and this year in Toronto and Vancouver, with additional performances scheduled for later this year and in other sites such as Ottawa and Boston. Also, in April the Collaborative Research Team to Study Bipolar Disorder began making available a DVD of the performance; the first public screening of the DVD occurred in Toronto in early May. The DVD comes with an associated discussion guide, and a future edition of the DVD will include a separate video of a postperformance discussion session.

Dr. Parikh said he had no disclosures.

We all understand that bipolar disorder is a mood disorder, characterized by periods of depression and mania, that many of us have seen in adults.

That manic component can include euphoric mood, pressured speech, hypersexual behavior, grandiosity, excessive spending, delusions, and diminished need for sleep. The degree of mania can sometimes reach a psychotic level, meaning its scale is disconnected from reality. For example, a manic adult’s delusions might include his ability to solve the energy crisis or move the world toward peace.

The manic adult is driven in a very active and pressured way. In fact, it’s not uncommon for them to end up in an emergency department. They might, for example, get on a plane as part of some grandiose delusion. When they land, they are alone, in a different city, and acting psychotic. This bizarre behavior gets them transferred to the nearest hospital. We all understand that that happens.

But are there any kinds of behaviors in childhood and adolescence that mimic, parallel, or predict this kind of adult behavior? Pediatric patients certainly experience depression, but are there behaviors that cycle and look like something we call "mania"?

The differential diagnosis is really essential, but it’s not easy. The pediatricians’ job with these children is to recognize a potential mood disorder in terms of depressive symptoms, agitation, and irritability. Consider the symptoms, the age, and the context.

Assess your patient for behaviors that are intense and outside the range of what you typically see in the primary care setting. A mood disorder that has become a daily, dominant feature in the family is telling. Look for a persistent, chronic pattern of agitation and irritability – with frequent explosive and sometimes violent outbursts – to move your diagnosis more solidly in the direction of potential bipolar disorder. A very strong family history of bipolar disorder or mood disorders can support this direction in your diagnosis.

Even child and adolescent psychiatrists have not reached a consensus on whether these behaviors reflect a childhood form of bipolar disorder, or instead a distinct proposed disorder in the DSM-5 (5th edition of the Diagnostic and Statistical Manual of Mental Disorders) called disruptive mood dysregulation disorder (DMDD). This is an area of active controversy in our field (more on that later).

There is enough behavior in childhood and adolescence that reflects dysregulation in temper and agitation about different things, so proceed slowly before you label your patient with a mood disorder. Be careful not to overlap your diagnosis with behaviors that might be related to a child’s temperament or social circumstances (in which the behaviors could be understood as coming from environmental/family factors rather than from an internal mood state). For example, abuse from a parent or older sibling can lead to a miserable life, and a child’s irritable, angry, and moody tantrum behaviors might be completely unrelated to bipolar disorder or temper dysregulation.

That being said, when you meet one of these kids or talk to people who live with them, it’s very clear there is something wrong. Although the term "bipolar disorder" could be overextended among children and adolescents, it does not mean that there is not a group of kids who are very, very difficult to manage because of their chronic mood state.

In your differential diagnosis, distinguish these behaviors from those associated with substance use, oppositional defiant disorder, and/or attention-deficit/hyperactive disorder that is unresponsive to treatment.

Substance use is certainly associated with moodiness and dysregulated behavior. If I told you that an adolescent was using cocaine or was a young alcoholic, you would not be surprised to find out that she also was depressed, irritable, and agitated with a labile mood.

The pattern of behaviors can be a clue as well. You might see similar behaviors in a child with oppositional defiant disorder, but the parents will report that the behaviors emerge in specific situations. For example, a child might throw a tantrum when he objects to something, but not spontaneously or as a matter of essentially daily routine.

Once a diagnosis of severe mood disorder is suspected (and when bipolar or DMDD is considered likely), the management of one of these kids is probably beyond the scope of a typical primary care practice. Pediatricians have a great role to play in child and family mental health, but the severity of these behaviors indicates the need to refer to a child and adolescent psychiatrist.

Part of the reason for the controversy in this area is that we’re at an early point of differentiating kids with these behaviors. In the absence of genetic or biochemical markers, we’re trying to figure this out through observation, interviews, family histories, and follow-up. Maybe there are two, three, or more subtypes of these mood states, and we’re lumping them together without a valid basis. Maybe there are threads in childhood that we can follow to adult bipolar disorder, or threads we can follow to the proposed DMDD. We just don’t know yet.

Currently, there are camps debating this dilemma within child psychiatry. Some of the roots of this controversy began with the identification of a subset of children with ADHD who also had additional comorbidity related to their mood. Some were comorbid with depression and did not respond well to their ADHD medication. Clinicians began to wonder – especially as they looked more closely – whether these children really did have ADHD, or did they have a mood disorder that included depression and behaviors that included irritability and agitation? This generated more questions: Did the behaviors come and go? Were their hyperactive symptoms really part of a manic mood? Is this an early form of bipolar disorder in childhood or early adolescence, especially with a relevant positive family history?

Clearly, these children were miserable. They were very difficult to raise because of their mood swings. Some displayed quite agitated temper tantrums that did not seem to make sense; they got upset over something minor or even out of the blue without explanation (again, an internally generated irritability and agitation).

In an effort to help these patients and their families, some child psychiatrists tried medication that was not typical for ADHD. They wanted to determine, for example, if medication that was indicated for mood disorders and even bipolar disorders in adults could stabilize these childhood behaviors. The ultimate goal was to help these children function better at home and school, and to live more happily.

In fact, some of the children responded to medications that were not for their original diagnosis of hyperactivity. Some people began calling those children "bipolar."

As often happens in medicine, some may have expanded the use of that term beyond its initial precision. These children didn’t have the family history, their depression was not as severe, or maybe their irritability could be explained through a more thorough evaluation.

As the number of children who were being diagnosed as bipolar increased, their age range went younger and many of them received powerful medications.

Others clinicians felt that this adult diagnosis was being inappropriately stretched to apply to children. They agreed that there are children who seem to have irritability, agitation, and violent temper tantrums, and to be very disruptive and difficult to manage at home and school. But they didn’t want to use an adult term to describe this behavior, or to call these children ADHD because they didn’t fit that diagnosis. The clinicians began using the term DMDD: These children were "dysregulated" because their moods were not regulated in the developmentally expected manner, and because temper and irritability were among the manifestations.

Additional guidance may come from the working groups for the DSM-5. As they prepare for it, experts are debating that we shouldn’t call kids with these symptoms bipolar, but rather DMDD, and that we should try to study them within that framework. But that view is not unanimous and the answer is not yet final.

Dr. Michael Jellinek is a professor of psychiatry and pediatrics at Harvard Medical School, Boston. He is also president of Newton (Mass.)–Wellesley Hospital and chief of clinical affairs, Partners HealthCare. He said he has no relevant disclosures.

We all understand that bipolar disorder is a mood disorder, characterized by periods of depression and mania, that many of us have seen in adults.

That manic component can include euphoric mood, pressured speech, hypersexual behavior, grandiosity, excessive spending, delusions, and diminished need for sleep. The degree of mania can sometimes reach a psychotic level, meaning its scale is disconnected from reality. For example, a manic adult’s delusions might include his ability to solve the energy crisis or move the world toward peace.

The manic adult is driven in a very active and pressured way. In fact, it’s not uncommon for them to end up in an emergency department. They might, for example, get on a plane as part of some grandiose delusion. When they land, they are alone, in a different city, and acting psychotic. This bizarre behavior gets them transferred to the nearest hospital. We all understand that that happens.

But are there any kinds of behaviors in childhood and adolescence that mimic, parallel, or predict this kind of adult behavior? Pediatric patients certainly experience depression, but are there behaviors that cycle and look like something we call "mania"?

The differential diagnosis is really essential, but it’s not easy. The pediatricians’ job with these children is to recognize a potential mood disorder in terms of depressive symptoms, agitation, and irritability. Consider the symptoms, the age, and the context.

Assess your patient for behaviors that are intense and outside the range of what you typically see in the primary care setting. A mood disorder that has become a daily, dominant feature in the family is telling. Look for a persistent, chronic pattern of agitation and irritability – with frequent explosive and sometimes violent outbursts – to move your diagnosis more solidly in the direction of potential bipolar disorder. A very strong family history of bipolar disorder or mood disorders can support this direction in your diagnosis.

Even child and adolescent psychiatrists have not reached a consensus on whether these behaviors reflect a childhood form of bipolar disorder, or instead a distinct proposed disorder in the DSM-5 (5th edition of the Diagnostic and Statistical Manual of Mental Disorders) called disruptive mood dysregulation disorder (DMDD). This is an area of active controversy in our field (more on that later).

There is enough behavior in childhood and adolescence that reflects dysregulation in temper and agitation about different things, so proceed slowly before you label your patient with a mood disorder. Be careful not to overlap your diagnosis with behaviors that might be related to a child’s temperament or social circumstances (in which the behaviors could be understood as coming from environmental/family factors rather than from an internal mood state). For example, abuse from a parent or older sibling can lead to a miserable life, and a child’s irritable, angry, and moody tantrum behaviors might be completely unrelated to bipolar disorder or temper dysregulation.

That being said, when you meet one of these kids or talk to people who live with them, it’s very clear there is something wrong. Although the term "bipolar disorder" could be overextended among children and adolescents, it does not mean that there is not a group of kids who are very, very difficult to manage because of their chronic mood state.

In your differential diagnosis, distinguish these behaviors from those associated with substance use, oppositional defiant disorder, and/or attention-deficit/hyperactive disorder that is unresponsive to treatment.

Substance use is certainly associated with moodiness and dysregulated behavior. If I told you that an adolescent was using cocaine or was a young alcoholic, you would not be surprised to find out that she also was depressed, irritable, and agitated with a labile mood.

The pattern of behaviors can be a clue as well. You might see similar behaviors in a child with oppositional defiant disorder, but the parents will report that the behaviors emerge in specific situations. For example, a child might throw a tantrum when he objects to something, but not spontaneously or as a matter of essentially daily routine.

Once a diagnosis of severe mood disorder is suspected (and when bipolar or DMDD is considered likely), the management of one of these kids is probably beyond the scope of a typical primary care practice. Pediatricians have a great role to play in child and family mental health, but the severity of these behaviors indicates the need to refer to a child and adolescent psychiatrist.

Part of the reason for the controversy in this area is that we’re at an early point of differentiating kids with these behaviors. In the absence of genetic or biochemical markers, we’re trying to figure this out through observation, interviews, family histories, and follow-up. Maybe there are two, three, or more subtypes of these mood states, and we’re lumping them together without a valid basis. Maybe there are threads in childhood that we can follow to adult bipolar disorder, or threads we can follow to the proposed DMDD. We just don’t know yet.

Currently, there are camps debating this dilemma within child psychiatry. Some of the roots of this controversy began with the identification of a subset of children with ADHD who also had additional comorbidity related to their mood. Some were comorbid with depression and did not respond well to their ADHD medication. Clinicians began to wonder – especially as they looked more closely – whether these children really did have ADHD, or did they have a mood disorder that included depression and behaviors that included irritability and agitation? This generated more questions: Did the behaviors come and go? Were their hyperactive symptoms really part of a manic mood? Is this an early form of bipolar disorder in childhood or early adolescence, especially with a relevant positive family history?

Clearly, these children were miserable. They were very difficult to raise because of their mood swings. Some displayed quite agitated temper tantrums that did not seem to make sense; they got upset over something minor or even out of the blue without explanation (again, an internally generated irritability and agitation).

In an effort to help these patients and their families, some child psychiatrists tried medication that was not typical for ADHD. They wanted to determine, for example, if medication that was indicated for mood disorders and even bipolar disorders in adults could stabilize these childhood behaviors. The ultimate goal was to help these children function better at home and school, and to live more happily.

In fact, some of the children responded to medications that were not for their original diagnosis of hyperactivity. Some people began calling those children "bipolar."

As often happens in medicine, some may have expanded the use of that term beyond its initial precision. These children didn’t have the family history, their depression was not as severe, or maybe their irritability could be explained through a more thorough evaluation.

As the number of children who were being diagnosed as bipolar increased, their age range went younger and many of them received powerful medications.

Others clinicians felt that this adult diagnosis was being inappropriately stretched to apply to children. They agreed that there are children who seem to have irritability, agitation, and violent temper tantrums, and to be very disruptive and difficult to manage at home and school. But they didn’t want to use an adult term to describe this behavior, or to call these children ADHD because they didn’t fit that diagnosis. The clinicians began using the term DMDD: These children were "dysregulated" because their moods were not regulated in the developmentally expected manner, and because temper and irritability were among the manifestations.

Additional guidance may come from the working groups for the DSM-5. As they prepare for it, experts are debating that we shouldn’t call kids with these symptoms bipolar, but rather DMDD, and that we should try to study them within that framework. But that view is not unanimous and the answer is not yet final.

Dr. Michael Jellinek is a professor of psychiatry and pediatrics at Harvard Medical School, Boston. He is also president of Newton (Mass.)–Wellesley Hospital and chief of clinical affairs, Partners HealthCare. He said he has no relevant disclosures.

We all understand that bipolar disorder is a mood disorder, characterized by periods of depression and mania, that many of us have seen in adults.

That manic component can include euphoric mood, pressured speech, hypersexual behavior, grandiosity, excessive spending, delusions, and diminished need for sleep. The degree of mania can sometimes reach a psychotic level, meaning its scale is disconnected from reality. For example, a manic adult’s delusions might include his ability to solve the energy crisis or move the world toward peace.

The manic adult is driven in a very active and pressured way. In fact, it’s not uncommon for them to end up in an emergency department. They might, for example, get on a plane as part of some grandiose delusion. When they land, they are alone, in a different city, and acting psychotic. This bizarre behavior gets them transferred to the nearest hospital. We all understand that that happens.

But are there any kinds of behaviors in childhood and adolescence that mimic, parallel, or predict this kind of adult behavior? Pediatric patients certainly experience depression, but are there behaviors that cycle and look like something we call "mania"?

The differential diagnosis is really essential, but it’s not easy. The pediatricians’ job with these children is to recognize a potential mood disorder in terms of depressive symptoms, agitation, and irritability. Consider the symptoms, the age, and the context.

Assess your patient for behaviors that are intense and outside the range of what you typically see in the primary care setting. A mood disorder that has become a daily, dominant feature in the family is telling. Look for a persistent, chronic pattern of agitation and irritability – with frequent explosive and sometimes violent outbursts – to move your diagnosis more solidly in the direction of potential bipolar disorder. A very strong family history of bipolar disorder or mood disorders can support this direction in your diagnosis.

Even child and adolescent psychiatrists have not reached a consensus on whether these behaviors reflect a childhood form of bipolar disorder, or instead a distinct proposed disorder in the DSM-5 (5th edition of the Diagnostic and Statistical Manual of Mental Disorders) called disruptive mood dysregulation disorder (DMDD). This is an area of active controversy in our field (more on that later).

There is enough behavior in childhood and adolescence that reflects dysregulation in temper and agitation about different things, so proceed slowly before you label your patient with a mood disorder. Be careful not to overlap your diagnosis with behaviors that might be related to a child’s temperament or social circumstances (in which the behaviors could be understood as coming from environmental/family factors rather than from an internal mood state). For example, abuse from a parent or older sibling can lead to a miserable life, and a child’s irritable, angry, and moody tantrum behaviors might be completely unrelated to bipolar disorder or temper dysregulation.

That being said, when you meet one of these kids or talk to people who live with them, it’s very clear there is something wrong. Although the term "bipolar disorder" could be overextended among children and adolescents, it does not mean that there is not a group of kids who are very, very difficult to manage because of their chronic mood state.

In your differential diagnosis, distinguish these behaviors from those associated with substance use, oppositional defiant disorder, and/or attention-deficit/hyperactive disorder that is unresponsive to treatment.

Substance use is certainly associated with moodiness and dysregulated behavior. If I told you that an adolescent was using cocaine or was a young alcoholic, you would not be surprised to find out that she also was depressed, irritable, and agitated with a labile mood.

The pattern of behaviors can be a clue as well. You might see similar behaviors in a child with oppositional defiant disorder, but the parents will report that the behaviors emerge in specific situations. For example, a child might throw a tantrum when he objects to something, but not spontaneously or as a matter of essentially daily routine.

Once a diagnosis of severe mood disorder is suspected (and when bipolar or DMDD is considered likely), the management of one of these kids is probably beyond the scope of a typical primary care practice. Pediatricians have a great role to play in child and family mental health, but the severity of these behaviors indicates the need to refer to a child and adolescent psychiatrist.

Part of the reason for the controversy in this area is that we’re at an early point of differentiating kids with these behaviors. In the absence of genetic or biochemical markers, we’re trying to figure this out through observation, interviews, family histories, and follow-up. Maybe there are two, three, or more subtypes of these mood states, and we’re lumping them together without a valid basis. Maybe there are threads in childhood that we can follow to adult bipolar disorder, or threads we can follow to the proposed DMDD. We just don’t know yet.

Currently, there are camps debating this dilemma within child psychiatry. Some of the roots of this controversy began with the identification of a subset of children with ADHD who also had additional comorbidity related to their mood. Some were comorbid with depression and did not respond well to their ADHD medication. Clinicians began to wonder – especially as they looked more closely – whether these children really did have ADHD, or did they have a mood disorder that included depression and behaviors that included irritability and agitation? This generated more questions: Did the behaviors come and go? Were their hyperactive symptoms really part of a manic mood? Is this an early form of bipolar disorder in childhood or early adolescence, especially with a relevant positive family history?

Clearly, these children were miserable. They were very difficult to raise because of their mood swings. Some displayed quite agitated temper tantrums that did not seem to make sense; they got upset over something minor or even out of the blue without explanation (again, an internally generated irritability and agitation).

In an effort to help these patients and their families, some child psychiatrists tried medication that was not typical for ADHD. They wanted to determine, for example, if medication that was indicated for mood disorders and even bipolar disorders in adults could stabilize these childhood behaviors. The ultimate goal was to help these children function better at home and school, and to live more happily.

In fact, some of the children responded to medications that were not for their original diagnosis of hyperactivity. Some people began calling those children "bipolar."

As often happens in medicine, some may have expanded the use of that term beyond its initial precision. These children didn’t have the family history, their depression was not as severe, or maybe their irritability could be explained through a more thorough evaluation.

As the number of children who were being diagnosed as bipolar increased, their age range went younger and many of them received powerful medications.

Others clinicians felt that this adult diagnosis was being inappropriately stretched to apply to children. They agreed that there are children who seem to have irritability, agitation, and violent temper tantrums, and to be very disruptive and difficult to manage at home and school. But they didn’t want to use an adult term to describe this behavior, or to call these children ADHD because they didn’t fit that diagnosis. The clinicians began using the term DMDD: These children were "dysregulated" because their moods were not regulated in the developmentally expected manner, and because temper and irritability were among the manifestations.

Additional guidance may come from the working groups for the DSM-5. As they prepare for it, experts are debating that we shouldn’t call kids with these symptoms bipolar, but rather DMDD, and that we should try to study them within that framework. But that view is not unanimous and the answer is not yet final.

Dr. Michael Jellinek is a professor of psychiatry and pediatrics at Harvard Medical School, Boston. He is also president of Newton (Mass.)–Wellesley Hospital and chief of clinical affairs, Partners HealthCare. He said he has no relevant disclosures.

A $75 million demonstration project aims to see if Medicaid patients with a psychiatric emergency would get better, more efficient care from a psychiatric hospital.

Under current law, Medicaid cannot pay for care provided in psychiatric hospitals. Patients with a psychiatric emergency – those expressing homicidal or suicidal thoughts or actions – generally are treated in the emergency department, which may not be staffed or equipped provide adequate care for them, officials from the Centers for Medicare and Medicaid Services said in announcing the demonstration March 13.

"This new demonstration will help ensure patients receive appropriate, high quality care when they need it most and save states money," acting CMS administrator Marilyn Tavenner said in a statement.

The three-year project – funded under the Affordable Care Act – covers Medicaid enrollees aged 21-64 years in 11 states and the District of Columbia. The project was designed based on proposals from the participating states: Alabama, California, Connecticut, Illinois, Maine, Maryland, Missouri, North Carolina, Rhode Island, Washington, and West Virginia.

Medicaid programs in participating states will receive federal matching funds to help pay for services needed by Medicaid patients being treated at private psychiatric hospitals. They'll also be required to match nearly 45% of federal dollars, resulting in $115 million to $120 million in total spending, said Mark Covall, president and CEO of the National Association of Psychiatric Health Systems. Following the demonstration, Medicaid programs will participate in a survey to evaluate changes in quality of care and program costs.

The American Psychiatric Association has opposed the Medicaid exclusion of private psychiatric hospitals since long before passage of the Affordable Care Act, Nicholas Meyers, APA director of government relations, said in an interview. He added that the organization is relieved that CMS is listening.

"We’re delighted to see that CMS has moved forward with this," Mr. Meyers said. "It will test what happened when a contradiction in federal law is eliminated and thus it will help insure that patients get the appropriate treatment and hospitals get reimbursed for the services they’re required to be providing."

Mr. Covall said the demonstration was approved because of both the increased awareness of the need for inpatient psychiatric care and the burden on the emergency care system. Since most emergency rooms don’t have enough beds to meet the demand, Mr. Covall said patients are often forced to stay in emergency rooms for hours, days, and sometimes even weeks. He added that the demonstration will help address barriers to access as well as cost implications.

"This will allow those patients that are in these emergency departments to be quickly triaged and sent over to the freestanding psychiatric hospital where they will be able to be fully assessed and then admitted to an impatient psychiatric unit," Mr. Covall said in an interview.

In addition to testing the affect of Medicaid reimbursement on the quality of care at psychiatric emergency facilities, the demonstration is also test whether expanded coverage will reduce the burden on general acute care hospital emergency departments.

A $75 million demonstration project aims to see if Medicaid patients with a psychiatric emergency would get better, more efficient care from a psychiatric hospital.

Under current law, Medicaid cannot pay for care provided in psychiatric hospitals. Patients with a psychiatric emergency – those expressing homicidal or suicidal thoughts or actions – generally are treated in the emergency department, which may not be staffed or equipped provide adequate care for them, officials from the Centers for Medicare and Medicaid Services said in announcing the demonstration March 13.

"This new demonstration will help ensure patients receive appropriate, high quality care when they need it most and save states money," acting CMS administrator Marilyn Tavenner said in a statement.

The three-year project – funded under the Affordable Care Act – covers Medicaid enrollees aged 21-64 years in 11 states and the District of Columbia. The project was designed based on proposals from the participating states: Alabama, California, Connecticut, Illinois, Maine, Maryland, Missouri, North Carolina, Rhode Island, Washington, and West Virginia.

Medicaid programs in participating states will receive federal matching funds to help pay for services needed by Medicaid patients being treated at private psychiatric hospitals. They'll also be required to match nearly 45% of federal dollars, resulting in $115 million to $120 million in total spending, said Mark Covall, president and CEO of the National Association of Psychiatric Health Systems. Following the demonstration, Medicaid programs will participate in a survey to evaluate changes in quality of care and program costs.

The American Psychiatric Association has opposed the Medicaid exclusion of private psychiatric hospitals since long before passage of the Affordable Care Act, Nicholas Meyers, APA director of government relations, said in an interview. He added that the organization is relieved that CMS is listening.

"We’re delighted to see that CMS has moved forward with this," Mr. Meyers said. "It will test what happened when a contradiction in federal law is eliminated and thus it will help insure that patients get the appropriate treatment and hospitals get reimbursed for the services they’re required to be providing."

Mr. Covall said the demonstration was approved because of both the increased awareness of the need for inpatient psychiatric care and the burden on the emergency care system. Since most emergency rooms don’t have enough beds to meet the demand, Mr. Covall said patients are often forced to stay in emergency rooms for hours, days, and sometimes even weeks. He added that the demonstration will help address barriers to access as well as cost implications.

"This will allow those patients that are in these emergency departments to be quickly triaged and sent over to the freestanding psychiatric hospital where they will be able to be fully assessed and then admitted to an impatient psychiatric unit," Mr. Covall said in an interview.

In addition to testing the affect of Medicaid reimbursement on the quality of care at psychiatric emergency facilities, the demonstration is also test whether expanded coverage will reduce the burden on general acute care hospital emergency departments.

A $75 million demonstration project aims to see if Medicaid patients with a psychiatric emergency would get better, more efficient care from a psychiatric hospital.

Under current law, Medicaid cannot pay for care provided in psychiatric hospitals. Patients with a psychiatric emergency – those expressing homicidal or suicidal thoughts or actions – generally are treated in the emergency department, which may not be staffed or equipped provide adequate care for them, officials from the Centers for Medicare and Medicaid Services said in announcing the demonstration March 13.

"This new demonstration will help ensure patients receive appropriate, high quality care when they need it most and save states money," acting CMS administrator Marilyn Tavenner said in a statement.

The three-year project – funded under the Affordable Care Act – covers Medicaid enrollees aged 21-64 years in 11 states and the District of Columbia. The project was designed based on proposals from the participating states: Alabama, California, Connecticut, Illinois, Maine, Maryland, Missouri, North Carolina, Rhode Island, Washington, and West Virginia.

Medicaid programs in participating states will receive federal matching funds to help pay for services needed by Medicaid patients being treated at private psychiatric hospitals. They'll also be required to match nearly 45% of federal dollars, resulting in $115 million to $120 million in total spending, said Mark Covall, president and CEO of the National Association of Psychiatric Health Systems. Following the demonstration, Medicaid programs will participate in a survey to evaluate changes in quality of care and program costs.

The American Psychiatric Association has opposed the Medicaid exclusion of private psychiatric hospitals since long before passage of the Affordable Care Act, Nicholas Meyers, APA director of government relations, said in an interview. He added that the organization is relieved that CMS is listening.

"We’re delighted to see that CMS has moved forward with this," Mr. Meyers said. "It will test what happened when a contradiction in federal law is eliminated and thus it will help insure that patients get the appropriate treatment and hospitals get reimbursed for the services they’re required to be providing."

Mr. Covall said the demonstration was approved because of both the increased awareness of the need for inpatient psychiatric care and the burden on the emergency care system. Since most emergency rooms don’t have enough beds to meet the demand, Mr. Covall said patients are often forced to stay in emergency rooms for hours, days, and sometimes even weeks. He added that the demonstration will help address barriers to access as well as cost implications.

"This will allow those patients that are in these emergency departments to be quickly triaged and sent over to the freestanding psychiatric hospital where they will be able to be fully assessed and then admitted to an impatient psychiatric unit," Mr. Covall said in an interview.

In addition to testing the affect of Medicaid reimbursement on the quality of care at psychiatric emergency facilities, the demonstration is also test whether expanded coverage will reduce the burden on general acute care hospital emergency departments.

LAS VEGAS – In a 6-month study, the use of adjunctive moderately dosed lithium to optimized treatment in patients with bipolar disorder was well tolerated yet did not lead to improved outcomes or decreased suicidality. However, use of adjunctive lithium resulted in a significant reduction in the use of second-generation antipsychotics.

Those are key findings from the Bipolar Trials Network Lithium Treatment Moderate Dose Study, a randomized trial that compared the use of lithium plus optimized treatment with optimized treatment alone.

Doug Brunk/Elsevier Global Medical News

"Currently, only about one-third of bipolar patients take lithium," Dr. Michael E. Thase said during a psychopharmacology conference sponsored by the Nevada Psychiatric Association. "And outpatients uncommonly take lithium in higher, well-established doses. Today it’s more commonly used in moderate doses in combination with newer generation therapies. However, the value of lower dose, combination strategies has not been well-studied."

For the outpatient study, known as the Lithium treatment – moderate dose use study, or LiTMUS, and led by Dr. Andrew A. Nierenberg at the Massachusetts General Hospital, investigators at six clinical sites enrolled 283 patients with bipolar I or bipolar II disorder with a Clinical Global Impressions-Bipolar Scale (CGI-BP-S) score of 3 or greater to assess whether lithium, in moderate doses, "could be a useful platform upon which other newer treatments could be evaluated," said Dr. Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia.

"We were working in partnership with colleagues at the National Institute of Mental Health to do this study in a real-world, relevant way, meaning that it must be inclusive so that people with common comorbidities needed to be in the study, that it needed to be administered in an open way so that the results would be generalizable," said Dr. Thase, who also pointed out that there was no placebo control group.

The investigators compared lithium plus optimized treatment or optimized treatment without lithium. Patients in the lithium arm were started on 300 mg b.i.d. and sustained on 600 mg/day for 8 weeks, adjusted as needed thereafter. The Texas Implementation of Medication Algorithms for bipolar disorder informed care.

The two main outcomes assessed at 6 months were the CGI-BP-S and the number of Necessary Clinical Adjustments (NCAs), a measure of how difficult treatment was to implement. "This takes into account how many times you had to change the treatment in response to side effects or in response to the treatment not working," Dr. Thase explained. "The higher the NCA count, the stormier the treatment course."

A secondary measure was side effect burden as measured by the Frequency and Intensity of Side Effects Ratings, "which provides composite ratings of tolerability rather than focusing on specific side effects," he said. "These were completed at each study visit by the treating psychiatrist."

Dr. Thase reported that 84% of patients completed the 6 months of treatment. The attrition rate was not significantly different among those who received lithium, compared with those who did not receive the drug. The modal dose of lithium was 600 mg/day, and the average lithium levels ranged between 0.5-0.6 mEq/L.

Patients who received lithium did not have better outcomes compared with those who did not in terms of overall change in the CGI-BP-S (–1.5 vs. –1.2, respectively). "The average level of improvement for all of our patients was only about a 30% reduction in symptom burden," Dr. Thase said. "Thus, despite using guideline-based treatment algorithms, more patients remained ill than got better."

No statistically significant differences were found between groups in terms of depression and manic symptom severity based on the CGI-BP-S, the Quick Inventory of Depressive Symptoms Score, the Quality of Life Enjoyment and Satisfaction Questionnaire Score, and the Modified Scale for Suicidal Ideation Score.

One significant difference in the study was noted at week 2, when patients who received adjunctive lithium required fewer NCAs, compared with those who did not receive the drug. "Keep in mind, however, that the lithium dose was set at 300 b.i.d. for the first 8 weeks, so unless you were deviating from the protocol you couldn’t adjust the lithium dose," Dr. Thase said. "As a result, the fact that there are fewer adjustments of lithium in the first few weeks of treatment is determined by the [study] protocol. Across the whole 6 months there were no fewer necessary clinical adjustments in the lithium-treated group than in those who received optimized treatment without lithium."

Another significant finding was that patients who received lithium carried a slightly greater side effect burden during the initial 2 months of treatment (P less than .05), "but it was not different after that time period," he said. "The intensity of side effects was also greater in the lithium group during the first two months but was not different [than the optimized treatment without lithium group] after that time period."

There were no serious adverse events specifically related to lithium therapy, but two events (one case of dehydration and one case of acute renal failure) involved medical considerations related to lithium therapy.

The only significant difference in medication use between the two groups pertained to second-generation antipsychotics. Patients who received adjunctive lithium were 15-20% less likely to receive a second-generation antipsychotic (SGA) over the course of the study. "Put another way, if you don’t use lithium in your practice, you are going to be 15-20% more likely to be prescribing SGAs," Dr. Thase noted.

He acknowledged certain limitations of LiTMUS, including the study’s silence on "the utility of higher doses of lithium or the merits of lithium at higher doses in patients taking simpler psychopharmacology regimens."

While LiTMUS found that the use of lithium as an adjunct "did not improve the simplicity of the treatment regiment, it didn’t increase it, either," Dr. Thase said. "So if you know doctors who say ‘I don’t use lithium because it’s too complicated,’ remind them that we did not find lithium complicated in this study.

"In fact ... lithium was associated with a clinically meaningful reduction in the use of SGAs, "which means that using it lead to less patient exposure to the newer generation antipsychotics.

Dr. Thase disclosed that he has received research funding from the Agency for Healthcare Research and Quality, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceuticals, and Sepracor. He also has received honoraria or is on the scientific board of several pharmaceutical companies.

LAS VEGAS – In a 6-month study, the use of adjunctive moderately dosed lithium to optimized treatment in patients with bipolar disorder was well tolerated yet did not lead to improved outcomes or decreased suicidality. However, use of adjunctive lithium resulted in a significant reduction in the use of second-generation antipsychotics.

Those are key findings from the Bipolar Trials Network Lithium Treatment Moderate Dose Study, a randomized trial that compared the use of lithium plus optimized treatment with optimized treatment alone.

Doug Brunk/Elsevier Global Medical News

"Currently, only about one-third of bipolar patients take lithium," Dr. Michael E. Thase said during a psychopharmacology conference sponsored by the Nevada Psychiatric Association. "And outpatients uncommonly take lithium in higher, well-established doses. Today it’s more commonly used in moderate doses in combination with newer generation therapies. However, the value of lower dose, combination strategies has not been well-studied."

For the outpatient study, known as the Lithium treatment – moderate dose use study, or LiTMUS, and led by Dr. Andrew A. Nierenberg at the Massachusetts General Hospital, investigators at six clinical sites enrolled 283 patients with bipolar I or bipolar II disorder with a Clinical Global Impressions-Bipolar Scale (CGI-BP-S) score of 3 or greater to assess whether lithium, in moderate doses, "could be a useful platform upon which other newer treatments could be evaluated," said Dr. Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia.

"We were working in partnership with colleagues at the National Institute of Mental Health to do this study in a real-world, relevant way, meaning that it must be inclusive so that people with common comorbidities needed to be in the study, that it needed to be administered in an open way so that the results would be generalizable," said Dr. Thase, who also pointed out that there was no placebo control group.

The investigators compared lithium plus optimized treatment or optimized treatment without lithium. Patients in the lithium arm were started on 300 mg b.i.d. and sustained on 600 mg/day for 8 weeks, adjusted as needed thereafter. The Texas Implementation of Medication Algorithms for bipolar disorder informed care.

The two main outcomes assessed at 6 months were the CGI-BP-S and the number of Necessary Clinical Adjustments (NCAs), a measure of how difficult treatment was to implement. "This takes into account how many times you had to change the treatment in response to side effects or in response to the treatment not working," Dr. Thase explained. "The higher the NCA count, the stormier the treatment course."

A secondary measure was side effect burden as measured by the Frequency and Intensity of Side Effects Ratings, "which provides composite ratings of tolerability rather than focusing on specific side effects," he said. "These were completed at each study visit by the treating psychiatrist."

Dr. Thase reported that 84% of patients completed the 6 months of treatment. The attrition rate was not significantly different among those who received lithium, compared with those who did not receive the drug. The modal dose of lithium was 600 mg/day, and the average lithium levels ranged between 0.5-0.6 mEq/L.

Patients who received lithium did not have better outcomes compared with those who did not in terms of overall change in the CGI-BP-S (–1.5 vs. –1.2, respectively). "The average level of improvement for all of our patients was only about a 30% reduction in symptom burden," Dr. Thase said. "Thus, despite using guideline-based treatment algorithms, more patients remained ill than got better."

No statistically significant differences were found between groups in terms of depression and manic symptom severity based on the CGI-BP-S, the Quick Inventory of Depressive Symptoms Score, the Quality of Life Enjoyment and Satisfaction Questionnaire Score, and the Modified Scale for Suicidal Ideation Score.

One significant difference in the study was noted at week 2, when patients who received adjunctive lithium required fewer NCAs, compared with those who did not receive the drug. "Keep in mind, however, that the lithium dose was set at 300 b.i.d. for the first 8 weeks, so unless you were deviating from the protocol you couldn’t adjust the lithium dose," Dr. Thase said. "As a result, the fact that there are fewer adjustments of lithium in the first few weeks of treatment is determined by the [study] protocol. Across the whole 6 months there were no fewer necessary clinical adjustments in the lithium-treated group than in those who received optimized treatment without lithium."

Another significant finding was that patients who received lithium carried a slightly greater side effect burden during the initial 2 months of treatment (P less than .05), "but it was not different after that time period," he said. "The intensity of side effects was also greater in the lithium group during the first two months but was not different [than the optimized treatment without lithium group] after that time period."

There were no serious adverse events specifically related to lithium therapy, but two events (one case of dehydration and one case of acute renal failure) involved medical considerations related to lithium therapy.

The only significant difference in medication use between the two groups pertained to second-generation antipsychotics. Patients who received adjunctive lithium were 15-20% less likely to receive a second-generation antipsychotic (SGA) over the course of the study. "Put another way, if you don’t use lithium in your practice, you are going to be 15-20% more likely to be prescribing SGAs," Dr. Thase noted.

He acknowledged certain limitations of LiTMUS, including the study’s silence on "the utility of higher doses of lithium or the merits of lithium at higher doses in patients taking simpler psychopharmacology regimens."

While LiTMUS found that the use of lithium as an adjunct "did not improve the simplicity of the treatment regiment, it didn’t increase it, either," Dr. Thase said. "So if you know doctors who say ‘I don’t use lithium because it’s too complicated,’ remind them that we did not find lithium complicated in this study.

"In fact ... lithium was associated with a clinically meaningful reduction in the use of SGAs, "which means that using it lead to less patient exposure to the newer generation antipsychotics.

Dr. Thase disclosed that he has received research funding from the Agency for Healthcare Research and Quality, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceuticals, and Sepracor. He also has received honoraria or is on the scientific board of several pharmaceutical companies.

LAS VEGAS – In a 6-month study, the use of adjunctive moderately dosed lithium to optimized treatment in patients with bipolar disorder was well tolerated yet did not lead to improved outcomes or decreased suicidality. However, use of adjunctive lithium resulted in a significant reduction in the use of second-generation antipsychotics.

Those are key findings from the Bipolar Trials Network Lithium Treatment Moderate Dose Study, a randomized trial that compared the use of lithium plus optimized treatment with optimized treatment alone.

Doug Brunk/Elsevier Global Medical News

"Currently, only about one-third of bipolar patients take lithium," Dr. Michael E. Thase said during a psychopharmacology conference sponsored by the Nevada Psychiatric Association. "And outpatients uncommonly take lithium in higher, well-established doses. Today it’s more commonly used in moderate doses in combination with newer generation therapies. However, the value of lower dose, combination strategies has not been well-studied."

For the outpatient study, known as the Lithium treatment – moderate dose use study, or LiTMUS, and led by Dr. Andrew A. Nierenberg at the Massachusetts General Hospital, investigators at six clinical sites enrolled 283 patients with bipolar I or bipolar II disorder with a Clinical Global Impressions-Bipolar Scale (CGI-BP-S) score of 3 or greater to assess whether lithium, in moderate doses, "could be a useful platform upon which other newer treatments could be evaluated," said Dr. Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia.

"We were working in partnership with colleagues at the National Institute of Mental Health to do this study in a real-world, relevant way, meaning that it must be inclusive so that people with common comorbidities needed to be in the study, that it needed to be administered in an open way so that the results would be generalizable," said Dr. Thase, who also pointed out that there was no placebo control group.

The investigators compared lithium plus optimized treatment or optimized treatment without lithium. Patients in the lithium arm were started on 300 mg b.i.d. and sustained on 600 mg/day for 8 weeks, adjusted as needed thereafter. The Texas Implementation of Medication Algorithms for bipolar disorder informed care.

The two main outcomes assessed at 6 months were the CGI-BP-S and the number of Necessary Clinical Adjustments (NCAs), a measure of how difficult treatment was to implement. "This takes into account how many times you had to change the treatment in response to side effects or in response to the treatment not working," Dr. Thase explained. "The higher the NCA count, the stormier the treatment course."

A secondary measure was side effect burden as measured by the Frequency and Intensity of Side Effects Ratings, "which provides composite ratings of tolerability rather than focusing on specific side effects," he said. "These were completed at each study visit by the treating psychiatrist."

Dr. Thase reported that 84% of patients completed the 6 months of treatment. The attrition rate was not significantly different among those who received lithium, compared with those who did not receive the drug. The modal dose of lithium was 600 mg/day, and the average lithium levels ranged between 0.5-0.6 mEq/L.

Patients who received lithium did not have better outcomes compared with those who did not in terms of overall change in the CGI-BP-S (–1.5 vs. –1.2, respectively). "The average level of improvement for all of our patients was only about a 30% reduction in symptom burden," Dr. Thase said. "Thus, despite using guideline-based treatment algorithms, more patients remained ill than got better."

No statistically significant differences were found between groups in terms of depression and manic symptom severity based on the CGI-BP-S, the Quick Inventory of Depressive Symptoms Score, the Quality of Life Enjoyment and Satisfaction Questionnaire Score, and the Modified Scale for Suicidal Ideation Score.

One significant difference in the study was noted at week 2, when patients who received adjunctive lithium required fewer NCAs, compared with those who did not receive the drug. "Keep in mind, however, that the lithium dose was set at 300 b.i.d. for the first 8 weeks, so unless you were deviating from the protocol you couldn’t adjust the lithium dose," Dr. Thase said. "As a result, the fact that there are fewer adjustments of lithium in the first few weeks of treatment is determined by the [study] protocol. Across the whole 6 months there were no fewer necessary clinical adjustments in the lithium-treated group than in those who received optimized treatment without lithium."

Another significant finding was that patients who received lithium carried a slightly greater side effect burden during the initial 2 months of treatment (P less than .05), "but it was not different after that time period," he said. "The intensity of side effects was also greater in the lithium group during the first two months but was not different [than the optimized treatment without lithium group] after that time period."

There were no serious adverse events specifically related to lithium therapy, but two events (one case of dehydration and one case of acute renal failure) involved medical considerations related to lithium therapy.

The only significant difference in medication use between the two groups pertained to second-generation antipsychotics. Patients who received adjunctive lithium were 15-20% less likely to receive a second-generation antipsychotic (SGA) over the course of the study. "Put another way, if you don’t use lithium in your practice, you are going to be 15-20% more likely to be prescribing SGAs," Dr. Thase noted.

He acknowledged certain limitations of LiTMUS, including the study’s silence on "the utility of higher doses of lithium or the merits of lithium at higher doses in patients taking simpler psychopharmacology regimens."

While LiTMUS found that the use of lithium as an adjunct "did not improve the simplicity of the treatment regiment, it didn’t increase it, either," Dr. Thase said. "So if you know doctors who say ‘I don’t use lithium because it’s too complicated,’ remind them that we did not find lithium complicated in this study.

"In fact ... lithium was associated with a clinically meaningful reduction in the use of SGAs, "which means that using it lead to less patient exposure to the newer generation antipsychotics.

Dr. Thase disclosed that he has received research funding from the Agency for Healthcare Research and Quality, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceuticals, and Sepracor. He also has received honoraria or is on the scientific board of several pharmaceutical companies.

I feel Dr. Goldberg’s article addressing ultra-rapid cycling (URC) bipolar disorder (BD) (“Ultra-rapid cycling bipolar disorder: A critical look,” Current Psychiatry, December 2011, p. 42-52), fell short in 2 critical regards. First, I believe evidence would have supported much stronger or less ambiguous conclusions. Although URC clearly is an observable symptomatic phenomenon, it’s not a valid construct within the BD spectrum, per se. To include it as such would only detract from the homogeneity that has been achieved with the resolution of that group to date, thereby dissipating the usefulness of the group from both a clinical and research standpoint. Even the Bottom Line stated that URC “has not been validated as a distinct clinical entity,” but “careful evaluation” is recommended “to differentiate URC from affective lability seen in other conditions,” thus implicitly validating using the term as a diagnostic entity.

Second, I am disturbed by the article’s absence of adult attention-deficit/hyperactivity disorder (ADHD), the secondary features of which easily rival BD in accounting for a significant proportion of symptoms commonly attributed to URC, if not the preponderance thereof. Notably, ADHD shares the “trait feature” status the article cites as unique to BD. A commonly cited figure places the prevalence of adult ADHD at 4.4% (using DSM-IV criteria) with 75% to 80% of those patients untreated and undiagnosed.^{Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).}

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY

I feel Dr. Goldberg’s article addressing ultra-rapid cycling (URC) bipolar disorder (BD) (“Ultra-rapid cycling bipolar disorder: A critical look,” Current Psychiatry, December 2011, p. 42-52), fell short in 2 critical regards. First, I believe evidence would have supported much stronger or less ambiguous conclusions. Although URC clearly is an observable symptomatic phenomenon, it’s not a valid construct within the BD spectrum, per se. To include it as such would only detract from the homogeneity that has been achieved with the resolution of that group to date, thereby dissipating the usefulness of the group from both a clinical and research standpoint. Even the Bottom Line stated that URC “has not been validated as a distinct clinical entity,” but “careful evaluation” is recommended “to differentiate URC from affective lability seen in other conditions,” thus implicitly validating using the term as a diagnostic entity.

Second, I am disturbed by the article’s absence of adult attention-deficit/hyperactivity disorder (ADHD), the secondary features of which easily rival BD in accounting for a significant proportion of symptoms commonly attributed to URC, if not the preponderance thereof. Notably, ADHD shares the “trait feature” status the article cites as unique to BD. A commonly cited figure places the prevalence of adult ADHD at 4.4% (using DSM-IV criteria) with 75% to 80% of those patients untreated and undiagnosed.^{Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).}

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY

I feel Dr. Goldberg’s article addressing ultra-rapid cycling (URC) bipolar disorder (BD) (“Ultra-rapid cycling bipolar disorder: A critical look,” Current Psychiatry, December 2011, p. 42-52), fell short in 2 critical regards. First, I believe evidence would have supported much stronger or less ambiguous conclusions. Although URC clearly is an observable symptomatic phenomenon, it’s not a valid construct within the BD spectrum, per se. To include it as such would only detract from the homogeneity that has been achieved with the resolution of that group to date, thereby dissipating the usefulness of the group from both a clinical and research standpoint. Even the Bottom Line stated that URC “has not been validated as a distinct clinical entity,” but “careful evaluation” is recommended “to differentiate URC from affective lability seen in other conditions,” thus implicitly validating using the term as a diagnostic entity.

Second, I am disturbed by the article’s absence of adult attention-deficit/hyperactivity disorder (ADHD), the secondary features of which easily rival BD in accounting for a significant proportion of symptoms commonly attributed to URC, if not the preponderance thereof. Notably, ADHD shares the “trait feature” status the article cites as unique to BD. A commonly cited figure places the prevalence of adult ADHD at 4.4% (using DSM-IV criteria) with 75% to 80% of those patients untreated and undiagnosed.^{Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).}

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY