Ahmed Z. Elmaadawi, MD

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

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

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

_

The origin of DMDD

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

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

_

DMDD or bipolar disorder?

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

Continue to: CASE 1

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

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

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

_

>

DMDD or oppositional defiant disorder?

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

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

Continue to: CASE 2

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

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

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

_

Treatment strategies for DMDD

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

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

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

Continue to: Stimulants

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

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

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

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

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

_

The origin of DMDD

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

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

_

DMDD or bipolar disorder?

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

Continue to: CASE 1

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

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

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

_

>

DMDD or oppositional defiant disorder?

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

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

Continue to: CASE 2

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

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

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

_

Treatment strategies for DMDD

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

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

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

Continue to: Stimulants

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

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

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

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

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

_

The origin of DMDD

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

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

_

DMDD or bipolar disorder?

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

Continue to: CASE 1

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

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

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

_

>

DMDD or oppositional defiant disorder?

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

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

Continue to: CASE 2

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

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

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

_

Treatment strategies for DMDD

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

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

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

Continue to: Stimulants

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

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

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

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

Circadian rhythm disruption in bipolar disorder

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

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

Rationale for use

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

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

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

Continue to: BLT for BD...

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bottom Line

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

Related Resource

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

Drug Brand Name
Lithium • Eskalith, Lithobid

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

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

Circadian rhythm disruption in bipolar disorder

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

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

Rationale for use

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

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

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

Continue to: BLT for BD...

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bottom Line

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

Related Resource

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

Drug Brand Name
Lithium • Eskalith, Lithobid

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

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

Circadian rhythm disruption in bipolar disorder

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

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

Rationale for use

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

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

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

Continue to: BLT for BD...

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bottom Line

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

Related Resource

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

Drug Brand Name
Lithium • Eskalith, Lithobid

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral