Bipolar Disorder

Patients with bipolar disorder and low levels of pharmacological treatment adherence have greater levels of cognitive impairment, according to Dr. Ileana Fuentes and her associates.

After taking a neurological battery, 12 bipolar disorder patients with low treatment adherence performed worse than did 22 bipolar disorder patients with high treatment adherence in nearly all cognitive functions tested, but the effect was significant in verbal memory testing. The low-adherence group performed significantly worse in verbal memory immediate free recall, immediate cued recall, delayed free recall, and delayed cued recall.

Other factors found to be associated with poorer executive function and processing speed were greater number of manic episodes, history of psychosis, and fewer years of education, reported Dr. Fuentes of the University of Guadalajara, Mexico.

“Despite limitations of the study, our findings are clinically important, and they contribute to better understanding of the cognitive profile in low compliance patients with bipolar disorder. Low compliance, cognitive performance, and asymptomatic phase are important markers in [bipolar disorder] for further studies,” the investigators noted.

Find the study here (J Affect Disord. 2016 May;195:215-20 [doi: 10.1016/j.jad.2016.02.005]).

[email protected]

Patients with bipolar disorder and low levels of pharmacological treatment adherence have greater levels of cognitive impairment, according to Dr. Ileana Fuentes and her associates.

After taking a neurological battery, 12 bipolar disorder patients with low treatment adherence performed worse than did 22 bipolar disorder patients with high treatment adherence in nearly all cognitive functions tested, but the effect was significant in verbal memory testing. The low-adherence group performed significantly worse in verbal memory immediate free recall, immediate cued recall, delayed free recall, and delayed cued recall.

Other factors found to be associated with poorer executive function and processing speed were greater number of manic episodes, history of psychosis, and fewer years of education, reported Dr. Fuentes of the University of Guadalajara, Mexico.

“Despite limitations of the study, our findings are clinically important, and they contribute to better understanding of the cognitive profile in low compliance patients with bipolar disorder. Low compliance, cognitive performance, and asymptomatic phase are important markers in [bipolar disorder] for further studies,” the investigators noted.

Find the study here (J Affect Disord. 2016 May;195:215-20 [doi: 10.1016/j.jad.2016.02.005]).

[email protected]

Patients with bipolar disorder and low levels of pharmacological treatment adherence have greater levels of cognitive impairment, according to Dr. Ileana Fuentes and her associates.

After taking a neurological battery, 12 bipolar disorder patients with low treatment adherence performed worse than did 22 bipolar disorder patients with high treatment adherence in nearly all cognitive functions tested, but the effect was significant in verbal memory testing. The low-adherence group performed significantly worse in verbal memory immediate free recall, immediate cued recall, delayed free recall, and delayed cued recall.

Other factors found to be associated with poorer executive function and processing speed were greater number of manic episodes, history of psychosis, and fewer years of education, reported Dr. Fuentes of the University of Guadalajara, Mexico.

“Despite limitations of the study, our findings are clinically important, and they contribute to better understanding of the cognitive profile in low compliance patients with bipolar disorder. Low compliance, cognitive performance, and asymptomatic phase are important markers in [bipolar disorder] for further studies,” the investigators noted.

Find the study here (J Affect Disord. 2016 May;195:215-20 [doi: 10.1016/j.jad.2016.02.005]).

[email protected]

Electroconvulsive therapy increased illness-free intervals and reduced manic and depressive episodes in bipolar patients, reported Dr. Gian Paolo Minnai of the psychiatry unit at San Martino Hospital in Oristano, Italy, and coauthors.

In a retrospective study of 41 patients with bipolar disorder, the investigators analyzed the number of episodes and admissions 5 years before and after ECT treatment. The duration of free intervals before and after ECT was also studied.

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The results showed “significantly longer” free intervals after treatment (13.2 ± 9.0 months before ECT to 25.1 ± 19.1 months after treatment [t = 3.8; P less than .0001]), Dr. Minnai and colleagues reported. In addition, the analysis found “significant reductions” in the number of manic and depressive episodes (5.9 ± 3.0 before ECT to 1.0 ± 1.7 after treatment [t = 9.3; P less than .0001]) and admissions (2.2 ± 1.3 before ECT to 0.2 ± 0.5 after treatment [t = 9.4; P less than .0001]).

The study suggests that “it is plausible that ECT, along with suspending antidepressant treatment, might carry intrinsic stabilizing effect on the course of [bipolar disorder],” the authors concluded.

No financial conflicts of interest were disclosed.

Read the full article in the Journal of Affective Disorders (May 2016;195:180-4).

[email protected]

Electroconvulsive therapy increased illness-free intervals and reduced manic and depressive episodes in bipolar patients, reported Dr. Gian Paolo Minnai of the psychiatry unit at San Martino Hospital in Oristano, Italy, and coauthors.

In a retrospective study of 41 patients with bipolar disorder, the investigators analyzed the number of episodes and admissions 5 years before and after ECT treatment. The duration of free intervals before and after ECT was also studied.

wildpixel/Thinkstock.com

The results showed “significantly longer” free intervals after treatment (13.2 ± 9.0 months before ECT to 25.1 ± 19.1 months after treatment [t = 3.8; P less than .0001]), Dr. Minnai and colleagues reported. In addition, the analysis found “significant reductions” in the number of manic and depressive episodes (5.9 ± 3.0 before ECT to 1.0 ± 1.7 after treatment [t = 9.3; P less than .0001]) and admissions (2.2 ± 1.3 before ECT to 0.2 ± 0.5 after treatment [t = 9.4; P less than .0001]).

The study suggests that “it is plausible that ECT, along with suspending antidepressant treatment, might carry intrinsic stabilizing effect on the course of [bipolar disorder],” the authors concluded.

No financial conflicts of interest were disclosed.

Read the full article in the Journal of Affective Disorders (May 2016;195:180-4).

[email protected]

Electroconvulsive therapy increased illness-free intervals and reduced manic and depressive episodes in bipolar patients, reported Dr. Gian Paolo Minnai of the psychiatry unit at San Martino Hospital in Oristano, Italy, and coauthors.

In a retrospective study of 41 patients with bipolar disorder, the investigators analyzed the number of episodes and admissions 5 years before and after ECT treatment. The duration of free intervals before and after ECT was also studied.

wildpixel/Thinkstock.com

The results showed “significantly longer” free intervals after treatment (13.2 ± 9.0 months before ECT to 25.1 ± 19.1 months after treatment [t = 3.8; P less than .0001]), Dr. Minnai and colleagues reported. In addition, the analysis found “significant reductions” in the number of manic and depressive episodes (5.9 ± 3.0 before ECT to 1.0 ± 1.7 after treatment [t = 9.3; P less than .0001]) and admissions (2.2 ± 1.3 before ECT to 0.2 ± 0.5 after treatment [t = 9.4; P less than .0001]).

The study suggests that “it is plausible that ECT, along with suspending antidepressant treatment, might carry intrinsic stabilizing effect on the course of [bipolar disorder],” the authors concluded.

No financial conflicts of interest were disclosed.

Read the full article in the Journal of Affective Disorders (May 2016;195:180-4).

[email protected]

Childhood maltreatment is associated with lifetime anxiety among people with bipolar disorder, Barbara Pavlova, Ph.D., and her associates reported.

The researchers recruited 174 adult outpatients with a diagnosis of bipolar disorder I or bipolar disorder II, of whom 29% had one anxiety disorder and 20% had two or more. More than half (56%) of the patients were female, and their median age was 42. The types of anxiety disorders among the patients ranged from generalized anxiety disorder (28%) to obsessive-compulsive disorder (4%).

wildpixel/Thinkstock.com

Dr. Pavlova and her associates assessed the patients’ history of maltreatment in childhood using the Childhood Trauma Questionnaire (CTQ), a 28-item self-report measure that asks about emotional, physical, and sexual abuse and about emotional and physical neglect. Anxiety disorders were assessed using the Mini-International Neuropsychiatric Interview (MINI), wrote Dr. Pavlova of the psychiatry department at Dalhousie University, Halifax, N.S.

They found that childhood maltreatment, indexed by higher CTQ total scores, was linked to a higher number of lifetime anxiety disorders (odds ratio, 1.5; 95% confidence interval, 1.01-2.14; P = .04). In addition, panic disorder was most strongly tied to childhood maltreatment (OR, 2.27; 95% CI, 1.28-4.02; P = .01).

The results suggest “that bipolar disorder with comorbid anxiety constitutes an [etiologic] subtype shaped to a greater extent by early environment,” the investigators wrote.

Read the full study here: (J Affect Dis. 2016 Mar 1;192:22-7).

[email protected]

On Twittter @ginalhenderson

Childhood maltreatment is associated with lifetime anxiety among people with bipolar disorder, Barbara Pavlova, Ph.D., and her associates reported.

The researchers recruited 174 adult outpatients with a diagnosis of bipolar disorder I or bipolar disorder II, of whom 29% had one anxiety disorder and 20% had two or more. More than half (56%) of the patients were female, and their median age was 42. The types of anxiety disorders among the patients ranged from generalized anxiety disorder (28%) to obsessive-compulsive disorder (4%).

wildpixel/Thinkstock.com

Dr. Pavlova and her associates assessed the patients’ history of maltreatment in childhood using the Childhood Trauma Questionnaire (CTQ), a 28-item self-report measure that asks about emotional, physical, and sexual abuse and about emotional and physical neglect. Anxiety disorders were assessed using the Mini-International Neuropsychiatric Interview (MINI), wrote Dr. Pavlova of the psychiatry department at Dalhousie University, Halifax, N.S.

They found that childhood maltreatment, indexed by higher CTQ total scores, was linked to a higher number of lifetime anxiety disorders (odds ratio, 1.5; 95% confidence interval, 1.01-2.14; P = .04). In addition, panic disorder was most strongly tied to childhood maltreatment (OR, 2.27; 95% CI, 1.28-4.02; P = .01).

The results suggest “that bipolar disorder with comorbid anxiety constitutes an [etiologic] subtype shaped to a greater extent by early environment,” the investigators wrote.

Read the full study here: (J Affect Dis. 2016 Mar 1;192:22-7).

[email protected]

On Twittter @ginalhenderson

Childhood maltreatment is associated with lifetime anxiety among people with bipolar disorder, Barbara Pavlova, Ph.D., and her associates reported.

The researchers recruited 174 adult outpatients with a diagnosis of bipolar disorder I or bipolar disorder II, of whom 29% had one anxiety disorder and 20% had two or more. More than half (56%) of the patients were female, and their median age was 42. The types of anxiety disorders among the patients ranged from generalized anxiety disorder (28%) to obsessive-compulsive disorder (4%).

wildpixel/Thinkstock.com

Dr. Pavlova and her associates assessed the patients’ history of maltreatment in childhood using the Childhood Trauma Questionnaire (CTQ), a 28-item self-report measure that asks about emotional, physical, and sexual abuse and about emotional and physical neglect. Anxiety disorders were assessed using the Mini-International Neuropsychiatric Interview (MINI), wrote Dr. Pavlova of the psychiatry department at Dalhousie University, Halifax, N.S.

They found that childhood maltreatment, indexed by higher CTQ total scores, was linked to a higher number of lifetime anxiety disorders (odds ratio, 1.5; 95% confidence interval, 1.01-2.14; P = .04). In addition, panic disorder was most strongly tied to childhood maltreatment (OR, 2.27; 95% CI, 1.28-4.02; P = .01).

The results suggest “that bipolar disorder with comorbid anxiety constitutes an [etiologic] subtype shaped to a greater extent by early environment,” the investigators wrote.

Read the full study here: (J Affect Dis. 2016 Mar 1;192:22-7).

[email protected]

On Twittter @ginalhenderson

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

The significantly increased risk of myocardial infarction or stroke in patients with bipolar I disorder appears to be tied more to preventive factors than to cardiovascular risk factors. However, bipolar I patients with a history of psychosis have an marginally increased risk of MI or stroke, a population-based cohort study showed.

The researchers came to those conclusions after analyzing residents’ health records and death certificates in Olmsted County, Minn., which were contained within the Rochester Epidemiology Project database. The study’s participants included 334 patients with bipolar I disorder and 334 people without bipolar disorder, although one of the patients who did not have bipolar I at the beginning of the study was later diagnosed with the disorder. All participants had been residents of Olmsted County from Jan. 1, 1966, through Dec. 31,1996.

Patients continued to be followed until Dec. 31, 2013, unless one of the following events occurred before that date: the patient had an MI or stroke, was lost to follow-up, or died before the end of the study. A patient experiencing an MI, stroke, or death or a patient disappearing from the database triggered an end to that patient’s participation in the study.

When an individual having an MI or a stroke was treated as a composite outcome, bipolar I disorder patients had a significantly increased risk of experiencing a fatal or non-fatal MI or stroke, compared with the individuals in the control group (P = .04). The risk was no longer significant after the researchers adjusted for the following potential baseline confounders of the association between bipolar disorder and cardiovascular disease: alcohol use disorder, diabetes, hypertension, and smoking (P = .46).

Meanwhile, a secondary analysis of the data showed that history of psychosis was indeed tied to a marginally increased risk of MI or stroke (P =.06).

“It will be fundamental to improve current preventive strategies to decrease the prevalence of smoking, alcohol use, hypertension, and diabetes among patients with bipolar disorder,” said Dr. Miguel L. Prieto of the department of psychiatry and psychology at the Mayo Medical School, Rochester, Minn., and his colleagues. “Moreover, we detected a possible higher risk of MI/stroke in the subgroup of patients with history of psychosis that certainly warrants replication.”

Future research also should seek to determine early biomarkers of atherosclerosis, the researchers said.

Read the study in Journal of Affective Disorders (doi: 10.1016/j.jad.2016.01.015).

[email protected]

In early December, I was fortunate to be invited to a film screening of “Touched With Fire,” starring Katie Holmes and Luke Kirby. The movie is about two young poets with bipolar disorder who meet and fall in love while on a psychiatric unit. It opens in theaters on Feb.12.

The screening was introduced by Johns Hopkins Hospital’s psychiatrist in chief Ray DePaulo and following the movie, director Paul Dalio and psychologist Kay Redfield Jamison, Ph.D., both gave short talks and answered questions. The movie was inspired by Dalio’s personal experience with bipolar disorder. Jamison, author of Touched With Fire: Manic-Depressive Illness and the Artistic Temperament (New York: Free Press, 1996) had offered hope to Dalio during a difficult moment with his illness. Numbed by the medications that made his moods tolerable, she had assured him that his creativity would reemerge, as indeed it did. Jamison’s book lent its name to the movie title, and she had a cameo role in the film. In the movie, Jamison, playing herself, tells the couple that it took a while for her moods to calibrate, but that medicines were a godsend and they helped her to become both happier and more productive.

“You’re concerned about losing your art and losing your passion,” Jamison says to Marco, the character played by Kirby. “Medication’s not going to take your personality away; it’s not going to take away your own gift. It’s a fire when it’s out of control, and what medication can do is tamp that down a bit without losing that gift.”

While this insight was helpful to the real-life Dalio, the character Marco struggles deeply as tries to hang on enough to love, work, and strive toward a future he longs for, all while mourning what he sees as the loss of himself. “I want the mania!” he tells Carla, played by Holmes, in one of the more poignant scenes.

Enough plot spoilers. The love story is emotional, and the portrayal of bipolar disorder is the best I have ever seen in the popular media. The characters are three-dimensional and about so much more than their illnesses, and many of the scenes ring so true. This is bipolar disorder with all its raw passion and pain laid out for an audience. No one has odd mannerisms and no one walks around dressed in plastic bags; instead, these are beautiful people ravaged by psychosis and the extremes of their moods, and when it’s not horrible, it’s absolutely wonderful.

In the question-and-answer session after the movie, a member of the audience asked Paul Dalio how to get treatment for someone who is manic. Dalio’s answer was swift: “You have to force them. There is no other way.” As someone who has been interested in patient responses to involuntary psychiatric care, I was a bit surprised to hear that answer from someone who has suffered with the condition and whom I presumed had been treated against his will. When I was asked a few weeks later if I’d like to interview Mr. Dalio, my answer was also swift: Yes, I would.

Dalio talked openly with me about his own psychiatric history, and he was quick to say that he shared Marco’s struggles. The love story that unfolded with Carla was fictional, but when I asked about several of the scenes, Dalio said, “Yes, that happened to me!”

Dalio has been admitted to the hospital four times, twice as an involuntary patient. “I know that in a manic state, no one is going to convince you to go into a hospital,” he said. “My experience was not good at all – it was horrific and frustrating – but it was the lesser of two evils. As difficult as it was, it doesn’t hold a candle to the pain. There is no way I can communicate the pain of bipolar depression.”

Like his character, Marco, Paul Dalio spent years ravaged by his illness. He worked in a warehouse, and he says that during those years he was not very likable. He credits his family with keeping him alive; his father would spend hours on the phone talking him out of committing suicide. The family researched treatment options, and eventually, Dalio began to travel from New York City to see a bipolar disorder expert in Baltimore. His treatment at Hopkins enabled his meeting with Kay Jamison.

“You can’t lie about this disorder,” Dalio said, “and you can’t sugarcoat it.”

Dalio’s life has done a turnaround from his days of being psychotic, suicidal, and unable to function. He holds a degree in screenwriting from New York University and has attended the NYU graduate program in filmmaking. He is married and has two small children.

I asked what helped.

“I resolved to stay on meds,” he said, “even if I felt numb. I don’t drink, not even a toast to the movie. I go to bed at 10 every night, drink green juices all day, use a light box, and take walks. Transcendental meditation helps. And patience – it took 3-5 years before I was really able to feel emotion again. I’ve been stable since 2007, but thriving since 2010, with rich emotions. I have a severe form of the condition.”

Dalio experiences symptoms if he misses even a couple of doses of medication, and with two toddlers, it can be difficult for his wife that he can’t help with the children in the middle of the night. It’s not all hard, though. “My wife is Eastern European, and she has a connection to the darkness. She was always attracted to crazy people and artists, and she finds a lot of pleasure in our lives.” Like Dalio, she is screenwriter, and they collaborate on their work.

Dalio is clear about his agenda for this movie. He sees his bipolar disorder as a gift that fuels creative pursuits, and he wants others to understand how people with this disorder struggle. He used the word “beautiful” to describe the intensity of emotions that Carla and Marco experience in the film, but tragedy and torment are also screaming on the big screen. His second agenda is a plug for mainstream psychiatry and a billboard for hope: take the medications, tolerate the downside, be patient; things will work out.

Well worth seeing.

Dr. Miller is a psychiatrist who practices in Baltimore.

In early December, I was fortunate to be invited to a film screening of “Touched With Fire,” starring Katie Holmes and Luke Kirby. The movie is about two young poets with bipolar disorder who meet and fall in love while on a psychiatric unit. It opens in theaters on Feb.12.

The screening was introduced by Johns Hopkins Hospital’s psychiatrist in chief Ray DePaulo and following the movie, director Paul Dalio and psychologist Kay Redfield Jamison, Ph.D., both gave short talks and answered questions. The movie was inspired by Dalio’s personal experience with bipolar disorder. Jamison, author of Touched With Fire: Manic-Depressive Illness and the Artistic Temperament (New York: Free Press, 1996) had offered hope to Dalio during a difficult moment with his illness. Numbed by the medications that made his moods tolerable, she had assured him that his creativity would reemerge, as indeed it did. Jamison’s book lent its name to the movie title, and she had a cameo role in the film. In the movie, Jamison, playing herself, tells the couple that it took a while for her moods to calibrate, but that medicines were a godsend and they helped her to become both happier and more productive.

“You’re concerned about losing your art and losing your passion,” Jamison says to Marco, the character played by Kirby. “Medication’s not going to take your personality away; it’s not going to take away your own gift. It’s a fire when it’s out of control, and what medication can do is tamp that down a bit without losing that gift.”

While this insight was helpful to the real-life Dalio, the character Marco struggles deeply as tries to hang on enough to love, work, and strive toward a future he longs for, all while mourning what he sees as the loss of himself. “I want the mania!” he tells Carla, played by Holmes, in one of the more poignant scenes.

Enough plot spoilers. The love story is emotional, and the portrayal of bipolar disorder is the best I have ever seen in the popular media. The characters are three-dimensional and about so much more than their illnesses, and many of the scenes ring so true. This is bipolar disorder with all its raw passion and pain laid out for an audience. No one has odd mannerisms and no one walks around dressed in plastic bags; instead, these are beautiful people ravaged by psychosis and the extremes of their moods, and when it’s not horrible, it’s absolutely wonderful.

In the question-and-answer session after the movie, a member of the audience asked Paul Dalio how to get treatment for someone who is manic. Dalio’s answer was swift: “You have to force them. There is no other way.” As someone who has been interested in patient responses to involuntary psychiatric care, I was a bit surprised to hear that answer from someone who has suffered with the condition and whom I presumed had been treated against his will. When I was asked a few weeks later if I’d like to interview Mr. Dalio, my answer was also swift: Yes, I would.

Dalio talked openly with me about his own psychiatric history, and he was quick to say that he shared Marco’s struggles. The love story that unfolded with Carla was fictional, but when I asked about several of the scenes, Dalio said, “Yes, that happened to me!”

Dalio has been admitted to the hospital four times, twice as an involuntary patient. “I know that in a manic state, no one is going to convince you to go into a hospital,” he said. “My experience was not good at all – it was horrific and frustrating – but it was the lesser of two evils. As difficult as it was, it doesn’t hold a candle to the pain. There is no way I can communicate the pain of bipolar depression.”

Like his character, Marco, Paul Dalio spent years ravaged by his illness. He worked in a warehouse, and he says that during those years he was not very likable. He credits his family with keeping him alive; his father would spend hours on the phone talking him out of committing suicide. The family researched treatment options, and eventually, Dalio began to travel from New York City to see a bipolar disorder expert in Baltimore. His treatment at Hopkins enabled his meeting with Kay Jamison.

“You can’t lie about this disorder,” Dalio said, “and you can’t sugarcoat it.”

Dalio’s life has done a turnaround from his days of being psychotic, suicidal, and unable to function. He holds a degree in screenwriting from New York University and has attended the NYU graduate program in filmmaking. He is married and has two small children.

I asked what helped.

“I resolved to stay on meds,” he said, “even if I felt numb. I don’t drink, not even a toast to the movie. I go to bed at 10 every night, drink green juices all day, use a light box, and take walks. Transcendental meditation helps. And patience – it took 3-5 years before I was really able to feel emotion again. I’ve been stable since 2007, but thriving since 2010, with rich emotions. I have a severe form of the condition.”

Dalio experiences symptoms if he misses even a couple of doses of medication, and with two toddlers, it can be difficult for his wife that he can’t help with the children in the middle of the night. It’s not all hard, though. “My wife is Eastern European, and she has a connection to the darkness. She was always attracted to crazy people and artists, and she finds a lot of pleasure in our lives.” Like Dalio, she is screenwriter, and they collaborate on their work.

Dalio is clear about his agenda for this movie. He sees his bipolar disorder as a gift that fuels creative pursuits, and he wants others to understand how people with this disorder struggle. He used the word “beautiful” to describe the intensity of emotions that Carla and Marco experience in the film, but tragedy and torment are also screaming on the big screen. His second agenda is a plug for mainstream psychiatry and a billboard for hope: take the medications, tolerate the downside, be patient; things will work out.

Well worth seeing.

Dr. Miller is a psychiatrist who practices in Baltimore.

In early December, I was fortunate to be invited to a film screening of “Touched With Fire,” starring Katie Holmes and Luke Kirby. The movie is about two young poets with bipolar disorder who meet and fall in love while on a psychiatric unit. It opens in theaters on Feb.12.

The screening was introduced by Johns Hopkins Hospital’s psychiatrist in chief Ray DePaulo and following the movie, director Paul Dalio and psychologist Kay Redfield Jamison, Ph.D., both gave short talks and answered questions. The movie was inspired by Dalio’s personal experience with bipolar disorder. Jamison, author of Touched With Fire: Manic-Depressive Illness and the Artistic Temperament (New York: Free Press, 1996) had offered hope to Dalio during a difficult moment with his illness. Numbed by the medications that made his moods tolerable, she had assured him that his creativity would reemerge, as indeed it did. Jamison’s book lent its name to the movie title, and she had a cameo role in the film. In the movie, Jamison, playing herself, tells the couple that it took a while for her moods to calibrate, but that medicines were a godsend and they helped her to become both happier and more productive.

“You’re concerned about losing your art and losing your passion,” Jamison says to Marco, the character played by Kirby. “Medication’s not going to take your personality away; it’s not going to take away your own gift. It’s a fire when it’s out of control, and what medication can do is tamp that down a bit without losing that gift.”

While this insight was helpful to the real-life Dalio, the character Marco struggles deeply as tries to hang on enough to love, work, and strive toward a future he longs for, all while mourning what he sees as the loss of himself. “I want the mania!” he tells Carla, played by Holmes, in one of the more poignant scenes.

Enough plot spoilers. The love story is emotional, and the portrayal of bipolar disorder is the best I have ever seen in the popular media. The characters are three-dimensional and about so much more than their illnesses, and many of the scenes ring so true. This is bipolar disorder with all its raw passion and pain laid out for an audience. No one has odd mannerisms and no one walks around dressed in plastic bags; instead, these are beautiful people ravaged by psychosis and the extremes of their moods, and when it’s not horrible, it’s absolutely wonderful.

In the question-and-answer session after the movie, a member of the audience asked Paul Dalio how to get treatment for someone who is manic. Dalio’s answer was swift: “You have to force them. There is no other way.” As someone who has been interested in patient responses to involuntary psychiatric care, I was a bit surprised to hear that answer from someone who has suffered with the condition and whom I presumed had been treated against his will. When I was asked a few weeks later if I’d like to interview Mr. Dalio, my answer was also swift: Yes, I would.

Dalio talked openly with me about his own psychiatric history, and he was quick to say that he shared Marco’s struggles. The love story that unfolded with Carla was fictional, but when I asked about several of the scenes, Dalio said, “Yes, that happened to me!”

Dalio has been admitted to the hospital four times, twice as an involuntary patient. “I know that in a manic state, no one is going to convince you to go into a hospital,” he said. “My experience was not good at all – it was horrific and frustrating – but it was the lesser of two evils. As difficult as it was, it doesn’t hold a candle to the pain. There is no way I can communicate the pain of bipolar depression.”

Like his character, Marco, Paul Dalio spent years ravaged by his illness. He worked in a warehouse, and he says that during those years he was not very likable. He credits his family with keeping him alive; his father would spend hours on the phone talking him out of committing suicide. The family researched treatment options, and eventually, Dalio began to travel from New York City to see a bipolar disorder expert in Baltimore. His treatment at Hopkins enabled his meeting with Kay Jamison.

“You can’t lie about this disorder,” Dalio said, “and you can’t sugarcoat it.”

Dalio’s life has done a turnaround from his days of being psychotic, suicidal, and unable to function. He holds a degree in screenwriting from New York University and has attended the NYU graduate program in filmmaking. He is married and has two small children.

I asked what helped.

“I resolved to stay on meds,” he said, “even if I felt numb. I don’t drink, not even a toast to the movie. I go to bed at 10 every night, drink green juices all day, use a light box, and take walks. Transcendental meditation helps. And patience – it took 3-5 years before I was really able to feel emotion again. I’ve been stable since 2007, but thriving since 2010, with rich emotions. I have a severe form of the condition.”

Dalio experiences symptoms if he misses even a couple of doses of medication, and with two toddlers, it can be difficult for his wife that he can’t help with the children in the middle of the night. It’s not all hard, though. “My wife is Eastern European, and she has a connection to the darkness. She was always attracted to crazy people and artists, and she finds a lot of pleasure in our lives.” Like Dalio, she is screenwriter, and they collaborate on their work.

Dalio is clear about his agenda for this movie. He sees his bipolar disorder as a gift that fuels creative pursuits, and he wants others to understand how people with this disorder struggle. He used the word “beautiful” to describe the intensity of emotions that Carla and Marco experience in the film, but tragedy and torment are also screaming on the big screen. His second agenda is a plug for mainstream psychiatry and a billboard for hope: take the medications, tolerate the downside, be patient; things will work out.

Well worth seeing.

Dr. Miller is a psychiatrist who practices in Baltimore.

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Smartphone surveys of mood and social stress might be useful in identifying mental changes in bipolar disorder patients, according to a pilot feasibility study by Stefani Schwartz of the department of psychiatry at Pennsylvania State University, Hershey, and her associates.

Ten bipolar disorder patients and 10 healthy controls recruited for the study were given smartphones and asked to complete surveys of mood and social stress twice a day at random for 14 days. The surveys included a visual analog scale to record ratings of mood, energy, speed of thoughts, and impulsivity, in which participants could choose any point along a scale of 0-100 by moving a sliding marker; and a Likert scale to measure social stress. For this part, participants revealed whether they were with others and whether they would rather be alone.

©Hocus Focus Studio/iStockphoto.com

Completion rates were similar among the groups: a median of 95% in the bipolar disorder group and 88% in the healthy control group (P = 0.68). Median scores of the 14-day mean mood and energy in the bipolar disorder group were significantly lower in the bipolar disorder group, while speed of thoughts, impulsivity, and social stress were not significantly different between the groups. Median scores of the 14-day range for mood, speed of thoughts, and impulsivity did differ from the healthy controls, while energy and social stress did not differ significantly.

Prolonged monitoring might be required to detect prodromal symptoms of an impending major episode among patients with bipolar disorder, the authors wrote. Also, the findings are preliminary in light of many factors, including the small sample. Nevertheless, the techniques used in this study “could be investigated in subjects in different treatment settings to explore the sensitivity of detection of changes in symptoms,” the investigators wrote.

Read the article in the Journal of Affective Disorders (http://dx.doi.org/10.1016/j.jad.2015.11.013).

Smartphone surveys of mood and social stress might be useful in identifying mental changes in bipolar disorder patients, according to a pilot feasibility study by Stefani Schwartz of the department of psychiatry at Pennsylvania State University, Hershey, and her associates.

Ten bipolar disorder patients and 10 healthy controls recruited for the study were given smartphones and asked to complete surveys of mood and social stress twice a day at random for 14 days. The surveys included a visual analog scale to record ratings of mood, energy, speed of thoughts, and impulsivity, in which participants could choose any point along a scale of 0-100 by moving a sliding marker; and a Likert scale to measure social stress. For this part, participants revealed whether they were with others and whether they would rather be alone.

©Hocus Focus Studio/iStockphoto.com

Completion rates were similar among the groups: a median of 95% in the bipolar disorder group and 88% in the healthy control group (P = 0.68). Median scores of the 14-day mean mood and energy in the bipolar disorder group were significantly lower in the bipolar disorder group, while speed of thoughts, impulsivity, and social stress were not significantly different between the groups. Median scores of the 14-day range for mood, speed of thoughts, and impulsivity did differ from the healthy controls, while energy and social stress did not differ significantly.

Prolonged monitoring might be required to detect prodromal symptoms of an impending major episode among patients with bipolar disorder, the authors wrote. Also, the findings are preliminary in light of many factors, including the small sample. Nevertheless, the techniques used in this study “could be investigated in subjects in different treatment settings to explore the sensitivity of detection of changes in symptoms,” the investigators wrote.

Read the article in the Journal of Affective Disorders (http://dx.doi.org/10.1016/j.jad.2015.11.013).

Smartphone surveys of mood and social stress might be useful in identifying mental changes in bipolar disorder patients, according to a pilot feasibility study by Stefani Schwartz of the department of psychiatry at Pennsylvania State University, Hershey, and her associates.

Ten bipolar disorder patients and 10 healthy controls recruited for the study were given smartphones and asked to complete surveys of mood and social stress twice a day at random for 14 days. The surveys included a visual analog scale to record ratings of mood, energy, speed of thoughts, and impulsivity, in which participants could choose any point along a scale of 0-100 by moving a sliding marker; and a Likert scale to measure social stress. For this part, participants revealed whether they were with others and whether they would rather be alone.

©Hocus Focus Studio/iStockphoto.com

Completion rates were similar among the groups: a median of 95% in the bipolar disorder group and 88% in the healthy control group (P = 0.68). Median scores of the 14-day mean mood and energy in the bipolar disorder group were significantly lower in the bipolar disorder group, while speed of thoughts, impulsivity, and social stress were not significantly different between the groups. Median scores of the 14-day range for mood, speed of thoughts, and impulsivity did differ from the healthy controls, while energy and social stress did not differ significantly.

Prolonged monitoring might be required to detect prodromal symptoms of an impending major episode among patients with bipolar disorder, the authors wrote. Also, the findings are preliminary in light of many factors, including the small sample. Nevertheless, the techniques used in this study “could be investigated in subjects in different treatment settings to explore the sensitivity of detection of changes in symptoms,” the investigators wrote.

Read the article in the Journal of Affective Disorders (http://dx.doi.org/10.1016/j.jad.2015.11.013).

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).