Bipolar Disorder

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

CHICAGO – Schizophrenia, bipolar disorder, and major depressive disorder all benefit from early diagnosis and aggressive therapy, and the new First Contact program at Northwestern Memorial Hospital is an attempt to provide it to all three disorders in an orderly way.

"A seamless integration of patient care from the very beginning" is how it was described by Dr. Will Cronenwett, medical director of outpatient psychiatry at Northwestern Memorial Hospital’s Stone Institute of Psychiatry in Chicago. Dr. Cronenwett outlined First Contact in a hospital seminar titled "Reinventing Inpatient Psychiatry."

In the conventional model of care, the prodromes of schizophrenia, bipolar disorder, or depression were each seen as a precursor to that particular illness. Patients were recruited based on the risk of the illness, and treatment and disease progression were studied in that light, according to Dr. Cronenwett’s presentation.

The First Contact model, by contrast, is a clinical staging model dependent on time, and not on predicted illness, said Dr. Cronenwett.

"It’s dependent on somebody’s index presentation. ... Either they’ve identified themselves ... or somebody else has talked to them about getting help," he said. Prospective patients may appear healthy because the program intends to get them as early as possible in the course of the illness, ideally within a year of disease onset.

"Our point is to look at this as a staging model, as opposed to a model where we understand specifically where people are headed," said Dr. Cronenwett.

The First Contact program has three dimensions: clinical, research, and outreach. The treatment goals are symptom relief; education and empowerment; and support for role functioning. A specialized early intervention program is core to First Contact, as are coordinated inpatient and outpatient services. The treatment team will be multidisciplinary and will include community outreach. Cognitive behavioral therapy will be incorporated because it is considered effective for mood symptoms and psychosis in early phases of illness (J. Clin. Psychiatry 2009;70:1206-12). The program’s goals include improving the patient’s adaptation to the illness and increasing their subjective quality of life. Self-management will therefore be stressed, as will cognitive enhancement therapy.

The patient, family, and caregiver will all be educated in the program’s goals.

Research will also be integrated into the First Contact program, seeking disease markers via imaging, genetics, and cognitive changes. Outreach will be used to increase public awareness, promote early self-detection, and encourage early referrals. Dr. Cronenwett said there is evidence, although inconclusive, that early therapy reduces the duration of untreated illness (Acta Psychiatr. Scand. 2008;117:440-8).

Ultimately, Northwestern hopes to create and share guidelines for treatment of these illnesses.

None of this will be easy. In the initial phases, all of these illnesses are difficult to identify with accuracy. The first diagnoses, before the disease prodrome, are often unstable, especially for psychosis, but also for bipolar disease.

"Most people identified as prodromal don’t end up converting to psychosis," said Dr. Cronenwett (Am. J. Psychiatry 2011;168:800-5).

In this particular study, only 35% converted to psychosis, whereas 24% remitted completely. Other diagnoses – including anxiety disorder, depression, mania, and substance use disorder – also remitted over time.

He went on to say that the schizophrenia prodrome is a complicated clinical picture, and that the initial presentation does not predict the outcome. "Schizophrenia prodrome has been the most studied phenomenon to date," he said. "Oftentimes the first symptomatic presentation for what later gets diagnosed as schizophrenia is depression."

The bipolar prodrome, with its age of onset at 0-6 years, can present with any number of characteristics, including "stubborn" and "overly sensitive."

"The bipolar prodrome is probably more confusing than schizophrenia," said Dr. Cronenwett. The most common clinical elements are depressed or elevated mood, anger, perceptual changes, energy changes, functional impairment (Bipolar Disord. 2008;10:555-65). He said it may be 10 years between presenting symptoms and final diagnosis . Major depressive disorder is the least-studied prodrome, and overlaps with other prodromal phenomena, he said.

Dr. Cronenwett disclosed research support from Novartis and from Sunovion Pharmaceuticals.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – Recently reported evidence implicating inflammatory mediators in the pathophysiology of bipolar disorder and major depression have opened the door to testing new agents for treating these psychiatric disorders or slowing their progression.

"Bipolar disorder is associated with neuroprogression, and oxidative stress, neurotrophins, and inflammation may underpin this process, Dr. Michael Berk said at the annual Congress of the European College of Neuropsychopharmacology. "Early interventions can potentially improve the outcome" of bipolar disorder, and the new findings give new opportunities to find effective neuroprotective agents, said Dr. Berk, professor and chairman of psychiatry at Deakin University in Geelong, Australia.

"We increasingly think there is a systemic biology that underpins" bipolar disorder and potentially other inflammatory diseases. "The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful," he said in an interview.

Based on this concept, and supported by suggestive results from epidemiologic studies, Dr. Berk said he and his associates are running a prospective, randomized study assessing a role for aspirin in treating bipolar disorder, and that they are seeking funding for a second study to test combined treatment with a statin and aspirin in bipolar disorder patients.

"We are only starting to understand the core elements of neuroprogression" in bipolar disorder patients, including the roles of neurogenesis, apoptosis, oxidative stress, and mitochondrial energy generation. "If we accept that these are determining long-term outcomes, it gives us a diversity of novel treatments we can begin to look at that might have a potential impact on these underlying processes. I think this is one of the most hopeful areas of psychiatry."

Evidence of a role for inflammation in bipolar disorder and major depression includes the finding by Dr. Berk and his associates that women who received statin treatment had about a 2% incidence of newly diagnosed major depressive disorder during 10 years of follow-up, significantly less than the 10% incidence rate among women who did not receive a statin, in a nonrandomized study that controlled for age (Psychother. Psychosom. 2010;79:323-5).

In another study, Dr. Berk and his associates found a link between elevated serum levels of high sensitivity C-reactive protein (hsCRP) and the incidence of major depressive disorder. They followed 644 randomly selected women aged 20-84 and with no history of depression at baseline for 10 years. During follow-up, the rate of new-onset major depressive disorder rose by a statistically significant 44% for each one standard deviation increase in the log-transformed level of serum hsCRP, after adjustment for baseline differences in weight, smoking history, and use of nonsteroidal anti-inflammatory drugs (Br. J. Psychiatry 2010;197:372-7).

Also, a 2006 report from Irish researchers had results from a study of the plasma levels of five different cytokines in 42 people aged 1-68, including nine with bipolar affective disorder in the depressive phase, 12 with bipolar affective disorder in the manic phase, and 21 control people with no personal or family history of a mood disorder. The results showed significantly elevated plasma levels of interleukin-8 and tumor necrosis factor-α in both subgroups of bipolar disorder patients studied compared with the controls (J. Affective Disorders 2006;90:263-7).

Dr. Berk also reported as yet unpublished results from his group that further supported a possible causal role for inflammation or autoimmunity in major depression. Results from one study showed significantly lower plasma levels of tumor necrosis factor-α in control subjects, compared with patients with melancholia or recurrent major depressive disorder. Results from a second study showed a significantly higher level of IgM that reacted against an oxidatively modified form of tryptophan in patients with new-onset major depressive disorder. "This may be a major cause of neuroprogression and a factor in chronicity and treatment resistance," he said.

In addition, recent findings on the trajectory of major depression and bipolar disorder also suggest a critical role for early treatment. Although Dr. Berk cautioned that "we need prospective data, and we need to be cautious in interpreting the data" now available, recent findings suggest that "the earlier on in illness the simpler treatment can be and the more likely is response to treatment," he said. Conversely, more advanced bipolar disorder appears to be more treatment resistant and only treatable with more complex regimens. The basis for these associations seems to be the progressive neuropathologic processes that underlie these disorders. "Mania appears to be the most neurotoxic phase of [bipolar disorder] illness," he said. "Prevention of mania may be most effective for preventing neuroprogression."

He cited clinical suggestions of progression to more treatment-resistant forms of disease. "You often see the history that initial treatment with antidepressant drugs helped, but later they did not." For example, in a recent meta-analysis of 12 treatment studies involving more than 4,000 total patients with bipolar disorder, Dr. Berk and his associates found patients in the earliest stages of their disease consistently had better responses to treatment, compared with patients who had experienced more episodes of mania or depression. "Vigorous attention needs to be paid to early diagnosis," they wrote in their report published earlier this year (Bipolar Dis. 2011;13:87-98). "There is every possibility that early and appropriate treatment and the prevention of new episodes may prevent this cascade," they wrote, but also added "this remains to be established."

Dr. Berk said he had been a speaker for, a consultant to, and has received research grants from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Servier; he has been a speaker for and consultant to AstraZeneca, Janssen Cilag, and Lundbeck; he has been a speaker for Merck, Sanofi Synthélabo, and Solvay and Wyeth, and he has received research grants from Organon, Novartis, and Mayne.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – A 21-week program of "functional remediation" for 220 adults with bipolar disorder was more effective than psychosocial education or usual treatment in improving psychosocial functioning at 6 months of follow-up.

The multicenter trial randomized euthymic adults with bipolar disorder type I or II at 10 centers in Spain to 21 weeks of treatment in one of three groups: weekly 90-minute group sessions for functional remediation; group psychoeducation sessions, or a control group that got treatment as usual. The functional remediation sessions covered aspects of cognition and psychosocial restoration, Dr. Eduard Vieta said at the annual congress of the European College of Neuropsychopharmacology.

The study measured functional status using the Functional Assessment Short Test (FAST). The FAST provides on objective measure, compared with assessments of quality of life that produce subjective results, said Dr. Vieta, director of the Bipolar Disorders Program at the Clinical Institute of Neuroscience, University of Barcelona. To be eligible for the study, patients had to have FAST scores of 18 or greater, which allowed room to show improvement, and only patients up to age 50 years were accepted in order to avoid cognitive deficits associated with older age.

Previous data using FAST show that patients with bipolar disorder have significantly lower functioning in measures of autonomy, cognition, financial issues, interpersonal functioning, leisure time, and overall scores compared with people without bipolar disorder (Bipolar Disord. 2009;11:401-9). In one study, cognitive function scores on the FAST at baseline predicted functional outcome 4 years later (J. Affect. Disord. 2010;121:156-60).

In the current study, there were no significant differences at baseline in functioning between groups as measured by FAST scores. In the functional remediation group, 30% discontinued treatment during the study compared with 27% in the psychoeducation group and 18% getting treatment as usual.

At 6-month follow-up, FAST scores of functioning were significantly better in the functional remediation group compared with the psychoeducation group or the control group. A preliminary analysis of results suggests that the difference in FAST scores was significant to a P value of .001, reported Dr. Vieta and his associate in the study, Carla Torrent, Ph.D., also with both of the University of Barcelona.

In an assessment of effect size, the functional remediation had a large effect, the psychoeducation had a small effect, and treatment as usual had essentially no effect, he said.

Among the various functional domains, functional remediation had the most impact on cognitive, interpersonal, and autonomy domains, each with a medium effect. Small effects were seen on leisure, financial, and occupational domains.

The functional remediation program addressed cognition and psychosocial restoration using neurocognitive techniques for daily life. It included education about cognitive deficits and their impact on daily life, and sought to increase insight regrading cognitive dysfunctions. The program provided patients with strategies to manage cognitive deficits, primarily in the areas of attention, memory, and executive function. In some cases, the patient’s family participated to help the patient practice the strategies and to reinforce the learning.

The neurocognitive behavioral approach in the program employed modeling techniques, role playing, verbal instructions, self-instructions, positive reinforcement, and metacognitive cues.

Each 90-minute session began with a 15-minute discussion of assigned homework and a 5-minute warm-up task, followed by 20 minutes of theory and cognitive strategies. Practical exercises for the next 45 minutes were followed by 5 minutes to focus on take-home points and tasks to do at home.

The 21 sessions focused on specific topics grouped within categories of education, attention, memory, executive functions, and improving communication, autonomy, and stress management. Sessions 12-16, for example, focused on executive functions, with sessions on self-instructions and self-monitoring of executive functions, programming and organizing activities, establishing priorities and time management, problem-solving techniques, and solving problems.

The investigators have not yet done a cost-benefit analysis, but a functional remediation program should not be too expensive, Dr. Vieta said. "You just need one neuropsychologist" or two to organize and lead the program, he said. Previous cost analyses have shown group psychoeducation to be cost effective. "This should be, too," he said.

Medication can treat acute episodes of bipolar disorder, and help prevent relapse and recurrences. Group psychoeducation is effective in reducing recurrences in euthymic bipolar patients, but it does not tackle cognitive impairment or functioning. Impaired cognition has been associated with nonadherence to therapy.

Previous studies suggest that impaired functioning remains in many patients even after successful treatment for bipolar disorder. In one study, conventional treatment produced syndromal recovery in 85% at 6 months and 98% at 2 years, but functional recovery was seen in only 30% at 6 months and 38% at 2 years (Am. J. Psychiatry 2000;157:220-8).

The ideal combination of treatments for bipolar disorder may be a combination of medication, patient and family psychoeducation, training in healthy habits, and functional remediation, he suggested.

Dr. Vieta disclosed financial relationships with several institutions , including Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, Sanofi-Aventis, the SENY Foundation,, Lundbeck, MSD, Takeda, UBC, Forest Research Institute, Jazz, Pierre-Fabre, Solvay, the Stanley Medical Research Institute, and the Spanish Ministry of Science and Education.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

PARIS – Many psychiatrists have overdiagnosed bipolar disorder in children and adolescents over the past decade, which has led to overly aggressive treatment with second-generation antipsychotic drugs, Dr. David Cohen said at a press briefing at the annual congress of the European College of Neuropsychopharmacology.

This issue might start to resolve with the scheduled publication in 2013 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), because the current draft establishes a new diagnostic category that Dr. Cohen said is more appropriate for many of these children: temper dysregulation disorder with dysphoria (TDDD).

(c) Mitchel L. Zoler/IMNG

"I’m very pleased that the DSM 5 Working Group intends to improve the way these kids will be characterized by changing the label to TDDD. I think this labeling will help to better characterize this disease and not confuse [these patients] with bipolar disorder," Dr. Cohen said in an interview. Results from follow-up studies suggest that children and adolescents with the spectrum of symptoms included in TDDD, which could also be labeled today as severe mood dysregulation, "may be risk factors for [the diagnosis of] bipolar disorder in adulthood, in perhaps 20% of patients, but many do not develop bipolar disorder," said Dr. Cohen, professor of psychiatry at the University of Paris and head of the department of child and adolescent psychiatry at La Salpêtrière Hospital in Paris.

"I have [results from] long follow-up studies that do not show that manic symptoms in children lead to bipolar disorder" when they become adults. Certain children with symptoms that often characterize bipolar disorder "may be at risk for having bipolar disorder as adults, but not at high rates. Only after a child is 11 or 12 years old and you see these symptoms can you be confident that it is likely bipolar disorder. Adolescence is when" the diagnosis of bipolar can start to be made with any confidence, he said.

"Puberty is a good threshold for talking about bipolar disorder. TDDD is a better diagnosis for pre-pubertal children" because at that stage of life the manic symptoms of bipolar disease, such as irritability, mood change, hyperactivity, and sleep disturbance, can serve as risk markers for the eventual development of bipolar disease, but not at high rates. "Only once a child is at least 11 or 12 years old can you see these symptoms and be confident that it is likely bipolar disease of adolescence or beyond." Adolescence is when the diagnosis of bipolar disease can truly start. A reliable diagnosis of bipolar disorder in a younger child "is really exceptional."

Dr. Cohen’s views are at odds with recent trends in the diagnosis of bipolar disorder among children in the United States. American psychiatrists have, over the past decade, diagnosed bipolar disorder in children as young as age 5 years, resulting in incidence rates that ballooned by as much as four-fold during the 2000s, according to insurance claims data, commented Dr. Rasin Somer Diler, medical director of the Inpatient Child and Adolescent Bipolar Services program at the University of Pittsbugh. Dr. Diler said that in his own program diagnosis rates in younger children have risen by about a third from the late 1990s through the late 2000s, but he added that this was in a referral program that might differ from what has occurred in U.S. community hospitals and office practices.*

This shift in practice has also led to inordinate prescribing of second-generation antipsychotics to children, Dr. Cohen said. "These drugs are only appropriate for bipolar disorder episodes in adolescents."

Psychiatrists "usually use adult criteria to diagnose bipolar disorder" in children and adolescents. "Manic symptoms can be quite frequent in children, but I don’t label them as having bipolar disorder. With manic episodes and bipolar disorder in children you need to see how the symptoms appear over time. You cannot do a proper differential diagnosis in a few days."

Another issue when diagnosing bipolar disorder in adolescents is the differential diagnosis, distinguishing bipolar disorder from schizophrenia or attention-deficit/hyperactivity disorder (ADHD), conditions that also can present with manic symptoms. "ADHD is much more prevalent in children than bipolar disorder. If you see a child with irritability, it is much more likely to be ADHD." Schizophrenia also poses a diagnostic challenge. "Sometimes, it is only by follow-up of adolescents that makes us confident that the diagnosis is bipolar disorder, compared with schizophrenia."

Adolescents who are accurately diagnosed with bipolar disease will likely require long-term treatment. Dr. Cohen reported his experience with about 60 patients first diagnosed with bipolar disease as adolescents he followed for an average of 8 years. From this group, only five patients did not experience relapses. "When you continue treatment, relapses are fewer and the symptoms remain under better control." But he acknowledged that his experience likely involves a referral bias because his service generally only sees the most severely affected adolescents. He said that he would consider attempting treatment withdrawal from an adolescent patient who has remained mood stabilized on treatment for about 5 years, but he avoids trying treatment withdrawal at times of life with elevated emotional stress, such as when schooling ends or when patients face issues in their sexual relationships.

When bipolar disease is appropriately diagnosed in an adolescent, treatment must be chosen judiciously. Dr. Cohen said he an his associates recently performed a meta-analysis of 41 controlled studies that examined treatment with second-generation antipsychotics in more than 4,000 children and adolescents, including 12 studies that involved youths with bipolar disorder. "Compared with adults, youths were found to be more vulnerable to the adverse effects of second-generation antipsychotics." These adverse effects included somnolence and sedation, weight gain, metabolic changes including prolactin effects, and extrapyramidal motor symptoms. "Tolerability profiles should be considered in making treatment decisions," he said. (see table). Patients who fail to adequately respond to at least two second-generation antipsychotic drugs can be considered candidates for electroconvulsive therapy (ECT).

"In cases of no response to pharmacological treatment, ECT has proven to be safe and effective for both manic and depressive episodes in adolescents with severe illness," Dr. Cohen said. In addition, these patients have generally had favorable reactions to ECT. "Despite negative views about ECT in public opinion, adolescent recipients and their patients share overall positive attitudes toward ECT," he said.

Dr. Cohen said he has received funding from Schering-Plough, Bristol-Myers Squibb. Otsuka, Janssen, Sanofi-Aventis, and Shire.

*9/5/11 -- Dr. Diler's statement and further clarification were added this story.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

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

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

Discuss this article at www.facebook.com/CurrentPsychiatry

Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HONOLULU – Regardless of the type of psychotropic medication used to treat patients with bipolar disorder, outcomes are about the same at 1 year, a retrospective chart review from the University of Toledo suggests.

All 121 patients in the study were treated with a mood stabilizer. Some of them had an added antipsychotic, and a significant number also had an antidepressant, lead author Dr. Ronald A. McGinnis said at the annual meeting of the American Psychiatric Association. Across the board, the findings proved consistent. "We found no medication regimen superior to any other," he said.

Those who did not respond to treatment were "as likely to be on an antidepressant, mood stabilizer, or atypical antipsychotic" as were those who did respond. "We looked at individual medications and combinations of medications. No matter how you sliced the data, there were really no statistical differences in medications," despite "a lot of algorithms to follow and expert advice," said Dr. McGinnis, medical director of the University of Toledo (Ohio) Medical Center.

Despite these findings, Dr. McGinnis said he thinks that people do need to be on medications to recover. The point is that the type of medication the patient is taking does not seem to matter. "There are probably some other factors that we are not aware of that have to do with response," he said.

In the study, those factors seemed to include psychological stressors, pain, and missed appointments, all of which are more common in nonresponders. Poverty was more common, too, but the finding was not statistically significant.

For coauthor Dr. Daniel J. Rapport of the department of psychiatry at the university, the take-home message is not that medication choice is irrelevant. On the contrary, he thinks the study suggests that clinicians have to work extra hard to find drugs that work in a given patient.

The assertion is based on the finding that sustained recovery was associated with longer lag times to recovery. It is likely that during that lag time, clinicians were working closely with patients to find the combination of drugs that ultimately worked for them, he said.

Although "it didn’t seem to matter what medications or combinations of medications these people received," specific drugs appear to be more effective and better tolerated in given individuals. "So don’t give up" looking for the right combination. "It’s not the class, it’s the [specific] drug" selected, Dr. Rapport said.

Overall, 43.8% [53] patients achieved at least 12 consecutive months of either euthymia, a much-improved mood, or improvement followed by relapse; 56.1% patients [68] did not respond to treatment, which also included psychotherapy.

"It’s the minority of people who get a clinically meaningful recovery," Dr. McGinnis noted.

In all, 84 patients were men, and most were white. Their average age was 43 years, and average age at diagnosis 25. They were treated for at least a year.

The 121 patients were narrowed down from an original list of 271 who were billed for bipolar disorder over 18 months. The researchers found that 150 of those patients did not actually meet DSM-IV criteria for the disorder.

"We want to go back and see why all these people were billed with bipolar disorder when they really didn’t meet DSM-IV criteria for it," Dr. Rapport said.

In general, when it comes to treating bipolar disorder, he said, "the first thing that you have to do is to stop the cycling, so you use anticycling agents first, like lamotrigine, lithium, Tegretol, or Depakote." Residual symptoms are tackled with "a touch of antidepressants."

Dr. McGinnis said he has no relevant disclosures. Dr. Rapport said he previously spoke on behalf of Lamictal for its maker, GlaxoSmithKline, and worked with other companies. The study received no outside funding.

HONOLULU – Regardless of the type of psychotropic medication used to treat patients with bipolar disorder, outcomes are about the same at 1 year, a retrospective chart review from the University of Toledo suggests.

All 121 patients in the study were treated with a mood stabilizer. Some of them had an added antipsychotic, and a significant number also had an antidepressant, lead author Dr. Ronald A. McGinnis said at the annual meeting of the American Psychiatric Association. Across the board, the findings proved consistent. "We found no medication regimen superior to any other," he said.

Those who did not respond to treatment were "as likely to be on an antidepressant, mood stabilizer, or atypical antipsychotic" as were those who did respond. "We looked at individual medications and combinations of medications. No matter how you sliced the data, there were really no statistical differences in medications," despite "a lot of algorithms to follow and expert advice," said Dr. McGinnis, medical director of the University of Toledo (Ohio) Medical Center.

Despite these findings, Dr. McGinnis said he thinks that people do need to be on medications to recover. The point is that the type of medication the patient is taking does not seem to matter. "There are probably some other factors that we are not aware of that have to do with response," he said.

In the study, those factors seemed to include psychological stressors, pain, and missed appointments, all of which are more common in nonresponders. Poverty was more common, too, but the finding was not statistically significant.

For coauthor Dr. Daniel J. Rapport of the department of psychiatry at the university, the take-home message is not that medication choice is irrelevant. On the contrary, he thinks the study suggests that clinicians have to work extra hard to find drugs that work in a given patient.

The assertion is based on the finding that sustained recovery was associated with longer lag times to recovery. It is likely that during that lag time, clinicians were working closely with patients to find the combination of drugs that ultimately worked for them, he said.

Although "it didn’t seem to matter what medications or combinations of medications these people received," specific drugs appear to be more effective and better tolerated in given individuals. "So don’t give up" looking for the right combination. "It’s not the class, it’s the [specific] drug" selected, Dr. Rapport said.

Overall, 43.8% [53] patients achieved at least 12 consecutive months of either euthymia, a much-improved mood, or improvement followed by relapse; 56.1% patients [68] did not respond to treatment, which also included psychotherapy.

"It’s the minority of people who get a clinically meaningful recovery," Dr. McGinnis noted.

In all, 84 patients were men, and most were white. Their average age was 43 years, and average age at diagnosis 25. They were treated for at least a year.

The 121 patients were narrowed down from an original list of 271 who were billed for bipolar disorder over 18 months. The researchers found that 150 of those patients did not actually meet DSM-IV criteria for the disorder.

"We want to go back and see why all these people were billed with bipolar disorder when they really didn’t meet DSM-IV criteria for it," Dr. Rapport said.

In general, when it comes to treating bipolar disorder, he said, "the first thing that you have to do is to stop the cycling, so you use anticycling agents first, like lamotrigine, lithium, Tegretol, or Depakote." Residual symptoms are tackled with "a touch of antidepressants."

Dr. McGinnis said he has no relevant disclosures. Dr. Rapport said he previously spoke on behalf of Lamictal for its maker, GlaxoSmithKline, and worked with other companies. The study received no outside funding.

HONOLULU – Regardless of the type of psychotropic medication used to treat patients with bipolar disorder, outcomes are about the same at 1 year, a retrospective chart review from the University of Toledo suggests.

All 121 patients in the study were treated with a mood stabilizer. Some of them had an added antipsychotic, and a significant number also had an antidepressant, lead author Dr. Ronald A. McGinnis said at the annual meeting of the American Psychiatric Association. Across the board, the findings proved consistent. "We found no medication regimen superior to any other," he said.

Those who did not respond to treatment were "as likely to be on an antidepressant, mood stabilizer, or atypical antipsychotic" as were those who did respond. "We looked at individual medications and combinations of medications. No matter how you sliced the data, there were really no statistical differences in medications," despite "a lot of algorithms to follow and expert advice," said Dr. McGinnis, medical director of the University of Toledo (Ohio) Medical Center.

Despite these findings, Dr. McGinnis said he thinks that people do need to be on medications to recover. The point is that the type of medication the patient is taking does not seem to matter. "There are probably some other factors that we are not aware of that have to do with response," he said.

In the study, those factors seemed to include psychological stressors, pain, and missed appointments, all of which are more common in nonresponders. Poverty was more common, too, but the finding was not statistically significant.

For coauthor Dr. Daniel J. Rapport of the department of psychiatry at the university, the take-home message is not that medication choice is irrelevant. On the contrary, he thinks the study suggests that clinicians have to work extra hard to find drugs that work in a given patient.

The assertion is based on the finding that sustained recovery was associated with longer lag times to recovery. It is likely that during that lag time, clinicians were working closely with patients to find the combination of drugs that ultimately worked for them, he said.

Although "it didn’t seem to matter what medications or combinations of medications these people received," specific drugs appear to be more effective and better tolerated in given individuals. "So don’t give up" looking for the right combination. "It’s not the class, it’s the [specific] drug" selected, Dr. Rapport said.

Overall, 43.8% [53] patients achieved at least 12 consecutive months of either euthymia, a much-improved mood, or improvement followed by relapse; 56.1% patients [68] did not respond to treatment, which also included psychotherapy.

"It’s the minority of people who get a clinically meaningful recovery," Dr. McGinnis noted.

In all, 84 patients were men, and most were white. Their average age was 43 years, and average age at diagnosis 25. They were treated for at least a year.

The 121 patients were narrowed down from an original list of 271 who were billed for bipolar disorder over 18 months. The researchers found that 150 of those patients did not actually meet DSM-IV criteria for the disorder.

"We want to go back and see why all these people were billed with bipolar disorder when they really didn’t meet DSM-IV criteria for it," Dr. Rapport said.

In general, when it comes to treating bipolar disorder, he said, "the first thing that you have to do is to stop the cycling, so you use anticycling agents first, like lamotrigine, lithium, Tegretol, or Depakote." Residual symptoms are tackled with "a touch of antidepressants."

Dr. McGinnis said he has no relevant disclosures. Dr. Rapport said he previously spoke on behalf of Lamictal for its maker, GlaxoSmithKline, and worked with other companies. The study received no outside funding.

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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