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Increased awareness needed of bipolar disorder in primary care
A significant number of patients with in primary care also have unrecognized bipolar disorder, according to researchers at the University of Manchester (England).
In a systematic review and meta-analysis published in General Hospital Psychiatry, the researchers searched Medline, Embase, Cochrane, and PsycINFO for that measured the rate of unrecognized bipolar disorder in primary care.
The overall prevalence of unrecognized bipolar disorder within the patient group was 17%; however, that rate varied significantly. Depending on the study, the range was 5%-28%. A subgroup analysis showed that studies that relied on clinical interviews for patients with confirmed bipolar disorder had lower rates than studies that relied on self-reporting. However, that difference did not reach statistical significance (14% vs. 22%; P = .121).
“There is ... an imperative need to improve the recognition of bipolar disorder in patients in primary care. A lack of effective training of primary care physicians, competing clinical demands, and reduced financial incentives ... are key reasons for the unrecognition of mental health conditions in primary care,” the investigators noted.
No conflicts of interest were reported.
SOURCE: Daveney J et al. Gen Hosp Psychiatry. 2019 Mar 27. doi: 10.1016/j.genhosppsych.2019.03.006.
A significant number of patients with in primary care also have unrecognized bipolar disorder, according to researchers at the University of Manchester (England).
In a systematic review and meta-analysis published in General Hospital Psychiatry, the researchers searched Medline, Embase, Cochrane, and PsycINFO for that measured the rate of unrecognized bipolar disorder in primary care.
The overall prevalence of unrecognized bipolar disorder within the patient group was 17%; however, that rate varied significantly. Depending on the study, the range was 5%-28%. A subgroup analysis showed that studies that relied on clinical interviews for patients with confirmed bipolar disorder had lower rates than studies that relied on self-reporting. However, that difference did not reach statistical significance (14% vs. 22%; P = .121).
“There is ... an imperative need to improve the recognition of bipolar disorder in patients in primary care. A lack of effective training of primary care physicians, competing clinical demands, and reduced financial incentives ... are key reasons for the unrecognition of mental health conditions in primary care,” the investigators noted.
No conflicts of interest were reported.
SOURCE: Daveney J et al. Gen Hosp Psychiatry. 2019 Mar 27. doi: 10.1016/j.genhosppsych.2019.03.006.
A significant number of patients with in primary care also have unrecognized bipolar disorder, according to researchers at the University of Manchester (England).
In a systematic review and meta-analysis published in General Hospital Psychiatry, the researchers searched Medline, Embase, Cochrane, and PsycINFO for that measured the rate of unrecognized bipolar disorder in primary care.
The overall prevalence of unrecognized bipolar disorder within the patient group was 17%; however, that rate varied significantly. Depending on the study, the range was 5%-28%. A subgroup analysis showed that studies that relied on clinical interviews for patients with confirmed bipolar disorder had lower rates than studies that relied on self-reporting. However, that difference did not reach statistical significance (14% vs. 22%; P = .121).
“There is ... an imperative need to improve the recognition of bipolar disorder in patients in primary care. A lack of effective training of primary care physicians, competing clinical demands, and reduced financial incentives ... are key reasons for the unrecognition of mental health conditions in primary care,” the investigators noted.
No conflicts of interest were reported.
SOURCE: Daveney J et al. Gen Hosp Psychiatry. 2019 Mar 27. doi: 10.1016/j.genhosppsych.2019.03.006.
FROM GENERAL HOSPITAL PSYCHIATRY
Consider iatrogenesis in patients with new psychiatric symptoms
CRYSTAL CITY, VA. – Be aware of the potential iatrogenic properties of medications prescribed when patients present with new psychiatric symptoms, Henry A. Nasrallah, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Drugs that can cause iatrogenic psychiatric symptoms include stimulants, anabolic steroids, ACE inhibitors, anticholinergics, tricyclic antidepressants, antiepileptics, benzodiazepines, beta-adrenergic blockers, dopamine receptor agonists, among many others. A diverse class of medications can cause depression, anxiety, mania, and psychotic symptoms, and some medications cause multiple iatrogenic effects.
“Iatrogenic psychopathology can occur with a wide array of medications that are used in general medical practice,” said Dr. Nasrallah, editor in chief of Current Psychiatry and professor and chairman of the department of neurology and psychiatry at Saint Louis University. For example, the drug reserpine can cause depression in about 10% of cases, and corticosteroids can cause mood disorders such as depression or mania in about 6% of cases.
In other situations, use of alcohol, cannabis, hallucinogens, opioids, and other recreational drugs can cause psychiatric symptoms, and withdrawal from alcohol and sedatives can induce psychosis.
The DSM-5 defines a psychiatric disorder as a disorder that is not caused by a general medical condition and is not attributable to recreational or prescription drugs. However, a direct causal connection is sometimes difficult to establish, said Dr. Nasrallah, because psychiatric symptoms that manifest during treatment with prescription medications also could be tied to an underlying medical illness, psychosocial factors, withdrawal from a different prescription medication, or an unrecognized psychopathology. To confirm the drug is causing the disorder, clinicians should also rechallenge the patient.
he said at the meeting presented by Global Academy for Medical Education. “First-episode psychiatric disorder is always suspect. Iatrogenesis can occur for the first time in a patient who never had that symptom before, so you suspect it might be iatrogenic.”
Some drugs might induce psychiatric symptoms at higher but not lower doses, he added.
Other risk factors for iatrogenesis include simultaneous use of prescription medications, administration method, narrow therapeutic index, and rapid titration. Patients with slow metabolisms or hepatic insufficiency are at risk for iatrogenesis, as are those who are very young or very old, in stressful settings, or in a postpartum period.
Evaluate when psychiatric symptoms occurred, whether symptoms worsened and when, the dates of medication use, rechallenge and dechallenge dates, and any previous history of psychiatric disorders, said Dr. Nasrallah, who holds the Sydney W. Souers Endowed Chair at the university. If a patient is using more than one medication at a time, record the dates of each drug and their discontinuations.
Determine when the iatrogenesis occurred with psychiatric drugs, Dr. Nasrallah noted. “Iatrogenesis can complicate the course and outcome of the main medical or psychiatric illness being treated. Sometimes psychiatric medication can cause iatrogenic medical conditions; it’s not just a one-way street.”
Dr. Nasrallah reported receiving research grants from Forest, Forum, and Otsuka. In addition, he is a consultant for Acadia, Alkermes, Boehringer Ingelheim, Forum, Janssen, Merck, Novartis, Otsuka, Sunovion, and Teva, and he serves on the speaker’s bureau for Acadia, Alkermes, Janssen, Otsuka, and Sunovion.
Global Academy and this news organization are owned by the same parent company.
CRYSTAL CITY, VA. – Be aware of the potential iatrogenic properties of medications prescribed when patients present with new psychiatric symptoms, Henry A. Nasrallah, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Drugs that can cause iatrogenic psychiatric symptoms include stimulants, anabolic steroids, ACE inhibitors, anticholinergics, tricyclic antidepressants, antiepileptics, benzodiazepines, beta-adrenergic blockers, dopamine receptor agonists, among many others. A diverse class of medications can cause depression, anxiety, mania, and psychotic symptoms, and some medications cause multiple iatrogenic effects.
“Iatrogenic psychopathology can occur with a wide array of medications that are used in general medical practice,” said Dr. Nasrallah, editor in chief of Current Psychiatry and professor and chairman of the department of neurology and psychiatry at Saint Louis University. For example, the drug reserpine can cause depression in about 10% of cases, and corticosteroids can cause mood disorders such as depression or mania in about 6% of cases.
In other situations, use of alcohol, cannabis, hallucinogens, opioids, and other recreational drugs can cause psychiatric symptoms, and withdrawal from alcohol and sedatives can induce psychosis.
The DSM-5 defines a psychiatric disorder as a disorder that is not caused by a general medical condition and is not attributable to recreational or prescription drugs. However, a direct causal connection is sometimes difficult to establish, said Dr. Nasrallah, because psychiatric symptoms that manifest during treatment with prescription medications also could be tied to an underlying medical illness, psychosocial factors, withdrawal from a different prescription medication, or an unrecognized psychopathology. To confirm the drug is causing the disorder, clinicians should also rechallenge the patient.
he said at the meeting presented by Global Academy for Medical Education. “First-episode psychiatric disorder is always suspect. Iatrogenesis can occur for the first time in a patient who never had that symptom before, so you suspect it might be iatrogenic.”
Some drugs might induce psychiatric symptoms at higher but not lower doses, he added.
Other risk factors for iatrogenesis include simultaneous use of prescription medications, administration method, narrow therapeutic index, and rapid titration. Patients with slow metabolisms or hepatic insufficiency are at risk for iatrogenesis, as are those who are very young or very old, in stressful settings, or in a postpartum period.
Evaluate when psychiatric symptoms occurred, whether symptoms worsened and when, the dates of medication use, rechallenge and dechallenge dates, and any previous history of psychiatric disorders, said Dr. Nasrallah, who holds the Sydney W. Souers Endowed Chair at the university. If a patient is using more than one medication at a time, record the dates of each drug and their discontinuations.
Determine when the iatrogenesis occurred with psychiatric drugs, Dr. Nasrallah noted. “Iatrogenesis can complicate the course and outcome of the main medical or psychiatric illness being treated. Sometimes psychiatric medication can cause iatrogenic medical conditions; it’s not just a one-way street.”
Dr. Nasrallah reported receiving research grants from Forest, Forum, and Otsuka. In addition, he is a consultant for Acadia, Alkermes, Boehringer Ingelheim, Forum, Janssen, Merck, Novartis, Otsuka, Sunovion, and Teva, and he serves on the speaker’s bureau for Acadia, Alkermes, Janssen, Otsuka, and Sunovion.
Global Academy and this news organization are owned by the same parent company.
CRYSTAL CITY, VA. – Be aware of the potential iatrogenic properties of medications prescribed when patients present with new psychiatric symptoms, Henry A. Nasrallah, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Drugs that can cause iatrogenic psychiatric symptoms include stimulants, anabolic steroids, ACE inhibitors, anticholinergics, tricyclic antidepressants, antiepileptics, benzodiazepines, beta-adrenergic blockers, dopamine receptor agonists, among many others. A diverse class of medications can cause depression, anxiety, mania, and psychotic symptoms, and some medications cause multiple iatrogenic effects.
“Iatrogenic psychopathology can occur with a wide array of medications that are used in general medical practice,” said Dr. Nasrallah, editor in chief of Current Psychiatry and professor and chairman of the department of neurology and psychiatry at Saint Louis University. For example, the drug reserpine can cause depression in about 10% of cases, and corticosteroids can cause mood disorders such as depression or mania in about 6% of cases.
In other situations, use of alcohol, cannabis, hallucinogens, opioids, and other recreational drugs can cause psychiatric symptoms, and withdrawal from alcohol and sedatives can induce psychosis.
The DSM-5 defines a psychiatric disorder as a disorder that is not caused by a general medical condition and is not attributable to recreational or prescription drugs. However, a direct causal connection is sometimes difficult to establish, said Dr. Nasrallah, because psychiatric symptoms that manifest during treatment with prescription medications also could be tied to an underlying medical illness, psychosocial factors, withdrawal from a different prescription medication, or an unrecognized psychopathology. To confirm the drug is causing the disorder, clinicians should also rechallenge the patient.
he said at the meeting presented by Global Academy for Medical Education. “First-episode psychiatric disorder is always suspect. Iatrogenesis can occur for the first time in a patient who never had that symptom before, so you suspect it might be iatrogenic.”
Some drugs might induce psychiatric symptoms at higher but not lower doses, he added.
Other risk factors for iatrogenesis include simultaneous use of prescription medications, administration method, narrow therapeutic index, and rapid titration. Patients with slow metabolisms or hepatic insufficiency are at risk for iatrogenesis, as are those who are very young or very old, in stressful settings, or in a postpartum period.
Evaluate when psychiatric symptoms occurred, whether symptoms worsened and when, the dates of medication use, rechallenge and dechallenge dates, and any previous history of psychiatric disorders, said Dr. Nasrallah, who holds the Sydney W. Souers Endowed Chair at the university. If a patient is using more than one medication at a time, record the dates of each drug and their discontinuations.
Determine when the iatrogenesis occurred with psychiatric drugs, Dr. Nasrallah noted. “Iatrogenesis can complicate the course and outcome of the main medical or psychiatric illness being treated. Sometimes psychiatric medication can cause iatrogenic medical conditions; it’s not just a one-way street.”
Dr. Nasrallah reported receiving research grants from Forest, Forum, and Otsuka. In addition, he is a consultant for Acadia, Alkermes, Boehringer Ingelheim, Forum, Janssen, Merck, Novartis, Otsuka, Sunovion, and Teva, and he serves on the speaker’s bureau for Acadia, Alkermes, Janssen, Otsuka, and Sunovion.
Global Academy and this news organization are owned by the same parent company.
REPORTING FROM FOCUS ON NEUROPSYCHIATRY 2019
Patients with mood disorders may have altered microbiome
Discuss dietary interventions, such as probiotics, as ‘supplemental therapeutic options’
CRYSTAL CITY, VA. – Individuals with mood disorders might have an altered microbiome, but more information is needed to understand how the microorganisms that make up the microbiome affect patients’ health, an expert said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“An increased understanding of the neurobiology of the microbiome is required so that the benefit that these microorganisms serve to human health can be fully harnessed,” said Emily G. Severance, PhD, assistant professor of pediatrics at John Hopkins University, Baltimore.
Diseases that involve the microbiome include those with a single identifiable infectious agent that produces persistent inflammation, central nervous system diseases with mucosal surface involvement, and diseases with “variable response to antibiotic and anti-inflammatory agents.”
“It’s becoming clear that [the microbiome is] integral for the modulation of the central nervous system,” which occurs through neurotransmitter production, Dr. Severance said at the meeting presented by Global Academy for Medical Education.
“We have an extensive enteric nervous system that has the very same receptors that the brain does,” she said. “If you have those receptors activated in the gut or [are] having the neurotransmitters produced in the gut, and if there’s a way for those neurotransmitters to reach the brain, that’s a very powerful mechanism to illustrate the gut-brain axis.”
In addition to neuropsychiatric diseases, the microbiome also can be involved in inflammatory gastrointestinal, systemic rheumatoid and autoimmune, chronic inflammatory lung, and periodontal diseases, as well as immune-mediated skin disorders. Mood disorders in particular have evidence for dysbiosis in low-level inflammation and leaky gut pathology, which is present in patients with depression, Dr. Severance said. “All these data suggest that We can do that because gut bacteria are easily accessed and can be altered through probiotics, prebiotics, diet, and fecal transplant, and in patients, Lactobacillus and Bifidobacterium combinations may improve mood, reduce anxiety, and enhance cognitive function.”
In addition, epidemiological studies show that antibiotic exposure can be a risk factor for developing mood disorders. One recent study found that anti-infective agents, particularly antibiotics, increased the risk of schizophrenia (hazard rate ratio, 2.05; 95% confidence interval, 1.77-2.38) and affective disorders (HRR, 2.59; 95% CI, 2.31-2.89), which the researchers attributed to brain inflammation, the microbiome, and environmental factors (Acta Psychiatr Scand. 2016 Nov 21. doi: 10.1111/acps.12671). In mice, other researchers found that those that received a fecal transplant with a “depression microbiota” showed symptoms of major depressive disorder, compared with mice that received a “healthy microbiota.” Those results suggest that change in microbiota can induce mood disorders (Mol Psychiatry. 2016 Apr 12. doi: 10.1038/mp.2016.44).
The evidence for probiotics is mixed, primarily because the study population in trials are so heterogeneous, but there is evidence for its efficacy in patients with mood disorders, Dr. Severance said. Probiotics have been shown to prevent rehospitalization for patients in mania. For example, one study showed reduced rehospitalization in patients with mania (8 of 33 patients) who received probiotics, compared with placebo (24 of 33 patients). Also, probiotic use was associated with fewer days of rehospitalization (Bipolar Disord. 2018 Apr 25. doi: 10. 1111/bdi.12652).
Meanwhile, a pilot study analyzing patients with irritable bowel syndrome and mild to moderate anxiety and/or depression found use of B. longum in this population reduced depression scores, but not anxiety or irritable bowel syndrome symptoms, compared with placebo (Gastroenterology. 2017 May 5. doi: 10.1053/j.gastro.2017.05.003).
Probiotic efficacy can be variable for patients with mood disorders, but the intervention is a “relatively low-risk, potentially high reward” option for these patients, Dr. Severance said. “Clinicians should inquire about patient GI conditions and overall GI health. Dietary interventions and the use of probiotics and their limitations should be discussed as supplemental therapeutic options.”
Dr. Severance reported no relevant financial disclosures.
Global Academy and this news organization are owned by the same parent company.
Discuss dietary interventions, such as probiotics, as ‘supplemental therapeutic options’
Discuss dietary interventions, such as probiotics, as ‘supplemental therapeutic options’
CRYSTAL CITY, VA. – Individuals with mood disorders might have an altered microbiome, but more information is needed to understand how the microorganisms that make up the microbiome affect patients’ health, an expert said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“An increased understanding of the neurobiology of the microbiome is required so that the benefit that these microorganisms serve to human health can be fully harnessed,” said Emily G. Severance, PhD, assistant professor of pediatrics at John Hopkins University, Baltimore.
Diseases that involve the microbiome include those with a single identifiable infectious agent that produces persistent inflammation, central nervous system diseases with mucosal surface involvement, and diseases with “variable response to antibiotic and anti-inflammatory agents.”
“It’s becoming clear that [the microbiome is] integral for the modulation of the central nervous system,” which occurs through neurotransmitter production, Dr. Severance said at the meeting presented by Global Academy for Medical Education.
“We have an extensive enteric nervous system that has the very same receptors that the brain does,” she said. “If you have those receptors activated in the gut or [are] having the neurotransmitters produced in the gut, and if there’s a way for those neurotransmitters to reach the brain, that’s a very powerful mechanism to illustrate the gut-brain axis.”
In addition to neuropsychiatric diseases, the microbiome also can be involved in inflammatory gastrointestinal, systemic rheumatoid and autoimmune, chronic inflammatory lung, and periodontal diseases, as well as immune-mediated skin disorders. Mood disorders in particular have evidence for dysbiosis in low-level inflammation and leaky gut pathology, which is present in patients with depression, Dr. Severance said. “All these data suggest that We can do that because gut bacteria are easily accessed and can be altered through probiotics, prebiotics, diet, and fecal transplant, and in patients, Lactobacillus and Bifidobacterium combinations may improve mood, reduce anxiety, and enhance cognitive function.”
In addition, epidemiological studies show that antibiotic exposure can be a risk factor for developing mood disorders. One recent study found that anti-infective agents, particularly antibiotics, increased the risk of schizophrenia (hazard rate ratio, 2.05; 95% confidence interval, 1.77-2.38) and affective disorders (HRR, 2.59; 95% CI, 2.31-2.89), which the researchers attributed to brain inflammation, the microbiome, and environmental factors (Acta Psychiatr Scand. 2016 Nov 21. doi: 10.1111/acps.12671). In mice, other researchers found that those that received a fecal transplant with a “depression microbiota” showed symptoms of major depressive disorder, compared with mice that received a “healthy microbiota.” Those results suggest that change in microbiota can induce mood disorders (Mol Psychiatry. 2016 Apr 12. doi: 10.1038/mp.2016.44).
The evidence for probiotics is mixed, primarily because the study population in trials are so heterogeneous, but there is evidence for its efficacy in patients with mood disorders, Dr. Severance said. Probiotics have been shown to prevent rehospitalization for patients in mania. For example, one study showed reduced rehospitalization in patients with mania (8 of 33 patients) who received probiotics, compared with placebo (24 of 33 patients). Also, probiotic use was associated with fewer days of rehospitalization (Bipolar Disord. 2018 Apr 25. doi: 10. 1111/bdi.12652).
Meanwhile, a pilot study analyzing patients with irritable bowel syndrome and mild to moderate anxiety and/or depression found use of B. longum in this population reduced depression scores, but not anxiety or irritable bowel syndrome symptoms, compared with placebo (Gastroenterology. 2017 May 5. doi: 10.1053/j.gastro.2017.05.003).
Probiotic efficacy can be variable for patients with mood disorders, but the intervention is a “relatively low-risk, potentially high reward” option for these patients, Dr. Severance said. “Clinicians should inquire about patient GI conditions and overall GI health. Dietary interventions and the use of probiotics and their limitations should be discussed as supplemental therapeutic options.”
Dr. Severance reported no relevant financial disclosures.
Global Academy and this news organization are owned by the same parent company.
CRYSTAL CITY, VA. – Individuals with mood disorders might have an altered microbiome, but more information is needed to understand how the microorganisms that make up the microbiome affect patients’ health, an expert said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“An increased understanding of the neurobiology of the microbiome is required so that the benefit that these microorganisms serve to human health can be fully harnessed,” said Emily G. Severance, PhD, assistant professor of pediatrics at John Hopkins University, Baltimore.
Diseases that involve the microbiome include those with a single identifiable infectious agent that produces persistent inflammation, central nervous system diseases with mucosal surface involvement, and diseases with “variable response to antibiotic and anti-inflammatory agents.”
“It’s becoming clear that [the microbiome is] integral for the modulation of the central nervous system,” which occurs through neurotransmitter production, Dr. Severance said at the meeting presented by Global Academy for Medical Education.
“We have an extensive enteric nervous system that has the very same receptors that the brain does,” she said. “If you have those receptors activated in the gut or [are] having the neurotransmitters produced in the gut, and if there’s a way for those neurotransmitters to reach the brain, that’s a very powerful mechanism to illustrate the gut-brain axis.”
In addition to neuropsychiatric diseases, the microbiome also can be involved in inflammatory gastrointestinal, systemic rheumatoid and autoimmune, chronic inflammatory lung, and periodontal diseases, as well as immune-mediated skin disorders. Mood disorders in particular have evidence for dysbiosis in low-level inflammation and leaky gut pathology, which is present in patients with depression, Dr. Severance said. “All these data suggest that We can do that because gut bacteria are easily accessed and can be altered through probiotics, prebiotics, diet, and fecal transplant, and in patients, Lactobacillus and Bifidobacterium combinations may improve mood, reduce anxiety, and enhance cognitive function.”
In addition, epidemiological studies show that antibiotic exposure can be a risk factor for developing mood disorders. One recent study found that anti-infective agents, particularly antibiotics, increased the risk of schizophrenia (hazard rate ratio, 2.05; 95% confidence interval, 1.77-2.38) and affective disorders (HRR, 2.59; 95% CI, 2.31-2.89), which the researchers attributed to brain inflammation, the microbiome, and environmental factors (Acta Psychiatr Scand. 2016 Nov 21. doi: 10.1111/acps.12671). In mice, other researchers found that those that received a fecal transplant with a “depression microbiota” showed symptoms of major depressive disorder, compared with mice that received a “healthy microbiota.” Those results suggest that change in microbiota can induce mood disorders (Mol Psychiatry. 2016 Apr 12. doi: 10.1038/mp.2016.44).
The evidence for probiotics is mixed, primarily because the study population in trials are so heterogeneous, but there is evidence for its efficacy in patients with mood disorders, Dr. Severance said. Probiotics have been shown to prevent rehospitalization for patients in mania. For example, one study showed reduced rehospitalization in patients with mania (8 of 33 patients) who received probiotics, compared with placebo (24 of 33 patients). Also, probiotic use was associated with fewer days of rehospitalization (Bipolar Disord. 2018 Apr 25. doi: 10. 1111/bdi.12652).
Meanwhile, a pilot study analyzing patients with irritable bowel syndrome and mild to moderate anxiety and/or depression found use of B. longum in this population reduced depression scores, but not anxiety or irritable bowel syndrome symptoms, compared with placebo (Gastroenterology. 2017 May 5. doi: 10.1053/j.gastro.2017.05.003).
Probiotic efficacy can be variable for patients with mood disorders, but the intervention is a “relatively low-risk, potentially high reward” option for these patients, Dr. Severance said. “Clinicians should inquire about patient GI conditions and overall GI health. Dietary interventions and the use of probiotics and their limitations should be discussed as supplemental therapeutic options.”
Dr. Severance reported no relevant financial disclosures.
Global Academy and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM FOCUS ON NEUROPSYCHIATRY 2019
Unipolar vs bipolar depression: A clinician’s perspective
Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.
At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.
Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.
In a previous article1 (“Controversies in bipolar disorder: Trust evidence or experience?,”
In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.
Misdiagnosis is common
Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient2-8 and inpatient9 settings, and in children and adolescents.10 Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.
Reliance on DSM-511 and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.
Continue to: DSM-5 also requires...
DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.
Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire14 and the Bipolar Spectrum Diagnostic Scale15 may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.
Distinguishing between these 2 types of depression
Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.
Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”
Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.22 However, overall rates of bipolar disorder may be slightly higher in men than in women.23 Unipolar melancholic depression occurs at approximately the same frequency in men and women.24
Continue to: Rapidity of onset
Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.
Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.25 Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.
ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.28
Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.29,30
Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.
Continue to: Sleep problems
Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.31 Yet these patients usually do not complain of sleepiness during the day.
Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.31 This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.
Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.
Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.
Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.
Continue to: Genetics
Genetics. Bipolar disorder is one of the most heritable of illnesses.32 Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”
Consequences of misdiagnosis
Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.5,8
Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.9 The STAR*D study,33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.35
When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.36 Because bipolar depression typically begins in youth,10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.
Depression and life stressors
Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.
Continue to: Our approach to treatment
Our approach to treatment
Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psychotherapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,37 but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.
The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.
Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.
Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.
Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.
Continue to: As we observed...
As we observed in our previous article,1 thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 138-41).
Box 1
Conventional laboratory reference ranges often indicate that thyroid-stimulating hormone (TSH) levels as high as 4.0, 4.5, or 5.0 mU/L are normal. A recent meta- analysis determined that treatment of subclinical hypothyroidism (elevated TSH with normal free thyroxine) does not benefit patients’ quality of life.38 Patients with mood disorders, however, often fail to respond to mood stabilizers and other psychiatric medications unless their TSH is <3.0 or even <2.5 mU/L.39,40 We typically augment with liothyronine because, unlike levothyroxine, it works quickly, does not require deiodination to be activated, and, contrary to some reports, its elimination and biologic half-life are sufficient for single daily dosing.41
Moving towards better diagnoses
The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 210,12,13,18,19,42).
Box 2
Based on our clinical experience treating thousands of patients over 25 years, we have 2 issues with DSM-5 regarding bipolar disorder:
1. The DSM-5 criteria for hypomania fail to reflect the features of clinical presentations commonly seen in our practice. The majority of patients with authentic bipolar syndromes do not have hypomanias that last for at least 4 days or reach the level of severity required for a DSM-5 diagnosis of hypomania. This results in misdiagnosis of patients with bipolar depression as suffering from unipolar depression, which leads to inappropriate treatment with antidepressant monotherapy.
2. Bipolar disorder frequently makes its first appearance in childhood and adolescence,10,18,19 and increasing numbers of young patients have been receiving this diagnosis.42 In our opinion, this increase reflects clinicians’ improved diagnostic skills. Perhaps alarmed by the increase in young people receiving a diagnosis of bipolar disorder, the authors of DSM-5 created a new diagnosis for children: disruptive mood dysregulation disorder. This diagnostic addition is based on the finding that children with these mood symptoms may not subsequently exhibit classic DSM-5 manic or hypomanic episodes. But the lack of such episodes does not preclude a diagnosis of bipolar disorder, because many adults with unequivocal bipolar spectrum disorders have subthreshold hypomanias and thus fail to exhibit classic manic or hypomanic episodes.12,13
A rose by any other name would smell as sweet. Children who exhibit symptoms of disruptive mood dysregulation disorder— chronic irritability and protracted temper outbursts—usually suffer from depression and mood instability. In our opinion, it is irrational and confusing to clinicians to separate out with a new diagnosis an arbitrarily defined group of children who exhibit substantially the same symptoms as those who receive a diagnosis of bipolar disorder.
Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.
CASE CONTINUED
Return to work
Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.
Bottom Line
Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.
Related Resources
- Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
- Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.
Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft
1. Miller GE, Noel RL. Controversies in bipolar disorder: trust evidence or experience? Current Psychiatry. 2009;8(2):27-28,31-33,39.
2. Glick ID. Undiagnosed bipolar disorder: new syndromes and new treatments. Prim Care Companion J Clin Psychiatry. 2004;6(1):27-33.
3. Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144.
4. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159(6):1005-1010.
5. Shi L, Thiebaud P, McCombs JS. The impact of unrecognized bipolar disorders for patients treated with antidepressants in the fee-for-services California Medicaid (Medi-Cal) program. J Affect Disord. 2004;82(3):373-383.
6. Sidor MM, MacQueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72(2):156-167.
7. Hughes T, Cardno A, West R, et al. Unrecognized bipolar disorder among UK primary care patients prescribed antidepressants: an observational study. Br J Gen Pract. 2016;66(643):e71-e77.
8. Keck PE Jr, Kessler RC, Ross R. Clinical and economic effects of unrecognized or inadequately treated bipolar disorder. J Psychiatric Pract. 2008;14(Suppl 2):31-38.
9. Goldberg JF, Harrow M, Whiteside JF. Risk for bipolar illness in inpatients initially hospitalized for unipolar depression. Am J Psychiatry. 2001:158(8):1265-1270.
10. Chilakamarri JK, Filkowski MM, Ghaemi SN. Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder. Ann Clin Psychiatry. 2011;23(1):25-29.
11. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
12. Bowden CL. A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord. 2005;84(2-3):117-125.
13. Baldassano C. Distinctions between bipolar I and bipolar II depression. Current Psychiatry. 2017;16(8):S7-S16.
14. Hirschfeld MA, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11):1873-1875.
15. Ghaemi SN, Miller CJ, Berv DA, et al. Sensitivity and specificity a new bipolar spectrum diagnostic scale. J Affect Disorder. 2005;84(2-3):273-277
16. Suppes T, Leverich G, Keck P, et al. The Stanley Foundation Continuing Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disorder. 2001;67(1-3):45-49.
17. Perlis RH, Miyahara S, Marangell LB. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP–BD). Biol Psychiatry. 2004;55(9):875-881.
18. Baldessarini RJ, Bolzani L, Kruz N, et al. Onset age of bipolar disorders at six international sites. J Affect Disord. 2010;121(1-2):143-146.
19. Post RM, Altshuler LL, Kupka R, et al. More childhood onset bipolar disorder in the United States than Canada or Europe: implications for treatment and prevention. Neurosci Biobehav Rev. 2017;74(Pt A):204-213.
20. Geller B, Luby J. Child and adolescent bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1997;36(9):1168-1176.
21. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord. 2001;3(4):202-210.
22. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.
23. Deflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010;22(5):437-452.
24. Bogren M, Brådvik L, Holmstrand C, et al. Gender differences in subtypes of depression by first incidence and age of onset: a follow-up of the Lunby population. Eur Arch Psychiatry Clin Neurosci. 2018;268(2):179-189.
25. Singhal A, Ross J, Seminog O, et al. Risks of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage. J R Soc Med. 2014;107(5):194-204.
26. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Amer. 2009;18(2):291-319.
27. Youngtrom EA, Arnold LE, Frazier TW. Bipolar and ADHD comorbidity: both artifact and outgrowth of shared mechanisms. Clin Psychol (New York). 2010;17(4):350-359.
28. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the International Mood Disorders Collaborative Project. Prime Care Companion J Clin Psychiatry. 2010;12(3). doi:10.4088/PCC.09m00861gry.
29. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiological Catchment Area (ECA) Study. JAMA. 1990;264(19):2511-2518.
30. Hunt GE, Malhi GS, Cleary M, et al. Prevalence of comorbid bipolar and substance use disorders in clinical settings, 1990-2015: systematic review and meta-analysis. J Affect Disord. 2016;206:331-349.
31. Agargun MY, Besiroglu L, Cilli AS, et al. Nightmares, suicide attempts, and melancholic features in patients with unipolar major depression. J Affect Disord. 2007;98(3):267-270.
32. Birmaher B, Axelson D, Monk K, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study. Arch Gen Psychiatry. 2009;66(3):287-296.
33. Rush AJ, Trivedi MH, Wisniewski SR, et al. Buproprion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
34. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
35. Kirsch I. Antidepressants and the placebo effect. Z Psychol. 2014;222(3):128-134.
36. U.S. Food and Drug Administration. Suicidality in children and adolescents being treated with antidepressant medications. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm161679.htm. Published February 5, 2018. Accessed May 10, 2019.
37. Jennissen S, Huber J, Ehrenthal JC, et al. Association between insight and outcome of psychotherapy; systematic review and meta-analysis. Am J Psychiatry. 2018;175(10):961-969.
38. Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism. JAMA. 2018;320(13):1349-1359.
39. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
40. Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord. 2018;229:410-414.
41. Koda-Kimbe MA, Alldredge BK. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs (10th ed). Baltimore, MD: Walters Klower Health/Lippincott Williams & Wilkins; 2012.
42. Moreno C, Laje G, Blanco C, et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.
At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.
Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.
In a previous article1 (“Controversies in bipolar disorder: Trust evidence or experience?,”
In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.
Misdiagnosis is common
Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient2-8 and inpatient9 settings, and in children and adolescents.10 Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.
Reliance on DSM-511 and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.
Continue to: DSM-5 also requires...
DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.
Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire14 and the Bipolar Spectrum Diagnostic Scale15 may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.
Distinguishing between these 2 types of depression
Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.
Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”
Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.22 However, overall rates of bipolar disorder may be slightly higher in men than in women.23 Unipolar melancholic depression occurs at approximately the same frequency in men and women.24
Continue to: Rapidity of onset
Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.
Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.25 Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.
ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.28
Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.29,30
Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.
Continue to: Sleep problems
Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.31 Yet these patients usually do not complain of sleepiness during the day.
Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.31 This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.
Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.
Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.
Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.
Continue to: Genetics
Genetics. Bipolar disorder is one of the most heritable of illnesses.32 Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”
Consequences of misdiagnosis
Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.5,8
Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.9 The STAR*D study,33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.35
When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.36 Because bipolar depression typically begins in youth,10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.
Depression and life stressors
Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.
Continue to: Our approach to treatment
Our approach to treatment
Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psychotherapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,37 but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.
The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.
Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.
Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.
Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.
Continue to: As we observed...
As we observed in our previous article,1 thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 138-41).
Box 1
Conventional laboratory reference ranges often indicate that thyroid-stimulating hormone (TSH) levels as high as 4.0, 4.5, or 5.0 mU/L are normal. A recent meta- analysis determined that treatment of subclinical hypothyroidism (elevated TSH with normal free thyroxine) does not benefit patients’ quality of life.38 Patients with mood disorders, however, often fail to respond to mood stabilizers and other psychiatric medications unless their TSH is <3.0 or even <2.5 mU/L.39,40 We typically augment with liothyronine because, unlike levothyroxine, it works quickly, does not require deiodination to be activated, and, contrary to some reports, its elimination and biologic half-life are sufficient for single daily dosing.41
Moving towards better diagnoses
The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 210,12,13,18,19,42).
Box 2
Based on our clinical experience treating thousands of patients over 25 years, we have 2 issues with DSM-5 regarding bipolar disorder:
1. The DSM-5 criteria for hypomania fail to reflect the features of clinical presentations commonly seen in our practice. The majority of patients with authentic bipolar syndromes do not have hypomanias that last for at least 4 days or reach the level of severity required for a DSM-5 diagnosis of hypomania. This results in misdiagnosis of patients with bipolar depression as suffering from unipolar depression, which leads to inappropriate treatment with antidepressant monotherapy.
2. Bipolar disorder frequently makes its first appearance in childhood and adolescence,10,18,19 and increasing numbers of young patients have been receiving this diagnosis.42 In our opinion, this increase reflects clinicians’ improved diagnostic skills. Perhaps alarmed by the increase in young people receiving a diagnosis of bipolar disorder, the authors of DSM-5 created a new diagnosis for children: disruptive mood dysregulation disorder. This diagnostic addition is based on the finding that children with these mood symptoms may not subsequently exhibit classic DSM-5 manic or hypomanic episodes. But the lack of such episodes does not preclude a diagnosis of bipolar disorder, because many adults with unequivocal bipolar spectrum disorders have subthreshold hypomanias and thus fail to exhibit classic manic or hypomanic episodes.12,13
A rose by any other name would smell as sweet. Children who exhibit symptoms of disruptive mood dysregulation disorder— chronic irritability and protracted temper outbursts—usually suffer from depression and mood instability. In our opinion, it is irrational and confusing to clinicians to separate out with a new diagnosis an arbitrarily defined group of children who exhibit substantially the same symptoms as those who receive a diagnosis of bipolar disorder.
Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.
CASE CONTINUED
Return to work
Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.
Bottom Line
Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.
Related Resources
- Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
- Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.
Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft
Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.
At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.
Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.
In a previous article1 (“Controversies in bipolar disorder: Trust evidence or experience?,”
In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.
Misdiagnosis is common
Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient2-8 and inpatient9 settings, and in children and adolescents.10 Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.
Reliance on DSM-511 and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.
Continue to: DSM-5 also requires...
DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.
Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire14 and the Bipolar Spectrum Diagnostic Scale15 may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.
Distinguishing between these 2 types of depression
Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.
Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”
Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.22 However, overall rates of bipolar disorder may be slightly higher in men than in women.23 Unipolar melancholic depression occurs at approximately the same frequency in men and women.24
Continue to: Rapidity of onset
Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.
Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.25 Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.
ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.28
Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.29,30
Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.
Continue to: Sleep problems
Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.31 Yet these patients usually do not complain of sleepiness during the day.
Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.31 This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.
Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.
Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.
Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.
Continue to: Genetics
Genetics. Bipolar disorder is one of the most heritable of illnesses.32 Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”
Consequences of misdiagnosis
Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.5,8
Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.9 The STAR*D study,33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.35
When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.36 Because bipolar depression typically begins in youth,10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.
Depression and life stressors
Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.
Continue to: Our approach to treatment
Our approach to treatment
Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psychotherapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,37 but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.
The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.
Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.
Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.
Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.
Continue to: As we observed...
As we observed in our previous article,1 thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 138-41).
Box 1
Conventional laboratory reference ranges often indicate that thyroid-stimulating hormone (TSH) levels as high as 4.0, 4.5, or 5.0 mU/L are normal. A recent meta- analysis determined that treatment of subclinical hypothyroidism (elevated TSH with normal free thyroxine) does not benefit patients’ quality of life.38 Patients with mood disorders, however, often fail to respond to mood stabilizers and other psychiatric medications unless their TSH is <3.0 or even <2.5 mU/L.39,40 We typically augment with liothyronine because, unlike levothyroxine, it works quickly, does not require deiodination to be activated, and, contrary to some reports, its elimination and biologic half-life are sufficient for single daily dosing.41
Moving towards better diagnoses
The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 210,12,13,18,19,42).
Box 2
Based on our clinical experience treating thousands of patients over 25 years, we have 2 issues with DSM-5 regarding bipolar disorder:
1. The DSM-5 criteria for hypomania fail to reflect the features of clinical presentations commonly seen in our practice. The majority of patients with authentic bipolar syndromes do not have hypomanias that last for at least 4 days or reach the level of severity required for a DSM-5 diagnosis of hypomania. This results in misdiagnosis of patients with bipolar depression as suffering from unipolar depression, which leads to inappropriate treatment with antidepressant monotherapy.
2. Bipolar disorder frequently makes its first appearance in childhood and adolescence,10,18,19 and increasing numbers of young patients have been receiving this diagnosis.42 In our opinion, this increase reflects clinicians’ improved diagnostic skills. Perhaps alarmed by the increase in young people receiving a diagnosis of bipolar disorder, the authors of DSM-5 created a new diagnosis for children: disruptive mood dysregulation disorder. This diagnostic addition is based on the finding that children with these mood symptoms may not subsequently exhibit classic DSM-5 manic or hypomanic episodes. But the lack of such episodes does not preclude a diagnosis of bipolar disorder, because many adults with unequivocal bipolar spectrum disorders have subthreshold hypomanias and thus fail to exhibit classic manic or hypomanic episodes.12,13
A rose by any other name would smell as sweet. Children who exhibit symptoms of disruptive mood dysregulation disorder— chronic irritability and protracted temper outbursts—usually suffer from depression and mood instability. In our opinion, it is irrational and confusing to clinicians to separate out with a new diagnosis an arbitrarily defined group of children who exhibit substantially the same symptoms as those who receive a diagnosis of bipolar disorder.
Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.
CASE CONTINUED
Return to work
Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.
Bottom Line
Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.
Related Resources
- Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
- Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.
Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft
1. Miller GE, Noel RL. Controversies in bipolar disorder: trust evidence or experience? Current Psychiatry. 2009;8(2):27-28,31-33,39.
2. Glick ID. Undiagnosed bipolar disorder: new syndromes and new treatments. Prim Care Companion J Clin Psychiatry. 2004;6(1):27-33.
3. Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144.
4. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159(6):1005-1010.
5. Shi L, Thiebaud P, McCombs JS. The impact of unrecognized bipolar disorders for patients treated with antidepressants in the fee-for-services California Medicaid (Medi-Cal) program. J Affect Disord. 2004;82(3):373-383.
6. Sidor MM, MacQueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72(2):156-167.
7. Hughes T, Cardno A, West R, et al. Unrecognized bipolar disorder among UK primary care patients prescribed antidepressants: an observational study. Br J Gen Pract. 2016;66(643):e71-e77.
8. Keck PE Jr, Kessler RC, Ross R. Clinical and economic effects of unrecognized or inadequately treated bipolar disorder. J Psychiatric Pract. 2008;14(Suppl 2):31-38.
9. Goldberg JF, Harrow M, Whiteside JF. Risk for bipolar illness in inpatients initially hospitalized for unipolar depression. Am J Psychiatry. 2001:158(8):1265-1270.
10. Chilakamarri JK, Filkowski MM, Ghaemi SN. Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder. Ann Clin Psychiatry. 2011;23(1):25-29.
11. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
12. Bowden CL. A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord. 2005;84(2-3):117-125.
13. Baldassano C. Distinctions between bipolar I and bipolar II depression. Current Psychiatry. 2017;16(8):S7-S16.
14. Hirschfeld MA, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11):1873-1875.
15. Ghaemi SN, Miller CJ, Berv DA, et al. Sensitivity and specificity a new bipolar spectrum diagnostic scale. J Affect Disorder. 2005;84(2-3):273-277
16. Suppes T, Leverich G, Keck P, et al. The Stanley Foundation Continuing Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disorder. 2001;67(1-3):45-49.
17. Perlis RH, Miyahara S, Marangell LB. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP–BD). Biol Psychiatry. 2004;55(9):875-881.
18. Baldessarini RJ, Bolzani L, Kruz N, et al. Onset age of bipolar disorders at six international sites. J Affect Disord. 2010;121(1-2):143-146.
19. Post RM, Altshuler LL, Kupka R, et al. More childhood onset bipolar disorder in the United States than Canada or Europe: implications for treatment and prevention. Neurosci Biobehav Rev. 2017;74(Pt A):204-213.
20. Geller B, Luby J. Child and adolescent bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1997;36(9):1168-1176.
21. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord. 2001;3(4):202-210.
22. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.
23. Deflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010;22(5):437-452.
24. Bogren M, Brådvik L, Holmstrand C, et al. Gender differences in subtypes of depression by first incidence and age of onset: a follow-up of the Lunby population. Eur Arch Psychiatry Clin Neurosci. 2018;268(2):179-189.
25. Singhal A, Ross J, Seminog O, et al. Risks of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage. J R Soc Med. 2014;107(5):194-204.
26. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Amer. 2009;18(2):291-319.
27. Youngtrom EA, Arnold LE, Frazier TW. Bipolar and ADHD comorbidity: both artifact and outgrowth of shared mechanisms. Clin Psychol (New York). 2010;17(4):350-359.
28. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the International Mood Disorders Collaborative Project. Prime Care Companion J Clin Psychiatry. 2010;12(3). doi:10.4088/PCC.09m00861gry.
29. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiological Catchment Area (ECA) Study. JAMA. 1990;264(19):2511-2518.
30. Hunt GE, Malhi GS, Cleary M, et al. Prevalence of comorbid bipolar and substance use disorders in clinical settings, 1990-2015: systematic review and meta-analysis. J Affect Disord. 2016;206:331-349.
31. Agargun MY, Besiroglu L, Cilli AS, et al. Nightmares, suicide attempts, and melancholic features in patients with unipolar major depression. J Affect Disord. 2007;98(3):267-270.
32. Birmaher B, Axelson D, Monk K, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study. Arch Gen Psychiatry. 2009;66(3):287-296.
33. Rush AJ, Trivedi MH, Wisniewski SR, et al. Buproprion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
34. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
35. Kirsch I. Antidepressants and the placebo effect. Z Psychol. 2014;222(3):128-134.
36. U.S. Food and Drug Administration. Suicidality in children and adolescents being treated with antidepressant medications. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm161679.htm. Published February 5, 2018. Accessed May 10, 2019.
37. Jennissen S, Huber J, Ehrenthal JC, et al. Association between insight and outcome of psychotherapy; systematic review and meta-analysis. Am J Psychiatry. 2018;175(10):961-969.
38. Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism. JAMA. 2018;320(13):1349-1359.
39. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
40. Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord. 2018;229:410-414.
41. Koda-Kimbe MA, Alldredge BK. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs (10th ed). Baltimore, MD: Walters Klower Health/Lippincott Williams & Wilkins; 2012.
42. Moreno C, Laje G, Blanco C, et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
1. Miller GE, Noel RL. Controversies in bipolar disorder: trust evidence or experience? Current Psychiatry. 2009;8(2):27-28,31-33,39.
2. Glick ID. Undiagnosed bipolar disorder: new syndromes and new treatments. Prim Care Companion J Clin Psychiatry. 2004;6(1):27-33.
3. Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52(1-3):135-144.
4. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159(6):1005-1010.
5. Shi L, Thiebaud P, McCombs JS. The impact of unrecognized bipolar disorders for patients treated with antidepressants in the fee-for-services California Medicaid (Medi-Cal) program. J Affect Disord. 2004;82(3):373-383.
6. Sidor MM, MacQueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72(2):156-167.
7. Hughes T, Cardno A, West R, et al. Unrecognized bipolar disorder among UK primary care patients prescribed antidepressants: an observational study. Br J Gen Pract. 2016;66(643):e71-e77.
8. Keck PE Jr, Kessler RC, Ross R. Clinical and economic effects of unrecognized or inadequately treated bipolar disorder. J Psychiatric Pract. 2008;14(Suppl 2):31-38.
9. Goldberg JF, Harrow M, Whiteside JF. Risk for bipolar illness in inpatients initially hospitalized for unipolar depression. Am J Psychiatry. 2001:158(8):1265-1270.
10. Chilakamarri JK, Filkowski MM, Ghaemi SN. Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder. Ann Clin Psychiatry. 2011;23(1):25-29.
11. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
12. Bowden CL. A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord. 2005;84(2-3):117-125.
13. Baldassano C. Distinctions between bipolar I and bipolar II depression. Current Psychiatry. 2017;16(8):S7-S16.
14. Hirschfeld MA, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11):1873-1875.
15. Ghaemi SN, Miller CJ, Berv DA, et al. Sensitivity and specificity a new bipolar spectrum diagnostic scale. J Affect Disorder. 2005;84(2-3):273-277
16. Suppes T, Leverich G, Keck P, et al. The Stanley Foundation Continuing Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disorder. 2001;67(1-3):45-49.
17. Perlis RH, Miyahara S, Marangell LB. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP–BD). Biol Psychiatry. 2004;55(9):875-881.
18. Baldessarini RJ, Bolzani L, Kruz N, et al. Onset age of bipolar disorders at six international sites. J Affect Disord. 2010;121(1-2):143-146.
19. Post RM, Altshuler LL, Kupka R, et al. More childhood onset bipolar disorder in the United States than Canada or Europe: implications for treatment and prevention. Neurosci Biobehav Rev. 2017;74(Pt A):204-213.
20. Geller B, Luby J. Child and adolescent bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1997;36(9):1168-1176.
21. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord. 2001;3(4):202-210.
22. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.
23. Deflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010;22(5):437-452.
24. Bogren M, Brådvik L, Holmstrand C, et al. Gender differences in subtypes of depression by first incidence and age of onset: a follow-up of the Lunby population. Eur Arch Psychiatry Clin Neurosci. 2018;268(2):179-189.
25. Singhal A, Ross J, Seminog O, et al. Risks of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage. J R Soc Med. 2014;107(5):194-204.
26. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Amer. 2009;18(2):291-319.
27. Youngtrom EA, Arnold LE, Frazier TW. Bipolar and ADHD comorbidity: both artifact and outgrowth of shared mechanisms. Clin Psychol (New York). 2010;17(4):350-359.
28. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the International Mood Disorders Collaborative Project. Prime Care Companion J Clin Psychiatry. 2010;12(3). doi:10.4088/PCC.09m00861gry.
29. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiological Catchment Area (ECA) Study. JAMA. 1990;264(19):2511-2518.
30. Hunt GE, Malhi GS, Cleary M, et al. Prevalence of comorbid bipolar and substance use disorders in clinical settings, 1990-2015: systematic review and meta-analysis. J Affect Disord. 2016;206:331-349.
31. Agargun MY, Besiroglu L, Cilli AS, et al. Nightmares, suicide attempts, and melancholic features in patients with unipolar major depression. J Affect Disord. 2007;98(3):267-270.
32. Birmaher B, Axelson D, Monk K, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study. Arch Gen Psychiatry. 2009;66(3):287-296.
33. Rush AJ, Trivedi MH, Wisniewski SR, et al. Buproprion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
34. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
35. Kirsch I. Antidepressants and the placebo effect. Z Psychol. 2014;222(3):128-134.
36. U.S. Food and Drug Administration. Suicidality in children and adolescents being treated with antidepressant medications. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm161679.htm. Published February 5, 2018. Accessed May 10, 2019.
37. Jennissen S, Huber J, Ehrenthal JC, et al. Association between insight and outcome of psychotherapy; systematic review and meta-analysis. Am J Psychiatry. 2018;175(10):961-969.
38. Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism. JAMA. 2018;320(13):1349-1359.
39. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
40. Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord. 2018;229:410-414.
41. Koda-Kimbe MA, Alldredge BK. Koda-Kimble and Young’s applied therapeutics: the clinical use of drugs (10th ed). Baltimore, MD: Walters Klower Health/Lippincott Williams & Wilkins; 2012.
42. Moreno C, Laje G, Blanco C, et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
Reappraisal in emotion regulation unrelated to working memory in bipolar disorder
Working memory may not function properly during the reappraisal process of emotion regulation in patients with bipolar disorder, according to Dong Hun Oh of the department of psychiatry at Yonsei University, Seoul, South Korea, and associates.
For the study, published in the Journal of Affective Disorders, 43 patients with euthymic bipolar I disorder were recruited from a psychiatric outpatient clinic in Seoul and compared with 48 healthy controls. The Korean versions of the operation span task (OSPAN), emotion regulation questionnaire (K-ERQ), ruminative response scale (K-RRS), and Difficulties in Emotion Regulation Scale (K-DERS) were administered to all the patients.
In a between-group comparison of scores on the four scales measured, patients with bipolar disorder had significantly lower scores on OSPAN (P = .031), on the brooding section of the K-RRS (P =.016), and on the nonacceptance section of the K-DERS (P = .039). In a regression analysis of the interaction between working memory and the four components of emotion regulation (reappraisal, expressive suppression, brooding, and reflective pondering), a significant interaction was found in OSPAN scores for reappraisal between healthy controls and the BD group (P = .007). Brooding scores were significantly lower in the control group, but the interaction was not significant.
A simple slope analysis showed that, while working memory was worse in patients with bipolar disorder, a relationship between cognitive capacity and the efficacy of reappraisal was found only in healthy controls, the investigators noted.
“The absence of interaction between [working memory capacity] and reappraisal in euthymic [bipolar disorder] patients that we report may indicate that the positive effects of cognitive remediation or [working memory] training previously reported for healthy people, may not effectively improve [emotion regulation] for patients with [bipolar disorder],” they wrote.
Furthermore, if this is the case, cognitive interventions aimed at improving emotion regulation in patients with bipolar disorder might not work.
The investigators cited several limitations. One limitation was the small sample size; another was the use of self-administered questionnaires.
The study was supported by a faculty research grant from Yonsei University. The authors did not report any conflicts of interest.
SOURCE: Oh DH et al. J Affect Disord. 2019 Apr 8. doi: 10.1016/j.jad.2019.04.042.
Working memory may not function properly during the reappraisal process of emotion regulation in patients with bipolar disorder, according to Dong Hun Oh of the department of psychiatry at Yonsei University, Seoul, South Korea, and associates.
For the study, published in the Journal of Affective Disorders, 43 patients with euthymic bipolar I disorder were recruited from a psychiatric outpatient clinic in Seoul and compared with 48 healthy controls. The Korean versions of the operation span task (OSPAN), emotion regulation questionnaire (K-ERQ), ruminative response scale (K-RRS), and Difficulties in Emotion Regulation Scale (K-DERS) were administered to all the patients.
In a between-group comparison of scores on the four scales measured, patients with bipolar disorder had significantly lower scores on OSPAN (P = .031), on the brooding section of the K-RRS (P =.016), and on the nonacceptance section of the K-DERS (P = .039). In a regression analysis of the interaction between working memory and the four components of emotion regulation (reappraisal, expressive suppression, brooding, and reflective pondering), a significant interaction was found in OSPAN scores for reappraisal between healthy controls and the BD group (P = .007). Brooding scores were significantly lower in the control group, but the interaction was not significant.
A simple slope analysis showed that, while working memory was worse in patients with bipolar disorder, a relationship between cognitive capacity and the efficacy of reappraisal was found only in healthy controls, the investigators noted.
“The absence of interaction between [working memory capacity] and reappraisal in euthymic [bipolar disorder] patients that we report may indicate that the positive effects of cognitive remediation or [working memory] training previously reported for healthy people, may not effectively improve [emotion regulation] for patients with [bipolar disorder],” they wrote.
Furthermore, if this is the case, cognitive interventions aimed at improving emotion regulation in patients with bipolar disorder might not work.
The investigators cited several limitations. One limitation was the small sample size; another was the use of self-administered questionnaires.
The study was supported by a faculty research grant from Yonsei University. The authors did not report any conflicts of interest.
SOURCE: Oh DH et al. J Affect Disord. 2019 Apr 8. doi: 10.1016/j.jad.2019.04.042.
Working memory may not function properly during the reappraisal process of emotion regulation in patients with bipolar disorder, according to Dong Hun Oh of the department of psychiatry at Yonsei University, Seoul, South Korea, and associates.
For the study, published in the Journal of Affective Disorders, 43 patients with euthymic bipolar I disorder were recruited from a psychiatric outpatient clinic in Seoul and compared with 48 healthy controls. The Korean versions of the operation span task (OSPAN), emotion regulation questionnaire (K-ERQ), ruminative response scale (K-RRS), and Difficulties in Emotion Regulation Scale (K-DERS) were administered to all the patients.
In a between-group comparison of scores on the four scales measured, patients with bipolar disorder had significantly lower scores on OSPAN (P = .031), on the brooding section of the K-RRS (P =.016), and on the nonacceptance section of the K-DERS (P = .039). In a regression analysis of the interaction between working memory and the four components of emotion regulation (reappraisal, expressive suppression, brooding, and reflective pondering), a significant interaction was found in OSPAN scores for reappraisal between healthy controls and the BD group (P = .007). Brooding scores were significantly lower in the control group, but the interaction was not significant.
A simple slope analysis showed that, while working memory was worse in patients with bipolar disorder, a relationship between cognitive capacity and the efficacy of reappraisal was found only in healthy controls, the investigators noted.
“The absence of interaction between [working memory capacity] and reappraisal in euthymic [bipolar disorder] patients that we report may indicate that the positive effects of cognitive remediation or [working memory] training previously reported for healthy people, may not effectively improve [emotion regulation] for patients with [bipolar disorder],” they wrote.
Furthermore, if this is the case, cognitive interventions aimed at improving emotion regulation in patients with bipolar disorder might not work.
The investigators cited several limitations. One limitation was the small sample size; another was the use of self-administered questionnaires.
The study was supported by a faculty research grant from Yonsei University. The authors did not report any conflicts of interest.
SOURCE: Oh DH et al. J Affect Disord. 2019 Apr 8. doi: 10.1016/j.jad.2019.04.042.
FROM THE JOURNAL OF AFFECTIVE DISORDERS
FDA expands use of Vraylar to treatment of bipolar-associated depressive episodes
The Food and Drug Administration on May 28 approved a supplemental New Drug Application for cariprazine (Vraylar) for the treatment of depressive episodes associated with bipolar I disorder.
Approval for the expanded label was based on results of the RGH-MD-53, RGH-MD-54, and RGH-MD-56 clinical trials, in which cariprazine was compared with placebo over a 6-week period in patients with bipolar I disorder. In all three trials, patients receiving 1.5 mg cariprazine had significantly greater improvement in their Montgomery-Åsberg Depression Rating scale after 6 weeks, compared with patients receiving placebo.
Cariprazine previously was indicated for the treatment of manic or mixed episodes associated with bipolar I disorder in adults. The most common adverse reactions reported in the clinical trials were nausea, akathisia, restlessness, and extrapyramidal symptoms; these symptoms are similar to those on the Vraylar label.
“Treating bipolar disorder can be very difficult, because people living with the illness experience a range of depressive and manic symptoms, sometimes both at the same time, and , specifically manic, mixed, and depressive episodes, with just one medication,” Stephen M. Stahl, MD, PhD, professor of psychiatry at the University of California, San Diego, said in the press release.
Find the full press release on the Allergan website.
The Food and Drug Administration on May 28 approved a supplemental New Drug Application for cariprazine (Vraylar) for the treatment of depressive episodes associated with bipolar I disorder.
Approval for the expanded label was based on results of the RGH-MD-53, RGH-MD-54, and RGH-MD-56 clinical trials, in which cariprazine was compared with placebo over a 6-week period in patients with bipolar I disorder. In all three trials, patients receiving 1.5 mg cariprazine had significantly greater improvement in their Montgomery-Åsberg Depression Rating scale after 6 weeks, compared with patients receiving placebo.
Cariprazine previously was indicated for the treatment of manic or mixed episodes associated with bipolar I disorder in adults. The most common adverse reactions reported in the clinical trials were nausea, akathisia, restlessness, and extrapyramidal symptoms; these symptoms are similar to those on the Vraylar label.
“Treating bipolar disorder can be very difficult, because people living with the illness experience a range of depressive and manic symptoms, sometimes both at the same time, and , specifically manic, mixed, and depressive episodes, with just one medication,” Stephen M. Stahl, MD, PhD, professor of psychiatry at the University of California, San Diego, said in the press release.
Find the full press release on the Allergan website.
The Food and Drug Administration on May 28 approved a supplemental New Drug Application for cariprazine (Vraylar) for the treatment of depressive episodes associated with bipolar I disorder.
Approval for the expanded label was based on results of the RGH-MD-53, RGH-MD-54, and RGH-MD-56 clinical trials, in which cariprazine was compared with placebo over a 6-week period in patients with bipolar I disorder. In all three trials, patients receiving 1.5 mg cariprazine had significantly greater improvement in their Montgomery-Åsberg Depression Rating scale after 6 weeks, compared with patients receiving placebo.
Cariprazine previously was indicated for the treatment of manic or mixed episodes associated with bipolar I disorder in adults. The most common adverse reactions reported in the clinical trials were nausea, akathisia, restlessness, and extrapyramidal symptoms; these symptoms are similar to those on the Vraylar label.
“Treating bipolar disorder can be very difficult, because people living with the illness experience a range of depressive and manic symptoms, sometimes both at the same time, and , specifically manic, mixed, and depressive episodes, with just one medication,” Stephen M. Stahl, MD, PhD, professor of psychiatry at the University of California, San Diego, said in the press release.
Find the full press release on the Allergan website.
Bipolar disorder during pregnancy: Lessons learned
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Racing thoughts: What to consider
Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech1—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.
Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.
Major depressive disorder
Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.2 Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.1 Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.3 These patients might benefit from augmentation with a mood stabilizer such as lithium4 or a second-generation antipsychotic.5
Other potential causes
Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table1).
In summary, when caring for a patient who reports having racing thoughts, consider:
- whether that patient actually does have racing thoughts
- the potential causes, severity, duration, and treatment of the racing thoughts
- the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
2. Benazzi F. Unipolar depression with racing thoughts: a bipolar spectrum disorder? Psychiatry Clin Neurosci. 2005;59:570-575.
3. Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37(4):851-864.
4. Bauer M, Adli M, Bschor T, et al. Lithium’s emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants. Neuropsychobiology. 2010;62(1):36-42.
5. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-991.
Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech1—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.
Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.
Major depressive disorder
Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.2 Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.1 Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.3 These patients might benefit from augmentation with a mood stabilizer such as lithium4 or a second-generation antipsychotic.5
Other potential causes
Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table1).
In summary, when caring for a patient who reports having racing thoughts, consider:
- whether that patient actually does have racing thoughts
- the potential causes, severity, duration, and treatment of the racing thoughts
- the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.
Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech1—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.
Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.
Major depressive disorder
Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.2 Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.1 Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.3 These patients might benefit from augmentation with a mood stabilizer such as lithium4 or a second-generation antipsychotic.5
Other potential causes
Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table1).
In summary, when caring for a patient who reports having racing thoughts, consider:
- whether that patient actually does have racing thoughts
- the potential causes, severity, duration, and treatment of the racing thoughts
- the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
2. Benazzi F. Unipolar depression with racing thoughts: a bipolar spectrum disorder? Psychiatry Clin Neurosci. 2005;59:570-575.
3. Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37(4):851-864.
4. Bauer M, Adli M, Bschor T, et al. Lithium’s emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants. Neuropsychobiology. 2010;62(1):36-42.
5. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-991.
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
2. Benazzi F. Unipolar depression with racing thoughts: a bipolar spectrum disorder? Psychiatry Clin Neurosci. 2005;59:570-575.
3. Undurraga J, Baldessarini RJ. Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Neuropsychopharmacology. 2012;37(4):851-864.
4. Bauer M, Adli M, Bschor T, et al. Lithium’s emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants. Neuropsychobiology. 2010;62(1):36-42.
5. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-991.
Young, angry, and in need of a liver transplant
CASE Rash, fever, extreme lethargy; multiple hospital visits
Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.
One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.
After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.
During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.
When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.
On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.
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The authors’ observations
The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.
Continue to: A review of the records...
A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.
Liver damage from valproic acid
Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches1 (Table 21). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.2 Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 31). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.3
There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid2:
- hyperammonemia
- acute liver failure and jaundice
- Myriad ProReye-like syndrome, which is generally seen in children.
In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.3 Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.2-4
At Visit 2, Ms. L’s presentation was not initially consistent with hepatic encephalopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).
Continue to: At Visit 2 in the ED...
At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.
In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.2 In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.2 This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.6 Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.2,6,7
Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.
EVALUATION Consent for transplantation
As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.
During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.
Continue to: Ms. L becomes agitated...
Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.
When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.
On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.
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The authors’ observations
L-carnitine supplementation
Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.8 Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.8 L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,10 and it is currently recommended in cases of valproic acid toxicity, especially in children.8 Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.11 It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,8 but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.12
TREATMENT Decompensation and transplantation
Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.
Continue to: On hospital Day 6...
On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.
On hospital Day 9, she undergoes a liver transplantation.
[polldaddy:10307652]
The authors’ observations
Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.
This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.
Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 41). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 513,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution.
Continue to: Consider patient-specific factors
Consider patient-specific factors
Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.
OUTCOME Discharged after 20 days
Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.
Bottom Line
Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.
Related Resource
- Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.
Drug Brand Names
Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene
1. Depakote [package insert]. North Chicago, IL: AbbVie, Inc.; 2019.
2. National Institutes of Health. U.S. Department of Health and Human Services. Drug Record: Valproate. https://livertox.nlm.nih.gov/Valproate.htm. Updated October 30, 2018. Accessed March 21, 2019.
3. Schmid MM, Freudenmann RW, Keller F, et al. Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry. 2013;46(2):63-68.
4. Patel N, Landry KB, Fargason RE, et al. Reversible encephalopathy due to valproic acid induced hyperammonemia in a patient with Bipolar I disorder: a cautionary report. Psychopharmacol Bull. 2017;47(1):40-44.
5. Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49(10):1358-1359.
6. Darban M and Bagheri B. Drug reaction with eosinophilia and systemic symptoms induced by valproic acid: a case report. Iran Red Crescent Med J. 2016;18(9): e35825.
7. van Zoelen MA, de Graaf M, van Dijk MR, et al. Valproic acid-induced DRESS syndrome with acute liver failure. Neth J Med. 2012;70(3):155.
8. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101-111.
9. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001;56(10):1405-1409.
10. Böhles H, Sewell AC, Wenzel D. The effect of carnitine supplementation in valproate-induced hyperammonaemia. Acta Paediatr. 1996;85(4):446-449.
11. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638.
12. Romero-Falcón A, de la Santa-Belda E, García-Contreras R, et al. A case of valproate-associated hepatotoxicity treated with L-carnitine. Eur J Intern Med. 2003;14(5):338-340.
13. National Institute for Health and Clinical Excellence. Bipolar disorder: the management of bipolar disorder in adults, children, and adolescents, in primary and secondary care. https://www.nice.org.uk/guidance/cg185. Updated April 2018. Accessed March 21, 2019.
14 . Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with biopolar disorder: second edition. American Psychiatric Association. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf. Published 2002. Accessed March 21, 2019.
CASE Rash, fever, extreme lethargy; multiple hospital visits
Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.
One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.
After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.
During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.
When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.
On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.
[polldaddy:10307646]
The authors’ observations
The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.
Continue to: A review of the records...
A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.
Liver damage from valproic acid
Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches1 (Table 21). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.2 Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 31). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.3
There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid2:
- hyperammonemia
- acute liver failure and jaundice
- Myriad ProReye-like syndrome, which is generally seen in children.
In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.3 Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.2-4
At Visit 2, Ms. L’s presentation was not initially consistent with hepatic encephalopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).
Continue to: At Visit 2 in the ED...
At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.
In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.2 In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.2 This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.6 Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.2,6,7
Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.
EVALUATION Consent for transplantation
As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.
During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.
Continue to: Ms. L becomes agitated...
Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.
When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.
On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.
[polldaddy:10307651]
The authors’ observations
L-carnitine supplementation
Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.8 Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.8 L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,10 and it is currently recommended in cases of valproic acid toxicity, especially in children.8 Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.11 It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,8 but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.12
TREATMENT Decompensation and transplantation
Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.
Continue to: On hospital Day 6...
On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.
On hospital Day 9, she undergoes a liver transplantation.
[polldaddy:10307652]
The authors’ observations
Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.
This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.
Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 41). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 513,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution.
Continue to: Consider patient-specific factors
Consider patient-specific factors
Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.
OUTCOME Discharged after 20 days
Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.
Bottom Line
Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.
Related Resource
- Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.
Drug Brand Names
Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene
CASE Rash, fever, extreme lethargy; multiple hospital visits
Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.
One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.
After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.
During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.
When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.
On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.
[polldaddy:10307646]
The authors’ observations
The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.
Continue to: A review of the records...
A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.
Liver damage from valproic acid
Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches1 (Table 21). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.2 Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 31). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.3
There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid2:
- hyperammonemia
- acute liver failure and jaundice
- Myriad ProReye-like syndrome, which is generally seen in children.
In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.3 Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.2-4
At Visit 2, Ms. L’s presentation was not initially consistent with hepatic encephalopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).
Continue to: At Visit 2 in the ED...
At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.
In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.2 In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.2 This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.6 Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.2,6,7
Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.
EVALUATION Consent for transplantation
As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.
During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.
Continue to: Ms. L becomes agitated...
Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.
When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.
On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.
[polldaddy:10307651]
The authors’ observations
L-carnitine supplementation
Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.8 Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.8 L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,10 and it is currently recommended in cases of valproic acid toxicity, especially in children.8 Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.11 It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,8 but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.12
TREATMENT Decompensation and transplantation
Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.
Continue to: On hospital Day 6...
On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.
On hospital Day 9, she undergoes a liver transplantation.
[polldaddy:10307652]
The authors’ observations
Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.
This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.
Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 41). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 513,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution.
Continue to: Consider patient-specific factors
Consider patient-specific factors
Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.
OUTCOME Discharged after 20 days
Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.
Bottom Line
Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.
Related Resource
- Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.
Drug Brand Names
Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene
1. Depakote [package insert]. North Chicago, IL: AbbVie, Inc.; 2019.
2. National Institutes of Health. U.S. Department of Health and Human Services. Drug Record: Valproate. https://livertox.nlm.nih.gov/Valproate.htm. Updated October 30, 2018. Accessed March 21, 2019.
3. Schmid MM, Freudenmann RW, Keller F, et al. Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry. 2013;46(2):63-68.
4. Patel N, Landry KB, Fargason RE, et al. Reversible encephalopathy due to valproic acid induced hyperammonemia in a patient with Bipolar I disorder: a cautionary report. Psychopharmacol Bull. 2017;47(1):40-44.
5. Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49(10):1358-1359.
6. Darban M and Bagheri B. Drug reaction with eosinophilia and systemic symptoms induced by valproic acid: a case report. Iran Red Crescent Med J. 2016;18(9): e35825.
7. van Zoelen MA, de Graaf M, van Dijk MR, et al. Valproic acid-induced DRESS syndrome with acute liver failure. Neth J Med. 2012;70(3):155.
8. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101-111.
9. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001;56(10):1405-1409.
10. Böhles H, Sewell AC, Wenzel D. The effect of carnitine supplementation in valproate-induced hyperammonaemia. Acta Paediatr. 1996;85(4):446-449.
11. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638.
12. Romero-Falcón A, de la Santa-Belda E, García-Contreras R, et al. A case of valproate-associated hepatotoxicity treated with L-carnitine. Eur J Intern Med. 2003;14(5):338-340.
13. National Institute for Health and Clinical Excellence. Bipolar disorder: the management of bipolar disorder in adults, children, and adolescents, in primary and secondary care. https://www.nice.org.uk/guidance/cg185. Updated April 2018. Accessed March 21, 2019.
14 . Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with biopolar disorder: second edition. American Psychiatric Association. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf. Published 2002. Accessed March 21, 2019.
1. Depakote [package insert]. North Chicago, IL: AbbVie, Inc.; 2019.
2. National Institutes of Health. U.S. Department of Health and Human Services. Drug Record: Valproate. https://livertox.nlm.nih.gov/Valproate.htm. Updated October 30, 2018. Accessed March 21, 2019.
3. Schmid MM, Freudenmann RW, Keller F, et al. Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry. 2013;46(2):63-68.
4. Patel N, Landry KB, Fargason RE, et al. Reversible encephalopathy due to valproic acid induced hyperammonemia in a patient with Bipolar I disorder: a cautionary report. Psychopharmacol Bull. 2017;47(1):40-44.
5. Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49(10):1358-1359.
6. Darban M and Bagheri B. Drug reaction with eosinophilia and systemic symptoms induced by valproic acid: a case report. Iran Red Crescent Med J. 2016;18(9): e35825.
7. van Zoelen MA, de Graaf M, van Dijk MR, et al. Valproic acid-induced DRESS syndrome with acute liver failure. Neth J Med. 2012;70(3):155.
8. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101-111.
9. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001;56(10):1405-1409.
10. Böhles H, Sewell AC, Wenzel D. The effect of carnitine supplementation in valproate-induced hyperammonaemia. Acta Paediatr. 1996;85(4):446-449.
11. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000;34(5):630-638.
12. Romero-Falcón A, de la Santa-Belda E, García-Contreras R, et al. A case of valproate-associated hepatotoxicity treated with L-carnitine. Eur J Intern Med. 2003;14(5):338-340.
13. National Institute for Health and Clinical Excellence. Bipolar disorder: the management of bipolar disorder in adults, children, and adolescents, in primary and secondary care. https://www.nice.org.uk/guidance/cg185. Updated April 2018. Accessed March 21, 2019.
14 . Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with biopolar disorder: second edition. American Psychiatric Association. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf. Published 2002. Accessed March 21, 2019.
Metabolite levels might help differentiate schizophrenia, bipolar
ORLANDO – Profiling metabolites found in the plasma could be a way to get an earlier handle on how a person’s mental illness will progress, researchers said the annual congress of the Schizophrenia International Research Society.
Investigators at the University of São Paulo found that certain substances – such as phospholipids and sphingolipids – were found in differing levels at the time of a first episode of psychosis, allowing them to accurately identify bipolar disorder or schizophrenia or healthy controls 87% of the time.
The findings suggest a way to help get patients more targeted treatment earlier in their disease course, said Helena Joaquim, MD, PhD, a postdoctoral fellow in the university’s psychiatry department.
“The levels of these metabolites can be a biomarker for psychosis, as well as a diagnostic marker for schizophrenia and bipolar disorder, aiding clinical practice,” the researchers wrote in a poster presentation.
At the time of a first episode of psychosis, the actual diagnosis can be difficult to pinpoint, making the illness more difficult to treat. Since lipid metabolism is altered in neuropsychiatric diseases, the researchers turned to the metabolite levels of patients to pin down a specific diagnosis sooner.
They collected plasma from 28 schizophrenia patients, 27 bipolar patients, and 30 healthy controls. They looked specifically at acylcarnitines, phospholipids, lysophospholipids and sphingolipids. They found that phospholipids were elevated in schizophrenia patients, compared with controls, and even more elevated in patients with bipolar disorder. A similar pattern was seen with lysophospholipids. Sphingolipids were found at lower levels in schizophrenia and elevated in bipolar disorder, compared with controls.
Levels of those three metabolites allowed researchers 87.1% of the time to correctly identify patients as a healthy control or as having schizophrenia or bipolar disorder. Acylcarnitines were not found to be differentiated between schizophrenia and bipolar disorder, the researchers found.
The most interesting part of their efforts so far, Dr. Joaquim said, was a shotgun analysis, an untargeted approach in which about 186 metabolites were measured and plotted on a graph. The compounds have not yet all been identified, but researchers found that levels of these substances were clustered in conspicuous ways.
“It seems like the negative schizophrenia patients are more like the depressive bipolar, and the positive symptoms are more like manic bipolar,” Dr. Joaquim said.
. For example, looking at metabolite levels might help determine whether schizophrenia patients are more likely to be troubled by positive symptoms, such as hallucinations.
“We have to look back,” Dr. Joaquim said, “and try to identify those metabolites that are the most different between the groups.”
Dr. Joaquim reported no relevant disclosures.
ORLANDO – Profiling metabolites found in the plasma could be a way to get an earlier handle on how a person’s mental illness will progress, researchers said the annual congress of the Schizophrenia International Research Society.
Investigators at the University of São Paulo found that certain substances – such as phospholipids and sphingolipids – were found in differing levels at the time of a first episode of psychosis, allowing them to accurately identify bipolar disorder or schizophrenia or healthy controls 87% of the time.
The findings suggest a way to help get patients more targeted treatment earlier in their disease course, said Helena Joaquim, MD, PhD, a postdoctoral fellow in the university’s psychiatry department.
“The levels of these metabolites can be a biomarker for psychosis, as well as a diagnostic marker for schizophrenia and bipolar disorder, aiding clinical practice,” the researchers wrote in a poster presentation.
At the time of a first episode of psychosis, the actual diagnosis can be difficult to pinpoint, making the illness more difficult to treat. Since lipid metabolism is altered in neuropsychiatric diseases, the researchers turned to the metabolite levels of patients to pin down a specific diagnosis sooner.
They collected plasma from 28 schizophrenia patients, 27 bipolar patients, and 30 healthy controls. They looked specifically at acylcarnitines, phospholipids, lysophospholipids and sphingolipids. They found that phospholipids were elevated in schizophrenia patients, compared with controls, and even more elevated in patients with bipolar disorder. A similar pattern was seen with lysophospholipids. Sphingolipids were found at lower levels in schizophrenia and elevated in bipolar disorder, compared with controls.
Levels of those three metabolites allowed researchers 87.1% of the time to correctly identify patients as a healthy control or as having schizophrenia or bipolar disorder. Acylcarnitines were not found to be differentiated between schizophrenia and bipolar disorder, the researchers found.
The most interesting part of their efforts so far, Dr. Joaquim said, was a shotgun analysis, an untargeted approach in which about 186 metabolites were measured and plotted on a graph. The compounds have not yet all been identified, but researchers found that levels of these substances were clustered in conspicuous ways.
“It seems like the negative schizophrenia patients are more like the depressive bipolar, and the positive symptoms are more like manic bipolar,” Dr. Joaquim said.
. For example, looking at metabolite levels might help determine whether schizophrenia patients are more likely to be troubled by positive symptoms, such as hallucinations.
“We have to look back,” Dr. Joaquim said, “and try to identify those metabolites that are the most different between the groups.”
Dr. Joaquim reported no relevant disclosures.
ORLANDO – Profiling metabolites found in the plasma could be a way to get an earlier handle on how a person’s mental illness will progress, researchers said the annual congress of the Schizophrenia International Research Society.
Investigators at the University of São Paulo found that certain substances – such as phospholipids and sphingolipids – were found in differing levels at the time of a first episode of psychosis, allowing them to accurately identify bipolar disorder or schizophrenia or healthy controls 87% of the time.
The findings suggest a way to help get patients more targeted treatment earlier in their disease course, said Helena Joaquim, MD, PhD, a postdoctoral fellow in the university’s psychiatry department.
“The levels of these metabolites can be a biomarker for psychosis, as well as a diagnostic marker for schizophrenia and bipolar disorder, aiding clinical practice,” the researchers wrote in a poster presentation.
At the time of a first episode of psychosis, the actual diagnosis can be difficult to pinpoint, making the illness more difficult to treat. Since lipid metabolism is altered in neuropsychiatric diseases, the researchers turned to the metabolite levels of patients to pin down a specific diagnosis sooner.
They collected plasma from 28 schizophrenia patients, 27 bipolar patients, and 30 healthy controls. They looked specifically at acylcarnitines, phospholipids, lysophospholipids and sphingolipids. They found that phospholipids were elevated in schizophrenia patients, compared with controls, and even more elevated in patients with bipolar disorder. A similar pattern was seen with lysophospholipids. Sphingolipids were found at lower levels in schizophrenia and elevated in bipolar disorder, compared with controls.
Levels of those three metabolites allowed researchers 87.1% of the time to correctly identify patients as a healthy control or as having schizophrenia or bipolar disorder. Acylcarnitines were not found to be differentiated between schizophrenia and bipolar disorder, the researchers found.
The most interesting part of their efforts so far, Dr. Joaquim said, was a shotgun analysis, an untargeted approach in which about 186 metabolites were measured and plotted on a graph. The compounds have not yet all been identified, but researchers found that levels of these substances were clustered in conspicuous ways.
“It seems like the negative schizophrenia patients are more like the depressive bipolar, and the positive symptoms are more like manic bipolar,” Dr. Joaquim said.
. For example, looking at metabolite levels might help determine whether schizophrenia patients are more likely to be troubled by positive symptoms, such as hallucinations.
“We have to look back,” Dr. Joaquim said, “and try to identify those metabolites that are the most different between the groups.”
Dr. Joaquim reported no relevant disclosures.
REPORTING FROM SIRS 2019