Bipolar Disorder

A physician’s mental health is important for the delivery of quality health care to his/her patients. Early identification and treatment of physicians with mental illnesses is challenging because physicians may neglect their own mental health due to the associated stigma, time constraints, or uncertainty regarding where to seek help. Physicians often worry about whom to confide in and harbor a fear that others will doubt his/her competence after recovery.¹ Physicians have higher rates of suicide than the general population.² According to data from the National Violent Death Reporting System, a diagnosed mental illness or a job problem significantly contribute to suicide among physicians.³ Additionally, physicians also have high rates of substance use and affective disorders.^1,4

Here, we present the case of a physician we treated on an inpatient psychiatry unit who stirred profound emotions in us as trainees, and discuss how we managed this complicated scenario.

CASE REPORT

Dr. P, a 35-year-old male endocrinologist, was admitted to our inpatient psychiatry unit with a diagnosis of bipolar disorder, manic, severe, with psychotic features. Earlier that day, Dr. P had walked out of his private outpatient practice where he still had several appointments. After he had been missing for several hours, he was picked up by the police. Dr. P had 2 prior psychiatric admissions; the last one had occurred >10 years ago. A few weeks before this admission, he stopped taking lithium, while continuing escitalopram. He had not been keeping his appointments with his outpatient psychiatrist.

At admission, Dr. P had pressured speech, grandiose delusions, an expansive affect, and aggressive behavior. He was responding to internal stimuli with no insight into his illness. He was evasive when asked about hallucinations. Dr. P believed he was superior in intelligence and physical prowess to everyone in the emergency department (ED), and for that reason, the ED staff was persecuting him. His urine toxicology was negative.

On the inpatient unit, because Dr. P exhibited posturing, mutism, and negativism, catatonia associated with bipolar disorder was added to his diagnosis. For the first 2 days, his catatonia was managed with oral lorazepam, 2 mg twice daily. Dr. P was also observed giving medical advice to other patients on the unit, and was told to stop. Throughout his hospitalization, he dictated his own treatment and would frequently debate with his treatment team on the pharmacologic basis for treatment decisions, asserting his expertise as a physician and claiming to have a general clinical knowledge of the acute management of bipolar disorder.

Dr. P was eventually stabilized on oral lithium, 450 mg twice daily, and aripiprazole, 10 mg/d. He also received oral clonazepam, as needed for acute agitation, which was eventually tapered and discontinued. He gradually responded to treatment, and demonstrated improved insight. The treatment team met with Dr. P’s parents, who also were physicians, to discuss treatment goals, management considerations, and an aftercare plan. After spending 8 days in the hospital, Dr. P was discharged home to the care of his immediate family, and instructed to follow up with his outpatient psychiatrist. We do not know if he resumed clinical duties.

Managing an extremely knowledgeable patient

During his hospitalization, Dr. P frequently challenged our clinical knowledge; he would repeatedly remind us that he was a physician and that we were still trainees, which caused us to second-guess ourselves. Eventually, the attending physician on our team was able to impress upon Dr. P the clearly established roles of the treatment team and the patient. It was also important to maintain open communication channels with Dr. P and his family, and to address his anxiety by discussing the treatment plan in detail.⁵

Continue to: Although his queries on medication...

Although his queries on medication pharmacodynamics and pharmacokinetics were daunting, we empathized with him, recognizing that his knowledge invariably contributed to his anxiety. We engaged with Dr. P and his parents and elaborated on the rationale behind treatment decisions. This earned his trust and tremendously facilitated his recovery.

We were also cautious about using benzodiazepines to treat Dr. P’s catatonia because we were concerned that his knowledge could aid him in feigning symptoms to obtain these medications. Physicians have a high rate of prescription medication abuse, mainly opiates and benzodiazepines.² The abuse of prescription medications by physicians is related to several psychological and psychiatric factors, including anxiety, depression, stress at work, personality problems, loss of loved ones, and pain. While treating physician patients, treatment decisions that include the use of opiates and benzodiazepines should be carefully considered.⁴

A complicated scenario

Managing a physician patient can be a rewarding experience; however, there are several factors that can impact the experience, including:

• The treating physicians’ anxiety and countertransference/transference dynamics. We repeatedly imagined ourselves in Dr. P’s position and thought long and hard about how this scenario could happen to anyone in the medical profession; these thoughts induced significant anxiety in each of us. Further, interacting with Dr. P was reminiscent of our training under senior residents and attendings. Dr. P viewed us—his treatment team—as his trainees and challenged our clinical knowledge and actions.
• The physician-patient’s emotional responses, which may include anxiety, despair, denial, and an inability to accept role reversal.

Our medical culture needs a paradigm shift. We need a model designed to encourage early self-disclosure and treatment-seeking among physicians with mental illness. This will reduce the stigma towards mental illness in our profession.

A physician’s mental health is important for the delivery of quality health care to his/her patients. Early identification and treatment of physicians with mental illnesses is challenging because physicians may neglect their own mental health due to the associated stigma, time constraints, or uncertainty regarding where to seek help. Physicians often worry about whom to confide in and harbor a fear that others will doubt his/her competence after recovery.¹ Physicians have higher rates of suicide than the general population.² According to data from the National Violent Death Reporting System, a diagnosed mental illness or a job problem significantly contribute to suicide among physicians.³ Additionally, physicians also have high rates of substance use and affective disorders.^1,4

Here, we present the case of a physician we treated on an inpatient psychiatry unit who stirred profound emotions in us as trainees, and discuss how we managed this complicated scenario.

CASE REPORT

Dr. P, a 35-year-old male endocrinologist, was admitted to our inpatient psychiatry unit with a diagnosis of bipolar disorder, manic, severe, with psychotic features. Earlier that day, Dr. P had walked out of his private outpatient practice where he still had several appointments. After he had been missing for several hours, he was picked up by the police. Dr. P had 2 prior psychiatric admissions; the last one had occurred >10 years ago. A few weeks before this admission, he stopped taking lithium, while continuing escitalopram. He had not been keeping his appointments with his outpatient psychiatrist.

At admission, Dr. P had pressured speech, grandiose delusions, an expansive affect, and aggressive behavior. He was responding to internal stimuli with no insight into his illness. He was evasive when asked about hallucinations. Dr. P believed he was superior in intelligence and physical prowess to everyone in the emergency department (ED), and for that reason, the ED staff was persecuting him. His urine toxicology was negative.

On the inpatient unit, because Dr. P exhibited posturing, mutism, and negativism, catatonia associated with bipolar disorder was added to his diagnosis. For the first 2 days, his catatonia was managed with oral lorazepam, 2 mg twice daily. Dr. P was also observed giving medical advice to other patients on the unit, and was told to stop. Throughout his hospitalization, he dictated his own treatment and would frequently debate with his treatment team on the pharmacologic basis for treatment decisions, asserting his expertise as a physician and claiming to have a general clinical knowledge of the acute management of bipolar disorder.

Dr. P was eventually stabilized on oral lithium, 450 mg twice daily, and aripiprazole, 10 mg/d. He also received oral clonazepam, as needed for acute agitation, which was eventually tapered and discontinued. He gradually responded to treatment, and demonstrated improved insight. The treatment team met with Dr. P’s parents, who also were physicians, to discuss treatment goals, management considerations, and an aftercare plan. After spending 8 days in the hospital, Dr. P was discharged home to the care of his immediate family, and instructed to follow up with his outpatient psychiatrist. We do not know if he resumed clinical duties.

Managing an extremely knowledgeable patient

During his hospitalization, Dr. P frequently challenged our clinical knowledge; he would repeatedly remind us that he was a physician and that we were still trainees, which caused us to second-guess ourselves. Eventually, the attending physician on our team was able to impress upon Dr. P the clearly established roles of the treatment team and the patient. It was also important to maintain open communication channels with Dr. P and his family, and to address his anxiety by discussing the treatment plan in detail.⁵

Continue to: Although his queries on medication...

Although his queries on medication pharmacodynamics and pharmacokinetics were daunting, we empathized with him, recognizing that his knowledge invariably contributed to his anxiety. We engaged with Dr. P and his parents and elaborated on the rationale behind treatment decisions. This earned his trust and tremendously facilitated his recovery.

We were also cautious about using benzodiazepines to treat Dr. P’s catatonia because we were concerned that his knowledge could aid him in feigning symptoms to obtain these medications. Physicians have a high rate of prescription medication abuse, mainly opiates and benzodiazepines.² The abuse of prescription medications by physicians is related to several psychological and psychiatric factors, including anxiety, depression, stress at work, personality problems, loss of loved ones, and pain. While treating physician patients, treatment decisions that include the use of opiates and benzodiazepines should be carefully considered.⁴

A complicated scenario

Managing a physician patient can be a rewarding experience; however, there are several factors that can impact the experience, including:

• The treating physicians’ anxiety and countertransference/transference dynamics. We repeatedly imagined ourselves in Dr. P’s position and thought long and hard about how this scenario could happen to anyone in the medical profession; these thoughts induced significant anxiety in each of us. Further, interacting with Dr. P was reminiscent of our training under senior residents and attendings. Dr. P viewed us—his treatment team—as his trainees and challenged our clinical knowledge and actions.
• The physician-patient’s emotional responses, which may include anxiety, despair, denial, and an inability to accept role reversal.

Our medical culture needs a paradigm shift. We need a model designed to encourage early self-disclosure and treatment-seeking among physicians with mental illness. This will reduce the stigma towards mental illness in our profession.

A physician’s mental health is important for the delivery of quality health care to his/her patients. Early identification and treatment of physicians with mental illnesses is challenging because physicians may neglect their own mental health due to the associated stigma, time constraints, or uncertainty regarding where to seek help. Physicians often worry about whom to confide in and harbor a fear that others will doubt his/her competence after recovery.¹ Physicians have higher rates of suicide than the general population.² According to data from the National Violent Death Reporting System, a diagnosed mental illness or a job problem significantly contribute to suicide among physicians.³ Additionally, physicians also have high rates of substance use and affective disorders.^1,4

Here, we present the case of a physician we treated on an inpatient psychiatry unit who stirred profound emotions in us as trainees, and discuss how we managed this complicated scenario.

CASE REPORT

Dr. P, a 35-year-old male endocrinologist, was admitted to our inpatient psychiatry unit with a diagnosis of bipolar disorder, manic, severe, with psychotic features. Earlier that day, Dr. P had walked out of his private outpatient practice where he still had several appointments. After he had been missing for several hours, he was picked up by the police. Dr. P had 2 prior psychiatric admissions; the last one had occurred >10 years ago. A few weeks before this admission, he stopped taking lithium, while continuing escitalopram. He had not been keeping his appointments with his outpatient psychiatrist.

At admission, Dr. P had pressured speech, grandiose delusions, an expansive affect, and aggressive behavior. He was responding to internal stimuli with no insight into his illness. He was evasive when asked about hallucinations. Dr. P believed he was superior in intelligence and physical prowess to everyone in the emergency department (ED), and for that reason, the ED staff was persecuting him. His urine toxicology was negative.

On the inpatient unit, because Dr. P exhibited posturing, mutism, and negativism, catatonia associated with bipolar disorder was added to his diagnosis. For the first 2 days, his catatonia was managed with oral lorazepam, 2 mg twice daily. Dr. P was also observed giving medical advice to other patients on the unit, and was told to stop. Throughout his hospitalization, he dictated his own treatment and would frequently debate with his treatment team on the pharmacologic basis for treatment decisions, asserting his expertise as a physician and claiming to have a general clinical knowledge of the acute management of bipolar disorder.

Dr. P was eventually stabilized on oral lithium, 450 mg twice daily, and aripiprazole, 10 mg/d. He also received oral clonazepam, as needed for acute agitation, which was eventually tapered and discontinued. He gradually responded to treatment, and demonstrated improved insight. The treatment team met with Dr. P’s parents, who also were physicians, to discuss treatment goals, management considerations, and an aftercare plan. After spending 8 days in the hospital, Dr. P was discharged home to the care of his immediate family, and instructed to follow up with his outpatient psychiatrist. We do not know if he resumed clinical duties.

Managing an extremely knowledgeable patient

During his hospitalization, Dr. P frequently challenged our clinical knowledge; he would repeatedly remind us that he was a physician and that we were still trainees, which caused us to second-guess ourselves. Eventually, the attending physician on our team was able to impress upon Dr. P the clearly established roles of the treatment team and the patient. It was also important to maintain open communication channels with Dr. P and his family, and to address his anxiety by discussing the treatment plan in detail.⁵

Continue to: Although his queries on medication...

Although his queries on medication pharmacodynamics and pharmacokinetics were daunting, we empathized with him, recognizing that his knowledge invariably contributed to his anxiety. We engaged with Dr. P and his parents and elaborated on the rationale behind treatment decisions. This earned his trust and tremendously facilitated his recovery.

We were also cautious about using benzodiazepines to treat Dr. P’s catatonia because we were concerned that his knowledge could aid him in feigning symptoms to obtain these medications. Physicians have a high rate of prescription medication abuse, mainly opiates and benzodiazepines.² The abuse of prescription medications by physicians is related to several psychological and psychiatric factors, including anxiety, depression, stress at work, personality problems, loss of loved ones, and pain. While treating physician patients, treatment decisions that include the use of opiates and benzodiazepines should be carefully considered.⁴

A complicated scenario

Managing a physician patient can be a rewarding experience; however, there are several factors that can impact the experience, including:

• The treating physicians’ anxiety and countertransference/transference dynamics. We repeatedly imagined ourselves in Dr. P’s position and thought long and hard about how this scenario could happen to anyone in the medical profession; these thoughts induced significant anxiety in each of us. Further, interacting with Dr. P was reminiscent of our training under senior residents and attendings. Dr. P viewed us—his treatment team—as his trainees and challenged our clinical knowledge and actions.
• The physician-patient’s emotional responses, which may include anxiety, despair, denial, and an inability to accept role reversal.

Our medical culture needs a paradigm shift. We need a model designed to encourage early self-disclosure and treatment-seeking among physicians with mental illness. This will reduce the stigma towards mental illness in our profession.

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

Patients with bipolar disorder I and II appear to have distinct brain structure networks that show up using a neuroimaging technique called parallel independent component analysis, or pICA, reported Wenhau Jiang and his associates.

pICA is a technique that enables researchers to analyze several modalities and the interconnections between them. The approach, which is considered fairly new, has been applied most often to neuropsychiatric disorders (Front Genet. 2015;6:276). The pICA involves using structural MRI and the Positive and Negative Syndrome Scale (PANSS) scores to assess the relationship between gray matter concentration in different areas of the brain and bipolar mood characteristics.

In the current study, published in NeuroImage: Clinical, Mr. Jiang and his associates used data from 110 patients with bipolar I and bipolar II from a large study conducted at the Norwegian Center for Mental Disorders Research in Oslo.

All patients were aged 18-65 years and had an IQ of over 70, and none had a history of severe head trauma. Most of the patients were women, about half had at least one psychotic episode, and all provided PANSS scores, reported Mr. Jiang of the department of psychology at Georgia State University in Atlanta and his associates.

After the patients were scanned, pICA was used to examine the preprocessed structural images and the PANSS item scores. The pICA showed two distinct profiles. One group showed preserved gray matter concentration in the right middle/superior temporal gyrus on the rMRI. These participants had more anxiety, and guilty feelings on the PANSS. Overall, participants with higher preserved gray matter concentration in bilateral, frontal, and parietal and left temporal regions show milder severity of these characteristics.

In the second pICA profile, participants with higher preserved gray matter concentration in bilateral front, parietal, and left temporal regions showed milder severity of several characteristics including blunted affect, emotional withdrawal, and passive/apathetic social withdrawal.

The investigators noted: “The mood profile was correlated with reductions in the right temporal gyrus, while the apathy/asocial profile correlated with a more widespread network including frontal, temporal, and parietal regions. It implicated the GM [gray matter] deficits in regional temporal lobe and frontal-temporal-parietal circuits that were separately related to clinical profiles as mood and apathy.”

The study was supported by the National Institutes of Health, the Research Council of Norway, the South-East Norway Health Authority, and the European Community’s Seventh Framework Programme. No author disclosures were stated.

[email protected]

SOURCE: Jiang W et al. Neuroimage Clin. 2019 Aug 19. doi: 10.1016/j.nicl.2019.101989.

Patients with bipolar disorder I and II appear to have distinct brain structure networks that show up using a neuroimaging technique called parallel independent component analysis, or pICA, reported Wenhau Jiang and his associates.

pICA is a technique that enables researchers to analyze several modalities and the interconnections between them. The approach, which is considered fairly new, has been applied most often to neuropsychiatric disorders (Front Genet. 2015;6:276). The pICA involves using structural MRI and the Positive and Negative Syndrome Scale (PANSS) scores to assess the relationship between gray matter concentration in different areas of the brain and bipolar mood characteristics.

In the current study, published in NeuroImage: Clinical, Mr. Jiang and his associates used data from 110 patients with bipolar I and bipolar II from a large study conducted at the Norwegian Center for Mental Disorders Research in Oslo.

All patients were aged 18-65 years and had an IQ of over 70, and none had a history of severe head trauma. Most of the patients were women, about half had at least one psychotic episode, and all provided PANSS scores, reported Mr. Jiang of the department of psychology at Georgia State University in Atlanta and his associates.

After the patients were scanned, pICA was used to examine the preprocessed structural images and the PANSS item scores. The pICA showed two distinct profiles. One group showed preserved gray matter concentration in the right middle/superior temporal gyrus on the rMRI. These participants had more anxiety, and guilty feelings on the PANSS. Overall, participants with higher preserved gray matter concentration in bilateral, frontal, and parietal and left temporal regions show milder severity of these characteristics.

In the second pICA profile, participants with higher preserved gray matter concentration in bilateral front, parietal, and left temporal regions showed milder severity of several characteristics including blunted affect, emotional withdrawal, and passive/apathetic social withdrawal.

The investigators noted: “The mood profile was correlated with reductions in the right temporal gyrus, while the apathy/asocial profile correlated with a more widespread network including frontal, temporal, and parietal regions. It implicated the GM [gray matter] deficits in regional temporal lobe and frontal-temporal-parietal circuits that were separately related to clinical profiles as mood and apathy.”

The study was supported by the National Institutes of Health, the Research Council of Norway, the South-East Norway Health Authority, and the European Community’s Seventh Framework Programme. No author disclosures were stated.

[email protected]

SOURCE: Jiang W et al. Neuroimage Clin. 2019 Aug 19. doi: 10.1016/j.nicl.2019.101989.

Patients with bipolar disorder I and II appear to have distinct brain structure networks that show up using a neuroimaging technique called parallel independent component analysis, or pICA, reported Wenhau Jiang and his associates.

pICA is a technique that enables researchers to analyze several modalities and the interconnections between them. The approach, which is considered fairly new, has been applied most often to neuropsychiatric disorders (Front Genet. 2015;6:276). The pICA involves using structural MRI and the Positive and Negative Syndrome Scale (PANSS) scores to assess the relationship between gray matter concentration in different areas of the brain and bipolar mood characteristics.

In the current study, published in NeuroImage: Clinical, Mr. Jiang and his associates used data from 110 patients with bipolar I and bipolar II from a large study conducted at the Norwegian Center for Mental Disorders Research in Oslo.

All patients were aged 18-65 years and had an IQ of over 70, and none had a history of severe head trauma. Most of the patients were women, about half had at least one psychotic episode, and all provided PANSS scores, reported Mr. Jiang of the department of psychology at Georgia State University in Atlanta and his associates.

After the patients were scanned, pICA was used to examine the preprocessed structural images and the PANSS item scores. The pICA showed two distinct profiles. One group showed preserved gray matter concentration in the right middle/superior temporal gyrus on the rMRI. These participants had more anxiety, and guilty feelings on the PANSS. Overall, participants with higher preserved gray matter concentration in bilateral, frontal, and parietal and left temporal regions show milder severity of these characteristics.

In the second pICA profile, participants with higher preserved gray matter concentration in bilateral front, parietal, and left temporal regions showed milder severity of several characteristics including blunted affect, emotional withdrawal, and passive/apathetic social withdrawal.

The investigators noted: “The mood profile was correlated with reductions in the right temporal gyrus, while the apathy/asocial profile correlated with a more widespread network including frontal, temporal, and parietal regions. It implicated the GM [gray matter] deficits in regional temporal lobe and frontal-temporal-parietal circuits that were separately related to clinical profiles as mood and apathy.”

The study was supported by the National Institutes of Health, the Research Council of Norway, the South-East Norway Health Authority, and the European Community’s Seventh Framework Programme. No author disclosures were stated.

[email protected]

SOURCE: Jiang W et al. Neuroimage Clin. 2019 Aug 19. doi: 10.1016/j.nicl.2019.101989.

COPENHAGEN – Bright light therapy is a well-established, guideline-recommended treatment for seasonal affective disorder, and many people prone to depression keep a light box at home. But are you ready to embrace the dark side – that is, dark therapy for bipolar mania, or its vastly more patient-friendly offshoot, virtual dark therapy?

Bruce Jancin/MDedge News

Virtual dark therapy using blue light spectrum–blocking glasses turns out to be a highly effective adjunct to standard antimanic medications in patients with bipolar mania. And it’s a lot easier on patients than the massive sensory deprivation imposed by the original form of dark therapy, which entails keeping a patient with mania in a completely dark room for 14 hours per night, Tone E.G. Henriksen, MD, observed at the annual congress of the European College of Neuropsychopharmacology.

She was lead author of a pioneering randomized controlled trial demonstrating that bipolar patients who wore blue-blocking, orange-tinted glasses for 14 hours per evening while hospitalized for a manic episode experienced a significant improvement in scores on the Young Mania Rating Scale (YMRS), compared with patients randomized to wearing clear lenses. Moreover, the between-group difference achieved strong significance in just 3 days.

That’s a remarkable result, because bipolar mania is such a challenge to treat pharmacologically. The standard medications – mood stabilizers and antipsychotic agents – are slow in onset of effect, observed Dr. Henriksen, a psychiatrist at the University of Bergen (Norway).

Backing up, she noted there is strong evidence of seasonality to bipolar disorder, as highlighted in a systematic review of 51 publications (J Affect Disord. 2014 Oct;168:210-23). This recognition has prompted numerous researchers to focus attention on the abnormal circadian rhythms prevalent in patients with bipolar disorder, for which the light/dark cycle is a powerful synchronizing signal to the hypothalamic suprachiasmatic nucleus, the master clock of circadian rhythms. This understanding led to a landmark case control pilot study by Italian investigators who exposed 16 bipolar inpatients experiencing a manic episode to 14 hours of complete darkness from 6 p.m. to 8 a.m. for 3 consecutive nights. The outcome was a dramatic reduction in YMRS scores in the dark therapy group, compared with 16 matched control inpatients, with all participants on pharmacologic treatment as usual (Bipolar Disord. 2005 Feb;7[1]:98-101).

“This was really something,” Dr. Henriksen recalled.

She and her colleagues were impressed by other investigators’ discovery of specialized retinal ganglion cells, known as intrinsically photosensitive retinal ganglion cells, which are responsible for conveying the daylight signal to the brain. These specialized cells contain melanopsin, which is blue light sensitive. The Norwegian investigators reasoned that it might not be necessary to expose patients with mania to prolonged utter darkness to achieve rapid symptomatic improvement, as the Italian psychiatrists did. Instead, they hypothesized, it might be sufficient just to block the blue light, low-wavelength end of the spectrum. And that turned out to be the case.

Their randomized, single-blind, multicenter study included 23 patients with bipolar disorder who were hospitalized for manic symptoms. All remained on their standard background psychiatric medications while being randomized to wear orange-tinted, blue light–blocking glasses, which allowed passage of almost all light above 530 nm, or clear glasses. Participants were instructed to wear their glasses from 6 p.m. to 8 a.m. for 7 consecutive nights. They took their glasses off when they switched off the lights at bedtime, but they had to put them back on if they turned on a light before 8 a.m. The patients also wore an activity monitor.

The results were dramatic: The blue-blocking glasses group had a mean 14.1-point drop in their YMRS score from a baseline of about 25, compared with a mere 1.7-point decline in the control group. Moreover, Dr. Henriksen said, this result might actually underrepresent the true clinical effect of blocking blue light to the brain, since two patients in the blue-blocking glasses group experienced such rapid symptomatic improvement that they were moved from an acute psychiatric ward to a local hospital midstudy, a sudden change that triggered transient worsening of manic symptoms in both patients.

The investigators documented improved sleep efficiency in the blue-blocking group. Another noteworthy finding was that, in the blue-blocking group, the elements of the YMRS related to increased activation declined before the measures of distorted thoughts and perceptions. So did motor activity as recorded by actigraph. Meanwhile, nighttime activity worsened in the control group; they received substantially more sedatives, hypnotics, anxiolytic agents, and antipsychotic medications (Bipolar Disord. 2016 May;18[3]:221-32).

The mechanism underlying the improvement in sleep regularity and manic symptoms achieved by blocking blue light is not understood. Dr. Henriksen finds “very compelling” a theory put forth by prominent chronobiologist Daniel Kripke, MD, of the University of California, San Diego. He has shown in animal studies that a change in light exposure can trigger bifurcation in the circadian rhythms of the suprachiasmatic nucleus. The resultant suppression of melatonin secretion results in excess production of hypothalamic triiodothyronine, which in turn affects production of other key hormones. In patients with bipolar disorder, this could trigger mania, according to Dr. Kripke (F1000Res. 2015 May 6;4:107.

Dr. Henriksen reported having no financial conflicts regarding her study, which was conducted free of commercial support. She serves as a consultant to Chrono Chrome AS.

[email protected]

COPENHAGEN – Bright light therapy is a well-established, guideline-recommended treatment for seasonal affective disorder, and many people prone to depression keep a light box at home. But are you ready to embrace the dark side – that is, dark therapy for bipolar mania, or its vastly more patient-friendly offshoot, virtual dark therapy?

Bruce Jancin/MDedge News

Virtual dark therapy using blue light spectrum–blocking glasses turns out to be a highly effective adjunct to standard antimanic medications in patients with bipolar mania. And it’s a lot easier on patients than the massive sensory deprivation imposed by the original form of dark therapy, which entails keeping a patient with mania in a completely dark room for 14 hours per night, Tone E.G. Henriksen, MD, observed at the annual congress of the European College of Neuropsychopharmacology.

She was lead author of a pioneering randomized controlled trial demonstrating that bipolar patients who wore blue-blocking, orange-tinted glasses for 14 hours per evening while hospitalized for a manic episode experienced a significant improvement in scores on the Young Mania Rating Scale (YMRS), compared with patients randomized to wearing clear lenses. Moreover, the between-group difference achieved strong significance in just 3 days.

That’s a remarkable result, because bipolar mania is such a challenge to treat pharmacologically. The standard medications – mood stabilizers and antipsychotic agents – are slow in onset of effect, observed Dr. Henriksen, a psychiatrist at the University of Bergen (Norway).

Backing up, she noted there is strong evidence of seasonality to bipolar disorder, as highlighted in a systematic review of 51 publications (J Affect Disord. 2014 Oct;168:210-23). This recognition has prompted numerous researchers to focus attention on the abnormal circadian rhythms prevalent in patients with bipolar disorder, for which the light/dark cycle is a powerful synchronizing signal to the hypothalamic suprachiasmatic nucleus, the master clock of circadian rhythms. This understanding led to a landmark case control pilot study by Italian investigators who exposed 16 bipolar inpatients experiencing a manic episode to 14 hours of complete darkness from 6 p.m. to 8 a.m. for 3 consecutive nights. The outcome was a dramatic reduction in YMRS scores in the dark therapy group, compared with 16 matched control inpatients, with all participants on pharmacologic treatment as usual (Bipolar Disord. 2005 Feb;7[1]:98-101).

“This was really something,” Dr. Henriksen recalled.

She and her colleagues were impressed by other investigators’ discovery of specialized retinal ganglion cells, known as intrinsically photosensitive retinal ganglion cells, which are responsible for conveying the daylight signal to the brain. These specialized cells contain melanopsin, which is blue light sensitive. The Norwegian investigators reasoned that it might not be necessary to expose patients with mania to prolonged utter darkness to achieve rapid symptomatic improvement, as the Italian psychiatrists did. Instead, they hypothesized, it might be sufficient just to block the blue light, low-wavelength end of the spectrum. And that turned out to be the case.

Their randomized, single-blind, multicenter study included 23 patients with bipolar disorder who were hospitalized for manic symptoms. All remained on their standard background psychiatric medications while being randomized to wear orange-tinted, blue light–blocking glasses, which allowed passage of almost all light above 530 nm, or clear glasses. Participants were instructed to wear their glasses from 6 p.m. to 8 a.m. for 7 consecutive nights. They took their glasses off when they switched off the lights at bedtime, but they had to put them back on if they turned on a light before 8 a.m. The patients also wore an activity monitor.

The results were dramatic: The blue-blocking glasses group had a mean 14.1-point drop in their YMRS score from a baseline of about 25, compared with a mere 1.7-point decline in the control group. Moreover, Dr. Henriksen said, this result might actually underrepresent the true clinical effect of blocking blue light to the brain, since two patients in the blue-blocking glasses group experienced such rapid symptomatic improvement that they were moved from an acute psychiatric ward to a local hospital midstudy, a sudden change that triggered transient worsening of manic symptoms in both patients.

The investigators documented improved sleep efficiency in the blue-blocking group. Another noteworthy finding was that, in the blue-blocking group, the elements of the YMRS related to increased activation declined before the measures of distorted thoughts and perceptions. So did motor activity as recorded by actigraph. Meanwhile, nighttime activity worsened in the control group; they received substantially more sedatives, hypnotics, anxiolytic agents, and antipsychotic medications (Bipolar Disord. 2016 May;18[3]:221-32).

The mechanism underlying the improvement in sleep regularity and manic symptoms achieved by blocking blue light is not understood. Dr. Henriksen finds “very compelling” a theory put forth by prominent chronobiologist Daniel Kripke, MD, of the University of California, San Diego. He has shown in animal studies that a change in light exposure can trigger bifurcation in the circadian rhythms of the suprachiasmatic nucleus. The resultant suppression of melatonin secretion results in excess production of hypothalamic triiodothyronine, which in turn affects production of other key hormones. In patients with bipolar disorder, this could trigger mania, according to Dr. Kripke (F1000Res. 2015 May 6;4:107.

Dr. Henriksen reported having no financial conflicts regarding her study, which was conducted free of commercial support. She serves as a consultant to Chrono Chrome AS.

[email protected]

COPENHAGEN – Bright light therapy is a well-established, guideline-recommended treatment for seasonal affective disorder, and many people prone to depression keep a light box at home. But are you ready to embrace the dark side – that is, dark therapy for bipolar mania, or its vastly more patient-friendly offshoot, virtual dark therapy?

Bruce Jancin/MDedge News

Virtual dark therapy using blue light spectrum–blocking glasses turns out to be a highly effective adjunct to standard antimanic medications in patients with bipolar mania. And it’s a lot easier on patients than the massive sensory deprivation imposed by the original form of dark therapy, which entails keeping a patient with mania in a completely dark room for 14 hours per night, Tone E.G. Henriksen, MD, observed at the annual congress of the European College of Neuropsychopharmacology.

She was lead author of a pioneering randomized controlled trial demonstrating that bipolar patients who wore blue-blocking, orange-tinted glasses for 14 hours per evening while hospitalized for a manic episode experienced a significant improvement in scores on the Young Mania Rating Scale (YMRS), compared with patients randomized to wearing clear lenses. Moreover, the between-group difference achieved strong significance in just 3 days.

That’s a remarkable result, because bipolar mania is such a challenge to treat pharmacologically. The standard medications – mood stabilizers and antipsychotic agents – are slow in onset of effect, observed Dr. Henriksen, a psychiatrist at the University of Bergen (Norway).

Backing up, she noted there is strong evidence of seasonality to bipolar disorder, as highlighted in a systematic review of 51 publications (J Affect Disord. 2014 Oct;168:210-23). This recognition has prompted numerous researchers to focus attention on the abnormal circadian rhythms prevalent in patients with bipolar disorder, for which the light/dark cycle is a powerful synchronizing signal to the hypothalamic suprachiasmatic nucleus, the master clock of circadian rhythms. This understanding led to a landmark case control pilot study by Italian investigators who exposed 16 bipolar inpatients experiencing a manic episode to 14 hours of complete darkness from 6 p.m. to 8 a.m. for 3 consecutive nights. The outcome was a dramatic reduction in YMRS scores in the dark therapy group, compared with 16 matched control inpatients, with all participants on pharmacologic treatment as usual (Bipolar Disord. 2005 Feb;7[1]:98-101).

“This was really something,” Dr. Henriksen recalled.

She and her colleagues were impressed by other investigators’ discovery of specialized retinal ganglion cells, known as intrinsically photosensitive retinal ganglion cells, which are responsible for conveying the daylight signal to the brain. These specialized cells contain melanopsin, which is blue light sensitive. The Norwegian investigators reasoned that it might not be necessary to expose patients with mania to prolonged utter darkness to achieve rapid symptomatic improvement, as the Italian psychiatrists did. Instead, they hypothesized, it might be sufficient just to block the blue light, low-wavelength end of the spectrum. And that turned out to be the case.

Their randomized, single-blind, multicenter study included 23 patients with bipolar disorder who were hospitalized for manic symptoms. All remained on their standard background psychiatric medications while being randomized to wear orange-tinted, blue light–blocking glasses, which allowed passage of almost all light above 530 nm, or clear glasses. Participants were instructed to wear their glasses from 6 p.m. to 8 a.m. for 7 consecutive nights. They took their glasses off when they switched off the lights at bedtime, but they had to put them back on if they turned on a light before 8 a.m. The patients also wore an activity monitor.

The results were dramatic: The blue-blocking glasses group had a mean 14.1-point drop in their YMRS score from a baseline of about 25, compared with a mere 1.7-point decline in the control group. Moreover, Dr. Henriksen said, this result might actually underrepresent the true clinical effect of blocking blue light to the brain, since two patients in the blue-blocking glasses group experienced such rapid symptomatic improvement that they were moved from an acute psychiatric ward to a local hospital midstudy, a sudden change that triggered transient worsening of manic symptoms in both patients.

The investigators documented improved sleep efficiency in the blue-blocking group. Another noteworthy finding was that, in the blue-blocking group, the elements of the YMRS related to increased activation declined before the measures of distorted thoughts and perceptions. So did motor activity as recorded by actigraph. Meanwhile, nighttime activity worsened in the control group; they received substantially more sedatives, hypnotics, anxiolytic agents, and antipsychotic medications (Bipolar Disord. 2016 May;18[3]:221-32).

The mechanism underlying the improvement in sleep regularity and manic symptoms achieved by blocking blue light is not understood. Dr. Henriksen finds “very compelling” a theory put forth by prominent chronobiologist Daniel Kripke, MD, of the University of California, San Diego. He has shown in animal studies that a change in light exposure can trigger bifurcation in the circadian rhythms of the suprachiasmatic nucleus. The resultant suppression of melatonin secretion results in excess production of hypothalamic triiodothyronine, which in turn affects production of other key hormones. In patients with bipolar disorder, this could trigger mania, according to Dr. Kripke (F1000Res. 2015 May 6;4:107.

Dr. Henriksen reported having no financial conflicts regarding her study, which was conducted free of commercial support. She serves as a consultant to Chrono Chrome AS.

[email protected]

Interleukin-6, IL-1 receptor antagonist (IL-1RA), and tumor necrosis factor–alpha (TNF-alpha) activity was associated with inflammation and neurodegeneration in patients with chronic bipolar disorder, according to Sercan Karabulut, MD, of Kepez State Hospital in Antalya, Turkey, and associates.

In a study published in the Turkish Journal of Psychiatry, the investigators collected enzyme-linked immunosorbent assays from 30 patients with early-stage bipolar disorder, 77 with chronic disease, and 30 healthy controls. Early-stage disease patients were significantly younger than chronic patients (25.3 years vs. 37.8 years). TNF-alpha, IL-6, IL-1RA, neuron-specific enolase, and S100 calcium-binding protein B (S100B) were measured, reported Dr. Karabulut and associates.

Patients with chronic bipolar disorder had significantly increased levels of all measured markers, compared with those with early-stage disease and the healthy controls. IL-6 and IL-1RA levels correlated with neuron-specific enolase and S100B, biomarkers that are associated with glial alterations and neuronal damage. TNF-alpha correlated with scores on the Clinical Global Impressions Scale and other measures.

“The present findings support in part the hypothesis that inflammation starts at later stages of [bipolar disorder], presumably as an associated effect of gliosis and neuronal loss, which appear to be particularly associated with IL-1RA and IL-6 activity,” the investigators wrote. “TNF-alpha ... might be a useful prognostic marker in patients with [bipolar disorder].”

No conflicts of interest were reported.

[email protected]

SOURCE: Karabulut S et al. Turk Psikiyatri Derg. 2019 Winter;30(2):75-81.

Interleukin-6, IL-1 receptor antagonist (IL-1RA), and tumor necrosis factor–alpha (TNF-alpha) activity was associated with inflammation and neurodegeneration in patients with chronic bipolar disorder, according to Sercan Karabulut, MD, of Kepez State Hospital in Antalya, Turkey, and associates.

In a study published in the Turkish Journal of Psychiatry, the investigators collected enzyme-linked immunosorbent assays from 30 patients with early-stage bipolar disorder, 77 with chronic disease, and 30 healthy controls. Early-stage disease patients were significantly younger than chronic patients (25.3 years vs. 37.8 years). TNF-alpha, IL-6, IL-1RA, neuron-specific enolase, and S100 calcium-binding protein B (S100B) were measured, reported Dr. Karabulut and associates.

Patients with chronic bipolar disorder had significantly increased levels of all measured markers, compared with those with early-stage disease and the healthy controls. IL-6 and IL-1RA levels correlated with neuron-specific enolase and S100B, biomarkers that are associated with glial alterations and neuronal damage. TNF-alpha correlated with scores on the Clinical Global Impressions Scale and other measures.

“The present findings support in part the hypothesis that inflammation starts at later stages of [bipolar disorder], presumably as an associated effect of gliosis and neuronal loss, which appear to be particularly associated with IL-1RA and IL-6 activity,” the investigators wrote. “TNF-alpha ... might be a useful prognostic marker in patients with [bipolar disorder].”

No conflicts of interest were reported.

[email protected]

SOURCE: Karabulut S et al. Turk Psikiyatri Derg. 2019 Winter;30(2):75-81.

Interleukin-6, IL-1 receptor antagonist (IL-1RA), and tumor necrosis factor–alpha (TNF-alpha) activity was associated with inflammation and neurodegeneration in patients with chronic bipolar disorder, according to Sercan Karabulut, MD, of Kepez State Hospital in Antalya, Turkey, and associates.

In a study published in the Turkish Journal of Psychiatry, the investigators collected enzyme-linked immunosorbent assays from 30 patients with early-stage bipolar disorder, 77 with chronic disease, and 30 healthy controls. Early-stage disease patients were significantly younger than chronic patients (25.3 years vs. 37.8 years). TNF-alpha, IL-6, IL-1RA, neuron-specific enolase, and S100 calcium-binding protein B (S100B) were measured, reported Dr. Karabulut and associates.

Patients with chronic bipolar disorder had significantly increased levels of all measured markers, compared with those with early-stage disease and the healthy controls. IL-6 and IL-1RA levels correlated with neuron-specific enolase and S100B, biomarkers that are associated with glial alterations and neuronal damage. TNF-alpha correlated with scores on the Clinical Global Impressions Scale and other measures.

“The present findings support in part the hypothesis that inflammation starts at later stages of [bipolar disorder], presumably as an associated effect of gliosis and neuronal loss, which appear to be particularly associated with IL-1RA and IL-6 activity,” the investigators wrote. “TNF-alpha ... might be a useful prognostic marker in patients with [bipolar disorder].”

No conflicts of interest were reported.

[email protected]

SOURCE: Karabulut S et al. Turk Psikiyatri Derg. 2019 Winter;30(2):75-81.

Fibroblast growth factor–21 (FGF21), a protein that regulates carbohydrate and lipid metabolism, could be a biomarker in patients with bipolar mania, a new study suggests.

“In addition, our data indicates that FGF21 may monitor and/or prevent metabolic abnormalities induced by psychotropic drugs,” wrote Qing Hu of Xiamen City Xianyue Hospital, in Fujian, China, and associates. The study was published in Psychiatry Research.

To investigate how the expression of FGF21 changes in response to psychotropics taken by patients with bipolar mania, the researchers recruited 99 inpatients with bipolar mania with or without psychosis and 99 healthy controls. Eighty-two of the patients received psychotropics only, and 17 received psychotropics and lipid-lowering or hypotensive agents. Those in the smaller group were later excluded from follow-up.

At baseline, no significant differences were found between the patients and controls on several metabolic measures, such as cholesterol and apolipoprotein. The patients with bipolar mania had higher uric acid and triglyceride levels, although the latter was not statistically significant. However, in the case of FGF21, serum levels were significantly higher in the bipolar mania patients at baseline, compared with the FGF21 serum levels of the controls.

After 4 weeks of taking the antipsychotics, the patients experienced increases in several metabolic measures, such as BMI (23.68 kg/m² vs. 24.02 kg/m²), LDL cholesterol (2.61 mg/dL vs. 2.98 mg/dL), and glucose (4.74 mg/dL vs. 4.88 mg/dL). However, their FGF21 levels declined, from 279.45 pg/mL to 215.12 pg/mL.

“In light of these findings, our future research will focus on investigating whether ... the change in FGF21 expression is a causal factor or a consequence of bipolar disorder,” the investigators wrote.

They cited several limitations. One is that psychotropic dosages were not discussed, and another is that evaluation data from the Young Mania Rating Scale were missing.

The researchers reported no conflicts of interest.

[email protected]

SOURCE: Hu Q et al. Psychiatry Res. 2019;272:643-8.

Fibroblast growth factor–21 (FGF21), a protein that regulates carbohydrate and lipid metabolism, could be a biomarker in patients with bipolar mania, a new study suggests.

“In addition, our data indicates that FGF21 may monitor and/or prevent metabolic abnormalities induced by psychotropic drugs,” wrote Qing Hu of Xiamen City Xianyue Hospital, in Fujian, China, and associates. The study was published in Psychiatry Research.

To investigate how the expression of FGF21 changes in response to psychotropics taken by patients with bipolar mania, the researchers recruited 99 inpatients with bipolar mania with or without psychosis and 99 healthy controls. Eighty-two of the patients received psychotropics only, and 17 received psychotropics and lipid-lowering or hypotensive agents. Those in the smaller group were later excluded from follow-up.

At baseline, no significant differences were found between the patients and controls on several metabolic measures, such as cholesterol and apolipoprotein. The patients with bipolar mania had higher uric acid and triglyceride levels, although the latter was not statistically significant. However, in the case of FGF21, serum levels were significantly higher in the bipolar mania patients at baseline, compared with the FGF21 serum levels of the controls.

After 4 weeks of taking the antipsychotics, the patients experienced increases in several metabolic measures, such as BMI (23.68 kg/m² vs. 24.02 kg/m²), LDL cholesterol (2.61 mg/dL vs. 2.98 mg/dL), and glucose (4.74 mg/dL vs. 4.88 mg/dL). However, their FGF21 levels declined, from 279.45 pg/mL to 215.12 pg/mL.

“In light of these findings, our future research will focus on investigating whether ... the change in FGF21 expression is a causal factor or a consequence of bipolar disorder,” the investigators wrote.

They cited several limitations. One is that psychotropic dosages were not discussed, and another is that evaluation data from the Young Mania Rating Scale were missing.

The researchers reported no conflicts of interest.

[email protected]

SOURCE: Hu Q et al. Psychiatry Res. 2019;272:643-8.

Fibroblast growth factor–21 (FGF21), a protein that regulates carbohydrate and lipid metabolism, could be a biomarker in patients with bipolar mania, a new study suggests.

“In addition, our data indicates that FGF21 may monitor and/or prevent metabolic abnormalities induced by psychotropic drugs,” wrote Qing Hu of Xiamen City Xianyue Hospital, in Fujian, China, and associates. The study was published in Psychiatry Research.

To investigate how the expression of FGF21 changes in response to psychotropics taken by patients with bipolar mania, the researchers recruited 99 inpatients with bipolar mania with or without psychosis and 99 healthy controls. Eighty-two of the patients received psychotropics only, and 17 received psychotropics and lipid-lowering or hypotensive agents. Those in the smaller group were later excluded from follow-up.

At baseline, no significant differences were found between the patients and controls on several metabolic measures, such as cholesterol and apolipoprotein. The patients with bipolar mania had higher uric acid and triglyceride levels, although the latter was not statistically significant. However, in the case of FGF21, serum levels were significantly higher in the bipolar mania patients at baseline, compared with the FGF21 serum levels of the controls.

After 4 weeks of taking the antipsychotics, the patients experienced increases in several metabolic measures, such as BMI (23.68 kg/m² vs. 24.02 kg/m²), LDL cholesterol (2.61 mg/dL vs. 2.98 mg/dL), and glucose (4.74 mg/dL vs. 4.88 mg/dL). However, their FGF21 levels declined, from 279.45 pg/mL to 215.12 pg/mL.

“In light of these findings, our future research will focus on investigating whether ... the change in FGF21 expression is a causal factor or a consequence of bipolar disorder,” the investigators wrote.

They cited several limitations. One is that psychotropic dosages were not discussed, and another is that evaluation data from the Young Mania Rating Scale were missing.

The researchers reported no conflicts of interest.

[email protected]

SOURCE: Hu Q et al. Psychiatry Res. 2019;272:643-8.

In patients with bipolar disorder currently in partial or full remission, self-reporting of anxiety to a smartphone-based system matched clinical evaluations of anxiety, according to Maria Faurholt-Jepsen, MD, and her associates.

Milan_Zokic/thinkstockphotos.com

A total of 84 patients with bipolar disorder who participated in the randomized, controlled, single-blind, parallel-group MONARCA II trial were included in the study, reported Dr. Faurholt-Jepsen of Rigshospitalet in Copenhagen, and her associates. All patients reported their anxiety to the smartphone-based system every day for a 9-month period; all patients underwent clinical evaluations of anxiety, functioning, patient-reported stress, and quality of life at five fixed time points over the study period. The study was published online by the Journal of Affective Disorders.

Self-reported anxiety was mild, with 19.3% of patients reporting anxiety during the study period, and 2.6% reporting severe anxiety. No association was seen between gender and anxiety days, or between bipolar disorder type and anxiety days. Patients reported depressed mood on 43.2% of the days when anxiety was also reported, and reported mania on 48.0% of the days when anxiety was reported.

Self-reported anxiety scores were positively associated with the anxiety subitems on a key rating scale (P = .0001). In addition, self-reported anxiety was associated with perceived stress, quality of life, and functioning (P = .0001 for all three).

“Smartphones allow for the assessments of an individual’s status in real time repeatedly over time and offer the opportunity to collect fine-grained data unobtrusively and outside the clinical setting. Frequent fine-grained monitoring in clinical, high-risk and epidemiological populations provides an opportunity to gain a better understanding of the nature, correlates, and clinical implications of [bipolar disorder],” the investigators wrote.

Three coauthors reported consulting with Eli Lilly, Astra Zeneca, Servier, Bristol-Myers Squibb, Lundbeck, Sunovion, and Medilink. Two coauthors are cofounders and shareholders in Monsenso.

[email protected]

SOURCE: Faurholt-Jepsen M et al. J Affect Disord. 2019. doi: 10.1016/j.jad.2019.07.029.

In patients with bipolar disorder currently in partial or full remission, self-reporting of anxiety to a smartphone-based system matched clinical evaluations of anxiety, according to Maria Faurholt-Jepsen, MD, and her associates.

Milan_Zokic/thinkstockphotos.com

A total of 84 patients with bipolar disorder who participated in the randomized, controlled, single-blind, parallel-group MONARCA II trial were included in the study, reported Dr. Faurholt-Jepsen of Rigshospitalet in Copenhagen, and her associates. All patients reported their anxiety to the smartphone-based system every day for a 9-month period; all patients underwent clinical evaluations of anxiety, functioning, patient-reported stress, and quality of life at five fixed time points over the study period. The study was published online by the Journal of Affective Disorders.

Self-reported anxiety was mild, with 19.3% of patients reporting anxiety during the study period, and 2.6% reporting severe anxiety. No association was seen between gender and anxiety days, or between bipolar disorder type and anxiety days. Patients reported depressed mood on 43.2% of the days when anxiety was also reported, and reported mania on 48.0% of the days when anxiety was reported.

Self-reported anxiety scores were positively associated with the anxiety subitems on a key rating scale (P = .0001). In addition, self-reported anxiety was associated with perceived stress, quality of life, and functioning (P = .0001 for all three).

“Smartphones allow for the assessments of an individual’s status in real time repeatedly over time and offer the opportunity to collect fine-grained data unobtrusively and outside the clinical setting. Frequent fine-grained monitoring in clinical, high-risk and epidemiological populations provides an opportunity to gain a better understanding of the nature, correlates, and clinical implications of [bipolar disorder],” the investigators wrote.

Three coauthors reported consulting with Eli Lilly, Astra Zeneca, Servier, Bristol-Myers Squibb, Lundbeck, Sunovion, and Medilink. Two coauthors are cofounders and shareholders in Monsenso.

[email protected]

SOURCE: Faurholt-Jepsen M et al. J Affect Disord. 2019. doi: 10.1016/j.jad.2019.07.029.

In patients with bipolar disorder currently in partial or full remission, self-reporting of anxiety to a smartphone-based system matched clinical evaluations of anxiety, according to Maria Faurholt-Jepsen, MD, and her associates.

Milan_Zokic/thinkstockphotos.com

A total of 84 patients with bipolar disorder who participated in the randomized, controlled, single-blind, parallel-group MONARCA II trial were included in the study, reported Dr. Faurholt-Jepsen of Rigshospitalet in Copenhagen, and her associates. All patients reported their anxiety to the smartphone-based system every day for a 9-month period; all patients underwent clinical evaluations of anxiety, functioning, patient-reported stress, and quality of life at five fixed time points over the study period. The study was published online by the Journal of Affective Disorders.

Self-reported anxiety was mild, with 19.3% of patients reporting anxiety during the study period, and 2.6% reporting severe anxiety. No association was seen between gender and anxiety days, or between bipolar disorder type and anxiety days. Patients reported depressed mood on 43.2% of the days when anxiety was also reported, and reported mania on 48.0% of the days when anxiety was reported.

Self-reported anxiety scores were positively associated with the anxiety subitems on a key rating scale (P = .0001). In addition, self-reported anxiety was associated with perceived stress, quality of life, and functioning (P = .0001 for all three).

“Smartphones allow for the assessments of an individual’s status in real time repeatedly over time and offer the opportunity to collect fine-grained data unobtrusively and outside the clinical setting. Frequent fine-grained monitoring in clinical, high-risk and epidemiological populations provides an opportunity to gain a better understanding of the nature, correlates, and clinical implications of [bipolar disorder],” the investigators wrote.

Three coauthors reported consulting with Eli Lilly, Astra Zeneca, Servier, Bristol-Myers Squibb, Lundbeck, Sunovion, and Medilink. Two coauthors are cofounders and shareholders in Monsenso.

[email protected]

SOURCE: Faurholt-Jepsen M et al. J Affect Disord. 2019. doi: 10.1016/j.jad.2019.07.029.

Acute upper respiratory infections (URIs) often lead to mild illnesses, but they can be severely destabilizing for individuals with mood disorders. Additionally, the medications patients often take to target symptoms of the common cold or influenza can interact with psychiatric medications to produce dangerous adverse events or induce further mood symptoms. In this article, we describe the relationship between URIs and mood disorders, the psychiatric diagnostic challenges that arise when evaluating a patient with a URI, and treatment approaches that emphasize psycho­education and watchful waiting, when appropriate.

A bidirectional relationship

Acute upper respiratory infections are the most common human illnesses, affecting almost 25 million people annually in the United States.¹ The common cold is caused by >200 different viruses; rhinovirus and coronavirus are the most common. Influenza, which also attacks the upper respiratory tract, is caused by strains of influenza A, B, or C virus.² The common cold may present initially with mild symptoms of headache, sneezing, chills, and sore throat, and then progress to nasal discharge, congestion, cough, and malaise. When influenza strikes, patients may have a sudden onset of fever, headache, cough, sore throat, myalgia, congestion, weakness, anorexia, and gastrointestinal (GI) symptoms. Production of URI symptoms results from viral cytopathic activity along with immune activation of inflammatory pathways.^2,3 The incidence of colds is inversely correlated with age; adults average 2 to 4 colds per year.^4,5 Cold symptoms peak at 1 to 3 days and typically last 7 to 10 days, but can persist up to 3 weeks.⁶ With influenza, fever and other systemic symptoms last for 3 days but can persist up to 8 days, while cough and lethargy can persist for another 2 weeks.⁷

Upper respiratory infections have the potential to disrupt mood. Large studies of psychiatrically-healthy undergraduate students have found that compared with healthy controls, participants with URIs endorsed a negative affect within the first week of viral illness,⁸ and that the number and intensity of URI symptoms caused by cold viruses were correlated with the degree of their negative affect.⁹ A few case reports have documented instances of individuals with no previous personal or family psychiatric history developing full manic episodes in the setting of influenza.^10-12 One case report described an influenza-induced manic episode in a patient with pre-existing psychiatric illness.¹³ There are no published case reports of common cold viruses inducing a full depressive or manic episode. If cold symptom severity correlates with negative affect among individuals with no psychiatric illness, and if influenza can induce manic episodes, then it is reasonable to expect that patients with pre-existing mood disorders could have an elevated risk for mood disturbances when they experience a URI (Box).

Box

Mood disorders may also be a risk factor for contracting URIs. Patients with mood disorders are more likely than healthy controls to be seropositive for markers of influenza A, influenza B, and coronavirus, and those with a history of suicide attempts are more likely to be seropositive for markers of influenza B.¹⁴ In a community sample of German adults age 18 to 65, those with mood disorders had a 35% higher likelihood of having had a cold within the last 12 months compared with those without a mood disorder.¹⁵ A survey of Korean employees found the odds of having had a cold in the last 4 months were up to 2.5 times greater for individuals with elevated scores on a depression symptom severity scale compared with those with lower scores.¹⁶ Because these studies were retrospective, recall bias may have impacted the results, as patients who are depressed are more likely to recall negative recent events.¹⁷

Proposed mechanisms

Researchers have proposed several mechanisms to explain the association of URIs with mood episodes. Mood disorders, such as bipolar disorder and major depressive disorder (MDD), are associated with chronic dysregulation of the innate immune system, which leads to elevated levels of cortisol and pro-inflammatory cytokines.^18,19 Men with chronic low-grade inflammation are more vulnerable to all types of infection, including those that cause respiratory illnesses.²⁰ High levels of stress,²¹ a negative affective style,²² and depression²³ have all been associated with reduced antibody response and/or cellular-mediated immunity following vaccination, which suggests a possible mechanism for the vulnerability to infection found in individuals with mood disorders. On the other hand, after influenza vaccination, patients with depression produce a greater and more prolonged release of the cytokine interleukin 6, which perpetuates the state of chronic low-grade inflammation.²⁴ Additionally, patients with mood disorders may engage in behaviors that reduce immune functioning, such as using illicit substances, drinking alcohol, smoking cigarettes, consuming an unhealthy diet, or living a sedentary lifestyle.

Conversely, there are several mechanisms by which a URI could induce a mood episode in a patient with a mood disorder. Animal studies have shown that a non-CNS viral infection can lead to depressive behavior by inducing peripheral interferon-beta release. This signaling protein binds to a receptor on the endothelial cells of the blood-brain barrier, inducing the release of additional cytokines that affect neuronal functioning.²⁵ Among patients receiving interferon treatments for hepatitis C, a history of depression increased their likelihood of becoming depressed during their treatment course, which suggests people with mood disorders have a sensitivity to peripheral cytokines.²⁶

Sleep interruptions from nighttime coughing or nasal congestion can increase the risk of a recurrence of hypomania or mania in patients with bipolar disorder,²⁷ or a recurrence of depression in a patient with MDD.²⁸ The stress that comes with missed work days or the inability to take care of other personal responsibilities due to a URI may increase the risk of becoming depressed in a patient with bipolar disorder or MDD. When present, GI symptoms such as vomiting and diarrhea can reduce the absorption of psychotropic medications and increase the risk of a mood recurrence. Finally, the treatments used for URIs may also contribute to mood instability. Case reports have described instances where patients with URIs developed mania or depression when exposed to medications such as intranasal corticosteroids,²⁹ nasal decongestants,^30,31 and anti-influenza treatments.^32,33

Continue to: A diagnostic challenge

Making the diagnosis of a major depressive episode can be challenging in patients who present with a URI, particularly in those who are highly vigilant for relapse and seek care soon after mood symptoms emerge. Many symptoms overlap between the conditions, including insomnia, hypersomnia, reduced interest, anhedonia, fatigue, impaired concentration, and anorexia. Symptoms that are more specific for a major depressive episode include depressed mood, pathologic guilt, worthlessness, and suicidal ideation. Of course, a major depressive episode and a URI are not mutually exclusive and can occur simultaneously. However, incorrectly diagnosing recurrence of a major depressive episode in a euthymic patient who has a URI could lead to unnecessary changes to psychiatric treatment.

Psychoeducation is key

Teach patients about the bidirectional relationship between URIs and mood symptoms to reduce anxiety and confusion about the cause of the return of mood symptoms. Telling patients that they can expect their mood symptoms to be of short duration and self-limiting due to the URI can provide helpful reassurance.

Because it is possible that the mood symptoms will be transient, increasing psychotropic doses or adding a new psychotropic medication may not be necessary. The decision to initiate such changes should be made collaboratively with patients and should be based on the severity and duration of the patient’s mood symptoms. Symptoms that may warrant a medication change include psychosis, suicidal ideation, or mania. If a patient taking lithium becomes dehydrated because of excessive vomiting, diarrhea, or anorexia, temporarily reducing the dose or stopping the medication until the patient is hydrated may be appropriate.

When a patient presents with a URI, make basic URI treatment recommendations, including rest, hydration, and the use of over-the-counter (OTC) anti-cold medications and zinc.³⁴ Encourage patients with suspected influenza to visit their primary care physician so that they may receive an anti-influenza medication. However, also remind patients about the psychiatric risks associated with some of these treatments and their potential interactions with psychotropics (Table). For example, many OTC cold formulations contain dextromethorphan or chlorpheniramine, both of which have weak serotonin reuptake properties and should not be combined with a monoamine oxidase inhibitor. Such cold formulations may also contain non-steroidal anti-inflammatory agents, which could elevate lithium levels. Codeine, which is often prescribed to suppress the coughing reflex, can lead a patient with a history of substance use to relapse on their drug of choice.

Also recommend lifestyle modifications to help patients reduce their risk of infection. These includes frequent hand washing, avoiding or limiting alcohol use, avoiding cigarettes, exercising regularly, consuming a Mediterranean diet, and receiving scheduled immunizations. To avoid contracting a URI and infecting patients, wash your hands or use an alcohol-based cleanser after shaking hands with patients. Finally, if a patient does not have a primary care physician, encourage him/her to find one to help manage subsequent infections.

Continue to: Bottom Line

Patients with mood disorders may have an increased risk of developing an upper respiratory infection (URI), which can worsen their mood. Clinicians must make psychotropic treatment changes cautiously and guide patients to select safe over-the-counter medications for relief of URI symptoms.

Related Resources

• Centers for Disease Control and Prevention. Cold versus flu. www.cdc.gov/flu/about/qa/coldflu.htm.
• Centers for Disease Control and Prevention. Nonspecific upper respiratory tract infection. www.cdc.gov/getsmart/community/materials-references/print-materials/hcp/adult-tract-infection.pdf.

Drug Brand Names

Clonazepam • Klonopin
Ipratropium • Atrovent
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oseltamivir • Tamiflu
Paroxetine • Paxil

Acute upper respiratory infections (URIs) often lead to mild illnesses, but they can be severely destabilizing for individuals with mood disorders. Additionally, the medications patients often take to target symptoms of the common cold or influenza can interact with psychiatric medications to produce dangerous adverse events or induce further mood symptoms. In this article, we describe the relationship between URIs and mood disorders, the psychiatric diagnostic challenges that arise when evaluating a patient with a URI, and treatment approaches that emphasize psycho­education and watchful waiting, when appropriate.

A bidirectional relationship

Acute upper respiratory infections are the most common human illnesses, affecting almost 25 million people annually in the United States.¹ The common cold is caused by >200 different viruses; rhinovirus and coronavirus are the most common. Influenza, which also attacks the upper respiratory tract, is caused by strains of influenza A, B, or C virus.² The common cold may present initially with mild symptoms of headache, sneezing, chills, and sore throat, and then progress to nasal discharge, congestion, cough, and malaise. When influenza strikes, patients may have a sudden onset of fever, headache, cough, sore throat, myalgia, congestion, weakness, anorexia, and gastrointestinal (GI) symptoms. Production of URI symptoms results from viral cytopathic activity along with immune activation of inflammatory pathways.^2,3 The incidence of colds is inversely correlated with age; adults average 2 to 4 colds per year.^4,5 Cold symptoms peak at 1 to 3 days and typically last 7 to 10 days, but can persist up to 3 weeks.⁶ With influenza, fever and other systemic symptoms last for 3 days but can persist up to 8 days, while cough and lethargy can persist for another 2 weeks.⁷

Upper respiratory infections have the potential to disrupt mood. Large studies of psychiatrically-healthy undergraduate students have found that compared with healthy controls, participants with URIs endorsed a negative affect within the first week of viral illness,⁸ and that the number and intensity of URI symptoms caused by cold viruses were correlated with the degree of their negative affect.⁹ A few case reports have documented instances of individuals with no previous personal or family psychiatric history developing full manic episodes in the setting of influenza.^10-12 One case report described an influenza-induced manic episode in a patient with pre-existing psychiatric illness.¹³ There are no published case reports of common cold viruses inducing a full depressive or manic episode. If cold symptom severity correlates with negative affect among individuals with no psychiatric illness, and if influenza can induce manic episodes, then it is reasonable to expect that patients with pre-existing mood disorders could have an elevated risk for mood disturbances when they experience a URI (Box).

Box

Mood disorders may also be a risk factor for contracting URIs. Patients with mood disorders are more likely than healthy controls to be seropositive for markers of influenza A, influenza B, and coronavirus, and those with a history of suicide attempts are more likely to be seropositive for markers of influenza B.¹⁴ In a community sample of German adults age 18 to 65, those with mood disorders had a 35% higher likelihood of having had a cold within the last 12 months compared with those without a mood disorder.¹⁵ A survey of Korean employees found the odds of having had a cold in the last 4 months were up to 2.5 times greater for individuals with elevated scores on a depression symptom severity scale compared with those with lower scores.¹⁶ Because these studies were retrospective, recall bias may have impacted the results, as patients who are depressed are more likely to recall negative recent events.¹⁷

Proposed mechanisms

Researchers have proposed several mechanisms to explain the association of URIs with mood episodes. Mood disorders, such as bipolar disorder and major depressive disorder (MDD), are associated with chronic dysregulation of the innate immune system, which leads to elevated levels of cortisol and pro-inflammatory cytokines.^18,19 Men with chronic low-grade inflammation are more vulnerable to all types of infection, including those that cause respiratory illnesses.²⁰ High levels of stress,²¹ a negative affective style,²² and depression²³ have all been associated with reduced antibody response and/or cellular-mediated immunity following vaccination, which suggests a possible mechanism for the vulnerability to infection found in individuals with mood disorders. On the other hand, after influenza vaccination, patients with depression produce a greater and more prolonged release of the cytokine interleukin 6, which perpetuates the state of chronic low-grade inflammation.²⁴ Additionally, patients with mood disorders may engage in behaviors that reduce immune functioning, such as using illicit substances, drinking alcohol, smoking cigarettes, consuming an unhealthy diet, or living a sedentary lifestyle.

Conversely, there are several mechanisms by which a URI could induce a mood episode in a patient with a mood disorder. Animal studies have shown that a non-CNS viral infection can lead to depressive behavior by inducing peripheral interferon-beta release. This signaling protein binds to a receptor on the endothelial cells of the blood-brain barrier, inducing the release of additional cytokines that affect neuronal functioning.²⁵ Among patients receiving interferon treatments for hepatitis C, a history of depression increased their likelihood of becoming depressed during their treatment course, which suggests people with mood disorders have a sensitivity to peripheral cytokines.²⁶

Sleep interruptions from nighttime coughing or nasal congestion can increase the risk of a recurrence of hypomania or mania in patients with bipolar disorder,²⁷ or a recurrence of depression in a patient with MDD.²⁸ The stress that comes with missed work days or the inability to take care of other personal responsibilities due to a URI may increase the risk of becoming depressed in a patient with bipolar disorder or MDD. When present, GI symptoms such as vomiting and diarrhea can reduce the absorption of psychotropic medications and increase the risk of a mood recurrence. Finally, the treatments used for URIs may also contribute to mood instability. Case reports have described instances where patients with URIs developed mania or depression when exposed to medications such as intranasal corticosteroids,²⁹ nasal decongestants,^30,31 and anti-influenza treatments.^32,33

Continue to: A diagnostic challenge

Making the diagnosis of a major depressive episode can be challenging in patients who present with a URI, particularly in those who are highly vigilant for relapse and seek care soon after mood symptoms emerge. Many symptoms overlap between the conditions, including insomnia, hypersomnia, reduced interest, anhedonia, fatigue, impaired concentration, and anorexia. Symptoms that are more specific for a major depressive episode include depressed mood, pathologic guilt, worthlessness, and suicidal ideation. Of course, a major depressive episode and a URI are not mutually exclusive and can occur simultaneously. However, incorrectly diagnosing recurrence of a major depressive episode in a euthymic patient who has a URI could lead to unnecessary changes to psychiatric treatment.

Psychoeducation is key

Teach patients about the bidirectional relationship between URIs and mood symptoms to reduce anxiety and confusion about the cause of the return of mood symptoms. Telling patients that they can expect their mood symptoms to be of short duration and self-limiting due to the URI can provide helpful reassurance.

Because it is possible that the mood symptoms will be transient, increasing psychotropic doses or adding a new psychotropic medication may not be necessary. The decision to initiate such changes should be made collaboratively with patients and should be based on the severity and duration of the patient’s mood symptoms. Symptoms that may warrant a medication change include psychosis, suicidal ideation, or mania. If a patient taking lithium becomes dehydrated because of excessive vomiting, diarrhea, or anorexia, temporarily reducing the dose or stopping the medication until the patient is hydrated may be appropriate.

When a patient presents with a URI, make basic URI treatment recommendations, including rest, hydration, and the use of over-the-counter (OTC) anti-cold medications and zinc.³⁴ Encourage patients with suspected influenza to visit their primary care physician so that they may receive an anti-influenza medication. However, also remind patients about the psychiatric risks associated with some of these treatments and their potential interactions with psychotropics (Table). For example, many OTC cold formulations contain dextromethorphan or chlorpheniramine, both of which have weak serotonin reuptake properties and should not be combined with a monoamine oxidase inhibitor. Such cold formulations may also contain non-steroidal anti-inflammatory agents, which could elevate lithium levels. Codeine, which is often prescribed to suppress the coughing reflex, can lead a patient with a history of substance use to relapse on their drug of choice.

Also recommend lifestyle modifications to help patients reduce their risk of infection. These includes frequent hand washing, avoiding or limiting alcohol use, avoiding cigarettes, exercising regularly, consuming a Mediterranean diet, and receiving scheduled immunizations. To avoid contracting a URI and infecting patients, wash your hands or use an alcohol-based cleanser after shaking hands with patients. Finally, if a patient does not have a primary care physician, encourage him/her to find one to help manage subsequent infections.

Continue to: Bottom Line

Patients with mood disorders may have an increased risk of developing an upper respiratory infection (URI), which can worsen their mood. Clinicians must make psychotropic treatment changes cautiously and guide patients to select safe over-the-counter medications for relief of URI symptoms.

Related Resources

• Centers for Disease Control and Prevention. Cold versus flu. www.cdc.gov/flu/about/qa/coldflu.htm.
• Centers for Disease Control and Prevention. Nonspecific upper respiratory tract infection. www.cdc.gov/getsmart/community/materials-references/print-materials/hcp/adult-tract-infection.pdf.

Drug Brand Names

Clonazepam • Klonopin
Ipratropium • Atrovent
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oseltamivir • Tamiflu
Paroxetine • Paxil

Acute upper respiratory infections (URIs) often lead to mild illnesses, but they can be severely destabilizing for individuals with mood disorders. Additionally, the medications patients often take to target symptoms of the common cold or influenza can interact with psychiatric medications to produce dangerous adverse events or induce further mood symptoms. In this article, we describe the relationship between URIs and mood disorders, the psychiatric diagnostic challenges that arise when evaluating a patient with a URI, and treatment approaches that emphasize psycho­education and watchful waiting, when appropriate.

A bidirectional relationship

Acute upper respiratory infections are the most common human illnesses, affecting almost 25 million people annually in the United States.¹ The common cold is caused by >200 different viruses; rhinovirus and coronavirus are the most common. Influenza, which also attacks the upper respiratory tract, is caused by strains of influenza A, B, or C virus.² The common cold may present initially with mild symptoms of headache, sneezing, chills, and sore throat, and then progress to nasal discharge, congestion, cough, and malaise. When influenza strikes, patients may have a sudden onset of fever, headache, cough, sore throat, myalgia, congestion, weakness, anorexia, and gastrointestinal (GI) symptoms. Production of URI symptoms results from viral cytopathic activity along with immune activation of inflammatory pathways.^2,3 The incidence of colds is inversely correlated with age; adults average 2 to 4 colds per year.^4,5 Cold symptoms peak at 1 to 3 days and typically last 7 to 10 days, but can persist up to 3 weeks.⁶ With influenza, fever and other systemic symptoms last for 3 days but can persist up to 8 days, while cough and lethargy can persist for another 2 weeks.⁷

Upper respiratory infections have the potential to disrupt mood. Large studies of psychiatrically-healthy undergraduate students have found that compared with healthy controls, participants with URIs endorsed a negative affect within the first week of viral illness,⁸ and that the number and intensity of URI symptoms caused by cold viruses were correlated with the degree of their negative affect.⁹ A few case reports have documented instances of individuals with no previous personal or family psychiatric history developing full manic episodes in the setting of influenza.^10-12 One case report described an influenza-induced manic episode in a patient with pre-existing psychiatric illness.¹³ There are no published case reports of common cold viruses inducing a full depressive or manic episode. If cold symptom severity correlates with negative affect among individuals with no psychiatric illness, and if influenza can induce manic episodes, then it is reasonable to expect that patients with pre-existing mood disorders could have an elevated risk for mood disturbances when they experience a URI (Box).

Box

Mood disorders may also be a risk factor for contracting URIs. Patients with mood disorders are more likely than healthy controls to be seropositive for markers of influenza A, influenza B, and coronavirus, and those with a history of suicide attempts are more likely to be seropositive for markers of influenza B.¹⁴ In a community sample of German adults age 18 to 65, those with mood disorders had a 35% higher likelihood of having had a cold within the last 12 months compared with those without a mood disorder.¹⁵ A survey of Korean employees found the odds of having had a cold in the last 4 months were up to 2.5 times greater for individuals with elevated scores on a depression symptom severity scale compared with those with lower scores.¹⁶ Because these studies were retrospective, recall bias may have impacted the results, as patients who are depressed are more likely to recall negative recent events.¹⁷

Proposed mechanisms

Researchers have proposed several mechanisms to explain the association of URIs with mood episodes. Mood disorders, such as bipolar disorder and major depressive disorder (MDD), are associated with chronic dysregulation of the innate immune system, which leads to elevated levels of cortisol and pro-inflammatory cytokines.^18,19 Men with chronic low-grade inflammation are more vulnerable to all types of infection, including those that cause respiratory illnesses.²⁰ High levels of stress,²¹ a negative affective style,²² and depression²³ have all been associated with reduced antibody response and/or cellular-mediated immunity following vaccination, which suggests a possible mechanism for the vulnerability to infection found in individuals with mood disorders. On the other hand, after influenza vaccination, patients with depression produce a greater and more prolonged release of the cytokine interleukin 6, which perpetuates the state of chronic low-grade inflammation.²⁴ Additionally, patients with mood disorders may engage in behaviors that reduce immune functioning, such as using illicit substances, drinking alcohol, smoking cigarettes, consuming an unhealthy diet, or living a sedentary lifestyle.

Conversely, there are several mechanisms by which a URI could induce a mood episode in a patient with a mood disorder. Animal studies have shown that a non-CNS viral infection can lead to depressive behavior by inducing peripheral interferon-beta release. This signaling protein binds to a receptor on the endothelial cells of the blood-brain barrier, inducing the release of additional cytokines that affect neuronal functioning.²⁵ Among patients receiving interferon treatments for hepatitis C, a history of depression increased their likelihood of becoming depressed during their treatment course, which suggests people with mood disorders have a sensitivity to peripheral cytokines.²⁶

Sleep interruptions from nighttime coughing or nasal congestion can increase the risk of a recurrence of hypomania or mania in patients with bipolar disorder,²⁷ or a recurrence of depression in a patient with MDD.²⁸ The stress that comes with missed work days or the inability to take care of other personal responsibilities due to a URI may increase the risk of becoming depressed in a patient with bipolar disorder or MDD. When present, GI symptoms such as vomiting and diarrhea can reduce the absorption of psychotropic medications and increase the risk of a mood recurrence. Finally, the treatments used for URIs may also contribute to mood instability. Case reports have described instances where patients with URIs developed mania or depression when exposed to medications such as intranasal corticosteroids,²⁹ nasal decongestants,^30,31 and anti-influenza treatments.^32,33

Continue to: A diagnostic challenge

Making the diagnosis of a major depressive episode can be challenging in patients who present with a URI, particularly in those who are highly vigilant for relapse and seek care soon after mood symptoms emerge. Many symptoms overlap between the conditions, including insomnia, hypersomnia, reduced interest, anhedonia, fatigue, impaired concentration, and anorexia. Symptoms that are more specific for a major depressive episode include depressed mood, pathologic guilt, worthlessness, and suicidal ideation. Of course, a major depressive episode and a URI are not mutually exclusive and can occur simultaneously. However, incorrectly diagnosing recurrence of a major depressive episode in a euthymic patient who has a URI could lead to unnecessary changes to psychiatric treatment.

Psychoeducation is key

Teach patients about the bidirectional relationship between URIs and mood symptoms to reduce anxiety and confusion about the cause of the return of mood symptoms. Telling patients that they can expect their mood symptoms to be of short duration and self-limiting due to the URI can provide helpful reassurance.

Because it is possible that the mood symptoms will be transient, increasing psychotropic doses or adding a new psychotropic medication may not be necessary. The decision to initiate such changes should be made collaboratively with patients and should be based on the severity and duration of the patient’s mood symptoms. Symptoms that may warrant a medication change include psychosis, suicidal ideation, or mania. If a patient taking lithium becomes dehydrated because of excessive vomiting, diarrhea, or anorexia, temporarily reducing the dose or stopping the medication until the patient is hydrated may be appropriate.

When a patient presents with a URI, make basic URI treatment recommendations, including rest, hydration, and the use of over-the-counter (OTC) anti-cold medications and zinc.³⁴ Encourage patients with suspected influenza to visit their primary care physician so that they may receive an anti-influenza medication. However, also remind patients about the psychiatric risks associated with some of these treatments and their potential interactions with psychotropics (Table). For example, many OTC cold formulations contain dextromethorphan or chlorpheniramine, both of which have weak serotonin reuptake properties and should not be combined with a monoamine oxidase inhibitor. Such cold formulations may also contain non-steroidal anti-inflammatory agents, which could elevate lithium levels. Codeine, which is often prescribed to suppress the coughing reflex, can lead a patient with a history of substance use to relapse on their drug of choice.

Also recommend lifestyle modifications to help patients reduce their risk of infection. These includes frequent hand washing, avoiding or limiting alcohol use, avoiding cigarettes, exercising regularly, consuming a Mediterranean diet, and receiving scheduled immunizations. To avoid contracting a URI and infecting patients, wash your hands or use an alcohol-based cleanser after shaking hands with patients. Finally, if a patient does not have a primary care physician, encourage him/her to find one to help manage subsequent infections.

Continue to: Bottom Line

Patients with mood disorders may have an increased risk of developing an upper respiratory infection (URI), which can worsen their mood. Clinicians must make psychotropic treatment changes cautiously and guide patients to select safe over-the-counter medications for relief of URI symptoms.

Related Resources

• Centers for Disease Control and Prevention. Cold versus flu. www.cdc.gov/flu/about/qa/coldflu.htm.
• Centers for Disease Control and Prevention. Nonspecific upper respiratory tract infection. www.cdc.gov/getsmart/community/materials-references/print-materials/hcp/adult-tract-infection.pdf.

Drug Brand Names

Clonazepam • Klonopin
Ipratropium • Atrovent
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oseltamivir • Tamiflu
Paroxetine • Paxil

The siblings of patients with bipolar disorder have a higher prevalence of dyslipidemia and higher rates of ischemic stroke than do controls, results of a longitudinal cohort study suggest.

Genetics might account for this elevated cardiometabolic risk in families with a bipolar disorder history, wrote Wen-Yen Tsao, MD, of the department of psychiatry at Taipei Veterans General Hospital in Taiwan, and associates. Previous research has identified several overlapping genes between cardiometabolic diseases and mood disorders. In addition, polymorphisms of several genes tied to obesity have been associated with bipolar disorder.

In the current study, Dr. Tsao and associates analyzed the Taiwan National Health Insurance Research Database, which includes health care data from more than 99% of the Taiwanese population (J Affect Disord. 2019 Jun 15. doi: 10.1016/j.jad.2019.04.094). Adults born before 1990 who had no psychiatric disorders, a sibling with bipolar disorder, and a metabolic disorder were enrolled as the study cohort. A control group was identified randomly. By way of ICD-9-CM codes, people with type 2 diabetes, hypertension, dyslipidemia, and obesity were identified in both cohorts. The investigators followed the metabolic status of 7,225 unaffected siblings of bipolar disorder patients and 28,900 controls from 1996 to 2011.

Dr. Tsao and associates found that the family members who had siblings with bipolar disorder had a higher prevalence of dyslipidemia (5.4% vs. 4.5%; P = .001), compared with controls. The group with siblings with bipolar disorder also were diagnosed with type 2 diabetes at a younger age (34.81 vs. 37.22; P = .024), and had a higher prevalence of any stroke (1.5 vs. 1.1%; P = .007) and ischemic stroke (0.7% vs. 0.4%, P = .001), compared with controls.

A subanalysis showed that the higher risk of any stroke (odds ratio, 1.38; 95% confidence interval, 1.02-1.85) and ischemic stroke (OR, 2.43; 95% CI, 1.60-3.70) pertained only to male siblings. That gender-specific finding might be attributed to differences in plasma triglyceride clearance between men and women, the researchers wrote.

The findings might not be generalizable to other populations, the investigators noted. In addition, they said, the prevalence of cardiometabolic disease in the groups studied might be underestimated.

“Our results may motivate additional studies to evaluate genetic factors, psychosocial factors, and other pathophysiology of bipolar disorder,” they wrote.

The study was funded by Taiwan’s Ministry of Science and Technology, and Taipei Veterans General Hospital. The researchers cited no conflicts of interest.

[email protected]

The siblings of patients with bipolar disorder have a higher prevalence of dyslipidemia and higher rates of ischemic stroke than do controls, results of a longitudinal cohort study suggest.

Genetics might account for this elevated cardiometabolic risk in families with a bipolar disorder history, wrote Wen-Yen Tsao, MD, of the department of psychiatry at Taipei Veterans General Hospital in Taiwan, and associates. Previous research has identified several overlapping genes between cardiometabolic diseases and mood disorders. In addition, polymorphisms of several genes tied to obesity have been associated with bipolar disorder.

In the current study, Dr. Tsao and associates analyzed the Taiwan National Health Insurance Research Database, which includes health care data from more than 99% of the Taiwanese population (J Affect Disord. 2019 Jun 15. doi: 10.1016/j.jad.2019.04.094). Adults born before 1990 who had no psychiatric disorders, a sibling with bipolar disorder, and a metabolic disorder were enrolled as the study cohort. A control group was identified randomly. By way of ICD-9-CM codes, people with type 2 diabetes, hypertension, dyslipidemia, and obesity were identified in both cohorts. The investigators followed the metabolic status of 7,225 unaffected siblings of bipolar disorder patients and 28,900 controls from 1996 to 2011.

Dr. Tsao and associates found that the family members who had siblings with bipolar disorder had a higher prevalence of dyslipidemia (5.4% vs. 4.5%; P = .001), compared with controls. The group with siblings with bipolar disorder also were diagnosed with type 2 diabetes at a younger age (34.81 vs. 37.22; P = .024), and had a higher prevalence of any stroke (1.5 vs. 1.1%; P = .007) and ischemic stroke (0.7% vs. 0.4%, P = .001), compared with controls.

A subanalysis showed that the higher risk of any stroke (odds ratio, 1.38; 95% confidence interval, 1.02-1.85) and ischemic stroke (OR, 2.43; 95% CI, 1.60-3.70) pertained only to male siblings. That gender-specific finding might be attributed to differences in plasma triglyceride clearance between men and women, the researchers wrote.

The findings might not be generalizable to other populations, the investigators noted. In addition, they said, the prevalence of cardiometabolic disease in the groups studied might be underestimated.

“Our results may motivate additional studies to evaluate genetic factors, psychosocial factors, and other pathophysiology of bipolar disorder,” they wrote.

The study was funded by Taiwan’s Ministry of Science and Technology, and Taipei Veterans General Hospital. The researchers cited no conflicts of interest.

[email protected]

The siblings of patients with bipolar disorder have a higher prevalence of dyslipidemia and higher rates of ischemic stroke than do controls, results of a longitudinal cohort study suggest.

Genetics might account for this elevated cardiometabolic risk in families with a bipolar disorder history, wrote Wen-Yen Tsao, MD, of the department of psychiatry at Taipei Veterans General Hospital in Taiwan, and associates. Previous research has identified several overlapping genes between cardiometabolic diseases and mood disorders. In addition, polymorphisms of several genes tied to obesity have been associated with bipolar disorder.

In the current study, Dr. Tsao and associates analyzed the Taiwan National Health Insurance Research Database, which includes health care data from more than 99% of the Taiwanese population (J Affect Disord. 2019 Jun 15. doi: 10.1016/j.jad.2019.04.094). Adults born before 1990 who had no psychiatric disorders, a sibling with bipolar disorder, and a metabolic disorder were enrolled as the study cohort. A control group was identified randomly. By way of ICD-9-CM codes, people with type 2 diabetes, hypertension, dyslipidemia, and obesity were identified in both cohorts. The investigators followed the metabolic status of 7,225 unaffected siblings of bipolar disorder patients and 28,900 controls from 1996 to 2011.

Dr. Tsao and associates found that the family members who had siblings with bipolar disorder had a higher prevalence of dyslipidemia (5.4% vs. 4.5%; P = .001), compared with controls. The group with siblings with bipolar disorder also were diagnosed with type 2 diabetes at a younger age (34.81 vs. 37.22; P = .024), and had a higher prevalence of any stroke (1.5 vs. 1.1%; P = .007) and ischemic stroke (0.7% vs. 0.4%, P = .001), compared with controls.

A subanalysis showed that the higher risk of any stroke (odds ratio, 1.38; 95% confidence interval, 1.02-1.85) and ischemic stroke (OR, 2.43; 95% CI, 1.60-3.70) pertained only to male siblings. That gender-specific finding might be attributed to differences in plasma triglyceride clearance between men and women, the researchers wrote.

The findings might not be generalizable to other populations, the investigators noted. In addition, they said, the prevalence of cardiometabolic disease in the groups studied might be underestimated.

“Our results may motivate additional studies to evaluate genetic factors, psychosocial factors, and other pathophysiology of bipolar disorder,” they wrote.

The study was funded by Taiwan’s Ministry of Science and Technology, and Taipei Veterans General Hospital. The researchers cited no conflicts of interest.

[email protected]