Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: [email protected].

Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: [email protected].

Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: [email protected].

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

[email protected]

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

[email protected]

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

[email protected]

Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

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Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

[email protected]

Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

[email protected]

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

[email protected]

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.